Bullous or blistering drug eruptions are among the most serious types of adverse drug reactions. They may be classified into the following categories:

1. Spongiotic or eczematous
2. Acute generalized exanthematous pustulosis (AGEP)
3. Fixed drug eruption (FDE)
4. Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN)
5. Drug-induced pemphigus
6. Drug-induced pemphigoid
7. Drug-induced linear immunoglobulin A (IgA) dermatosis (LAD)
8. Pseudo-porphyria cutanea tarda (pseudo-PCT)

Pathophysiology:
Pathophysiological mechanisms at various levels within the epidermis/dermoepidermal junction - exocytosis/spongiosis, formation of subcorneal spongiform pustules, cytolysis and keratinocytic necrosis, antiepidermal antibody formation, deposition of immunoglobulin at the basement membrane zone, and photo-induced collagen alterations that lead to a mechanobullous disorder. Most bullous drug reactions are the result of an immunologically mediated inflammatory response, although pseudo-PCT lacks significant inflammation.

Mortality/Morbidity:
Most bullous drug eruptions resolve without significant sequelae once the offending drug is removed. However, the morbidity of these reactions is proportional to the extent of skin surface area and mucous membrane involvement. Of patients who develop TEN, 25-30% will die. Elderly patients have a higher mortality rate with TEN. Sepsis is the most common cause of death in TEN. SJS and TEN may result in a residual cutaneous pigmentary disorder and possible scarring of the ocular mucosa in those who survive.
Sex: In general, adverse drug reactions occur more commonly in women, although EM has been reported to occur more frequently in men.
Age: Elderly patients who take multiple medications are at higher risk for the development of adverse drug reactions. Young men seem to be at higher risk for EM.

Signs and Symptoms:

History: Symptomatology of cutaneous reactions varies depending upon type and extent of skin involvement.
• Eczematous or spongiotic drug reactions may be the result of previous contact sensitization to the drug or may occur de novo.
o Incidence of contact eczematous reactions to topical medications may be as high as 12.1%. Systemic contact eczematous reactions, which result from systemic exposure (eg, oral, parenteral, rectal, intravenous, inhalation) to a previous contact sensitized drug, are more uncommon.
o Eczematous drug reactions begin with diffuse pruritus but also may cause headache, malaise, fever, nausea, vomiting, and diarrhea.
• AGEP (toxic pustuloderma) is a result of a systemic medication in 90% of cases.
o Onset is abrupt, usually 1-5 days after starting the medication.
o Patients complain of a diffuse pruritic or burning painful eruption associated with fever, malaise, and sometimes prostration. Seventeen percent of patients have a history of psoriasis.
• FDEs are a common cause of all drug eruptions and their frequency is second only to urticaria/angioedema.
o Careful patient assessment usually reveals that an FDE develops 6-48 hours after administration of the causative drug.
o Symptoms of pruritus and burning accompanied by fever are not uncommon. In those patients with multiple episodes of FDE, reports of increasing hyperpigmentation at the site of a previous lesion are common.
• Nosology of EM is controversial and somewhat confusing. Historically, EM has been divided into 3 groups: EM minor, EM major or SJS, and TEN. Considerable overlap may exist between these 3 subgroups and some authorities believe that TEN should be considered a distinct entity. An infectious agent, such as herpes simplex or mycoplasma, usually causes less severe cases of EM; drugs cause only 10% of cases. However, drugs cause most of the more severe and diffuse forms of EM.
o EM minor may begin with prodromal symptoms suggestive of an upper respiratory infection (eg, coryza, cough, pharyngitis), but within 7-10 days skin lesions begin to develop acrally and symmetrically on the hands, feet, and distal extremities. EM minor may have involvement of the oral mucosa, but involvement of 2 or more mucosal surfaces usually indicates SJS or TEN.
o Erythema multiforme major (SJS) affects young adult males more frequently. Prodromal symptoms of high fever, asthenia, muscular pains, diarrhea, vomiting, arthralgias, and pharyngitis precede mucosal involvement of 2 or more mucosal sites by several days. Skin involvement rapidly ensues. TEN has similar symptomatology but also demonstrates diffuse skin tenderness that resembles a severe sunburn.
• Drug-induced pemphigus can develop days, weeks, or months after taking the offending agent.
o Ruptured bullae leave painful erosions. Itching is not a common complaint. The oral mucosa frequently is involved; hoarseness, dysphagia, and unpleasant mouth odor follow.
o Drugs may serve as either a cause or a trigger for pemphigus. In those patients in whom drugs serve as a trigger, other autoimmune disorders such as lupus, bullous pemphigoid, and myasthenia gravis already may be present. Therefore, the development of drug-induced pemphigus seems to be determined in part by genetic predisposition.
• Drug-induced pemphigoid may follow oral or topical administration of drugs.
o Itching is a common symptom. Involvement of the epiglottis may lead to acute airway obstruction.
o Drug-induced pemphigoid patients are commonly younger than patients with idiopathic pemphigoid. Cicatricial pemphigoid is more common in patients of late middle age.
• Drug-induced LAD comprises a small portion of all cases of LAD.
o The clinical presentation of drug-induced LAD is indiscernible from other causes of LAD, except that mucosal involvement may be less likely in drug-induced LAD.
o Drug-induced LAD usually develops 1-2 weeks after taking the offending agent, although reactions may develop much sooner.
o Typical patients who develop LAD are seriously ill. Symptoms of severe burning and pruritus are common.
• Although patients with porphyria cutanea tarda (PCT) may have their disease precipitated or exacerbated by estrogens, iron overload, environmental hepatotoxins, and several drugs, patients who have drug-induced pseudoporphyria have no underlying abnormality of heme biosynthesis. The symptoms of photosensitivity, skin fragility, and blistering of the hands and forearms are the same in both conditions.

