Urticaria

Urticaria
Classification and external resources
Urticaria on the arm
ICD-10	L50
ICD-9	708
DiseasesDB	13606
MedlinePlus	000845
eMedicine	topic list
MeSH	D014581

Urticaria (from the Latin urtica, nettle (whence It. ortica, Sp. ortiga, Pg. urtiga, Fr. ortie) urere, to burn)^[1] (or hives) is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes. Most cases of hives lasting less than six weeks (acute urticaria) are the result of an allergic trigger. Chronic urticaria (hives lasting longer than six weeks) is rarely due to an allergy. The majority of patients with chronic hives have an unknown (idiopathic) cause. Perhaps as many as 30–40% of patients with chronic idiopathic urticaria will, in fact, have an autoimmune cause. Acute viral infection is another common cause of acute urticaria (viral exanthem). Less common causes of hives include friction, pressure, temperature extremes, exercise, and sunlight.

Contents 1 Appearance of symptoms 2 Classification 2.1 Acute 2.2 Chronic 2.3 Drug-induced type of urticaria 2.4 Physical urticaria 2.5 Pressure or delayed pressure 2.6 Cholinergic or stress 2.7 Cold 2.8 Heat 2.9 Solar 2.10 Water 2.11 Vibratory angioedema 2.12 Exercise-induced anaphylaxis 2.13 Related conditions 3 Cause 3.1 Medication 3.2 Diet 3.3 Physical agents 3.4 Other 4 Pathophysiology 5 Management 5.1 Antihistamines 5.2 Other 6 References 7 External links

Appearance of symptoms

Wheals (raised areas surrounded by a red base) from urticaria can appear anywhere on the surface of the skin. Whether the trigger is allergic or non-allergic, there is a complex release of inflammatory mediators, including histamine from cutaneous mast cells, resulting in fluid leakage from superficial blood vessels. Wheals may be pinpoint in size, or several inches in diameter. Angioedema is a related condition (also from allergic and non-allergic causes), though fluid leakage is from much deeper blood vessels. Individual hives that are painful, last more than 24 hours, or leave a bruise as they heal are more likely to be a more serious condition called urticarial vasculitis. Hives caused by stroking the skin (often linear in appearance) are due to a benign condition called dermographism.

Classification

Acute

Acute urticaria usually show up a few minutes after contact with the allergen, and can last a few hours to several weeks. Food allergic reactions often fit in this category.

Chronic

Chronic urticaria refers to hives that persists for 6 weeks or more. There are no visual differences between acute and chronic urticaria. Some of the more severe chronic cases have lasted more than 20 years. A survey indicated that chronic urticaria lasted a year or more in more than 50% of sufferers and 20 years or more in 20% of them.^[2]

Drug-induced type of urticaria

Drugs that have caused allergic reactions evidencing as Urticaria comprise: aspirin, penicillin, sulfonamides, anti-convulsants and anti-diabetic drugs such as suphonylurea. Drug-induced Urticaria has been known to affect upon in severe cardio-respiratory failure. The anti-diabetic sulphonylurea glimepiride (trade name Amaryl), in particular, has been authenticated to induce allergic reactions manifesting as Urticaria. Other such instances include dextroamphetamine and clotrimazole.

Physical urticaria

Also medically referred to as Dermatographism or Dermographism, this kind of Urticaria is marked by the appearance of weals or welts on the skin as a result of itching, scratching, or firm stroking of the skin. This is the most common type of physical Urticaria. The skin reaction usually becomes evident soon after the itching and disappears within 30 minutes. Dermographism is a common form of chronic hives. It is also recognised as "skin writing". Dermatographism is the most common form of a subset of chronic hives, acknowledged as `physical hives`. It happens in some degree in approximately 5 percent of the population

This most common type of Urticaria stands in contrast to the linear reddening that does not itch witnessed in healthy people that are scratched. In most cases the cause is unknown, although it may be preceded by a viral infection, antibiotic therapy, or emotional upset. Dermographism is diagnosed by taking a tongue blade and drawing it over the skin of the arm or back. The hives should develop within 1 to 3 minutes. Unless the skin is highly sensitive and reacts continually, treatment is not needed. Taking antihistamines can reduce the response in cases that are annoying to the patient.

