INTRODUCTION

Multiple drug allergy syndrome (MDAS), multiple drug intolerance syndrome (MDIS), and adverse drug reactions (ADR) are terms that have been used in the literature trying to differentiate each entity from the others.

We performed a PUBMED search from 1956 until January 7, 2024, searching the “[MeSH Terms]: multiple drug allergy syndrome (MDAS), multiple drug intolerance syndrome (MDIS), and adverse drug reactions (ADR), multiple drug reaction and drug reaction, and the most reliable publications agree that these terms had been improperly used. Some authors did a very thorough methodological search using 11 databases for the terms MDIS, MDAS and comparable terms without partiality by using Critical Appraisal Skills Programme cohort study checklist. The authors also concluded that there is a lack of appropriately designed studies performed utilizing consistent terms and analytical methodology to reach the terminology MDIS, MDAS, multiple drug reaction and or drug reaction [1]. This case is an example of one of these terminologies.

CASE REPORT

An obese, diabetic 61-year-old female presented to the dermatologist with multiple large, tense blisters and scattered, smaller blisters on her legs and axillae (Fig. 1a, black arrow). The patient started taking Advil^® due to an upper respiratory infection and was prescribed doxycycline. Besides the cutaneous eruption, she also experienced increased fever, gastrointestinal reflux, headache, cough, muscle ache, and elevated blood pressure. The patient was taking Micardis HCt; oral Metformin^® 850 mg tablets; Symlin^®, Lantus^® and Novolag^® subcutaneous for her longstanding diabetes and hypertension. The patient described a history of a previous drug allergy diagnosed by clinical and pathology studies. For this current episode, skin biopsies were taken for hematoxylin and eosin (H&E), direct immunofluorescence (DIF), and double immunohistochemistry (IHC) stains as described before [2–4]. The following antibodies were utilized from Agilent Dako, (Santa Clara, CA,USA): Mouse monoclonal anti-human CD4; cyclooxygenase-2 (COX-2), clone CX-294; and D2-40/podoplanin. The following antibodies were used from Novocastra (Chicago, Illinois, USA): anti-human CD4 clone 4B12.

Figure 1: In Fig 1a, multiple large, tense blisters (black arrow). Fig 1b, the H&E staining demonstrated diffuse, moderate epidermal spongiosis, with a subepidermal blister (blue asterisk) (100X). Lymphocytes and eosinophils were present under the blister around the superficial dermal blood vessels. Inflammatory infiltrate was also observed around the hair follicles and sweat glands. The blood vessels, mostly the lymphatics, significantly displayed damage based upon routine histology with presence of neutrophils and fibrin, and the D240 stain was seen in the entire upper dermis and also was seen at the level of the basal keratinocytes under the blister. Fig 1c, The DIF demonstrated mainly anti-human fibrinogen FITC conjugate (++++), focally located in a perivascular distribution. (400X, green stain, white arrows, the blue stain is Dapi for the nuclei and in red Ulex. Figs 1 e and Using IHC, the D2-40 stain (brown stain for lymphatics) was positive on lymphatic endothelial cells, highly expressed in the upper dermis, as well as in the keratinocytes at the basal membrane area that usually are not positive for D240. The lymphatics were fragmented, and the ones the larger ones were dilated (red arrows). In Fig 1f, we show the IHC using double staining with CD4 (in brown) showing a positive stain in the inflammatory infiltrate around the blood vessels and also positive underneath the blister colocalizing with a positive stain with the COX-2 antibody (fuchsia stain, black arrows, 200X). Box b, right top corner, contain an enlarged image of the dermal vessels.

The H&E staining demonstrated diffuse, moderate epidermal spongiosis, with a subepidermal blister (blue asterisk) (100X). Lymphocytes and eosinophils were present under the blister around the superficial dermal blood vessels (Fig. 1b). Inflammatory infiltrate was also observed around the hair follicles and sweat glands. The blood vessels, mostly the lymphatics, significantly displayed damage based upon routine histology with presence of neutrophils and fibrin, and the D240 stain was seen in the entire upper dermis and also was seen at the level of the basal keratinocytes under the blister. The given diagnosis was drug reaction and/or multiple drug reaction, and the patient was prescribed with 2% topical cortisone cream twice a day. Advil^® and doxycycline were stopped, and a short course of oral corticosteroids and Zyrtec^® (cetirizine) were prescribed). After a week and a half of treatment, the skin lesions as well as the systemic symptoms disappeared. His blood pressure also stabilized. We cannot confirm if this was a multiple drug eruption” and/or a drug reaction, the antibiotic, with the being completely Advil incidental.

