Dermal infiltrate of enlarged macrophages in patients receiving chemotherapy

A histologically distinct maculopapular eruption has heen associated with the use of recombinant forms of granulocyte and gran-ulocytte-inacrophage colony-stimulating factors (GCSF and GMCSF). One of the most distinctive features was an increase in the number and the size of dermal maerophages, which was proposed as a clue to diagnosis of these cytokine-induced dermatoses.
We describe 8 patients who received chemotherapy and who developed a maculopapular eruption, of which histological examination showed an increase in the numher and the size of dermal maerophages. Three patients had also received GM-CSF or G-CSF, before the onset of rash, but 5 patients had not.
In conclusion, an increase in the number and the size of dermal macrophages is not specific for the reaction to GM-CSF or G-CSF, and may also be observed in patients receiving chemotherapy.     

Granulocyte colony‐stimulating factor‐induced granulomatous dermatitis with enlarged histiocytes clinically manifesting as painful edematous nodules with high fever similar to Sweet's syndrome

A 72‐year‐old woman with a history of diffuse large B cell lymphoma and recent recurrence visited our department complaining of several painful edematous nodules with blisters on her face. She had iteratively developed cutaneous eruptions after every treatment with granulocyte colony‐stimulating factor (G‐CSF) for neutropenia, and each time the eruption improved after the cessation of the G‐CSF treatment. The blisters became crusty and the skin lesions slightly improved, but on the 24th hospital day, the eruption formed painful erythematous nodules with erosion, and the patient also developed a high fever of up to 38°C. A biopsy specimen showed a dermal infiltrate of increased and enlarged plump histiocytes, some of which indicated karyomitosis with a small number of lymphocytes. No increase in the number of eosinophils or neutrophils was noted. These eruptions lasted for 15 days and disappeared with the recovery of the peripheral blood count and attendant cessation of G‐CSF. We diagnosed this case as G‐CSF‐induced granulomatous dermatitis with enlarged histiocytes. Several cases with maculopapular rash and dermal inflammatory infiltrate composed of interstitially arranged large histiocytes have been reported. However, to the best of our knowledge, this is the first case report of G‐CSF‐induced granulomatous dermatitis with enlarged histiocytes clinically manifesting as painful edematous nodules with a high fever, similar to Sweet's syndrome. We speculated that the infiltrating cells were not neutrophils but histiocytes, presumably because of agranulocytosis.     

Immunohistochemical characterization of cutaneous drug eruptions by STI571

BACKGROUND: STI571, a selective BCR-ABL tyrosine kinase inhibitor, is a promising new drug for chronic myelogenous leukemia (CML). However, the drug has been reported to be associated with adverse cutaneous drug eruptions with high frequency. OBJECTIVE: In this study, the characteristics of the cutaneous drug eruptions by STI571 were investigated. METHODS: The clinical records of 10 patients diagnosed with drug eruption by STI571 were reviewed. We obtained 10 skin biopsy specimens from patients with drug eruption by STI571, 6 from the antibiotics-induced drug eruption group, and 5 from normal skin (control). Immunohistochemical analysis was performed to detect CD4, CD8, CD56, IL-18, IL-1beta and ICAM-1 expression in the cutaneous drug eruption. RESULTS: Seven out of 10 patients had maculopapular exanthema, 2/10 erythema multiforme, 1/10 urticaria. We analyzed the composition of T-lymphocyte subsets from the infiltrates at the STI571-induced drug eruption site in eight patients. Unlike other drug eruptions, the increase in the CD8 expression was statistically significant, especially in the dermoepidermal junction and the upper dermis (P < 0.01). The enhanced expression of IL-18 and IL-1beta was observed as well. In contrast, ICAM-1 was either weakly positive or negative. CONCLUSION: Drug eruption caused by STI571 was mostly expressed as a maculopapular exanthema. The histopathological findings were similar in drug eruption by antibiotics or STI571. Unlike the drug eruptions caused by antibiotics, where the expression of CD4 was dominant, CD8 was dominant in drug eruptions by STI571. The expression of IL-18 and IL-1beta was increased in both groups. This elevation of IL-18 and IL-1beta may assist in understanding the pathogenesis of cutaneous drug eruption.     