Pressure or delayed pressure

This type of Urticaria can occur right away, precisely after a pressure stimulus or as a deferred response to sustained pressure being enforced to the skin. In the deferred form, the hives only appear after approximately six hours from the initial application of pressure to the skin. Under normal circumstances, these hives are not the same as those witnessed with most Urticarias. Instead, the protrusion in the affected areas is typically more spread out. The hives may last from approximately 8 hours to three days. The source of the pressure on the skin can happen from tight fitted clothing, belts, clothing with tough straps, walking, leaning against an object, standing, sitting on a hard surface, etc. The areas of the body most commonly affected are the hands, feet, the trunk, the buttocks, legs and the face. Although this appears to be very similar to dermatographism, the cardinal difference is that the swelled skin areas do not become visible quickly and tend to last much longer. This form of the skin disease is however, rare.

Cholinergic or stress

This form of Urticaria is fairly widespread and occurs after exercise, sweating, or any activity that leads to a warming of the core body temperature such as warm or hot baths or showers. The hives that are produced are typically smaller than the classic hives. In severe cases, hundreds of tiny red itchy spots appear on the skin with exercising, when the individual is warm or when the individual is experiencing a high level of physical or emotional stress. The red spots manifest rather quickly and remain for approximately 60 to 90 minutes on average. It precisely becomes marked as multiple, small, 2 to 3 mm red hives on the upper trunk and arms, although it can occur from the neck to the thighs. Cholinergic type of Urticaria is known to cause itching, tingling, burning and heating-up of the skin.

It is believed that histamine is discharged in response to stimulation by the parasympathetic nervous system. Cholinergic Urticaria is diagnosed by historical measures and also multiplying the hives under certain conditions. Several times, the patient is asked to exercise by jogging instead of riding a stationary bike and the time it takes for hives to develop is noted down. Cholinergic Urticaria can be treated by delimiting the strenuous exercise. This type of Urticaria responds well to a medication named hydroxyzine, which serves as an antihistamine. However, the principal side effect of sleepiness is often not tolerated well. Standing under a shower of hot water may cause a release of histamine throughout the body, exhausting histamine stores and causing a 24-hour refractory period.

Cold

The Cold type of Urticaria or hives are caused by exposure of the skin to extreme cold temperatures. In particular, the hives appear on the skin areas that have been exposed to cold, damp and windy conditions. It comes about in two forms. The rare form is hereditary and becomes evident as hives all over the body 9 to 18 hours after cold exposure. The common form of cold Urticaria demonstrates itself with the rapid onset of hives on the face, neck, or hands after exposure to cold. Cold Urticaria is common and lasts for an average of 5 to 6 years. The population mostly impressed upon is young adults, aged between 18 to 25 years. Many people with cold Urticaria also are stung by dermographism and cholinergic Urticaria.

Severe reactions can be witnessed with exposure to cold water. Swimming in cold water is the most commonplace cause of a severe reaction. This can cause a massive discharge of histamine ensuing in low blood pressure, fainting, shock and even loss of life. Cold Urticaria is diagnosed by dabbing an ice cube against the skin of the forearm for 1 to 5 minutes. A distinct hive should develop if a patient is down with cold Urticaria. This is different than the normal redness that can be viewed in people without cold Urticaria. Patients with cold Urticaria needs to learn to protect themselves from a hasty drop in body temperature. Regular antihistamines however are not generally efficacious. The particular antihistamine, cyproheptadine (Periactin) has been found to be of much usefulness. The tricyclic antidepressant doxepin has also been found to be an effective blocking agent of histamine discharge. Finally, a medication named ketotifen, which keeps mast cells from discharging histamine, has also been employed with widespread success.

Heat

This rare form of Urticaria is triggered by the continued application of heat on the skin. Hives begin to germinate within 2 to 5 minutes on the area of the skin that was exposed to heat. The hives however, generally do not last more than an hour.

Solar

This is a form of the disease and is stimulated on areas of the skin that have mostly been exposed to the sun. The skin condition becomes evident within minutes of the sun vulnerability. Although, after the individual is no longer exposed to the sun, the condition starts to weaken out within a few minutes to a few hours and hardly ever lasts longer than 24 hours. Solar Urticaria is classified into 6 different types, depending upon the wavelength of light involved. Since glass absorbs light with a wavelength of 320 nanometre and below, people suffering from solar Urticaria in response to wavelengths of less than 320 nanometre are protected by glass.

