The clinical features associated with type IV hypersensitivity are variable and categorized into distinct clinical conditions, each with their 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 as 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. 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 as a granulomatosis entity with 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.[16][17]

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.

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. 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.

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 Xray is warranted. In granulomatous disease such as sarcoidosis, chest Xray, 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][18][19][20]

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. 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. In schistosomiasis, praziquantel can be used. 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.[17][19][21][22][23][24]

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.[25]

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.[17][20]

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.[26] Severe Steven Johnson syndrome/toxic epidermal necrolysis can result in permanent skin scarring.

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.

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.