Continuing Education Activity

Type four hypersensitivity reaction is a cell-mediated reaction that can occur in response to contact with certain allergens resulting in what is called contact dermatitis or in response to some diagnostic procedures as in the tuberculin skin test. Certain allergens must be avoided to treat this condition. This activity reviews the evaluation and management of type four hypersensitivity reactions and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Describe the epidemiology of type four hypersensitivity reactions.
• Summarize the pathophysiology of type four hypersensitivity reactions.
• Explain the common physical exam findings associated with type four hypersensitivity reactions.
• Review the importance of collaboration and care coordination among the interprofessional team to enhance the care of patients with type four hypersensitivity reactions.

Introduction

Our immune system plays a crucial role in protecting our body against pathogens, but sometimes there is an exaggerated response. This exaggerated response is triggered by the interaction of the immune system with an antigen (allergen) and is referred to as hypersensitivity. Hypersensitivity reactions are classified into four types by Coombs and Gell. The first three types are considered immediate hypersensitivity reactions because they occur within 24 hours. The fourth type is considered a delayed hypersensitivity reaction because it usually occurs more than 12 hours after exposure to the allergen, with a maximal reaction time between 48 and 72 hours. The four types of hypersensitivity are: 

• Type I: reaction mediated by IgE antibodies
• Type II: cytotoxic reaction mediated by IgG or IgM antibodies
• Type III: reaction mediated by immune complexes
• Type IV: delayed reaction mediated by cellular response 

A Type IV hypersensitivity reaction is mediated by T cells that provoke an inflammatory reaction against exogenous or endogenous antigens. In certain situations, other cells, such as monocytes, eosinophils, and neutrophils, can be involved. After antigen exposure, an initial local immune and inflammatory response occurs that attracts leukocytes. The antigen engulfed by the macrophages and monocytes is presented to T cells, which then becomes sensitized and activated. These cells then release cytokines and chemokines, which can cause tissue damage and may result in illnesses. Examples of illnesses resulting from type IV hypersensitivity reactions include contact dermatitis and drug hypersensitivity. Type IV reactions are further subdivided into type IVa, IVb, IVc, and IVd based on the type of T cell (CD4 T-helper type 1 and type 2 cells) involved and the cytokines/chemokines produced.[1] 

Delayed hypersensitivity plays a crucial role in our body's ability to fight various intracellular pathogens such as mycobacteria and fungi. They also play a principal role in tumor immunity and transplant rejection. Since patients with acquired immunodeficiency syndrome (AIDS) have a progressive decline in the number of CD4 cells, they also have a defective type four hypersensitivity reaction.[2][3]

Etiology

Type IV hypersensitivity reactions are, to some extent, normal physiological events that help fight infections, and dysfunction in this system can predispose to multiple opportunistic infections. Adverse events can also occur due to these reactions when an undesirable interaction between the immune system and an allergen happens. Exposure to poison ivy resulting in contact dermatitis is a classic example.[4] Several drugs (antibiotics, anticonvulsants) can trigger type IV hypersensitivity reactions leading to drug hypersensitivity and other clinical syndromes.

Certain viral infections, when exposed to certain drugs, can trigger a reaction, such as cytomegalovirus with antibiotics, Epstein Barr virus with amoxicillin, and herpesvirus 6 with anticonvulsants. Allopurinol and, more recently, lamotrigine have been implicated in type IV hypersensitivity reactions. Latex exposure can cause both type I and type IV hypersensitivity reactions in susceptible patients.[5]

Epidemiology

Type four hypersensitivity is a common disorder among susceptible individuals. For example, the prevalence of contact hypersensitivity is around 1%-6% among the population. Another minor subtype of type four hypersensitivity reaction is called drug allergy. Drug allergy is sometimes considered a distinct disease and constitutes around one-seventh of the side effects of drugs. 2%-3% of hospitalized patients show allergic reactions on their skin. In Western Europe, epidemiological research shows the relationship between atopy in healthy people and purified protein derivative (PPD) response.[6] A large cross-sectional study done in Sweden shows PPD reactions of more than 3 millimeters, which is somewhat more frequent in patients with atopy than the normal population (15.1% vs. 14.7%). However, PPD responses with a result of more than 10 millimeters were found to be 1.4% in normal children vs. 1.2% in the allergic population.[1][4]

Pathophysiology

The pathophysiology of type four hypersensitivity depends on the underlying cause. For instance, granulomatous disease occurs when T cells are stimulated by antigen-presenting cells that are unable to destroy engulfed antigens. Afterward, antigen-presenting cells become giant multinucleated cells, and for this to be done, a lot of cytokines are secreted, including interleukin-2 (IL-2) and tumor necrosis factor-alpha, and beta. Another mechanism occurs in contact dermatitis when irritants or antigens are applied to the skin; this will cause an inflammatory reaction mediated by over-expression of ICAM-1, VCAM-1, ELAM-1. Drug hypersensitivity occurs when various drug particles bind to a T cell receptor, even if not metabolized by antigen-presenting cells nor presented by major histocompatibility complex molecules.[7][8][9]

There are three subtypes of Type IV hypersensitivity: Contact dermatitis, tuberculin-type hypersensitivity, and granulomatous-type hypersensitivity.