Water

This type of Urticaria is also termed as rare and occurs upon contact with water. The response is not temperature dependent and the skin appears similar to cholinergic form of the disease. The appearance of hives is within 1 to 15 minutes of contact with the water and can last from 10 minutes to two hours. The hives that last for 10 to 120 minutes, do not seem to be stimulated by histamine discharge like the other physical hives. Most researchers believe that this condition is actually most delicate skin sensitivity to additives in the water such as chlorine. Water Urticaria is diagnosed by dabbing tap water and distilled water to the skin and observing the gradual response. Aquagenic type of Urticaria is treated with a cream named as capsaicin (Zostrix), that is administered to the chafed skin. This is the same treatment utilised for shingles. Antihistamines are of questionable benefit in this instance, since histamine is not the conducive factor in water Urticaria.

Vibratory angioedema

This is a very rare form of hives that develops in reply to contact with vibration. Angioedema is an intense and more painful form of hives. In vibratory angioedema, symptoms develop within 2 to 5 minutes after contact with vibration and dissolve after approximately 1 hour. Patients with this disorder do not suffer from dermographism or pressure Urticaria. Vibratory angioedema is diagnosed by administering a laboratory vortex to the forearm for 4 minutes. Speedy swelling of the whole forearm extending into the upper arm is also noted down later. The principal treatment of vibratory angioedema is avoidance of vibratory stimulants. Antihistamines have also been proven helpful.

Exercise-induced anaphylaxis

This type of Urticaria is a condition that was first distinguished in 1980. People with this condition experience hives, itchiness, shortage of breath and low blood pressure 5 to 30 minutes after the inception of exercise. These symptoms can progress to shock and even sudden demise. Jogging is the most common type of exercise that causes exercise-induced anaphylaxis. People with exercise-induced anaphylaxis do not get these symptoms after a hot shower, fever, or with fretfulness. This differentiates exercise-induced anaphylaxis from cholinergic Urticaria.

Exercise-Induced anaphylaxis sometimes comes about only when someone exercises within 30 minutes of eating particular foods such as wheat and shellfish. For these individuals, exercising alone or eating the injuring food without exercising, produces no symptoms. Such type of Urticaria can be diagnosed by having the patient exercise and then observing the symptoms that germinate. This method must be utilised with caution and only in such a circumstance with the appropriate resuscitative measures ready at hand. Exercise-induced anaphylaxis can be differentiated from cholinergic Urticaria by the hot water immersion test. In this test, the patient is immersed in water at 43 degrees Celsius (109.4 degrees Fahrenheit). Someone with exercise-induced anaphylaxis will not develop hives, while a person with cholinergic Urticaria will develop the characteristic small hives, especially on the neck and chest.

The immediate symptoms of this uncanny type of Urticaria are treated with antihistamines, epinephrine and airway support. Taking antihistamines prior to exercise may be effective. A medication referred to as ketotifen, is acknowledged to stabilise mast cells and prevents histamine release and has been effective in treating this hives disorder. Avoiding exercise or foods that cause the mentioned symptoms, is very important. In particular circumstances, tolerance can be brought on by regular exercise, but this must be under secure medical supervision.

Related conditions

Angioedema is similar to urticaria,^[3] but in angioedema, the swelling occurs in a lower layer of the dermis than it does in urticaria,^[4] as well as in the subcutis. This swelling can occur around the mouth, in the throat, in the abdomen, or in other locations. Urticaria and angioedema sometimes occur together in response to an allergen and is a concern in severe cases as angioedema of the throat can be fatal.

Cause

Many different substances in the environment may cause urticaria including: medications, food and physical agents.

Medication

The anti-diabetic sulphonylurea glimepiride (trade name Amaryl), in particular, has been documented to induce allergic reactions manifesting as urticaria. Other cases include dextroamphetamine,^[5] aspirin, ibuprofen, penicillin, clotrimazole, sulfonamides and anticonvulsants.

