Effective management of allergic diseases relies on the ability to make an accurate diagnosis. Allergy testing can help confirm or rule out allergies. Correct diagnosis, counseling, and avoidance advice based on valid allergy test results reduces the incidence of symptoms and need for medications, and improves quality of life. To assess the presence of allergen-specific IgE antibodies, two different methods can be used: a skin prick test, or an allergy blood test. Both methods are recommended, and they have similar diagnostic value.

Skin prick tests and blood tests are equally cost-effective, and health economic evidence shows that both tests were cost-effective compared with no test. Also, early and more accurate diagnoses save cost due to reduced consultations, referrals to secondary care, misdiagnosis, and emergency admissions.

Allergy undergoes dynamic changes over time. Regular allergy testing of relevant allergens provides information on if and how patient management can be changed, in order to improve health and quality of life. Annual testing is often the practice for determining whether allergy to milk, egg, soy, and wheat have been outgrown, and the testing interval is extended to 2–3 years for allergy to peanut, tree nuts, fish, and crustacean shellfish. Results of follow-up testing can guide decision-making regarding whether and when it is safe to introduce or re-introduce allergenic food into the diet.

The Arthus reaction involves the in situ formation of antigen/antibody complexes after the intradermal injection of an antigen. If the animal/patient was previously sensitized (has circulating antibody), an Arthus reaction occurs. Typical of most mechanisms of the type III hypersensitivity, Arthus manifests as local vasculitis due to deposition of IgG-based immune complexes in dermal blood vessels. Activation of complement primarily results in cleavage of soluble complement proteins forming C5a and C3a, which activate recruitment of PMNs and local mast cell degranulation (requiring the binding of the immune complex onto FcγRIII), resulting in an inflammatory response. Further aggregation of immune complex-related processes induce a local fibrinoid necrosis with ischemia-aggravating thrombosis in the tissue vessel walls. The end result is a localized area of redness and induration that typically lasts a day or so.

Arthus reactions have been infrequently reported after vaccinations containing diphtheria and tetanus toxoid. The CDC's description:

Arthus reactions (type III hypersensitivity reactions) are rarely reported after vaccination and can occur after tetanus toxoid–containing or diphtheria toxoid–containing vaccines. An Arthus reaction is a local vasculitis associated with deposition of immune complexes and activation of complement. Immune complexes form in the setting of high local concentration of vaccine antigens and high circulating antibody concentration. Arthus reactions are characterized by severe pain, swelling, induration, edema, hemorrhage, and occasionally by necrosis. These symptoms and signs usually occur 4–12 hours after vaccination. ACIP has recommended that persons who experienced an Arthus reaction after a dose of tetanus toxoid–containing vaccine should not receive Td more frequently than every 10 years, even for tetanus prophylaxis as part of wound management.

Type III hypersensitivity occurs when there is an excess of antigen, leading to small immune complexes being formed that fix complement and are not cleared from the circulation. It involves soluble antigens that are not bound to cell surfaces (as opposed to those in type II hypersensitivity). When these antigens bind antibodies, immune complexes of different sizes form. Large complexes can be cleared by macrophages but macrophages have difficulty in the disposal of small immune complexes. These immune complexes insert themselves into small blood vessels, joints, and glomeruli, causing symptoms. Unlike the free variant, a small immune complex bound to sites of deposition (like blood vessel walls) are far more capable of interacting with complement; these medium-sized complexes, formed in the slight excess of antigen, are viewed as being highly pathogenic.

Such depositions in tissues often induce an inflammatory response, and can cause damage wherever they precipitate. The cause of damage is as a result of the action of cleaved complement anaphylotoxins C3a and C5a, which, respectively, mediate the induction of granule release from mast cells (from which histamine can cause urticaria), and recruitment of inflammatory cells into the tissue (mainly those with lysosomal action, leading to tissue damage through frustrated phagocytosis by PMNs and macrophages).

The reaction can take hours, days, or even weeks to develop, depending on whether or not there is immunological memory of the precipitating antigen. Typically, clinical features emerge a week following initial antigen challenge, when the deposited immune complexes can precipitate an inflammatory response. Because of the nature of the antibody aggregation, tissues that are associated with blood filtration at considerable osmotic and hydrostatic gradient (e.g. sites of urinary and synovial fluid formation, kidney glomeruli and joint tissues respectively) bear the brunt of the damage. Hence, vasculitis, glomerulonephritis and arthritis are commonly associated conditions as a result of type III hypersensitivity responses.