Patch testing in cutaneous reactions caused by carbamazepine

The usefulness of patch testing in the diagnosis of carbamazepine-induced allergic skin eruptions was studied in 18 patients with previous histories of skin eruptions caused by carbamazepine. The etiological role of carbamazepine was ascertained by peroral or topical provocation in 15 (out of 18) patients. The clinical reactions caused by the drug were classified as maculopapular exanthema with general symptoms (7 patients), other type of exanthema (3). exfoliative dermatitis (erythroderma) (3), fixed drug eruption (3), erythema multiforme (1) and urticaria (1). Patch testing showed positive reactions to carbamazepine in 7 patients; in addition. 2 patients had doubtful reactions. Positive patch test reactions were seen only in patients with exfoliative dermatitis (all 3 patients) and maculopapular exanthema (4 out of 7). None of the patients with fixed drug eruption, erythema multiforme or urticaria, or the control subjects, had positive patch test reactions 10 carbamazepine. The present study suggests that patch testing is useful in the diagnosis of carbamazepine allergy in patients with maculopapular eruptions or erythrodermas.     

Suramin-induced skin reactions.

BACKGROUND AND DESIGN--Suramin sodium, a polysulfonated naphthylurea, has been used for more than 70 years as a chemotherapeutic agent for a variety of diseases. In a phase II trial of suramin, 20 patients with metastatic prostate carcinoma refractory to hormonal manipulation were evaluated retrospectively for evidence of skin toxicity. RESULTS--Three types of skin reaction were noted: generalized, erythematous, maculopapular eruption (10 patients); keratoacanthoma (two patients); and disseminated superficial actinic porokeratosis (one patient). A total of 15 episodes of some form of skin reaction occurred in 13 patients. The maculopapular eruptions resolved in 3 to 5 days despite continued treatment with suramin. CONCLUSIONS--Cutaneous toxicity was a frequent and, often, self-limited side effect of suramin therapy, occurring in 13 (65%) patients. Keratoacanthoma and disseminated superficial actinic porokeratosis have not previously been reported to occur with suramin therapy. The immunosuppressive effect of suramin may induce the keratoacanthoma and disseminated superficial actinic porokeratosis lesions.     

Increased drug reactions in HIV-1-positive patients: a possible explanation based on patterns of immune dysregulation seen in HIV-1 disease*

Drug reactions are common in HIV-1 disease, with the incidence having been reported to increase with increasing stage and with CD4+ T-cell counts below 200/μl. However, there have been numerous reports of patients in which rechallenge, dosing changes or continued therapy have resulted in no recurrence or else clearing of the eruption. We followed 974 HIV-1-positive patients for 46 months as a part of a military study of HIV-1 disease. Within this group there were a total of 283 drug eruptions, with cutaneous manifestations in 201 patients in which clinical characteristics were noted and 86 patients in which cutaneous biopsies were performed. Serological evidence of reactivation or acute Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infections were also noted, as well as peripheral eosinophilia. The incidence of drug eruptions significantly increased with increasing Walter Reed stage and decreasing CD4 counts and CD4/CD8 ratio, as well as with increasing age and in patients with increased numbers of other dermatological diagnoses. In addition, white patients had significantly more drug eruptions than did black. Serological or culture evidence of acute or reactivated EBV or CMV was significantly increased in patients with drug eruptions. The majority of the eruptions were maculopapular or morbilliform with a predominantly perivascular mononuclear cell infiltrate.     

