Figure 1. Morbilliform eruption with facial edema.
Minocycline, taken for short term, appears safe except for the common side effect of vertigo. Vertigo causes falls. The lives of HD mice given minocycline have been extended in Friedlander's study. However HD mice on minocycline had more side effects from the drug than did the controls. Vertigo in four footed mice is less serious than vertigo in humans.
Those taking minocycline and their doctors should be aware of the following information. 05/19/99
Cas clinique,Annales de dermatologie et de vénéréologie 1999;126:518,Antunes A. et al.
Drug hypersensitivity syndrome is a rare drug reaction, the typical form of which includes severe cutaneous signs, fever, lymphadenopathy, eosinophilia and cholestatic and cytolytic hepatitis.
The 16-year-old girl had minocycline-induced hypersensitivity syndrome with a generalised pustular eruption after one month's treatment with 100 mg/day minocycline for acne. Patch tests with minocycline diluted in petrolatum were positive at 48 hours.
This case of minocycline-induced hypersensitivity syndrome is unusual in the positive reaction on subsequent patch testing, producing the same lesions as in the initial reaction. Various drugs have been identified as the causal agents of drug hypersensitivity syndrome, the most common being anticonvulsants. Several reports have been published in recent years of reactions following ingestion of minocycline. Although such cases are rare, it appears that minocycline is the cycline most commonly associated with clinical features such as drug hypersensitivity syndrome, acute disseminated lupus erythematosus, pulmonary eosinophilia and serum sickness-like disease.
It is necessary to be aware of such side-effects and to encourage all patients to cease treatment and consult a physician if symptoms such as hyperthermia, lymphadenopathy, joint pain or eruption appear.
It is advisable to perform minocycline patch tests 4 - 6 weeks after the eruption.
Minocycline is a second generation, semi-synthetic derivate of the tetracycline family. Its main indication in dermatology is for acne. It has been reported to cause rare, severe drug reactions such as induced lupus [1, 2, 3, 4, 5], serum sickness-like disease [4, 6] and drug hypersensitivity syndrome (DHS). DHS is an acute, severe delayed reaction, associating fever, exanthema, lymphadenopathy, blood eosinophilia and visceral involvement [4, 7, 8].
We report a case of minocycline-induced DHS which was unusual in the positive response on patch testing which reproduced the same reactions as the initial skin lesions.
The 16-year-old Caucasian girl, who was healthy and had no relevant previous history, was referred to the Dermatology Department with a 24-hour history of febrile, generalized papulo-pustular eruption fig. 1 . She had been treated for one month with 100 mg/day minocycline chlorhydrate for acne, combined with topical erythromycin solution for 48 hours. There was considerable edema of the face and neck. Her temperature swung between 37.8o and 39oC and she was generally unwell. Painful lymph nodes measuring 1 - 2 cm could be felt in cervical, axillary and inguinal areas on palpation. Blood tests on the second day of the eruption revealed leukocytes at 13,000 mm3, of which 520 were eosinophils and 1170 hyperbasophils. Liver and kidney function tests were normal, as were lung X-ray and electrocardiogram. Investigations to reveal autoantibodies and immune complexes were negative. Serology investigations over two weeks showed no signs of recent infection (CMV, EBV, hepatitis A, B and C, coxsackia, rubella, HIV, parvovirus B19, syphilis, toxoplasmosis). Total IgE was higher than 2000 KU/l and investigation of pneumoallergen-specific IgE was positive. Histological examination of a papule from the arm revealed a non-specific inflammatory perivascular dermal infiltrate, without immunoglobulin or complement deposits on direct immunofluorescence.
Minocycline and the erythromycin solution were withdrawn on the first day of the eruption. After partial regression, the exanthema became maculopapular and generalised on the fifth day, leaving no uninvolved skin. Eosinophilia was at 3440 cells/mm3 on the eighth day.
Corticosteroid treatment was successful with 1 mg/kg/day prednisone commenced on day 8, with disappearance of the cutaneous symptoms and normalization of biological perturbations in two weeks, without recurrence on withdrawal of corticosteroids after two months.
Patch tests were performed three months after the onset of the first symptoms. They were positive for minocycline chlorhydrate, with the same intensity for three concentrations (0.1%, 1% and 10% in petrolatum), reproducing the initial elementary papulo-pustular lesions fig. 2 and with features of intraepidermal, unilocular eosinophils on histological examination fig. 3 (biopsy of patch test at 0.1%). There was no distal reaction to these tests.
The diagnosis of minocycline-induced DHS was made in this case on the basis of the sudden onset of a febrile, generalized papulo-pustular eruption one month after commencing treatment with minocycline, associated with multiple lymphadenopathy, eosinophilia and hyperbasophilic lymphocytosis. Causality (scored according to the French system of intrinsic imputability [9]) was I4 (very probable), with symptomatology S3 (probable) and chronology C3 (probable) (according to Bocquet et al) with an interval of one month between the introduction of the drug and the appearance of the syndrome [9, 10]. The patient could not recall having previously taken tetracyclines.