As observed under methods of histopathology, acute necrotizing vasculitis within the affected tissues is observed concomitant to neutrophilic infiltration, along with notable eosinophilic deposition (fibrinoid necrosis). Often, immunofluorescence microscopy can be used to visualize the immune complexes. Skin response to a hypersensitivity of this type is referred to as an Arthus reaction, and is characterized by local erythema and some induration. Platelet aggregation, especially in microvasculature, can cause localized clot formation, leading to blotchy hemorrhages. This typifies the response to injection of foreign antigen sufficient to lead to the condition of serum sickness.

An allergy blood test is quick and simple, and can be ordered by a licensed health care provider ("e.g.", an allergy specialist), GP, or PED. Unlike skin-prick testing, a blood test can be performed irrespective of age, skin condition, medication, symptom, disease activity, and pregnancy. Adults and children of any age can take an allergy blood test. For babies and very young children, a single needle stick for allergy blood testing is often more gentle than several skin tests.

An allergy blood test is available through most laboratories. A sample of the patient's blood is sent to a laboratory for analysis, and the results are sent back a few days later. Multiple allergens can be detected with a single blood sample. Allergy blood tests are very safe, since the person is not exposed to any allergens during the testing procedure.

The test measures the concentration of specific IgE antibodies in the blood. Quantitative IgE test results increase the possibility of ranking how different substances may affect symptoms. A rule of thumb is that the higher the IgE antibody value, the greater the likelihood of symptoms. Allergens found at low levels that today do not result in symptoms can nevertheless help predict future symptom development. The quantitative allergy blood result can help determine what a patient is allergic to, help predict and follow the disease development, estimate the risk of a severe reaction, and explain cross-reactivity.

A low total IgE level is not adequate to rule out sensitization to commonly inhaled allergens. Statistical methods, such as ROC curves, predictive value calculations, and likelihood ratios have been used to examine the relationship of various testing methods to each other. These methods have shown that patients with a high total IgE have a high probability of allergic sensitization, but further investigation with allergy tests for specific IgE antibodies for a carefully chosen of allergens is often warranted.

Laboratory methods to measure specific IgE antibodies for allergy testing include enzyme-linked immunosorbent assay (ELISA, or EIA), radioallergosorbent test (RAST) and fluorescent enzyme immunoassay (FEIA).

The Arthus reaction was discovered by Nicolas Maurice Arthus in 1903. Arthus repeatedly injected horse serum subcutaneously into rabbits. After four injections, he found that there was edema and that the serum was absorbed slowly. Further injections eventually led to gangrene.

Diagnosis is based on history given by patient, including recent medications.

Some clinical examples:

Other examples are:

- Subacute bacterial endocarditis

- Symptoms of malaria

It is estimated that 2—3 percent of hospitalised patients are affected by a drug eruption, and that serious drug eruptions occur in around 1 in 1000 patients.

Drug eruptions are diagnosed mainly from the medical history and clinical examination. However, they can mimic a wide range of other conditions, thus delaying diagnosis (for example, in drug-induced lupus erythematosus, or the acne-like rash caused by erlotinib). A skin biopsy, blood tests or immunological tests can also be useful.

Drug reactions have characteristic timing. The typical amount of time it takes for a rash to appear after exposure to a drug can help categorize the type of reaction. For example, Acute generalized exanthematous pustulosis usually occurs within 4 days of starting the culprit drug. Drug Reaction with Eosinophilia and Systemic Symptoms usually occurs between 15 and 40 days after exposure. Toxic epidermal necrolysis and Stevens-Johnson syndrome typically occur 7–21 days after exposure. Anaphylaxis occurs within minutes. Simple exanthematous eruptions occur between 4 and 14 days after exposure.

TEN and SJS are severe cutaneous drug reactions that involve the skin and mucous membranes. To accurately diagnose this condition, a detailed drug history is crucial. Often, several drugs may be causative and allergy testing may be helpful. Sulfa drugs are well-known to induce TEN or SJS in certain people. For example, HIV patients have an increased incidence of SJS or TEN compared to the general population and have been found to express low levels of the drug metabolizing enzyme responsible for detoxifying sulfa drugs. Genetics plays an important role in predisposing certain populations to TEN and SJS. As such, there are some FDA recommended genetic screening tests available for certain drugs and ethnic populations to prevent the occurrence of a drug eruption. The most well known example is carbamezepine (an anti-convulsant used to treat seizures) hypersensitivity associated with the presence of HLA-B*5801 genetic allele in Asian populations.

DIHS is a delayed onset drug eruption, often occurring a few weeks to 3 months after initiation of a drug. Interestingly, worsening of systemic symptoms occurs 3-4 days after cessation of the offending drug. There are genetic risk alleles that are predictive of the development of DIHS for particular drugs and ethnic populations. The most important of which is abacavir (an anti-viral used in the treatment of HIV) hypersensitivity associated with the presence of the HLA-B*5701 allele in European and African population in the United States and Australians.