Diet

The most common food allergies in adults are shellfish and nuts. The most common food allergies in children are shellfish, nuts, peanuts, eggs, wheat, and soy. It is uncommon for patients to have more than 2 true food allergies. A less common cause is exposure to certain bacteria, such as streptococcus or possibly Helicobacter pylori.^[6]

Physical agents

A number of physical urticarias include

• Aquagenic: Reaction to water (exceedingly rare)
• Cholinergic: Reaction to body heat, such as when exercising or after a hot shower
• Cold (Chronic cold urticaria): Reaction to cold, such as ice, cold air or water - worse with sudden change in temperature
• Delayed Pressure: Reaction to standing for long periods, bra-straps, elastic bands on undergarments, belts
• Dermatographic: Reaction when skin is scratched (very common)
• Heat: Reaction to hot food or objects (rare)
• Solar: Reaction to direct sunlight (rare, though more common in those with fair skin)
• Vibration: Reaction to vibration (rare)
• Adrenergic: Reaction to adrenaline / noradrenaline (extremely rare)

Other

Urticaria can be a complication and symptom of a parasitic infection as fascioliasis (Fasciola hepatica) and ascariasis (Ascaris lumbricoides).

The rash that develops from poison ivy, poison oak, and poison sumac contact is commonly mistaken for urticaria. This rash is caused by contact with urushiol and results in a form of contact dermatitis called Urushiol-induced contact dermatitis. Urushiol is spread by contact, but can be washed off with a strong grease/oil dissolving detergent and cool water and rubbing ointments.

Pathophysiology

The skin lesions of urticarial disease are caused by an inflammatory reaction in the skin, causing leakage of capillaries in the dermis, and resulting in an edema which persists until the interstitial fluid is absorbed into the surrounding cells.

Urticaria are caused by the release of histamine and other mediators of inflammation (cytokines) from cells in the skin. This process can be the result of an allergic or non-allergic reaction, differing in the eliciting mechanism of histamine release.

Allergic urticaria 

Histamine and other pro-inflammatory substances are released from mast cells in the skin and tissues in response to the binding of allergen-bound IgE antibodies to high affinity cell surface receptors. Basophils and other inflammatory cells are also seen to release histamine and other mediators, and are thought to play an important role, especially in chronic urticarial diseases.

Autoimmune urticaria 

In the past decade, it has been noted that many cases of chronic idiopathic urticaria are the result of an autoimmune trigger. For example, roughly one third of patients with chronic urticaria spontaneously develop auto-antibodies directed at the receptor FcεRI located on skin mast cells. Chronic stimulation of this receptor leads to chronic hives. Patients often have other autoimmune conditions such as autoimmune thyroiditis.

Infections 

Hive-like rashes commonly accompany viral illnesses, such as the common cold. They usually appear 3–5 days after the cold has started, and may even appear a few days after the cold has resolved.

Non-allergic urticaria 

Mechanisms other than allergen-antibody interactions are known to cause histamine release from mast cells. Many drugs, for example morphine, can induce direct histamine release not involving any immunoglobulin molecule. Also, a diverse group of signaling substances called neuropeptides have been found to be involved in emotionally induced urticaria. Dominantly inherited cutaneous and neurocutaneous porphyrias (porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria and erythropoietic protoporphyria) have been associated with solar urticaria. The occurrence of drug-induced solar urticaria may be associated with porphyrias. This may be caused by IgG binding not IgE.

Dietary histamine poisoning 

This is termed scombroid food poisoning. Ingestion of free histamine released by bacterial decay in fish flesh may result in a rapid-onset allergic-type symptom complex which includes urticaria. However, the urticaria produced by scombroid is reported not to include wheals.^[7]

Stress and chronic idiopathic urticaria 

Chronic idiopathic urticaria has been anecdotally linked to stress since the 1940s.^[8] There is a large body of evidence demonstrating an association between this condition and both poor emotional well-being^[9] and reduced health related quality of life.^[10] A link between stress and this condition has also been shown.^[11] A recent study involving the Department of Immunology at Derriford Hospital and the University of Plymouth has demonstrated an association between stressful life events (e.g. bereavement, divorce, etc.) and chronic idiopathic urticaria ^[12] and also an association between posttraumatic stress and chronic idiopathic urticaria.^[13]

Management

Chronic urticaria can be difficult to treat. There are no guaranteed treatments or means of controlling attacks, and some sub-populations are treatment-resistant, with medications spontaneously losing their effectiveness and requiring new medications to control attacks. It can be difficult to determine appropriate medications since some, such as loratadine, require a day or two to build up to effective levels and since the condition is intermittent and outbreaks typically clear up without any treatment.