Physical: The physical findings of bullous drug eruptions will vary greatly depending on the type of reaction.
• On physical examination, the features of an eczematous drug eruption are similar to that of a diffuse contact dermatitis.
o These features include diffuse patches of erythema, microvesiculation, vesicles, crusts, and oozing.
o Other more specific features may include dyshidrotic hand dermatitis, EM-like lesions, purpura, urticarial lesions, and vasculitis-like lesions.
o Recrudescence of a positive patch test reaction may occur after systemic exposure to the offending medication. A diffuse eczematous eruption may mimic severe atopic dermatitis.

• Acute generalized exanthematous pustulosis
o AGEP presents as a diffuse scarlatiniform rash that rapidly develops numerous (>100) small pustules.
o Pustules measure between 1-5 mm in size
o Nikolsky sign may be positive.
o Some pustules may coalesce into bulla.
o Facial swelling, purpura, and targetoid lesions may occur.
o Oral mucosa may be involved in about 20% of cases. Once the offending drug is discontinued, the eruption rapidly dries up and desquamates within 2 weeks.

• Fixed drug eruption
o FDEs start as a few sharply demarcated erythematous macules that rapidly become erythematous plaques occurring more commonly on the lips, genitalia, and trunk.
o Lesions heal with hyperpigmentation and occur in the same site with readministration of the responsible drug
o In 30% of cases, macules may become vesicles and bullae, which may lead to a more severe reaction known as generalized bullous FDE resembling SJS-TEN. In patients with generalized bullous FDE, physical examination will reveal clearly demarcated erythematous and edematous patches surrounded by bullae that contain clear fluid.
• The characteristic physical finding of EM is the target or iris lesion
These lesions begin as sharply marginated erythematous annular macules or patches that become slightly raised.

o A concentric color change takes place; the center of the lesion becomes darker, dusky, or more violaceous, and the periphery develops a ring of erythema. The classic iris lesion has 3 zones, a central dusky area with purpura and an edematous pale ring surrounded by an erythematous ring. The central dusky macule may actually form a tense vesicle or bulla.
o These typical iris or target lesions are seen more commonly in EM minor caused by infections and occur acrally and progress in a centripetal fashion.
o Larger, confluent, irregularly-shaped, coalescing lesions with involvement of the trunk and 2 or more mucosal sites are common with SJS. The mouth and lips are the most commonly affected mucosal site in SJS but other sites, such as the pharynx, larynx, esophagus, bronchi, and genital mucosa may be involved.

o TEN demonstrates diffuse sunburnlike erythema that often begins on the face and spreads downward. The hairy scalp is spared. Maximal extension occurs within 2-3 days. A characteristic feature of TEN is the sheetlike separation of the epidermis in the involved areas. Flaccid bullae may form. Nikolsky sign is positive. Two or more mucosal sites are involved in 85-95% of patients with TEN.

