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Year : 2011  |  Volume : 3  |  Issue : 2  |  Page : 82-84

Bullous allergic drug eruption with presence of myeloperoxidase and reorganization of the dermal vessels observed by using CD34 and collagen IV antibodies

1 Georgia Dermatopathology Associates, Atlanta, Georgia, USA
2 Statesboro Dermatology, Statesboro, Georgia, USA
3 Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

Date of Web Publication9-Nov-2011

Correspondence Address:
Ana Maria Abreu-Velez
Georgia Dermatopathology Associates, Atlanta, Georgia, USA. 1534 North Decatur Road NE Atlanta, GA
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Source of Support: None, Conflict of Interest: None

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Context: Bullous allergic reactions are inflammatory skin disorders, presenting usually as a result of some type of reaction to medication. Case Report: A 67-year-old female was evaluated for the presence of diffuse patches of erythema, microvesiculation, vesicles, crusts, and oozing of sudden appearance on the extremities and on the rest of the body after taking sulfamethoxazole in combination with trimethoprim. Skin biopsies for hematoxylin and eosin examination, as well as for direct immunofluorescence and immunohistochemistry analysis were performed. H&E staining demonstrated classic features. Direct immunofluorescence revealed strong deposits of fibrinogen in the vessels of the skin. The immunohistochemistry stain showed strong positivity of myeloperoxidase within the blister cavity. The distribution of the vessels around the inflammatory process were noticed by using antibodies to CD34 as well to collagen IV. Conclusions: sulfamethoxazole is catalysed by CYP2C9 and/or myeloperoxidase. Thus, myeloperoxidase appears to be of importance in this disorder.

Keywords: CD34, bullous drug eruption, myeloperoxidase, collagen IV.

How to cite this article:
Abreu-Velez AM, Klein DA, Smoller BR, Howard MS. Bullous allergic drug eruption with presence of myeloperoxidase and reorganization of the dermal vessels observed by using CD34 and collagen IV antibodies. North Am J Med Sci 2011;3:82-4

How to cite this URL:
Abreu-Velez AM, Klein DA, Smoller BR, Howard MS. Bullous allergic drug eruption with presence of myeloperoxidase and reorganization of the dermal vessels observed by using CD34 and collagen IV antibodies. North Am J Med Sci [serial online] 2011 [cited 2023 Mar 21];3:82-4. Available from: https://www.najms.org/text.asp?2011/3/2/82/86352

  Introduction Top

Bullous or blistering drug eruptions and drug-induced anaphylaxis and hypersensitivity syndromes are amongst the most serious types of adverse drug reactions. Based on the various mechanisms, bullous drug eruptions may be classified into the following categories: spongiotic or eczematous, acute generalized exanthematous pustulosis, fixed drug eruption, erythema multiforme,  Stevens-Johnson syndrome More Details (SJS) or toxic epidermal necrolysis (TEN) [1],[2] .

As with other bullous disorders, drug-induced blistering reactions take place via a diversity of pathophysiological mechanisms and at different levels within the epidermis and or at the dermoepidermal junction. Examples of these mechanisms comprise the following: exocytosis and/or spongiosis, formation of subcorneal spongiform pustules, cytolysis and keratinocytic necrosis, antiepidermal antibody formation, deposition of immunoglobulin at the basement membrane zone (BMZ), and photo-induced matrix and collagen alterations that lead to a mechanobullous disorder [1],[2] .

  Case Report Top

A 67-year-old Female presented with clinical blisters and sudden prutitus, initially in the extremities that extended to the rest of the body, associated with diffuse patches of erythema, microvesiculation, vesicles, crusts, and oozing. The patients were taking sulfamethoxazole in combination with trimethoprim. A lesional skin biopsy was taken for hematoxylin and eosin (H & E) analysis. In addition, a direct immunofluorescence (DIF) and immunohistochemistry (IHC) studies were performed.


In brief, skin cryosections were prepared, and incubated with multiple fluorescein isothiocyanate as previously reported [3],[4],[5],[6] .


It was performed as previously described [3],[4],[5],[6] .

Microscopic Description

Examination of the H&E tissue sections demonstrated a subepidermal blistering disorder. Within the blister lumen, numerous lymphocytes, histiocytes, eosinophils and neutrophils were present. Mast cells were rare. Focal, superficial dermal scarring was present. In addition, the dermis displayed a superficial, perivascular infiltrate of lymphocytes, histiocytes, neutrophils and occasional eosinophils [Figure 1].
Figure 1:a (10x) b (20x) H&E tissue sections demonstrates a subepidermal blistering and within the blister lumen, numerous lymphocytes, histiocytes, eosinophils and neutrophils are present (black arrows). c (10x) and d (40x). IHC positive myeloperoxidase positive inside the blister (red arrows). e . DIF showing positive stain against the superficial dermal vessels under the inflammatory process when using anti-human fibrinogen-FITCI conjugated (green stain, white arrows). The red stain is antibody to collagen IV corroborating that these are vessels. f . H&E shows reorganization of the vessels around the hair follicles (black arrows). g through i . IHC using CD34, showing how most of the vessels around the inflammatory process are reorganized and loss their normal distribution on the skin (red arrows). j . DIF, showing positive stain with anti-collagen VI antibody (yellowish stain, red arrow) at the base membrane zone (BMZ) of the skin as well as also show reorganization of the superficial and intermediate vessels around the inflammatory process (blue arrows). k . IHC using anti-body against collagen IV (dark stain) shows the stain on the sweat glands, and also show some reorganization of the vessels around the sweat glands with some kind of polarization towards the inflammation (red arrows). 1 DIF, showing positive stain with anti-human IgM-FITCI conjugated to the sweat glands (yellow stain (white arrow). The nuclei were counterstained with Dapi (blue) and the sweat glands with mapped with anti-collagen VI antibody (red stain).