AGEP is often caused by antimicrobial, anti-fungal or antimalarial drugs. Diagnosis is often carried out by patch testing. This testing should be performed within one month after resolution of the rash and patch test results are interpreted at different time points: 48 hours, 72hours and even later at 96 hours and 120 hours in order to improve the sensitivity.

Avoidance of antitoxins that may cause serum sickness is the best way to prevent serum sickness. Although, sometimes, the benefits outweigh the risks in the case of a life-threatening bite or sting. Prophylactic antihistamines or corticosteroids may be used concomitant with the antitoxin. Skin testing may be done beforehand in order to identify individuals who may be at risk of a reaction. Physicians should make their patients aware of the drugs or antitoxins to which they are allergic if there is a reaction. The physician will then choose an alternate antitoxin if it's appropriate or continue with prophylactic measures.

An example of a tuberculosis (TB) infection that comes under control: "M. tuberculosis" cells are engulfed by macrophages after being identified as foreign, but due to an immuno-escape mechanism peculiar to mycobacteria, TB bacteria are able to block the fusion of their enclosing phagosome with lysosomes which would destroy the bacteria. Thereby TB can continue to replicate within macrophages. After several weeks, the immune system somehow [mechanism as yet unexplained] ramps up and, on stimulation with IFN-gamma, the macrophages become capable of killing "M. tuberculosis" by forming phagolysosomes and nitric oxide radicals. The hyper-activated macrophages secrete TNF-α which recruits multiple monocytes to the site of infection. These cells differentiate into epithelioid cells which wall off the infected cells, but results in significant inflammation and local damage.

Some other clinical examples:

- Temporal arteritis

- Leprosy

- Coeliac disease

- Graft-versus-host disease

- Chronic transplant rejection

All patients with symptomatic cryoglobulinemia are advised to avoid, or protect their extremities, from exposure to cold temperatures. Refrigerators, freezers, and air-conditioning represent dangers of such exposure.

The first stage involves exposing the skin to Aspergillus fumigatus antigens; an immediate reaction is hallmark of ABPA. The test should be performed first by skin prick testing, and if negative followed with an intradermal injection. Overall sensitivity of the procedure is around 90%, though up to 40% of asthmatic patients without ABPA can still show some sensitivity to Aspergillus antigens (a phenomenon likely linked to a less severe form of ABPA termed severe asthma with fungal sensitization (SAFS)).

Serum blood tests are an important marker of disease severity, and are also useful for the primary diagnosis of ABPA. When serum IgE is normal (and patients are not being treated by glucocorticoid medications), ABPA is excluded as the cause of symptoms. A raised IgE increases suspicion, though there is no universally accepted cut-off value. Values can be stated in international units (IU/mL) or ng/mL, where 1 IU is equal to 2.4 ng/mL. Since studies began documenting IgE levels in ABPA during the 1970s, various cut-offs between 833–1000 IU/mL have been employed to both exclude ABPA and to warrant further serological testing. Current consensus is that a cut-off of 1000 IU/mL should be employed, as lower values are encountered in SAFS and asthmatic sensitization.

IgG antibody precipitin testing from serum is useful, as positive results are found in between 69–90% of patients, though also in 10% of asthmatics with and without SAFS. Therefore, it must be used in conjunction with other tests. Various forms exist, including enzyme-linked immunosorbent assay (ELISA) and fluorescent enzyme immunoassay (FEIA). Both are more sensitive than conventional counterimmunoelectrophoresis. IgG may not be entirely specific for ABPA, as high levels are also found in chronic pulmonary aspergillosis (CPA) alongside more severe radiological findings.

Until recently, peripheral eosinophilia (high eosinophil counts) was considered partly indicative of ABPA. More recent studies show that only 40% of ABPA sufferers present with eosinophilia, and hence a low eosinophil count does not necessary exclude ABPA; for example patients undergoing steroid therapy have lower eosinophil counts.

Cryoglobulinemia and cryoglobulinemic disease must be distinguished from cryofibrinogenemia or cryofibrinogenemic disease, conditions which involve the cold-induced intravascular deposition of circulating native fibrinogens. The cryoglobulins in plasma or serum precipitate at lower temperatures (e.g. 4°C). Since cryofibrinogens are present in plasma but greatly depleted in serum, precipitation tests for them are positive in plasma but negative in serum. Cryofibrinogenemia is occasionally found in cases of cryoglobulinemic disease. Cryoglobulinemic disease must also be distinguished from frostbite as well as numerous other conditions that have a clinical (particularly cutaneous) presentation similar to cryoglobulinemic disease but are not exacerbated by cold temperature, e.g. dysfibrinogenemia and dysfibrinogenemic disease (conditions involving the intravascular deposition of genetically abnormal circulating fibrinogens), purpura fulminans, cholesterol emboli, warfarin necrosis, ecthyma gangrenosum, and various hypercoagulable states.