Photodermatosis induced by hydroxychloroquine: 4 cases]

BACKGROUND: Hydroxychloroquine is an antimalarial drug often used in dermatology for its photo-protective effects. Four cases of photodermatosis induced by hydroxychloroquine are reported. CASE REPORTS: Four patients, aged from 21 to 68 years, developed a photolocalized eruption from 6 days to 10 weeks after starting hydroxychloroquine. The minimal erythemal dose was decreased in the total spectra and UVA at the onset of the eruption and became normal after stopping hydroxychloroquine in the 2 patients that were controlled. In 3 cases, hydroxychloroquine was the only single drug imputable; chronological imputability was plausible. In the last case, both hydroxychloroquine, carbamazepine and fluvoxamine had a common imputability which was plausible. In the 4 cases, a favourable outcome was observed after stopping hydroxychloroquine, and no recurrence occurred with a mean follow-up of 3.8 years (1-4 years). In one case, a photodistributed eruption occurred during treatment with a related molecule: chloroquine. DISCUSSION: Photodermatosis with hydroxychloroquine have rarely been described in the literature, while quinine from which hydroxychloroquine is derived, is well known for its risk of photosensibilization. The main differential diagnosis of these drug eruptions is an eruption caused by the photodermatosis that initially required treatment with hydroxychloroquine.     

Histopathologic features seen with radiation recall or enhancement eruptions

Background: Although a radiation recall or enhancement eruption has been associated with a number of chemotherapeutic drugs, the histologic features have rarely been described. Objective: Our goal was to define the histologic features of radiation recall and enhancement eruptions in order to better understand their pathogenesis. Methods: We present ten patients on chemotherapeutic agents who developed erythematous maculopapular to psoriasiform eruptions often with associated follicular pustules. These eruptions occurred at the sites of prior or concurrent radiation therapy. Results: The most common class of drugs inducing these reactions were antibiotic chemotherapeutic agents alone or in combination with other chemotherapeutic drugs. In addition to routine histology, in four patients immunohistochemical staining for p53 was performed at the sites of the eruptions after resolution and at noninvolved sites matched for ultraviolet radiation (UVR) exposure. Histologic features in patients receiving concurrent radiation therapy included epidermal dysplasia, keratinocytes showing features of necrosis, increased mitotic figures, and a mixed inflammatory infiltrate. At sites of prior radiation therapy, the biopsy specimens showed a similar spectrum of epidermal changes and, in some cases, psoriasiform dermatitis with clearing within cells in the upper layers of the epidermis. Additional dermal changes included dermal fibrosis, vasodilatation, and atypical fibroblasts. Moderate to marked solar elastosis was seen in the majority of biopsy specimens. Immunohistochemical studies after resolution showed only a modest increase in p53 staining in epidermal keratinocytes in 3 of 4 sites of recall and enhancement eruptions after resolution of the reactions compared to skin that was matched for similar UVR exposure. Conclusion: Cumulative direct DNA damage and oxidative stress are probably important in radiation recall and enhancement eruptions, and these changes may be modulated by underlying nutritional deficits. Cumulative p53 mutations may play some role but are probably not a major factor in these eruptions. Mitochondrial dysfunction, which is known to occur with prior and concurrent radiation and chemotherapy, may be important in these eruptions. In addition to improvements in general nutrition, topical or oral antioxidant therapy may be a potential therapy to avoid radiation enhancement and recall reactions     

Diltiazem-induced acute generalised exanthematous pustulosis

Pustulation is a major feature in several different dermatoses, and it may also occur as a manifestation of drug: hypersensitivity. Acute generalized exanthematous pustulosis (AGEP) is an uncommon eruption characterized by acute, extensive formation of sterile pustules, fever and peripheral blood leucucytosis. It shares several clinical and historical features in common with pustular psoriasis. Most reported cases have been triggered by ingestion of broad spectrum antibiotics, particularly betalactams and macrolides. There is usually rapid resolution of the eruption on drug withdrawal. We report the case of a 58 year-old woman who developed AGEP shortly after commencing treatment with the calcium channel binder diltiazem hydro-chloride. The eruption followed a biphasic course, and improved following treatment with systemic corti-costeroids and methotrexate. AGEP appears to be a rare adverse cutaneous reaction to diltiazem, whereas a wide range of other skin eruptions have been reported more commonly with this drug.     