According to Bonnetblanc [7], DHS is defined as any severe or acute generalized cutaneous sign associated with fever and blood eosinophilia, with or without serious visceral involvement and without other explanation. He adds that the cutaneous signs may in certain cases be absent and [11] that some clinical patterns which are similar to those described cannot be drug-induced. The mechanism is still not fully explained [7] and the signs occur suddenly two to six weeks after initiation of treatment [8].
The cutaneous signs of DHS are severe, generalized and often polymorphous. There is most commonly non-specific maculopapular exanthema which may, as in our patient, be associated with edema mainly in the head and neck [7, 8]. The pustular form is rare, whatever the causal drug. Kleier et al [12] reported two cases of pustular follicular eruption with anticonvulsant-induced DHS, with histological evidence of superficial pustular folliculitis. In our patient the pustules were also intraepidermal but not follicular. This is the fourth case of pustular eruption in minocycline-induced DHS [13, 14].
The associated signs are fever and possibly visceral involvement (especially hepatic, but also cardiac, pulmonary, renal, cerebral or thyroid) [7, 8]. Other clinical features reported include multiple lymphadenopathy, arthralgia and myalgia. Biological signs include leukocytosis, lymphocytosis with stimulated hyperbasophilic lymphocytes, blood eosinophilia, which is sometimes major and often delayed in relation to the cutaneous signs, and, in 50% of cases, biological signs of hepatitis which is classically cytolytic and cholestatic [7, 8, 12].
DHS and drug-induced pseudolymphoma have for some time been confused because some drugs, principally anticonvulsants, can be responsible for both conditions. Bocquet et al [10] and Callot et al [15] have recently separated the two clinical entities.
Hepatocellular insufficiency, myocarditis, renal insufficiency or severe pulmonary and cutaneous involvement can render DHS life-threatening [7, 8]. It is essential to withdraw the drug as soon as symptoms occur, allowing spontaneous recovery in most cases [7, 8, 12]. Systemic corticosteroids were necessary for our patient in view of the severe cutaneous symptoms which persisted after withdrawal of minocycline. Although there has been no randomized study to prove their effectiveness, corticosteroids are often used at doses of 0.5 - 1 mg/kg/day in severe forms [8].
Anticonvulsants and sulfonamides are the drugs most frequently associated with DHS [8]. Knowles et al [4] identified only 11 cases of minocycline-induced DHS in the literature in 1996 and themselves reported 7 further cases. Beneton et al [16] reported 7 cases. Shapiro et al [17] recently compared the safety of various currently used tetracyclines and identified 19 published cases of minocycline-induced DHS, including 2 reported by Beneton [16]. They found only 2 cases of DHS due to tetracyclines and one case due to doxycycline. In most cases where the indication was given, minocycline was prescribed for acne and the dosage was 100 mg/day.
Minocycline was considered to be the causal drug in more than 30 cases of pulmonary eosinophilia [18, 19, 20, 21, 22, 23, 24, 25] and in 14 cases of hepatic hypersensitivity reactions [4, 11, 12, 26]. As emphasized by Bonnetblanc, in the cases reported in the non-dermatological literature, although sometimes only one organ is involved, there is often a cutaneous eruption without any information suggestive of DHS. Rare cases of nephritis [27] and myocarditis have been reported [14], one which was fatal.
In our patient the causality of minocycline was confirmed by patch tests. Rechallenge was rejected in view of the severity of the initial cutaneous signs. Minocycline patch testing was positive at 48 hours, reproducing the initial papulo-pustular lesions, whereas it was negative in 20 eczema patients screened by patch testing [28]. Although the value of patch tests is disputed in investigations into drug reactions, Barbaud et al [29] recently reported on their value. The diagnosis of minocycline-induced DHS was supported by patch tests with minocycline diluted at 0.1, 1 and 10% in petrolatum, as with anticonvulsants, which are frequently found to be causal agents in DHS. This is the first case of severe, delayed hypersensitivity to minocycline confirmed by patch tests to our knowledge.
Although the clinical picture is rare and does not contraindicate the use of minocycline in the treatment of acne, Shapiro et al [17] emphasized the predominance of minocycline among tetracyclines in the occurrence of severe side effects (DHS, serum sickness, lupus, lung disease). The explanation of the phenomenon seems not to be related to greater use of minocycline but rather to the metabolism of the drug.
It is important to recognise the side effects and to warn patients about those which necessitate immediate withdrawal of the drug and to seek medical advice as quickly as possible [30].
Figure 1. Morbilliform eruption with facial edema.
Figure 2. Positive patch test with 0.1% minocycline in petrolatum.
 Figure 3. Histological examination of patch test demonstrating eosinophilic pustule. |  Not related photo of Mount Whitney from the Alabama Hills by Jerry. The Pustule/Whitney height ratio is ~10-7 10/16/00 |
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