Most treatment plans for urticaria involve being aware of one's triggers, but this can be difficult since there are several forms of urticaria and people often exhibit more than one type. Also, since symptoms are often idiopathic (unknown reason) there might not be any clear trigger. If one's triggers can be identified then outbreaks can often be managed by limiting one's exposure to these situations.

Antihistamines

Drug treatment is typically in the form of antihistamines such as fexofenadine, diphenhydramine, hydroxyzine, cetirizine and other H₁ receptor antagonists.^[14] These are taken on a regular basis to protective effect, lessening or halting attacks. Treatments such as stress management can sometimes lessen severity and occurrence. Additionally, methods similar to psychological pain management can be used to shift focus away from the discomfort and itchiness during an attack.

Other

Tricyclic antidepressants, such as doxepin, also are often potent H₁ and H₂ antagonists and may have a role in therapy, although side effects limit their use. For very severe outbreaks, an oral corticosteroid such as Prednisone is sometimes prescribed. However this form of treatment is controversial because of the extensive side effects common with corticosteroids and as such is not a recommended long-term treatment option. For acute urticaria, some topical creams such as Hydrocortisone, Fluocinonide, Desonate can also be prescribed to relieve itching. To boost relief for severe anaphylactic urticaria, a dermatologist will also administer steroid shots intramuscularly.

As of 2008 an Australian company is performing clinical trials with an analogue of alpha-melanocyte-stimulating hormone called afamelanotide (formerly CUV1647)^[15] for the treatment of solar urticaria,^[16][17] a type of urticaria that develops in response to exposure to specific wavelengths of light.^[18]

References

External links

• Urticaria photo library at Dermnet

Diseases of the skin and appendages by morphology Growths Epidermal wart · callus · seborrheic keratosis · acrochordon · molluscum contagiosum · actinic keratosis · squamous cell carcinoma · basal cell carcinoma · merkel cell carcinoma · nevus sebaceous · trichoepithelioma Pigmented Freckles · lentigo · melasma · nevus · melanoma Dermal and subcutaneous epidermal inclusion cyst · hemangioma · dermatofibroma · keloid · lipoma · neurofibroma · xanthoma · Kaposi's sarcoma · infantile digital fibromatosis · granular cell tumor · leiomyoma · lymphangioma circumscriptum · myxoid cyst Rashes With epidermal involvement Eczematous contact dermatitis · atopic dermatitis · seborrheic dermatitis · stasis dermatitis · lichen simplex chronicus · Darier's disease · glucagonoma syndrome · langerhans cell histiocytosis · lichen sclerosus · pemphigus foliaceus · Wiskott-Aldrich syndrome · Zinc deficiency Scaling psoriasis · tinea (corporis · cruris · pedis · manuum · faciei) · pityriasis rosea · secondary syphillis · mycosis fungoides · systemic lupus erythematosus · pityriasis rubra pilaris · parapsoriasis · ichthyosis Blistering herpes simplex · herpes zoster · varicella · bullous impetigo · acute contact dermatitis · pemphigus vulgaris · bullous pemphigoid · dermatitis herpetiformis · porphyria cutanea tarda · epidermolysis bullosa simplex Papular scabies · insect bite reactions · lichen planus · miliaria · keratosis pilaris · lichen spinulosus · transient acantholytic dermatosis · lichen nitidus · pityriasis lichenoides et varioliformis acuta Pustular acne vulgaris · acne rosacea · folliculitis · impetigo · candidiasis · gonococcemia · dermatophyte · coccidioidomycosis · subcorneal pustular dermatosis Hypopigmented tinea versicolor · vitiligo · pityriasis alba · postinflammatory hyperpigmentation · tuberous sclerosis · idiopathic guttate hypomelanosis · leprosy · hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized drug eruptions · viral exanthems · toxic erythema · systemic lupus erythematosus Localized cellulitis · abscess · boil · erythema nodosum · carcinoid syndrome · fixed drug eruption Specialized urticaria · erythema (multiforme · migrans · gyratum repens · annulare centrifugum · ab igne) Nonblanchable Purpura Macular thrombocytopenic purpura · actinic purpura Papular disseminated intravascular coagulation · vasculitis Indurated scleroderma/morphea · granuloma annulare · lichen sclerosis et atrophicus · necrobiosis lipoidica Miscellaneous disorders Ulcers Hair telogen effluvium · androgenic alopecia · trichotillomania · alopecia areata · systemic lupus erythematosus · tinea capitis · loose anagen syndrome · lichen planopilaris · folliculitis decalvans · acne keloidalis nuchae Nail onychomycosis · psoriasis · paronychia · ingrown nail Mucous membrane aphthous stomatitis · oral candidiasis · lichen planus · leukoplakia · pemphigus vulgaris · mucous membrane pemphigoid · cicatricial pemphigoid · herpesvirus · coxsackievirus · syphilis · systemic histoplasmosis · squamous cell carcinoma

