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Histological features indicative of drug reaction:

1. Presence of eosinophils
2. Activated lymphocytes (larger in size)
3. Apoptotic keratinocytes
4. Presence of plasma cells in some cases.
5. Extravasation of red blood cells
6. Edema in some cases
7. Endothelial cells lining the blood vessels are swollen.
 

Drugs causing cutaneous reaction:

1. Antibiotics (Eg. Co-trimoxazole,ampicillin, amoxycillin,  penicillin, sulphonamides etc.
2. Non-steroidal anti-inflammatory drugs ( Eg. Aspirin, indomethacin, ibuprofen, phenylbutazone, mefenamic acid. 
3. Phenytoin sodium (anticonvulsant)
4. Psychotropic drugs (tricyclic antidepressants, lithium, tranquilizers)  
5. Anticancer chemotherapeutic drugs ( Eg. fluorouracil, doxorubicin, methotrexate etc)
6. Gold
7. Thiazide diuretics
8. Antimalarial drugs
9. Beta- blockers
10.Recombinant cytokines
11. Retinoids

DermAtlas Image1    Image2   Image3

1. Exanthematous drug reaction:

Drugs associated with this reaction include Ampicillin,  amoxyllin, allopurinol, co-trimoxazole, penicillin, erythromycin, streptomycin, tetracyclin etc.  Reaction develops on the first day or within 3 weeks.
Morphological  features:
Erythematous papules and macules.  First appears on the trunk or on areas of  trauma or pressure and later spreads to the extremities.
Microscopic features:  Small foci of spongiosis, vacuolar degeneration in the basal layer, apoptotic keratinocytes.
Activated lymphocytes, some eosinophils and plasma cells in the papillary dermis. 

2. Halogenoderma (iododerma, bromoderma, fluroderma):

Caused by ingestion of iodides,bromides and fluorides.
Clinically, lesions may occur on face, neck , back or extremities as papules, pustules or vegetating nodules.
Microscopic features: Pseudoepitheliomatous hyperplasia of the epidermis, intraepidermal abscesses and in some cases dermal abscesses.
Differential diagnosis:  Chromomycosis and sporotrichosis.

3. Urticaria:

Acute urticaria in infants may be  caused by furazolidone used in the  treatment of diarrhea.
Chronic urticaria may be aggravated by salicylates.
Cold urticaria may follow use of penicillin & griseofulvin.
Clinically, urticaria is characterized by transient pruritic, edematous, erythematous papules with central clearing.
Microscopic features: There is mild, perivascular inflammatory infiltrate (mostly lymphocytes, sometimes eosinophils and mast cells) and dermal edema. In early case intravascular and perivascular neutrophils may be noted.
In coexisting angioedema there is edema of subcutaneous tissue and mucous membrane.

4. Drug induced lichenoid / interface patterns:
         A: Lichenoid drug eruption
         B: Fixed drug eruption
         C: Erythema multiforme
         D: Lupus erythematosus

A. Lichenoid drug eruption:

Drugs : Beta-adrenergic blockers, methyldopa, antimalarial drugs, penicillamine etc.
Clinically the lesions mimick lichen planus. Postinflammatory pigmentation is more prominent than LP.
Microscopic features: Focal parakeratosis. Mild basal vacuolar change.Few eosinophils and sometimes plasma cells are present. Less dense & less band like inflammatory infiltrate. More pigment incontinence. Differential diagnosis: Lichen planus.

B. Fixed drug eruption:

Drugs: Sulphonamides, Co-trimoxazole, tetracyline, tranquilizer, quinine & others.
Clinically round or oval erythematous lesion.  
Microscopic features: Prominent vacuolar change. Civatte body formation at and above the level of basal layer. Inflammation obliterate dermoepidermal junction. The inflammatory cells in drug eruption extends to mid & upper epidermis. Few neutrophils are present. Differential diagnosis:  Erythema multiforme.

C. Erythema multiforme:

 Drugs: Sulfonamides, non-steroidal anti-inflammatory drugs and numerous other drugs.
Microscopic features - Divided into epidermal,dermal or mixed types depending on the histological features. Interphase reaction pattern.Mild to moderate inflammatory infiltrate at the dermoepidermal junction. Apopotic body at and above the basal layer. Subepidermal cleft formation in the vesicular lesions.   Image1 ; Image2

D. Lupus erythematosus:

Subacute:  Drugs: Thiazide, antihistamine,calcium channel blocker, griseofulvin, terbinafine etc. DermAtlas
Systemic:   Drugs: Procainamide,isoniazid,sulphonamide,
quinidine, penicillamine, phenylbutazone and many others.
Microscopic  features: Features of interphase dermatitis. Superficial & deep dermal infiltrate. Basal vacuolar change & occasional Civatte bodies. Epidermal atrophy, dermal edema, superficial mucin, basement membrane thickening.Follicular plugging.  Eosinophils may be present in drug induced cases.   DermAtlas

5. Toxic epidermal necrolysis:       Image1  ;  Image2

Severe form of Erythema multiforme. Clinically, presents as generalized erythema which progresses to blistering lesions with peeling of skin.
        Classification based on epidermal detachment:
Steven-Johnson Syndrome- Less than10% of body surface.    DermAtlas
Steven-Johnson Syndrome/ toxic epidermal necrolysis-
Between 10% - 30% of body surface.
Toxic epidermal necrolysis- More than 30%.
Drugs implicated:   Sulphonamide, anticonvulsants,non-steroidal antinflammatory drugs ,allopurinol,rantidine etc.
Microscopic features:   Subepidermal bulla. Necrosis of epidermis. Satellite cell necrosis.  Perivascular lymphocytic infiltrate. Necrosis of sweat ducts.

6. Drug related vesiculobullous & pustular reactions:

Subcorneal pustular dermatosis:  Cephalosporin etc
Acute generalized exanthematous pustulosis: Paracetamol , antimalarial, amoxicillin.
Pemphigus vulgaris & vegetans:  Ampicillin
Pemphigus foliaceus & erythematous:  Aspirin etc
Subepidermal bulla :
   Cell poor-  Pseudoporphyria- Sulphonamide
   Eosinophils- Bullous pemphigoid- Ampicillin etc
   Neutrophils- Linear IgA bullous dermatosis- Frusemide
   Scarring-  Cicatricial pemphigoid-  Azathioprine etc
   Necrosis-   Drug overdose related- morphine, barbiturate

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