Type IV Hypersensitivity Reaction

Etiology

Delayed hypersensitivity reactions are a common immune response that occurs when sensitized T cells are activated upon contact with an antigen. These reactions are crucial in defending the body against intracellular pathogens such as mycobacteria, fungi, certain parasites, and in tumor immunity. The dysfunction of this system is evident in patients with AIDS. The loss of CD4+ lymphocytes weakens the immune response, leaving affected individuals unable to combat intracellular pathogens effectively. As a result, they are highly susceptible to opportunistic infections, including fungal infections, mucocutaneous candidiasis, and mycobacterial infections. Additionally, type IV hypersensitivity serves as the basis for the purified protein derivative test, which is used to diagnose TB.

Adverse events occur due to delayed hypersensitivity reactions when the immune system has an undesirable interaction with an antigen. Common causes of type IV hypersensitivity reactions include:

• Mycobacterium tuberculosis
• Fungi
• Parasites
• Metals, such as nickel
• Transplanted organs
• Medications
• Cosmetics and personal care items
• Viral infections
• Mycoplasma infections
• Rhus genus of plants, such as poison ivy, oak, and sumac
• Latex [2][3][4]

These exposures can lead to contact dermatitis, transplant rejection, maculopapular rashes, AGEP, drug fever, SJS, TEN, DIHS, drug-induced autoimmunity, TB, and fixed drug eruptions (FDEs). 

Affected patients have an increased risk of drug-induced delayed hypersensitivity reactions when they are exposed to certain viral infections or during an exacerbation of an autoimmune disease. A classic example is patients who develop a rash when treated with amoxicillin while infected with Epstein-Barr virus (EBV). Similarly, patients infected with cytomegalovirus (CMV) may develop a rash when exposed to ampicillin or related β-lactam antibiotics. Patients infected with human herpesvirus 6 (HHV-6), when given anticonvulsant medications, may develop DIHS. In addition, anticonvulsants can reactivate HHV-6, leading to the subsequent development of DIHS. Drug-induced delayed hypersensitivity reactions are often influenced by the duration of treatment and medication dosage. Most reactions occur with drugs dosed between 100 and 1000 mg/d and typically develop in patients receiving medications for more than 3 days.[5][6]

Procainamide, phenytoin, isoniazid, sulfasalazine, amiodarone, minocycline, and penicillamine are known to cause a lupus-like disease. Penicillamine and captopril can trigger pemphigus vulgaris and pemphigus foliaceus, while vancomycin, ceftriaxone, metronidazole, and ciprofloxacin may lead to immunoglobulin A (IgA) bullous dermatosis. Additionally, multiple medications, such as sulfonamides, can cause FDEs.[7] Some drug reactions are more likely to occur in patients with specific human leukocyte antigen (HLA) types. For example, DIHS and SJS or TEN are more common in patients taking allopurinol who carry the HLA-B*58:01 type.[8]

Epidemiology

Delayed hypersensitivity reactions are common in the general population. Approximately 20% of individuals have a contact allergy, with nickel being the most frequently identified allergen.[9] The prevalence of contact allergies tends to increase with age and is higher in females than in males. Maculopapular exanthems occur in about 2% to 4% of hospitalized patients. Severe reactions such as SJS and TEN affect 1.4 to 12.7 individuals per million each year, with incidence rates nearly twice as high in females compared to males. The risk is greatest among patients aged 50 or older, those with HIV, connective tissue disorders, malignancy, or individuals of Black or Asian descent.[10][11][12] 

DIHS affects approximately 1 to 2 per 100,000 patients annually and is more frequently seen in adults than in children.[13] Additionally, between 50% and 75% of the United States population is sensitized to poison ivy, sumac, and oak, and between 10 million and 50 million people seek medical care for dermatitis caused by poison ivy each year.[14]

Pathophysiology

The pathophysiology of type IV hypersensitivity varies depending on the underlying cause. Delayed hypersensitivity reactions are classified into 4 distinct types, based on the type of T cell involved—either CD4 T-helper type 1 (Th1) or type 2 (Th2)—and the specific cytokines or chemokines they produce.[15][16][17][18]

Many delayed hypersensitivity reactions result from drug exposure. In their native state, most drugs are too small to interact with immune receptors strongly enough to stimulate B- and T cells. However, when bound to intracellular proteins such as albumin or integrins, they become large enough to act as haptens. This hapten-carrier complex functions as a new self-antigen and can stimulate an immunological response from both B- and T cells when presented to the HLA complex. Drugs that are not initially reactive but become reactive after being metabolized in the liver, forming a hapten, are called "prohaptens." Alternatively, some drugs can directly and reversibly bind to immune receptors—a mechanism known as "p-i reactions." This interaction stimulates T cells and leads to hypersensitivity reactions.