Contact hypersensitivity dermatitis occurs when haptens, which are considered as exogenous antigens, penetrate the skin with proximity to epidermal and dermal cells, resulting in an inflammatory reaction. Dermal dendritic cells and Langerhans cells play an important role in antigen presentation and sensitization of these haptens to CD4 and CD8 T-cell lymphocytes. The latter secrete cytokines and other enzymes to recruit other immune cells to the site of hapten exposure.[4] Additionally, keratinocytes help in recruiting immune cells by secreting other groups of cytokines such as IL-8. This results in inflammation of the skin with swelling, itchiness, and pain.

Tuberculin-type hypersensitivity can be seen after intradermal injection of purified protein derivative (PPD) called tuberculin (product of tuberculosis bacillus), which produces measurable local induration and swelling, typically measured in millimeters between 48 to 72 hours after the injection.[10] This local reaction indicates the presence of type four hypersensitivity. The tuberculin test is a validated method to diagnose tuberculosis infection, even if latent.

Granulomatous-type hypersensitivity can occur in response to a variety of antigens. Macrophages that engulfed antigens are unable to destroy them and recruit several more macrophages to the site of these antigens. A collection of macrophages filled with intracellular antigens is termed granuloma. One example of granulomatous-type hypersensitivity is sarcoidosis disease, which is a systemic granulomatous disease of unknown cause, with a wide variety of clinical presentations. Sometimes, sarcoidosis is called reduced type four hypersensitivity due to the slow progression of this disease.[11][12][13][14][15][16][17]

Histopathology

After the injection of tuberculin in the skin, immune cells will infiltrate in the dermis layer of the skin, and these immune cells can be seen after staining with hematoxylin and eosin. In the granulomatous-type of hypersensitivity, a biopsy of a granuloma can show caseous necrosis surrounded by multinucleated giant cells consisting of macrophages and epithelioid cells. These granulomas are usually surrounded by lymphocytes and other immune cells. In contact hypersensitivity, mononuclear cells migrate within the epidermis and dermis. When a biopsy is taken from the skin, microvesicles can be seen between the dermis and epidermis. These microvesicles are caused as a result of edema in the skin. In irritant contact dermatitis, neutrophils are usually observed in the biopsies taken from the epidermis.[9][18]

History and Physical

The clinical features associated with type IV hypersensitivity are variable and categorized into distinct clinical conditions, each with its own unique features.

Contact dermatitis occurs after the skin is exposed to an allergen (topical medication, poison ivy) and, over a period of time, develops into a very erythematous pruritic rash, often with swelling and edema progressing to vesicles and bullae. Some of these vesicles and bullae can rupture with subsequent crust formation. When the reaction is prolonged with lichenification and scaling, the condition can be termed subacute or chronic contact dermatitis. Some of the agents implicated in the development of contact dermatitis include gloves, clothing, acrylics, preservatives, and an array of industrial chemicals.[19] It is, therefore, prudent to ask the patients about their occupations, hobbies, and daily activities. 

Granulomatous-type hypersensitivity can be seen in tuberculosis and sarcoidosis. Sarcoidosis is considered a granulomatosis entity with an unknown cause, with a systemic involvement of any organ in the body. It results in the formation of granulomas by the immune system in affected organs. The most frequent organs to be affected in sarcoidosis are the lymphatic system, especially in the mediastinum, lungs, eyes, and skin. In 20% to 50% of the cases, ophthalmic involvement is found. Moreover, up to 30% of patients can present with non-specific symptoms, such as weakness, weight loss, or fever. When the lungs are affected, patients usually present with shortness of breath, breathing difficulty, dry cough, and chest pain. Occasionally, these symptoms progress to pulmonary fibrosis, with a progressive decline in pulmonary functions.[18][20]

Acute generalized exanthematous pustulosis (AGEP) is a rare drug reaction presenting as generalized pustular rash manifesting within 24 hours after exposure to an offending drug.

Drug fever: Certain drugs such as trimethoprim-sulfamethoxazole or tetracyclines can cause fever as the only manifestation, and certain conditions appear to increase this susceptibility when exposed to certain drugs. Patients with acute human immunodeficiency virus (HIV) infection are more prone to get drug fever when treated with antiretroviral therapy.[21]

Stevens-Johnson syndrome/toxic epidermal necrolysis: These are life-threatening conditions that present with severe skin and mucosal necrosis with fluid losses and can present with hypovolemic shock.[22] There is severe blistering of the skin with pain, sloughing of the epidermis that resembles a third-degree burn. Commonly implicated agents are nonsteroidal anti-inflammatory drugs (NSAIDs), anticonvulsants, and sulfa drugs. 