Urticaria and erythema (L50–L54, 695, 708) Urticaria (acute/chronic) Allergic urticaria Urticarial allergic eruption Physical urticaria Cold urticaria (Familial) · Primary cold contact urticaria · Secondary cold contact urticaria · Reflex cold urticaria Heat urticaria · Localized heat contact urticaria · Solar urticaria Dermatographic urticaria Vibratory angioedema · Pressure urticaria Cholinergic urticaria Aquagenic urticaria Other urticaria Acquired C1 esterase inhibitor deficiency · Adrenergic urticaria · Exercise urticaria · Galvanic urticaria · Schnitzler syndrome · Urticaria-like follicular mucinosis Angioedema Episodic angioedema with eosinophilia · Hereditary angioedema Erythema Erythema multiforme/ drug eruption Erythema multiforme minor · Erythema multiforme major (Stevens–Johnson syndrome, Toxic epidermal necrolysis) · panniculitis (Erythema nodosum) · Acute generalized exanthematous pustulosis Figurate erythema Erythema annulare centrifugum · Erythema marginatum · Erythema migrans · Erythema gyratum repens Other erythema Necrolytic migratory erythema · Erythema toxicum · Erythroderma · Palmar erythema · Generalized erythema M: INT, SF, LCT anat/phys/devp noco(i/b/d/q/u/r/p/m/k/v/f)/cong/tumr(n/e/d), sysi/epon proc, drug (D2/3/4/5/8/11)

Immune disorders: hypersensitivity and autoimmune diseases (279.5–6) Type I/allergy/atopy (IgE) Foreign Atopic dermatitis · Allergic urticaria · Hay fever · Allergic asthma · Anaphylaxis · Food allergy (Milk, Egg, Peanut, Tree nut, Seafood, Soy, Wheat), Penicillin allergy Autoimmune none Type II/ADCC (IgM, IgG) Foreign Pernicious anemia · Hemolytic disease of the newborn Autoimmune Cytotoxic Autoimmune hemolytic anemia · Idiopathic thrombocytopenic purpura  · Bullous pemphigoid  · Pemphigus vulgaris · Rheumatic fever · Goodpasture's syndrome "Type 5"/receptor Graves' disease · Myasthenia gravis Type III (Immune complex) Foreign Henoch–Schönlein purpura · Hypersensitivity vasculitis · Reactive arthritis · Farmer's lung · Post-streptococcal glomerulonephritis · Serum sickness · Arthus reaction Autoimmune Systemic lupus erythematosus · Subacute bacterial endocarditis · Rheumatoid arthritis Type IV/cell-mediated (T-cells) Foreign Allergic contact dermatitis · Mantoux test Autoimmune Diabetes mellitus type 1 · Hashimoto's thyroiditis · Guillain–Barré syndrome  · Multiple sclerosis  · Coeliac disease · Giant-cell arteritis GVHD Transfusion-associated graft versus host disease Unknown/ multiple Foreign Hypersensitivity pneumonitis (Allergic bronchopulmonary aspergillosis) · Transplant rejection · Latex allergy (I+IV) Autoimmune Sjögren's syndrome · Autoimmune hepatitis · Autoimmune polyendocrine syndrome (APS1, APS2) · Autoimmune adrenalitis · Systemic autoimmune disease M: LMC cell/phys/auag/auab/comp, igrc imdf/ipig/hyps/tumr proc, drug(L3/4)