• Drug-induced pemphigus may be clinically indistinguishable from idiopathic pemphigus vulgaris or pemphigus foliaceus.

o Lesions are superficial, flaccid bullae ranging in size from 1-10 cm.
o They may initially occur in the mouth.
o Nikolsky sign is positive when pressure is applied lateral to the bulla.
o Lesions rupture easily, leaving denuded and weeping areas, which secondarily become crusted.

• Tense bullae on normal skin or on an erythematous base is the typical finding in drug-induced pemphigoid
o Denuded areas, which are left after bullae rupture, heal spontaneously.
o Erythematous patches, urticarial plaques, and targetoid lesions also may be seen. Lesions may be found on the face, trunk, limbs, palms, soles, and mucous membranes.
o Nikolsky sign may be positive, unlike in idiopathic pemphigoid.
o Cicatricial pemphigoid is distinguished from other forms of pemphigoid by the presence of scarring. Cicatricial pemphigoid occurs on the mucous membranes of the eyes, pharynx, genitalia, or anus. Adhesions, strictures, and the loss of function may result from the scarring process.

• Physical examination of a drug-induced LAD lesion may reveal one of several pictures.

o The most common presentations include urticated plaques, papulovesicles resembling dermatitis herpetiformis, targetoid lesions like EM, and bullae resembling those found in bullous pemphigoid.
o Bullous eruptions can become hemorrhagic.
o Lesions are located most commonly on the trunk and limbs.
o Cases of palmar lesions, although uncommon, have been reported.
• Pseudoporphyria demonstrates tense blisters, erosions, and milia especially on the dorsum of the hands and forearms.Features of hypertrichosis, dyspigmentation, and skin sclerosis are not seen in pseudoporphyria as they are in true porphyria.

Causes:
• Contact sensitization to certain topical medications may result in a predisposition to a systemic eczematous reaction to the same or chemically-related medication.
o Contact sensitivity to penicillin may cause a diffuse eczematous reaction to systemically administered penicillin or even the small amounts of penicillin in cow's milk taken orally.
o Contact sensitivity to topical sulfonamides may cause a reaction to systemically administered sulfamethoxazole or sulfonyl ureas (tolbutamide, carbutamide) but not to dapsone or sulfapyridine.
o Contact sensitivity to ethylenediamine found as a preservative in some topical medications may predispose an individual to a reaction to systemically administered aminophylline, theophylline, tripelennamine, antazoline, methapyrilene, hydroxyzine, and pyrilamine.
o Contact sensitivity to tetramethylthiuram disulfide will predispose a reaction to the antialcohol treatment Antabuse (tetraethylthiuram disulfide).
o Patients sensitized to paraphenylenediamine may react to azo dyes taken orally or the group of para drugs.
o Other drugs that may cause an eczematous eruption but are not preceded by contact sensitivity are the following: carbamazepine, gold, griseofulvin, phenytoin, piroxicam, thiazide diuretics, and vitamin K.

• The most commonly implicated drugs in causing AGEP are the antibiotics, especially beta-lactams, macrolides, and co-trimoxazole.
o Diltiazem has been reported to cause AGEP several times.
o Other causes include the following: carbamazepine, hydroxychloroquine, clindamycin, ticlopidine, terbinafine, high-dose chemotherapy, chromium picolinate, chloramphenicol, sulfapyridine, metronidazole, lacquer chicken, protease inhibitors, progesterones, mercury, nystatin, amoxapine, paracetamol, chloroquine and proguanil, nifuroxazide, lansoprazole, minocycline, dexamethasone injection, propicillin, aspirin, doxycycline, and buphenine.