Increased levels of interleukin 5 are associated with the generation of eosinophilia in drug-induced hypersensitivity syndrome

Hypersensitivity syndrome (HSS) usually refers to severe drug eruption associated with systemic symptoms and eosinophilia. Interleukin (IL)-5 regulates eosinophil counts with the help of IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF). Blood IL-5 levels have been reported to be increased in patients with eosinophilia secondary to parasitic infections or idiopathic eosinophilia, but have never been evaluated in drug-induced eosinophilia. The aim of our study was to determine whether IL-5, IL-3 and GM-CSF are involved in eosinophilia in patients with drug-induced HSS. Plasma levels of IL-3, IL-5 and GM-CSF were assayed by ELISA in seven patients with drug-induced HSS, in eight patients with cutaneous adverse drug reactions not associated with eosinophilia, and in five patients with eosinophilia unrelated to drug treatment. IL-5 levels were normal in all eight patients with drug eruptions without eosinophilia, and increased in five of the seven patients with HSS. In the latter patients, IL-5 levels peaked several days before highest eosinophil counts were noted, and returned to normal within a few days, even when eosinophilia persisted. In patients with eosinophilia unrelated to drug treatment, IL-5 levels, although significantly increased, remained lower than in HSS patients. IL-3 and GM-CSF could not be detected in any group, at any time. Our results show that IL-5 is involved in drug-related eosinophilia. As IL-5 production was only involved in the early stages of the reaction, it is suggested that IL-5 mainly derives from activated lymphocytes rather than eosinophils. Our results support the clinical relevance of previous in vitro findings. Further studies are needed to test whether assays of IL-5 production by lymphocytes of patients stimulated by the suspected drug and/or its metabolites, are useful in establishing causality in drug-induced reactions associated with eosinophilia.     

Linear IgA bullous dermatosis in a patient with acute lymphocytic leukemia: possible involvement of granulocyte colony-stimulating factor

We describe a case of linear IgA bullous dermatosis (LABD) in a patient with acute lymphocytic leukemia during treatment with granulocyte colony-stimulating factor (G-CSF). After a drug eruption due to imipenem cilastatin sodium had disappeared, bullous lesions appeared on the trunk. Results of histopathological studies and direct immunofluorescence studies of the lesion were consistent with LABD. Reinstitution of G-CSF after the resolution, however, did not reproduce the bullous eruptions. This suggests that in addition to G-CSF, the presence of precipitating factors that can synergistically enhance or accelerate the outbreak of the disease is required for the development of bullous lesions. Various cytokines, such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), endogenously produced from activated lymphocytes during the drug eruption might have provided a favorable milieu for the onset of G-CSF-induced LABD. We suggest that patients with LABD will need special attention with respect to the type of cytokines or combination of cytokines given as therapeutic modalities.     

Drug eruptions in Bangkok: a 1-year study at Ramathibodi Hospital

Background As new drugs are introduced onto the market, it is important to determine those that can cause cutaneous reactions and with what frequency. In addition, drugs that have been used for a long period of time may cause new types of eruption that have not been observed previously. The purpose of this study was to evaluate the types of drug eruption and the causative agents in a hospital-based population for a period of 1 year. Methods All in- and outpatients consulting for drug eruptions at the Dermatology Clinic, Ramathibodi Hospital from June 1995 to May 1996 were included in the study. The history and physical examination were performed by one of the authors. In suspected cases, a skin biopsy was carried out to confirm the diagnosis. Rechallenge tests with suspected drugs were performed with informed consent. Results One hundred and thirty-two patients were enrolled in the study. The most common types of drug eruption were maculopapular eruption, fixed drug eruption, and urticaria. Antimicrobial agents were found to be the most common causative drugs, followed by antipyretic/anti-inflammatory agents and drugs acting on the central nervous system. Conclusions Although the most common type of drug eruption and the most common causative agents were not different from those found in previous studies, the new generation of antibiotics and antifungal agents were found to be a frequent cause of drug eruptions. New types of drug eruption, such as generalized exanthematous pustulosis and acral erythema, were observed in this study.     