Subdivisions of Type IV Hypersensitivity Reactions

Type IVa: Common examples of type IVa delayed hypersensitivity reactions include contact dermatitis, which may also involve type IVc reactions, and granulomatous hypersensitivity. In these reactions, activated Th1 cells secrete cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, which further activate macrophages. These cytokines recruit additional immune cells to the site of infection. Macrophages are transformed into epithelioid histiocytes, enhancing their ability to kill intracellular pathogens. The epithelioid cells then fuse to form multinucleated giant cells, and along with macrophages and lymphocytes, they create a granuloma to contain the antigen. Examples of granulomatous hypersensitivity include sarcoidosis, TB, and Crohn disease.[19][20][21][22][23][24][25] 

Contact dermatitis occurs when contact allergens penetrate the skin's stratum corneum and bind to skin proteins, forming hapten-protein complexes.[2][26] Langerhans cells engulf the hapten complex and present it to T cells in the lymph nodes. Following the initial exposure, the patient develops hapten-specific memory T cells, which undergo clonal expansion and circulate throughout the body until recruited to the skin upon reexposure to the offending antigen.[27] Following initial hapten exposure, Langerhans cells mature and express CD83, adhesion molecules (such as intercellular adhesion molecule-1 [ICAM-1]), and stimulatory molecules (including CD40, CD80, and CD86). Upon reexposure to the same antigen, the antigen-presenting cells present the hapten complex to memory T cells in the dermis and epidermis.

The initial damage primarily results from major histocompatibility complex (MHC) class I CD8+ T cells infiltrating the skin and inducing keratinocyte apoptosis via the perforin/granzyme or Fas/FasL pathway. This leads to intercellular edema and vesiculation due to the cleavage of intracellular adhesion molecules and lymphocyte infiltration into the epidermis. Infiltrating CD8+ T cells release cytokines such as IFN-γ and TNF-α, which stimulate keratinocytes, resulting in the upregulation of ICAM-1 and MHC class II molecules. This cascade recruits neutrophils, macrophages, and eosinophils, causing skin inflammation, swelling, itchiness, and pain. The precise role of CD4+ T cells remains unclear, as they appear later in the reaction than CD8+ T cells. These CD4+ T cells also secrete large amounts of IFN-γ and TNF-α and may contribute to cytotoxicity against cells expressing MHC II, act as mediators of the inflammatory response, or serve a regulatory function. 

Type IVb: Type IVb hypersensitivity reactions involve Th2 cells that secrete interleukins, such as IL-4, IL-13, and IL-5, promoting B-cell production of IgE and IgG4 while triggering an inflammatory response from eosinophils and mast cells. These reactions are likely associated with DRESS/DIHS and allergic asthma.

The exact pathophysiology of DRESS/DIHS remains unclear. Currently, 2 prevailing mechanisms are believed to contribute to its pathogenesis—a drug-specific immune response and reactivation of HHV, followed by a subsequent antiviral immune response. The offending drug acts as a hapten, with evidence of Th2 skewing in the immune response, indicated by increased levels of IL-5. Additionally, nearly 75% of patients with DRESS/DIHS experience reactivation of viruses from the Herpesviridae family, such as HHV-6, HHV-7, EBV, and CMV.[28][29] 

Some authors suggest that the reactivation in DRESS/DIHS is due to an immunocompromised state in the early stages, as T regulatory cell numbers increase while B cell counts and immunoglobulin levels decrease. Others believe that certain drugs, such as valproic acid and amoxicillin, directly promote the replication of HHV-6 and CMV.[30][31] DRESS/DHIS is more common in patients taking allopurinol and carrying the HLA-B*58:01 allele. Interestingly, abacavir-associated DRESS/DIHS occurs only in patients with the HLA-B*57:01 allele. Carbamazepine is another common trigger, particularly in patients of Han Chinese, Thai, Malaysian, and Indian descent with the HLA-B*15:02.[32][33]

Type IVc: Type IVc hypersensitivity reactions involve cytotoxic T cells that migrate to sites of inflammation, such as the liver or skin, inducing cell death primarily by apoptosis. Experts believe that these cytotoxic T cells are involved in drug reactions, including contact dermatitis, maculopapular and bullous drug eruptions, and drug-induced hepatitis, interstitial nephritis, or pneumonitis.[34] Both SJS and TEN are also believed to involve type IVc hypersensitivity reactions. Perforin, granzyme B, and granulysin mediate the cytotoxic effects.[35] Type IVc reactions may present as exanthematous drug reactions or be confined to a single organ without skin involvement. 