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DIF results

The test was performed and displayed the following results: IgG(-); IgG3(-); IgG4 (-); IgA(-); IgM(-); IgE (-); complement/C1q (-); complement/C3 (-); albumin (+, weak dermal perivascular) and fibrinogen (++, dermal perivascular). No deposits of complement and or immunoglobulins were seen in the BMZ.

IHC results

Immunohistochemistry showed the presence of myeloperoxidase in the entire subepidermal blister. In addition, we also noted alteration in the distribution and reorganization of the dermal vessels being closely located under the blister as determined by the CD34 and collagen IV antibodies [Figure 1]. (Usually the superficial vessels not inflamed are located in the upper vascular plexus of the skin, with some space between the epidermis and them by the papillary dermis.

  Discussion Top

In general, the incidence of adverse cutaneous reactions to drugs has been estimated at 0.1-2.2% of treatment courses; however, some penicillins and sulfamethoxazole/trimethoprim may have a significantly elevated incidence at 3-5% of treatment courses. Patients infected with human immunodeficiency virus infection may be at greater risk for adverse cutaneous drug reactions. SJS and TEN have are more frequent in those younger than 20 years and older than 65 years [1],[2] .

Sulfamethoxazole is also administered in combination with trimethoprim, as co-trimoxazole, for prophylaxis and treatment of HIV-associated infections. Unfortunately, sulfamethoxazole administration is associated with the development of adverse drug reactions in between 1 and 5% of patients. The most common adverse events the development of cutaneous symptoms. Such reactions are thought to be immune mediated. To generate a drug antigen, sulfamethoxazole is metabolised in liver, blood cells and keratinocytes to a hydroxylamine metabolite [2],[7],[8],[9],[10] . These reactions are catalysed by CYP2C9 and/or myeloperoxidase. However, polymorphisms in other drug metabolizing enzymes such as myeloperoxidase may be important to be considered.

We conclude that in all blistering diseases it is ideal to perform not only the biopsy for H & E, but also DIF and if possible some immunohistochemistry stains. A full pathologic understanding of this process seems to require not only the inflammatory cells to possible contribute to induce the blisters, but also requires some reorganization with polarization of the vessels where these inflammatory arrive into the dermis. As shown some of these inflammatory cells (mainly neutrophils released strong myeloperoxidase that can also contribute to the blistering formation). Collagen IV and CD34 (vessels markers), also indicated that the vessels get physically closers to the main inflammatory target (in this case the blister)

In[Figure 1], we demonstrate some of the most prominent findings using H&E, DIF and IHC stains.

  Acknowledgments Top

Jonathan S. Jones HT (ASCP), and Lynn K. Nabers HT, HTL (ASCP) at GDA for excellent technical assistance.

  References Top

1.Sassolas B, Duong TA. Dermatology and the effects of medication on the skin. Soins 2010; 748:42-44.  Back to cited text no. 1
2.Naisbit DJ. Drug hypersensitivity reactions in skin: understanding mechanisms and the development of diagnostic and predictive tests. Toxicology 2004; 194: 179-196.  Back to cited text no. 2
3.Abreu Velez AM, Howard MS, Pinto FJ Jr. Dyshidrotic eczema: relevance to the immune response in situ. North Am J Med Sci 2009; 1: 117-120.  Back to cited text no. 3
4.Abreu Velez AM, Smith G Jr, Howard MS. Neutrophil extracellular traps (NETS), IgD, myeloperoxidase (MPO) and antineutrophil cytoplasmic antibody (ANCA) associated vasculitides. North Am J Med Sci 2009; 1: 309-313.  Back to cited text no. 4
5.Abreu Velez AM, Girald J, Howard MSJ Antigen presenting cells in a patient with hair loss of and systemic lupus erythematosus. North Am J Med Sci 2009; 1: 205-210.  Back to cited text no. 5
6.Abreu Velez AM, Billie Jackson B, Howard MA. Deposition of immunoreactants in a cutaneous allergic drug reaction. North Am J Med Sci 2009; 1: 180-183.  Back to cited text no. 6
7.Paquet P, De Groote D, Piérard GE. Functionally active macrophage-derived myeloperoxidase in the skin of drug-induced toxic epidermal necrolysis. Dermatology 2010; 220:201-207.  Back to cited text no. 7
8.Cribb AE, Miller M, Tesoro A, Spielberg SP. Peroxidase-dependent oxidation of sulfonamides by monocytes and neutrophils from humans and dogs. Mol Pharmacol 1990; 38: 744-751.  Back to cited text no. 8
9.Cribb AE, Spielberg SP, Griffin GP. N4-hydroxylationof sulfamethoxazole by cytochrome P450 of the cytochrome P4502C subfamily and reduction of sulfamethoxazole hydroxylamine in human and rat hepatic microsomes. Drug Metab Dispos 1995; 23, 406-414.  Back to cited text no. 9
10.Reilly TP, Lash, LH, Doll MA, Hein DW, Woster PM., Svensson CK. A role for bioactivation and covalent binding within epidermal keratinocytes in sulfonamide-induced cutaneous drug reactions. J Invest Dermatol 2000; 114: 1164-1173.  Back to cited text no. 10


  [Figure 1]

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