Histopathology of cutaneous reaction to granulocyte colony-stimulating factor: another pseudomalignancy

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor (HGF) with many applications in cancer therapy. The most important applications are reduction in the incidence of febrile neutropenia, acceleration of neutrophil recovery after chemotherapy or bone marrow transplantation, and mobilization of progenitor cells. Many cutaneous adverse reactions associated with HGF have been reported in recent years, including injection site reactions, pyoderma gangrenosum, Sweet's syndrome, cutaneous leucocytoclastic vasculitis, and widespread folliculitis. The presence of large histiocytes on the dermis between collagen bundles has been proposed as a characteristic histopathologic finding in cutaneous eruptions secondary to granulocyte colony-stimulanting factor and granulocyte-macrophage colony-stimulating factor. We report on a patient with a high-risk ductal infiltrating carcinoma of the breast who received high-dose chemotherapy (HDC) with peripheral blood progenitor cell (PBPC) rescue. The patient received G-CSF after PBPC for a faster granulocyte recovery. She developed a cutaneous eruption located on back, buttocks, axillae, groin and sites where electrocardiography electrodes had been placed. From the histopathological point of view, the eruption was characterized by the presence of numerous large, atypical histiocytes in the dermis with several mitotic figures, mimicking involvement of the dermis by a malignant process.     

Neutrophilic Dermatoses in Two Children with Idiopathic Neutropenia: Association with Granulocyte Colony-Stimulating Factor (G-CSF) Therapy

Painful neutrophilic skin lesions were observed in two children receiving granulocyte colony-stimulating factor (G-CSF) for treatment of idiopathic neutropenia. A girl with cystic fibrosis and cyclic neutropenia developed an erythematous papular eruption without fever or neutrophilia 7 months after commencing therapy with G-CSF. A skin biopsy specimen revealed microscopic, sterile, neutrophilic abscesses. A boy with chronic neutropenia and recurrent inflammatory skin lesions developed multiple erythematous nodules following administration of G-CSF. A biopsy specimen showed neutrophilic panniculitis. We believe that these skin eruptions belong to a spectrum of neutrophilic dermatoses that can be induced or aggravated by G-CSF therapy.     

Dermatomyositis-like eruption and leg ulceration caused by hydroxyurea in a patient with psoriasis

We report the case of an elderly woman who had been on hydroxyurea for long-standing widespread psoriasis. After approximately 5 years's treatment with hydroxyurea, she developed a symmetrical dermatomyositis-like eruption on her hands, together with bilateral leg ulceration. Although similar skin eruptions have been reported after long-term hydroxyurea treatment, all of the previous patients were being treated for myeloproliferative disorders. A dermatomyositis-like eruption has not previously been reported to occur as a consequence of hydroxyurea treatment for psoriasis. Its recognition is important to prevent unnecessary investigation or treatment withdrawal.     

Newborn infant with hemophagocytic lymphohistiocytosis and generalized skin eruptions

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease resulting from abnormal proliferation of histiocytes in tissues and organs. The incidence of HLH is 1:50,000-300,000. Cutaneous eruptions have been reported in 6-65% of the cases. It's important to differentiate the eruptions from other systemic diseases. We present an infant with prominent skin manifestations of HLH. On the 11th day of life, she was admitted to our hospital with complaint of a generalized rash that had started the previous day. The eruptions consisted of irregularly shaped maculopapular erythematous rash and purpura. Bone marrow aspiration on the 25th day of life revealed hemophagocytosis with increased macrophages and histiocytes, consistent with HLH. Treatment was started with dexamethasone followed by induction chemotherapy with etoposide. All skin manifestations resolved in a few days. Although the clinical features are nonspecific, HLH should be kept in mind as an accompanying disease in neonates presenting with skin eruptions.     

Drug Eruptions: An 8-year Study Including 106 Inpatients at a Dermatology Clinic in Turkey

Background:

Few clinical studies are found in the literature about patients hospitalized with a diagnosis of cutaneous drug eruption.

Aims:

To determine the clinical types of drug eruptions and their causative agents in a hospital-based population.

Materials and Methods:

This retrospective study was performed in the Dermatology Department of Haseki General Hospital. Through 1751 patients hospitalized in this department between 2002 and 2009, inpatients diagnosed as drug eruption were evaluated according to WHO causality definitions. 106 patients composed of probable and possible cases of cutaneous drug eruptions were included in this study.