Patients with certain HLA haplotypes are predisposed to SJS and TEN. These haplotypes are specific to certain ethnicities and medications.[36] For example, patients with cytochrome P450 2C9 enzyme variants, which result in reduced drug clearance, are at increased risk for severe cutaneous reactions due to phenytoin. Similarly, individuals with a slow acetylator phenotype, which impairs the detoxification of reactive drug metabolites, have an elevated risk of TEN when exposed to sulfonamides.[37][38] The initial step in the pathogenesis of SJS and TEN involves the drug binding to the HLA receptor on antigen-presenting cells or directly to the T-cell receptor.

Researchers propose various models explaining how different drugs induce T-cell activation in patients with SJS and TEN:

• Beta-lactam–induced drug hypersensitivity: The antigen covalently binds to a protein, forming a hapten-carrier complex. This complex elicits an immune response when presented to the T-cell receptor with the HLA molecule.[39]  
• Carbamazepine-induced SJS/TEN: In patients with HLA B*15:02, carbamazepine or its metabolite directly binds to the HLA molecule or the T-cell receptor, thereby causing SJS and TEN.[40]
• Abacavir-related SJS and TEN: This occurs when the drug binds to the HLA molecule, inducing a conformational change that alters the peptides presented to T cells, thereby triggering a T-cell response. 
• T-cell receptor binding: When a drug binds to the T-cell receptor, it can induce conformational changes that modify the peptides presented to the T cells, thereby triggering a T-cell response. 

Once activated, cytotoxic CD8+ T cells release proteins that induce epidermal necrolysis. Natural killer (NK) and Th17 cells also contribute to the process. Full epidermal detachment occurs with the involvement of granulysin, the Fas ligand, perforin or granzyme, TNF-α, IL-15, and TNF-related apoptosis-inducing ligand.[35] 

Experts believe that immune-mediated drug-induced liver injury (DILI) occurs when a drug covalently binds to the host's tissues, altering the presented peptides. These altered peptides can either act as direct toxins or appear as new antigens, triggering an immune response.

Type IVd: Type IVd hypersensitivity is driven by CD8+ and Th17 immune responses, resulting in neutrophilic inflammation. During sensitization, CD8+ and Th17 cells become primed, and in the elicitation phase, they migrate to the skin, releasing chemokines such as IFN-8, IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These chemokines attract neutrophils, leading to the formation of sterile pustules. A key clinical manifestation of this reaction includes AGEP and pustular psoriasis.

Histopathology

The key histopathological feature of TB is the presence of epithelioid granulomas made up of lymphocytes, epithelioid histiocytes, and Langhans giant cells with central caseation necrosis. Alternatively, the granulomas associated with sarcoidosis are non-necrotizing and contain cytoplasmic inclusions such as asteroid bodies, Schaumann bodies, and birefringent crystalline particles consisting of calcium oxalate and other calcium salts.[41] 

In hypersensitivity reactions caused by contact allergens, mononuclear cells infiltrate the epidermis and dermis. Biopsy findings include microvesicles at the dermoepidermal junction, resulting from edema within the skin. In contrast, contact dermatitis caused by irritants typically shows neutrophilic infiltration in the epidermis.[17][42]

Microscopic examination of an FDE shows melanin accumulation in the upper dermis and dermal macrophages, vacuolization of basal keratinocytes, and dyskeratotic or squamous cells with premature or abnormal keratinization in the epidermis. The dermis exhibits lymphocytic infiltration and dermal melanophages. In inactive lesions, memory CD8+ lymphocytes localize along the epidermal side of the dermoepidermal junction.[43]

History and Physical

Type IV hypersensitivity reactions present in various clinical forms, each representing distinct conditions with specific features. This section highlights several common and severe delayed hypersensitivity reactions but does not provide an exhaustive list of all potential clinical presentations.

Contact Dermatitis

Contact dermatitis develops following exposure to allergens or irritants. Acute irritant contact dermatitis typically appears within minutes to hours of exposure, often presenting with burning or stinging sensations, erythema, edema, vesicles, bullae, and oozing at the contact site, commonly affecting the hands or face. Continued exposure can lead to chronic symptoms such as lichenification, hyperkeratosis, and fissuring.

Similarly, allergic contact dermatitis occurs in areas directly exposed to the allergen, with the hands, face, and eyelids most frequently affected, although the scalp, neck, dorsum of the feet, trunk, and axillae may also be involved. Lesions are typically erythematous, indurated, scaly, and pruritic, with chronic exposure potentially causing lichenification and fissures. A thorough patient history may identify possible triggers, including hair dyes, shampoos, cosmetics, shoe materials, clothing dyes, metals in jewelry, rubber components in clothing, hygiene products, and fragrances.[44] 

Granulomatous-Type Hypersensitivity

Sarcoidosis and TB are 2 conditions characterized by granulomatous-type hypersensitivity. Sarcoidosis is a systemic disease characterized by granuloma formation across multiple organ systems, most commonly affecting the lymphatic system, particularly the mediastinum, and the lungs, eyes, and skin. In nearly half of the cases, the disease is identified incidentally through imaging performed for unrelated concerns.