Rheumatoid factor is a sensitive test for cryoglobulinemia. The precipitated cryoglobulins are examined by immunoelectrophoresis and immunofixation to detect and quantify the presence of monoclonal IgG, IgM, IgA, κ light chain, or λ light chain immunoglobins. Other routine tests include measuring blood levels of rheumatoid factor activity, complement C4, other complement components, and hepatitic C antigen. Biopsies of skin lesions and, where indicated, kidney or other tissues can help in determining the nature of the vascular disease (immunoglobulin deposition, cryoglobulinemic vasculitis, or, in cases showing the presence of cryfibrinogenemia, fibrinogen deposition. In all events, further studies to determine the presence of hematological, infections, and autoimmune disorders are conducted on the basis of these findings as well as each cases clinical findings.

Treatment usually involves adrenaline (epinephrine), antihistamines, and corticosteroids.

If the entire body is involved, then anaphylaxis can take place, which is an acute, systemic reaction that can prove fatal.

Nickel allergy can be confirmed by a properly trained health care provider based on the medical history, physical exam and a painless specialized patch test— when necessary. A significant number of people may self-diagnose, and not contact medical professionals, which could result in massive underreporting of the problem by scientific researchers.

Confirming the diagnosis of Ni-ACD specifically involves inducing the skin to demonstrate a rash where the chemicals are applied (a delayed type hypersensitivity reaction), evidence that the patient is exposed to nickel, and establishing that the reaction and the exposure explain the current rash/symptoms under question. The patch test plays a significant role in diagnosing ACD.

The patch test evokes a delayed, Type IV hypersensitivity reaction, which is a cell-mediated, antibody independent, immune response. Patch testing is the "gold standard" diagnostic tool for Ni-ACD. In this sense, a positive patch test to nickel establishes that the subject has been previously exposed and is therefore sensitized to nickel. It does not necessarily indicate that the patch reaction is the cause of the current clinical disease. A negative test demonstrates that the patient is sub-threshold, either minimally or not sensitized. Cumulatively, clinical reasoning and a patch test help determine if nickel could be the cause of a current dermatitis reaction.

This is an additional type that is sometimes (especially in the UK) used as a distinction from Type 2.

Instead of binding to cell surfaces, the antibodies recognise and bind to the cell surface receptors, which either prevents the intended ligand binding with the receptor or mimics the effects of the ligand, thus impairing cell signaling.

Some clinical examples:

- Graves' disease

- Myasthenia gravis

The use of Type 5 is rare. These conditions are more frequently classified as Type 2, though sometimes they are specifically segregated into their own subcategory of Type 2.

Type I hypersensitivity (or immediate hypersensitivity) is an allergic reaction provoked by reexposure to a specific type of antigen referred to as an allergen. Type I is not to be confused with type II, type III, or type IV hypersensitivities, nor is it to be confused with Type I Diabetes or Type I of any other disease or reaction.

Exposure may be by ingestion, inhalation, injection, or direct contact.

Hypersensitivity (also called hypersensitivity reaction or intolerance) is a set of undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over- reaction of the immune system and these reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized (immune) state of the host. They are classified in four groups after the proposal of P. G. H. Gell and Robin Coombs in 1963.

Allergic inflammation is an important pathophysiological feature of several disabilities or medical conditions including allergic asthma, atopic dermatitis, allergic rhinitis and several ocular allergic diseases. Allergic reactions may generally be divided into two components; the early phase reaction, and the late phase reaction. While the contribution to the development of symptoms from each of the phases varies greatly between diseases, both are usually present and provide us a framework for understanding allergic disease.

The early phase of the allergic reaction typically occurs within minutes, or even seconds, following allergen exposure and is also commonly referred to as the immediate allergic reaction or as a Type I allergic reaction. The reaction is caused by the release of histamine and mast cell granule proteins by a process called degranulation, as well as the production of leukotrienes, prostaglandins and cytokines, by mast cells following the cross-linking of allergen specific IgE molecules bound to mast cell FcεRI receptors. These mediators affect nerve cells causing itching, smooth muscle cells causing contraction (leading to the airway narrowing seen in allergic asthma), goblet cells causing mucus production, and endothelial cells causing vasodilatation and edema.