Results:

Seventy one females and 35 males were evolved. Mean age was 44.03±15.14. Duration between drug intake and onset of reaction varied from 5 minutes to 3 months. The most common clinical type was urticaria and/or angioedema in 48.1% of the patients, followed by maculopapular rash in 13.2%, and drug rash with eosinophilia and systemic symptoms in 8.5%. Drugs most frequently associated with cutaneous drug eruptions were antimicrobial agents in 40.5% of the patients, followed by antipyretic/anti-inflammatory analgesics in 31.1%, and antiepileptics in 11.3%.

Conclusion:

Urticaria and/or angioedema and maculopapular rash comprised majority of the drug eruptions. Rare reactions such as acute generalized exanthematous pustulosis, sweet syndrome, oral ulceration were also found. Antimicrobial agents and antipyretic/anti-inflammatory analgesics were the most commonly implicated drugs. Infrequently reported adverse reactions to myorelaxant agents, newer cephalosporins and fluoroquinolones were also detected. We suppose that studies on drug eruptions should continue, because the pattern of consumption of drugs is changing in every country at different periods and many new drugs are introduced on the market continuously.     

Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis.

BACKGROUND--Mesna is used to abolish urotoxicity of cyclophosphamide and related compounds in immunosuppressive and antineoplastic treatment schedules. Adverse reactions to this drug have been reported only rarely. OBSERVATIONS--Drug eruptions to mesna have developed in seven of 15 patients with autoimmune disorders treated with monthly pulses of intravenous cyclophosphamide. Two different types of drug eruptions were observed: five patients had development of a macular and partly papular or urticarial rash and angioedema and two patients had a generalized fixed drug eruption, primarily and predominantly at the sites of previous skin lesions of their underlying condition. The results of prick, patch, and intradermal tests were similar in both types of rash; however, the two patients with fixed drug eruption had developed a generalized eruption upon prick testing with mesna. CONCLUSIONS--Two distinct eruptions to mesna have been induced in these patients during cyclophosphamide/corticosteroid therapy; these eruptions are not thought to share a common pathogenic mechanism. The results of skin and challenge tests do not support the hypothesis that a type 1 or a type 4 immune reaction may be responsible for these eruptions. The unusually high incidence (about 50%) of these reactions and their clinical presentation make it important to distinguish them from an exacerbation of the preexistent autoimmune disorder.     

Ritodrine-induced erythematous papular eruption in 14 pregnant women

Background Ritodrine hydrochloride, a β2‐adrenergic agonist, has been used for the treatment of pre‐term labor as a relatively safe agent, although tolerable side‐effects have been occasionally reported. Objective The purpose of this study was to assess our clinical experience of skin eruptions caused by ritodrine. Methods Fourteen pregnant women with pruritic skin eruptions associated with the administration of ritodrine for pre‐term labor were examined in Saitama Medical Center Hospital between 2005 and 2008. Results Patients included both primigravidas and multigravidas. Their mean age was 33.7 years (range: 27–41 years). Almost all subjects were in the third trimester of pregnancy. Skin eruptions occurred 7–27 days (mean: 14.9 days) after the start of intravenous or oral ritodrine. In eight patients, the eruption occurred after an increase in the dose of the drug. The reaction was characterized by a pruritic, erythematous, papular eruption, mainly distributed on the abdomen and upper extremities. Lymphocyte transformation tests for ritodrine were positive in five of the eight patients. Conclusions Ritodrine‐induced, erythematous, papular eruption probably occurs more frequently than has been previously estimated. An immunologic mechanism may play a role in the development of this eruption caused by ritodrine, although the reaction is somewhat dependent on the dose.     

Amoxycillin-induced flexural exanthem

We describe a 37-year-old man who developed an acute, inflammatory flexural eruption shortly after taking amoxycillin, then erythema multiforme-like lesions on the palms and soles. The eruption resolved with systemic corticosteroids, and positive patch tests with amoxycillin supported a drug-induced aetiology. A few similar cases have been described as the 'baboon syndrome' or intertriginous drug eruptions. We draw attention to this rare, distinctive drug eruption.