Around 95% of patients experience involvement of the lungs or thoracic lymph nodes, with common symptoms such as cough, shortness of breath, fatigue, and chest pain. Other frequent features include fever, malaise, weight loss, and persistent fatigue. Additional manifestations may include erythema nodosum, facial rashes, kidney stones, swelling of the parotid and salivary glands, facial nerve palsy, uveitis, and dry eyes.[42][45][46]

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

SJS and TEN are considered a continuum of the same illness. Clinicians differentiate between the two conditions based on the percentage of body surface area affected by skin detachment: SJS involves less than 10%, between 10% and 30% represents an overlap of the 2 conditions, and more than 30% describes TEN. The illness typically begins with a prodromal phase characterized by malaise, fever, myalgia, sore throat, and conjunctivitis. A rash initially appears on the face and thorax, presenting as erythematous macules that progressively develop into purpuric lesions, atypical target lesions, and flaccid bullae. As the condition advances, patients experience sheet-like skin detachment. Mucosal involvement occurs in nearly 90% of cases, with erosions and blisters affecting the oral, nasopharyngeal, buccal, and anogenital surfaces.[47] Ocular, renal, and pulmonary involvement are also common. Please see StatPearls' companion resources, "Stevens-Johnson Syndrome" and "Toxic Epidermal Necrolysis," for more information.

Drug Reaction with Eosinophilia and Systemic Symptoms

The latency phase of DIHS/DRESS ranges from 2 to 8 weeks. Symptoms often begin with nonspecific prodromal signs such as fever, malaise, and lymphadenopathy. The classic rash associated with DIHS/DRESS is a profoundly erythematous, maculopapular, symmetric eruption on the trunk and extremities, often coalescing to cover more than 50% of the body's surface. Nearly 70% of patients exhibit significant facial edema, a key diagnostic clue, while mild mucosal involvement occurs in approximately 50% of cases.

Additional symptoms depend on the organ system involved. Pulmonary manifestations may include shortness of breath, dry cough, or respiratory failure due to conditions such as acute interstitial pneumonitis, lymphocytic interstitial pneumonia, pleuritis, and acute respiratory distress syndrome. Cardiac involvement, which is a poor prognostic indicator, presents with hypotension, tachycardia, chest pain, and dyspnea, often due to hypersensitivity myocarditis or acute necrotizing eosinophilic myocarditis.[50] Nervous system involvement may present as Bell palsy, peripheral neuropathy, aseptic meningitis, cerebral vasculitis, and limbic encephalitis.[51]

Maculopapular Drug Eruptions

The latency period for maculopapular drug eruptions varies based on whether the patient has experienced prior sensitization. For patients who have not been previously sensitized, symptoms typically appear within 7 to 10 days. In those with prior sensitization, symptoms may develop within 6 to 12 hours, although the typical time frame is 1 to 3 days. The classic presentation includes erythematous macules or papules, predominantly affecting the trunk and proximal extremities, often accompanied by mild pruritus and a low-grade fever. In more severe cases, lesions may extend to the face, palms, and soles. A variant known as SDRIFE is most commonly associated with antibiotic exposure. This condition is characterized by sharply demarcated, V-shaped erythema in the gluteal, perianal, inguinal, or perigenital areas, often involving at least a flexural region.[52][53] 

Acute Generalized Exanthematous Pustulosis

The latency period for AGEP ranges from a few hours to a few days, with antibiotics typically having the shortest latency. Patients develop hundreds of sterile, tiny pustules in a nonfollicular distribution overlying erythematous and edematous skin. The pustules often first appear on the face or intertriginous areas before rapidly spreading to the trunk and extremities. Fever is common, and facial edema may occur, although oral mucosal involvement is rare. When present, oral involvement is typically limited to the lips.

Drug Fever

Fever may be the sole manifestation of DIHS. Common causative agents include carbamazepine, azathioprine, sulfasalazine, trimethoprim-sulfamethoxazole, minocycline, and tacrolimus. Patients with acute HIV infection are at increased risk of developing drug fever when receiving antiretroviral therapy.[54] Drug fever typically develops within a few hours to a few months after drug initiation, although chronic medications should not be excluded as potential causes. Clinicians should consider drug fever in patients who present with fever but otherwise appear well. The fever pattern may vary, with the most common being a constant fever with wide temperature fluctuations. Approximately 30% of patients may exhibit cutaneous manifestations, such as morbilliform eruptions, hives, and nonfollicular pustules.[48] 

Fixed Drug Eruption 

FDE is a cutaneous drug reaction that typically presents as a solitary, well-demarcated, round or oval dusky red macular lesion, most commonly on the lips, genitalia, perianal area, hands, and feet. The lesions may progress to form vesicles or blisters. Lesions usually appear within 8 hours of drug exposure, although a delay of up to 2 weeks can occur. Upon reexposure to the drug, the lesion recurs at the same site. Postinflammatory hyperpigmentation is often observed following the resolution of the lesion.