The DIF demonstrated mainly anti-human fibrinogen FITC conjugate (++++), focally located in a perivascular distribution. Using IHC, the D2-40 stain shows positive on lymphatic endothelial cells, highly expressed in the upper dermis, as well as in the keratinocytes at the basal membrane area that usually are not positive for D240. The lymphatics were fragmented, and the ones the larger ones were dilated. IHC revealed double staining with CD4 showing a positive stain in the inflammatory infiltrate around the blood vessels and also positive underneath the blister colocalizing with a positive stain with the COX-2 antibody (Figs. 1c – 1f).

DISCUSSION

The different terms such “multiple drug allergy syndrome” (MDAS), or “multiple drug intolerance syndrome” (MDIS), or “adverse drug reaction” (ADR) should be used more strictly since these terms confuse dermatologists, allergologists, immunologists, and health workers. A recent study used a methodical literature examination across eleven 11 databases (01 January 2000-06 November 2020) for the terms MDIS, MDAS and conveyed terms [1]. The authors use the Critical Appraisal Skills Programme cohort study checklist. They concluded that terms are well not systematically confirmed [1]. Before these terms ADR, MDAS, MDIS classifications, the classic Gell and Coombs classification was widely used [5]. The Gell-Coombs’s classification divides drug hypersensitivity and other immune reactions into four categories, known as type I-IV reactions. In a case like the one we have presented, we observed an immune response that features several units of the Gell-Coombs’s classification, manifested by our COX-2 staining, and positive CD4 lymphocytes and peri-vascular fibrinogen findings all combined. Gell and Coombs were the first to classify hypersensitivity immune responses into 4 types based upon pathophysiology, but additional current knowledge into the intricate pathological and immunological mechanisms of these disorders have since be adjusted the original classification system [6].

Non-steroidal anti-inflammatory drugs (NSAIDs) such Advil^®, as well doxycycline as frequently cause adverse drug reactions. Some authors noticed the same [7,8] findings as we report in this case; however, the therapeutic approach needs to be taken into consideration individually based on the risk factors and other medical conditions. It has been described that medications selectively inhibiting COX-2 are safe options in patients with drug related reactions and some hypersensitivities [7,8].

This patient was taking multiple medications for the control of blood glucose, as well as for high blood pressure and she was obese was obese. The dilation and alterations of the lymphatics could be related to her medical conditions.

However, at least based on this case, it is important to look for lymphatics dilatation and change in the shape and forms of them as shown in this case. Lymphatics have receptors for multiple neurotransmitters, cytokines, and inflammatory mediators. Lymphatics are influenced by both stimulating as well as inhibitory molecules. Some of the multiple include neurotensin receptor; vasoactive intestinal peptide 5HT, pituitary adenylate cyclase-activating polypeptide muscarinic acetylcholine receptor; serotonin; calcitonin receptor-like; dopamine; neurokinin 1 receptor; neuromedin B receptor; neuropeptide Y noradrenaline (an a-adrenoceptor agonist with some b adrenoceptor stimulation). Some of these molecules can increase and or decrease lymphatic tone. Some drugs had an excitatory effect and some have an inhibitory effects in lymphatics due to the receptors preset in the lymphatics such cyclooxygenase 2, leukotriene; cysteinyl leukotriene receptor; sodium nitroprusside, PGD receptor; histamine; histidine decarboxylase; IFN, interferon; interferon alpha/beta receptor; IL, interleukins; sodium nitroprusside prostaglandin; phospholipase 2; reactive oxygen species among many others [9].

CONCLUSIONS

The approach and assessment of patients with possible drug reactions with ensuing cyclooxygenase 2 expression, as well as the presence of alterations on the lymphatics, may be important to watch for. Even when a drug predominantly targets arteries and/or veins (or additional cells and tissues), there may be resultant consequences on lymphatics based upon the inflammation caused by the drug reactions. Increasing capillary permeability leading to augmented lymphatic flow, alterations in shape and even fragmentation, may result caused by the release of inflammatory agents from adjacent tissues.