Drug-induced hypersensitivity syndrome (DiHS) is another severe drug-induced type IV hypersensitivity reaction presenting with rash, fever, and multiorgan involvement, particularly the heart, lungs, liver, and kidneys.

Evaluation

The diagnosis of contact dermatitis can be made by clinical features alone, and in rare instances, a skin biopsy may be needed. To identify the offending allergen, skin patch tests may be helpful. The patients are usually tested with a wide variety of allergens and antigens to evaluate the skin response. Occasionally, immunological tests such as a complete blood count with differential, CD4, CD8, and radioallergosorbent tests may be helpful.  

If tuberculosis is suspected, tuberculin can be injected intradermally, and according to the size of the reaction that results, the patient can be diagnosed with tuberculosis. If positive, a chest X-ray is warranted. In a granulomatous disease such as sarcoidosis, chest X-ray, lymph node biopsy, elevated serum angiotensin-converting enzyme level (not diagnostic), or testing the salivary glands or mediastinum for gallium fixation can be considered.[4][23][24][25]

Treatment / Management

Treatment of type IV hypersensitivity depends on the clinical condition that resulted from this reaction.

Contact dermatitis: Removing the offending agent is the most crucial aspect of managing this condition. The severity of the skin condition dictates the type of therapy, which would almost always include topical steroids, titrating the strength of the steroid to the severity of the dermatitis.

For Steven Johnson syndrome/toxic epidermolysis, aggressive life-saving therapy would be required, including admission to an intensive care unit, optimal fluid therapy, antibiotics if there is a secondary infection, and systemic corticosteroids.

For granulomatous conditions, therapy depends on the type of clinical condition. In both systemic and ocular sarcoidosis, steroid therapy is the standard treatment.[20] In addition to steroids, methotrexate has shown efficacy in pulmonary sarcoidosis. In Crohn's disease, anti-tumor necrosis factor (TNF) monoclonal antibodies can be used as an effective way to manage the disease.[24][26][24] In schistosomiasis, praziquantel can be used.[27] Once the tuberculin test has revealed a positive result, the treatment of tuberculosis must be started, and one of the commonest regimens is to give rifampin, isoniazid, pyrazinamide, and ethambutol.[28][29]

Differential Diagnosis

Viral exanthems and certain bacterial infections can present with maculopapular rashes that can appear similar to contact dermatitis. The exposure to an allergen and the temporal relationship to the offending agent can help differentiate these conditions. 

Sarcoidosis can present with pulmonary symptoms, and a chest Xray can reveal hilar lymphadenopathy. This presentation, sometimes, can be similar to tuberculosis. However, the treatment is completely different; antibiotics are prescribed in tuberculosis, while steroid therapy is needed in sarcoidosis.[30]

Prognosis

Prognosis depends on the manifested clinical condition. Most contact dermatitis resolves with generally no sequelae. Studies show that up to 40% percent of patients who avoid the allergen had not experienced any more dermatitis. 

New acute sarcoidosis is more common among Whites than Blacks and with a higher chance of spontaneous remission within two years. This remission occurs in two-thirds of patients. However, the rest of them usually progress to chronic sarcoidosis, which usually presents with exacerbations and remissions. Mortality in sarcoidosis is usually attributed to respiratory failure and can be up to 5% of patients. In tuberculosis, the prognosis is favorable with early diagnosis and treatment with antimicrobials.[20][25]

Complications

Granulomatous diseases can affect any organ in the body, but for each type of granulomatous disease, there are common organs that are usually affected. For instance, sarcoidosis disease usually affects the lungs, eyes, and kidneys, resulting in pneumonia, lung fibrosis, pulmonary failure, cataracts, glaucoma, and kidney failure. In addition to the lungs, tuberculosis usually affects the vertebra and joints, resulting in back pain, joint stiffness, and arthritis.

In contact dermatitis, auto-eczematization can occur, which is a systemic flare of skin inflammation after the second exposure to a specific allergen. This skin inflammation disrupts the normal skin, which is the most important barrier in our body. Disruption of the skin can result in an increased risk of secondary infection of the skin by bacteria and other infectious organisms.[31] Severe Steven Johnson syndrome/toxic epidermal necrolysis can result in permanent skin scarring.

Deterrence and Patient Education

Early recognition and awareness of the occurrence of type IV hypersensitivity reactions can help patients manage their condition optimally. Patients should be educated about the common offending agents that they are susceptible to and strategies to avoid that exposure. Once the reaction occurs, prompt removal of the agent and initiation of anti-inflammatory therapy can shorten the discomfort and reduce the duration of illness.

Enhancing Healthcare Team Outcomes

Type IV hypersensitivity reaction can occur due to a wide variety of reasons affecting multiple organs, depending on individual susceptibility. Coordination of care between primary clinicians and specialists (allergists/infectious disease) can help accomplish optimal outcomes for these patients.