Drug-Induced Liver Injury

DILI is often asymptomatic; however, when symptoms do occur, patients commonly report malaise, vomiting, right upper quadrant pain, acholic stools, dark urine, pruritus, and anorexia. On physical examination, some patients may exhibit hepatomegaly, jaundice, and excoriations from scratching.

Evaluation

Assessing patients with delayed hypersensitivity reactions requires a systematic approach, starting with a comprehensive history and physical examination. 

Contact Dermatitis

Clinicians suspecting contact dermatitis should obtain a comprehensive history to identify potential allergens or irritants. The history should include details about occupational and recreational exposures, as well as the use of personal care products. Notably, long-term exposure to potential triggers does not rule them out as causes. In addition, inquiring about seasonal or temporal variations in symptoms can offer clues regarding photo-aggravation, photoallergy, or whether the exposure is related to the workplace or leisure activities.

Routine laboratory tests are generally unnecessary unless the diagnosis remains uncertain. A potassium hydroxide examination or skin culture can help eliminate fungal or bacterial causes. A skin biopsy may be required if the diagnosis remains unclear. However, as irritant contact, atopic, nummular, dyshidrotic, and seborrheic dermatitis all present with eosinophilic spongiosis on histopathology, a skin biopsy is not helpful in distinguishing between these conditions. Patch testing can be useful for identifying specific allergens or when the diagnosis is uncertain. If symptoms improve following a therapeutic trial of allergen or irritant avoidance and empiric treatment, the diagnosis of contact dermatitis is supported, and patch testing may not be necessary.

Granulomatous-Type Hypersensitivity

The diagnostic evaluation of patients with granulomatous-type hypersensitivity reactions depends on the suspected underlying illness. For example, in patients at increased risk for TB, clinicians should perform screening with a tuberculin skin test (TST) or an IFN-γ release assay (IGRA), both of which assess cell-mediated immunity. If screening results suggest TB infection, further evaluation should include chest radiography and sputum analysis for acid-fast bacilli smear and nucleic acid amplification testing. Please see StatPearls' companion resources, "Tuberculosis Screening" and "Tuberculosis Overview," for more information.

In patients with suspected sarcoidosis, clinicians should conduct a comprehensive medical, occupational, and environmental history to rule out silicosis, histoplasmosis, malignancy, immunodeficiency, and hypersensitivity pneumonitis. The initial evaluation typically includes a chest radiograph, often followed by a computed tomography (CT) scan of the chest. When appropriate, testing for tuberculosis and other fungal infections should be performed. Additional laboratory assessments may include a complete blood count with differential, liver function tests, blood urea nitrogen, creatinine, glucose, electrolytes, serum calcium, HIV screening, an electrocardiogram, and an ophthalmological examination.[2][49][50][51] 

Up to 50% of affected patients develop hypercalciuria, while 10% experience hypercalcemia. Activated mononuclear cells, such as macrophages in the lungs and lymph nodes, convert calcidiol to calcitriol independent of parathyroid hormone, leading to increased intestinal calcium absorption. Serum angiotensin-converting enzyme levels are elevated in approximately 75% of patients with sarcoidosis. However, due to its low sensitivity and specificity, this marker has limited utility in diagnosing sarcoidosis. Please see StatPearls' companion resource, "Sarcoidosis," for more information.

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

The evaluation of suspected SJS and TEN requires comprehensive laboratory testing, including a complete blood count with differential, coagulation studies, metabolic panel, liver function tests, and inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein. If an infection is suspected, clinicians should obtain bacterial and fungal cultures from the skin, blood, and mucosa, as well as polymerase chain reaction or serology for Mycoplasma pneumoniae in patients without a clear drug-related cause. Additionally, chest radiography is essential to assess potential pulmonary involvement.

Drug Reaction With Eosinophilia and Systemic Symptoms

Healthcare professionals should suspect DRESS/DIHS when a patient presents with characteristic cutaneous findings and systemic symptoms, such as fever and lymphadenopathy, after starting a new drug within the preceding 2 to 8 weeks. Initial laboratory studies to establish the diagnosis and assess for visceral involvement include a complete blood count, liver function tests, serum creatinine, amylase and lipase, cardiac enzymes and troponin, and serology for acute hepatitis, HHV-6, HHV-7, EBV, and CMV.