• Many drugs are capable of causing FDEs. Some of the more common etiologic agents of FDEs include aspirin, barbiturates, co-trimoxazole, phenolphthalein, pheprazone, sulfonamides, and tetracycline.
o Causative agents in generalized bullous FDEs include aminophenazone, antipyrine, barbiturates, co-trimoxazole, diazepam, mefenamic acid, paracetamol, phenazones, phenylbutazone, piroxicam, sulfadiazine, and sulfathiazole.
o Knowledge of the potential drugs involved in a FDE is especially important because certain drugs have a predilection to cause FDEs at certain sites. Aspirin has a predilection for the trunk and limbs, tetracyclines for the genitalia, and phenylbutazone for the lips.

• No reproducible tests for the etiology of EM exist. Association with infectious agents, such as herpes simplex and mycoplasma, has been well described. Precipitation of SJS or TEN most commonly has been associated with certain medications. The most commonly associated medications are the following: antibiotics (sulfonamides, trimethoprim-sulfamethoxazole, penicillins, cephalosporins, chloramphenicol, clindamycin, griseofulvin, rifampin, streptomycin, tetracycline), nonsteroidal anti-inflammatory agents (ibuprofen, acetylsalicylic acid, ketotifen, naproxen, piroxicam, sulindac), antihypertensives, anticonvulsants (phenobarbital, carbamazepine, phenytoin), and allopurinol.

• The thiol group of drugs is the most common agent implicated in drug-induced pemphigus. Drugs known to cause pemphigus include amoxicillin, ampicillin, captopril, cephalosporins, penicillamine, penicillin, pyritinol, and rifampin. Thiol drugs are more likely to cause pemphigus whereas nonthiol drugs are more likely to trigger pemphigus. For this reason, spontaneous recovery is lower in non–thiol-induced pemphigus where other factors may be predisposing a patient to develop pemphigus.

• Sulfur-containing drugs commonly cause drug-induced pemphigoid with furosemide being the most common cause. Other agents commonly known to cause drug-induced pemphigoid include amoxicillin, ampicillin, phenacetin, penicillin, penicillamine, and psoralen-ultraviolet-A light. Cicatricial pemphigoid has occurred after the use of drugs including practolol, topical echothiophate, D-penicillamine, clonidine, topical pilocarpine, topical demecarium, indomethacin, topical glaucoma, and sulfadoxine.

• Vancomycin is the most common cause of drug-induced LAD. Other drugs known to cause LAD include diclofenac, somatostatin, lithium, phenytoin, captopril, amiodarone, and cefamandole.
• True PCT may be precipitated by barbiturates, estrogens, griseofulvin, rifampicin and sulfonamides. The drugs that are known to induce pseudoporphyria include furosemide, nabumetone, nalidixic acid, naproxen, oxaprozin, and tetracycline.

Investigations:

Lab Studies:
• Laboratory studies during an eczematous drug eruption may disclose eosinophilia, leukocytosis, and elevated sedimentation rate.
• In AGEP, laboratory studies demonstrate a neutrophilia in 90% and eosinophilia in 30%. Liver function is usually normal.
• Laboratory studies in FDE may show leukocytosis, hypereosinophilia, and hypergammaglobulinemia. However, clinical and histologic features are the mainstay of diagnosis.
• Apart from leukocytosis, laboratory studies may not be helpful in the evaluation of EM patients. Patients with widespread lesions may develop electrolyte abnormalities and hypoalbuminemia. Immunofluorescence studies are negative.
• Antinuclear antibodies may be found in patients with thiol drug-induced pemphigus.
• Blood eosinophilia and increased amounts of soluble interleukin-2 (IL-2) receptors may be present in patients with drug-induced pemphigoid. The sera and blister fluids in drug-induced pemphigoid may show increased amounts of eosinophilic cationic protein and neutrophil derived myeloperoxidase.
• Laboratory studies are not particularly helpful in diagnosing drug-induced LAD.
• In pseudoporphyria, laboratory studies do not demonstrate any abnormality in heme biosynthesis or hepatic abnormalities.