The late phase of a Type 1 reaction (which develops 8–12 hours and is mediated by mast cells) should not be confused with delayed hypersensitivity Type IV allergic reaction (which takes 48–72 hours to develop and is mediated by T cells). The products of the early phase reaction include chemokines and molecules that act on endothelial cells and cause them to express Intercellular adhesion molecule (such as vascular cell adhesion molecule and selectins), which together result in the recruitment and activation of leukocytes from the blood into the site of the allergic reaction. Typically, the infiltrating cells observed in allergic reactions contain a high proportion of lymphocytes, and especially, of eosinophils. The recruited eosinophils will degranulate releasing a number of cytotoxic molecules (including Major Basic Protein and eosinophil peroxidase) as well as produce a number of cytokines such as IL-5. The recruited T-cells are typically of the Th2 variety and the cytokines they produce lead to further recruitment of mast cells and eosinophils, and in plasma cell isotype switching to IgE which will bind to the mast cell FcεRI receptors and prime the individual for further allergic responses.

Drug allergies are attributed to "drug hypersensitivity," otherwise known as objectively reproducible symptoms or signs initiated by exposure to a drug at a dose normally tolerated by non-hypersensitive persons. Drug hypersensitivity reactions are the mediators of a drug allergy.

There are two mechanisms for a drug allergy to occur: IgE or non-IgE mediated. In IgE-mediated reactions, also known as Immunoglobulin E mediated reactions, drug allergens bind to IgE antibodies, which are attached to mast cells and basophils, resulting in IgE cross-linking, cell activation and release of preformed and newly formed mediators.

In type II hypersensitivity (also tissue-specific, or cytotoxic hypersensitivity) the antibodies produced by the immune response bind to antigens on the patient's own cell surfaces. The antigens recognized in this way may either be intrinsic ("self" antigen, innately part of the patient's cells) or extrinsic (adsorbed onto the cells during exposure to some foreign antigen, possibly as part of infection with a pathogen). These cells are recognized by macrophages or dendritic cells, which act as antigen-presenting cells. This causes a B cell response, wherein antibodies are produced against the foreign antigen.

An example of type II hypersensitivity is the ABO blood incompatibility where the red blood cells have different antigens, causing them to be recognized as different; B cell proliferation will take place and antibodies to the foreign blood type are produced. IgG and IgM antibodies bind to these antigens to form complexes that activate the classical pathway of complement activation to eliminate cells presenting foreign antigens. That is, mediators of acute inflammation are generated at the site and membrane attack complexes cause cell lysis and death. The reaction takes hours to a day.

Type II reactions can affect healthy cells. Examples include red blood cells in autoimmune hemolytic anemia and acetylcholine receptors in myasthenia gravis.

Another example of type II hypersensitivity reaction is Goodpasture's syndrome where the basement membrane (containing collagen type IV) in the lung and kidney is attacked by one's own antibodies.

Another form of type II hypersensitivity is called antibody-dependent cell-mediated cytotoxicity (ADCC). Here, cells exhibiting the foreign antigen are tagged with antibodies (IgG or IgM). These tagged cells are then recognised by natural killer cells (NK) and macrophages (recognised via IgG bound (via the Fc region) to the effector cell surface receptor, CD16 (FcγRIII)), which in turn kill these tagged cells.

A detailed history allows physicians to determine whether the presenting symptoms are due to an allergen or another source. Diagnostic tests such as conjunctival scrapings to look for eosinophils are helpful in determining the cause of the allergic response. Antihistamines, medication that stabilizes mast cells, and NSAIDs are safe and usually effective. Corticosteroids are reserved for more severe cases of ocular allergy disease, and their use should be monitored by an eye care physician due to possible side-effects. When an allergen is identified, the person should avoid the allergen as much as possible.

Type 4 hypersensitivity is often called delayed type hypersensitivity as the reaction takes several days to develop. Unlike the other types, it is not antibody-mediated but rather is a type of cell-mediated response.

CD4+ T1 helper T cells recognize antigen in a complex with the MHC class II major histocompatibility complex on the surface of antigen-presenting cells. These can be macrophages that secrete IL-12, which stimulates the proliferation of further CD4+ T1 cells. CD4+ T cells secrete IL-2 and interferon gamma, inducing the further release of other T1 cytokines, thus mediating the immune response. Activated CD8+ T cells destroy target cells on contact, whereas activated macrophages produce hydrolytic enzymes and, on presentation with certain intracellular pathogens, transform into multinucleated giant cells.

If the allergen is encountered and the symptoms are mild, a cold compress can be used to provide relief.