Imaging tests, such as an echocardiogram, cardiac magnetic resonance imaging (MRI), ultrasound, or CT, may be necessary depending on symptoms and laboratory findings. A skin biopsy can help exclude alternative diagnoses. Clinicians should recognize that not all characteristic features of DRESS/DIHS will be present simultaneously. Common abnormalities on a complete blood count include eosinophilia, leukocytosis, neutrophilia, lymphocytosis, monocytosis, atypical lymphocytes, and lymphocytopenia. Although eosinophilia occurs in 80% to 95% of affected individuals, it is not required to establish the diagnosis. 

Healthcare professionals can use the Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system to confirm or exclude the diagnosis.[52] The system assigns points based on the presence or absence of specific clinical and laboratory findings, including:

• Fever of 101.3 °F (38.5 °C) or higher
• Organ involvement
• Lymphadenopathy
• Atypical lymphocytes
• Resolution taking longer than 15 days
• Skin rash 
• Eosinophilia
• Exclusion of alternative diagnoses

As some of the variables used in the scoring system may not be present during the initial patient evaluation, the scoring system is most effectively applied retrospectively. 

Maculopapular Drug Eruptions

The diagnosis of maculopapular drug eruptions is primarily clinical and is based on the patient's history and physical examination. A skin biopsy does not reliably differentiate these eruptions from rashes associated with viral exanthems and is thus not helpful in confirming the diagnosis.

Acute Generalized Exanthematous Pustulosis

Patients with suspected AGEP should undergo a complete blood count with differential, Gram stain and pustule culture, and a skin biopsy to rule out alternative causes of pustular lesions. The presence of neutrophils in the stratum corneum and epidermis on skin biopsy confirms the diagnosis.

Clinicians diagnose AGEP based on the following criteria:

• Rapid onset of a pustular eruption with fever within hours to days of initiating a drug.
• Dozens to hundreds of pinhead-sized, nonfollicular pustules overlying edematous and erythematous skin.
• Leukocytosis with a marked neutrophilia, generally greater than 7000/µL.
• Gram stain and pustule cultures that are negative for bacteria.
• Rapid resolution of the rash following drug discontinuation.

Patch testing can be useful 4 to 6 weeks after symptom resolution. Although a positive patch test can be informative, its low sensitivity in AGEP patients means a negative result does not rule out the medication as the cause.[53][54]

Drug Fever

Drug fever is a diagnosis of exclusion, made after eliminating alternative causes for fever such as infection, malignancy, and autoimmune conditions. The evaluation for alternative causes of fevers varies based on the clinical findings, patient characteristics, and the severity of illness. Many patients will have undergone a complete blood count, urinalysis, and serum transaminase testing during their initial assessment.

Potential laboratory abnormalities commonly associated with drug fever include:

• Leukocytosis with eosinophilia in 20% of patients [55]
• Neutropenia or agranulocytosis [56] 
• Abnormal serum transaminases
• Eosinophiluria on urine Gram stain, indicating interstitial nephritis

The diagnosis is often confirmed by discontinuing the offending medication. Symptoms typically resolve within 72 to 96 hours.

Fixed Drug Eruption

The diagnosis of FDE is clinical, based on the characteristic features of the lesions, a history of drug intake hours to days before lesion development, and the recurrence of lesions at the same site upon reexposure to the same drug. A skin biopsy should be considered if the diagnosis is unclear or if systemic or unusual symptoms are present. If the offending drug is not identified, patients may undergo an oral provocation test or patch testing. However, the sensitivity of patch testing is low, making oral provocation the preferred method.[57] Clinicians should avoid performing provocation testing in patients with generalized reactions of FDE.

Drug-Induced Liver Injury

DILI is a diagnosis of exclusion. Key historical data should include any exposure to potential hepatotoxins, risk factors for viral hepatitis, and concurrent health conditions associated with liver disease. Important factors in diagnosing DILI include a temporal relationship between drug exposure and liver damage, the exclusion of other potential causes of liver disease, and improvement in liver function after discontinuing the drug. Additionally, reexposure to the drug usually results in rapid and severe recurrence of liver injury, although rechallenge is not recommended.

Necessary laboratory tests and imaging in patients with elevated liver function tests may include:

• Acetaminophen level
• Viral hepatitis testing
• Antinuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney microsomal antibodies type 1, and IgG
• Serum ceruloplasmin  and urinary copper level
• Serum creatinine kinase or aldolase
• Urinalysis for proteinuria in pregnant patients
• Serum iron, total iron-binding capacity, and ferritin levels
• Alpha-1 antitrypsin level
• Serum cortisol and plasma corticotropin
• Tissue transglutaminase antibodies
• Abdominal ultrasound or computed tomography

Liver biopsy is generally not required to establish the diagnosis of DILI, but it may be considered when excluding alternative causes of elevated serum transaminases. 