Other Tests:
• Patch testing suspected drugs that cause eczematous drug reactions may be positive.
• Patch testing of the offending drug in AGEP may result in a pustular patch test reaction.
• Patch testing and oral provocation testing may be used to implicate a specific drug in a FDE.
• Apart from skin biopsy, other tests are not helpful in evaluating EM. First-degree relatives of patients with TEN have lymphocytes that are more susceptible to the toxic effect of the culprit drug than controls.
• Direct and indirect immunofluorescence studies in drug-induced pemphigus are identical to studies in idiopathic pemphigus. Deposition of immunoglobulin G (IgG) and complement 3 (C3) is seen intercellularly on direct immunofluorescence. On indirect immunofluorescence, pemphigus antibodies are found in the patient's serum.
• Linear deposits of IgG and C3 may be visualized along the basement membrane zone with direct immunofluorescence in patients with drug-induced pemphigoid. Indirect immunofluorescence studies are positive for circulating antibodies against the basement membrane zone. However, circulating antibodies are found less commonly in cicatricial pemphigoid.
• Direct immunofluorescence studies reveal the presence of IgA at the basement membrane zone in LAD. Indirect immunofluorescence studies using monkey esophagus or saline split human skin are usually negative for IgA at the basement membrane zone.
• Pseudoporphyria demonstrates normal urine and serum porphyrins.

Medicinal management:
Withdrawal of the offending medication is the most important aspect of treatment of bullous drug reactions. Most reactions are self-limited. Conservative treatment involves using wet compresses.

Homoeopathic medicines:

1. SKIN - ERUPTIONS - blisters
ail.; alum.; alum-sil.; am-c.; anac.; ant-c.; ars.; ars-s-f.; aur.; aur-ar.; aur-s.; borx.; bry.; bufo; canth.; carb-an.; carbn-s.; caust.; cham.; clem.; crot-h.; dulc.; graph.; hep.; kali-ar.; kali-bi.; kali-c.; kali-s.; kali-sil.; lach.; mag-c.; merc.; nat-ar.; nat-c.; nat-m.; nat-p.; nat-s.; nit-ac.; petr.; phos.; ran-b.; ran-s.; rhus-t.; rhus-v.; sep.; sil.; sulph.;

2. SKIN - ERUPTIONS - pemphigus
acon.; anac.; antip.; ars.; arum-t.; bell.; bufo; calth; canth.; carbn-o.; caust.; chin.; cop.; crot-h.; cur.; dulc.; hep.; hydrc.; jug-c.; lach.; lipp.; lyc.; manc.;br mer.c; mer-.c; nat-m.; nat-s.; nat-sal.;br nit-ac.; ph-ac.; phos.; psor.; ran-b.; ran-b.; ran-s.; ran-s.; raph.;br raph.; .; rhus-t.; sars.; scroph-xyz.; sep.; sil.; sul-a.; sulph.; syph.; thuj.; thuj.;

3. SKIN - ERUPTIONS - antibiotics; from rhus-v.;

Prognosis:
• Eczematous or spongiotic drug reactions usually have a good prognosis and resolve without significant sequelae.
• AGEP has a good prognosis and resolves without sequelae once the causative agent is removed.
• Bullous generalized FDEs have a favorable prognosis.
• EM most often has a good prognosis but SJS and TEN can be lethal depending on the extent of skin involvement and the age of the patient.
• Pemphigus has a mortality rate approaching 10%. However, drug-induced pemphigus usually resolves with removal of the offending agent. In some patients, lesions may progress or persist. In these cases, the drug likely is serving as a trigger rather than a cause in patients who already are prone to develop pemphigus.
• Drug-induced pemphigoid has an excellent prognosis with discontinuation of the drug. However, some cases may involve persistent lesions. Cicatricial pemphigoid, in comparison to idiopathic bullous pemphigoid, shows a small tendency for remission. In severe cases of ocular cicatricial pemphigoid, scarring and blindness in both eyes has been reported.
• Drug-induced LAD has a good prognosis.
• Drug-induced PCT has a good prognosis.