Treatment / Management

Management of type IV hypersensitivity varies based on the clinical condition associated with the reaction. In general, the primary approach involves the removal or avoidance of the offending agent. For patients with contact dermatitis and drug-related illnesses, discontinuing the causative substance is essential. Patients with workplace or environmental exposures, as well as allergic or irritant contact dermatitis, should wear protective gloves and clothing. For symptom management, treatment options include topical corticosteroids, topical calcineurin inhibitors such as tacrolimus, and the topical selective Janus kinase (JAK) inhibitor ruxolitinib. Additionally, liberal use of emollients can help soothe the skin.[58] In cases of severe disease, systemic corticosteroids may be required.

More severe illnesses, such as SJS and TEN, require intensive supportive care, including wound management, fluid and electrolyte balance, nutritional support, and pain control. As sepsis is a leading cause of mortality, infection prevention and management are critical. Ocular involvement can lead to extensive sloughing of the bulbar conjunctiva, necessitating the use of preservative-free corticosteroid drops and additional protective measures to prevent long-term damage. Systemic therapy may include corticosteroids, although their overall benefit remains unclear.[59] Patients who develop SJS or TEN due to a drug must be advised to avoid the offending medication and related compounds in the future.(B2)

Systemic glucocorticoid therapy is the standard treatment for granulomatous conditions such as pulmonary sarcoidosis.[45] For patients who do not respond to or cannot tolerate glucocorticoids, methotrexate is an alternative option. In Crohn's disease, treatment typically involves oral glucocorticoids or a combination therapy, which may include an anti-TNF agent and an immunomodulator such as azathioprine or methotrexate, depending on the severity of the disease.[50][60] Traditional therapy for pulmonary TB consists of rifampin, isoniazid, pyrazinamide, and ethambutol.[61][62][63][64](B3)

Differential Diagnosis

The potential differential diagnoses are extensive and vary based on the underlying conditions mentioned below.

Contact Dermatitis

• Seborrheic dermatitis
• Eczema
• Psoriasis
• Stasis dermatitis
• Mycosis fungoides
• Tinea manuum

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

• Erythema multiforme
• Generalized bullous fixed drug eruption
• Staphylococcal scalded skin syndrome
• Acute graft-versus-host disease
• Reactive infectious mucocutaneous eruption 
• Paraneoplastic pemphigus
• Linear IgA bullous dermatosis

Drug Reaction with Eosinophilia and Systemic Symptoms

• Lymphoma
• Acute cutaneous lupus erythematosus
• Hypereosinophilic syndromes

Maculopapular Drug Eruptions

• Viral infections such as measles, rubella, HHV-6, HHV-7, and HIV
• Bacterial infections such as M. pneumoniae, group A Streptococcus, and Treponema pallidum
• Acute cutaneous lupus erythematosus
• Juvenile idiopathic arthritis
• Adult-onset Still disease

Acute Generalized Exanthematous Pustulosis

• Generalized acute pustular psoriasis
• Subcorneal pustular dermatosis
• Bullous impetigo

Drug Fever

• Infection
• Malignancy
• Autoimmune conditions
• Thromboembolism
• Postmyocardiotomy syndrome
• Neuroleptic malignant syndrome
• Serotonin syndrome
• Postsurgical fever
• Endocrine disorders such as thyroid dysfunction

Fixed Drug Eruption

• Bullous pemphigoid
• Erythema multiforme
• Large plaque parapsoriasis [65]
• Autoimmune progesterone dermatitis
• Aphthous stomatitis [66]

Drug-Induced Liver Injury

• Chronic viral hepatitis 
• Alcohol-associated liver disease
• Hemochromatosis
• Steatotic liver disease
• Autoimmune hepatitis
• Wilson disease
• Alpha-1 antitrypsin deficiency
• Congestive hepatopathy
• Adult bile ductopenia
• Malignancy
• Inborn errors of muscle metabolism
• Thyroid disorders
• Celiac disease
• Adrenal insufficiency
• Anorexia nervosa

Prognosis

Except for SJS and TEN, the overall prognosis for acute conditions mediated by type IV hypersensitivity reactions is generally favorable. While contact dermatitis can significantly impact quality of life and work productivity, death from contact dermatitis is rare. The prognosis for acute irritant and allergic contact dermatitis is good when the offending agent is identified, removed, and avoided. However, the prognosis for work-related irritant contact dermatitis is less favorable if the patient is unable to avoid the causative agent. In patients with acute irritant contact dermatitis, symptoms typically resolve within 4 weeks, although skin hyperreactivity can persist for up to 10 weeks. Chronic irritant contact dermatitis carries a poorer prognosis, with only 43% of patients showing improvement after 1 year.[67]

The overall prognosis for SJS and TEN is less favorable than that of many other illnesses caused by delayed hypersensitivity reactions. The overall mortality rate is approximately 25%, with sepsis, acute respiratory distress syndrome, disseminated intravascular coagulation, and multiple organ failure being the most common causes of death. Affected patients remain at an increased risk of mortality for up to 12 months following diagnosis.

The overall prognosis for sarcoidosis is generally favorable, with many patients achieving remission or experiencing symptom improvement with treatment. Although rare, patients with cardiac involvement are at an increased risk of ventricular arrhythmias, heart block, heart failure, and death. The overall mortality rate associated with sarcoidosis ranges from 1% to 5%.[68] If left untreated, TB can be fatal; however, most patients who undergo treatment experience a cure.

Most patients with DILI recover fully after discontinuing the offending medication. However, some cases may progress to severe liver damage, requiring transplantation. Poor prognostic indicators include alanine aminotransferase levels exceeding 3 times the upper limit of normal with jaundice, acute liver failure in children caused by antiepileptic drugs, and acetaminophen-induced liver failure requiring dialysis.[69][70] Elevated serum creatinine and preexisting liver disease further increase the risk of severe outcomes. Additionally, patients with cholestatic liver injury are more likely to develop chronic liver disease, and a Model for End-Stage Liver Disease (MELD) score above 19 predicts higher liver-related mortality in DILI.

Patients with DRESS/DIHS have an overall mortality rate of 2% to 10%, with older age, severe organ involvement, and multiorgan failure being the primary predictors of mortality.[71][72] Most patients with AGEP experience complete symptom resolution without complications, with a mortality rate of approximately 2%.[73] 

Complications

Many complications associated with delayed hypersensitivity reactions are specific to the underlying illness.

Contact Dermatitis

• Lichen simplex chronicus
• Secondary infection
• Adverse effects of medications, including hyperglycemia, cataract formation, adrenal insufficiency, topical steroid withdrawal, and skin atrophy
• Skin hyperpigmentation and hypopigmentation

Granulomatous-Type Hypersensitivity

Sarcoidosis can affect multiple organ systems, leading to various potential complications, including:

• Arthritis
• Arrhythmias
• Heart failure
• Heart block
• Myocarditis
• Dysphagia
• Uveitis
• Glaucoma
• Cataracts
• Pulmonary hypertension
• Kidney failure
• Nephrolithiasis
• Hypercalcemia
• Venous thromboembolism and pulmonary embolism
• Medication-related complications, such as metabolic syndrome, cataract formation, increased cardiovascular risk, and increased risk of infection
• Facial nerve palsy
• Seizures
• Hypopituitarism
• Headache
• Anemia
• Leukopenia
• Thrombocytopenia
• Granulomatous meningitis [74][75][76][77][78][79]

Common complications associated with TB include septic shock, airway obstruction, pneumonia, bronchiectasis, empyema, broncho-pleural fistula, hemoptysis, meningitis, osteomyelitis, peritonitis, renal abscess, and infertility. Hepatitis and optic neuritis are well-known adverse effects associated with TB treatment.

Acute Generalized Exanthematous Pustulosis

• Secondary skin infection
• Hypocalcemia
• Liver and kidney dysfunction

Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

• Dry eyes
• Photophobia
• Ingrown eyelashes
• Visual impairment
• Blindness
• Keratitis
• Xerostomia
• Gingivitis
• Chronic oral pain at the site of ulcerations
• Urethral stenosis
• Dyspareunia
• Stenosis of the vaginal introitus
• Urinary retention
• Phimosis
• Chronic bronchitis
• Chronic bronchiolitis
• Anxiety
• Death
• Depression [80][81][82] 

Drug Reaction with Eosinophilia and Systemic Symptoms

• Autoimmune thyroiditis
• Vitiligo
• Alopecia areata
• Alopecia universalis
• Autoimmune hemolytic anemia
• Lupus erythematosus
• Type 1 diabetes 

Drug Fever

Misdiagnosis is the primary complication associated with drug fever, often leading to prolonged hospital stays, unnecessary testing, and treatments.

Fixed Drug Eruption

• Pain
• Infections
• Hypopigmentation or hyperpigmentation
• Secondary infections

Drug-Induced Liver Injury

• Liver failure requiring liver transplant
• Complications associated with medications required after liver transplantation include infection, metabolic syndrome, increased cardiovascular risk, acute and chronic kidney disease, osteoporosis, malignancy, hyperuricemia, central nervous system issues, and organ rejection
• Hepatic encephalopathy
• Coagulopathy
• Portal hypertension
• Cirrhosis
• Secondary sclerosing cholangitis
• Vanishing bile duct syndrome
• Sinusoidal obstruction syndrome
• Ascites [83]