Delayed Hypersensitivity Reactions

Delayed hypersensitivity diseases can develop in humans due to mycobacteria, protozoa, and fungi, although in another granulomatous disease such as Crohn disease, no infectious microbes have been found. Some of the most critical diseases include leprosy, tuberculosis, schistosomiasis, sarcoidosis, and Crohn disease.[7][15][16]

Leprosy is divided clinically into three essential types: tuberculoid, borderline, and lepromatous. In tuberculoid leprosy, the affected skin has a few, well-defined, hypopigmented patches that show epithelioid infiltrate with no microorganisms. In lepromatous shows, multiple confluent skin lesions characterized by numerous bacilli. Borderline leprosy shows physical findings of the two others.

Tuberculosis in the lungs causes a granulomatous reaction that leads to cavitation and the spread of bacteria. There are extensive areas of fibrosis that can see in the chest x-ray. This lesion is typically granulomatous.

Schistosomiasis causes by schistosomes, once the body is sensitized by a granulomatous reaction developed in the parasitized tissue mediated by Th2 lymphocytes.

Sarcoidosis is a chronic and idiopathic disease in which activated macrophage and granuloma accumulate in many tissues along with fibrosis. The condition can be characterized by the presence of enlarged lymph nodes, which may be identified in chest radiographs. This disease is associated with depression of cell-mediated immunity both in vivo and in vitro. A tuberculin test is negative in this disease. The clinical manifestations include granuloma development in the lungs, lymph nodes, nervous system, bones, and skin and are associated with fever, malaise, and shortness of breath due to lung fibrosis.

Crohn disease is another granulomatous disease that is not caused by a microorganism. Granulomas are prominent. It is a chronic disease that affects ileum and colon, and where T-helper cells and APC accumulate in all layers of the intestines.

These reactions can be diagnosed by a skin test of delayed hypersensitivity using antigens and confirmed by history and clinical presentation. For example, the tuberculin test in a patient with pulmonary tuberculosis can give an overwhelming reaction, but this would not occur in a patient with sarcoidosis. A patient should be tested with an array of allergens to prove which of them is causing the problem. The culture of microorganisms can be useful in demonstrating the cause of the delayed hypersensitivity disorder, especially for tuberculosis (sputum culture). Histopathology can be of chief importance in making a diagnosis of a DH reaction or disease. The suspected tissue can be biopsied to prove the nature of the disease and treated accordingly. Immunological testing should be carried out routinely and include complete blood cell count (CBC), T-cell subpopulation, radioallergosorbent test (RAST), and other tests include serology, chest x-ray, body radiographs, and also diagnostic ultrasound and computed tomography (CT) scan.[17][18]

Treatment of type 4 HR involves the treatment of the elicitating cause.[17][18][19]

The most common drugs to treat tuberculosis include isoniazid, rifampin, ethambutol, and pyrazinamide. For drug-resistant TB, a combination of antibiotics such as amikacin, kanamycin, or capreomycin for 20 to 30 months should be used.   

The most common drugs to treat leprosy include rifampicin and clofazimine in combination with dapsone for multibacillary leprosy. A single dose of antimicrobial combination to cure single lesion paucibacillary leprosy comprises ofloxacin (400 mg), rifampicin (600 mg), and minocycline (100 mg).

Praziquantel can be useful for treating infections caused by all Schistosoma species.

Hydroxychloroquine and chloroquine can use in the therapy of sarcoidosis involving the skin, lungs, and the nervous system.      

The use of anti-TNF monoclonal antibodies such as adalimumab and certolizumab have been approved for Crohn disease.

One of the most critical differential diagnoses in DHR is to rule out sarcoidosis from tuberculosis. Both cause a granulomatous reaction and have many things in common, but the cause of tuberculosis is a microbe that can isolate in the laboratory, which is Mycobacterium tuberculosis. Sarcoidosis is a non-infectious form of the granulomatous disease, and therefore, the culture of lesions will render non-pathogenic bacteria or another type of microbe. Primary T-cell immunodeficiency and hematologic malignancies are also considered in the differential diagnosis. Some of the diseases to consider are as follows: 

• DiGeorge Syndrome
• Hodgkin Lymphoma
• Severe Combined Immunodeficiency
• Tuberculosis
• Wiskott-Aldrich Syndrome
• HIV infection
• Measles infection

The prognosis of tuberculosis is better if the disease can diagnose and promptly treat with the antimicrobials. Leprosy can also be a curable disease, but it depends on the stage of this disease and patient compliance with multidrug therapy (MDT). Some skin lesions may persist after treatment. Schistosomiasis is associated with high morbidity both as acute and chronic illness. The prognosis of sarcoidosis is guarded, and the overall death rate is less than 7%. Some patients may require treatment if a complication such as pneumonia and nephropathy develops. Crohn disease has a reserved prognosis; it cannot be cured.

Complications of Tuberculosis

• Back pain and stiffness
• Tuberculous arthritis 
• Heart, liver, and kidney diseases
• Meningitis

Complications of Leprosy Without Treatment

• Permanent damage to skin, nerves, nose, and limbs
• Claw-like hands
• Nosebleeds 

Complications of Schistosomiasis

• Gastrointestinal (GI) bleeding and obstruction
• Nephropathy
• Hematuria
• Hemospermia

Complications of Sarcoidosis

• Pneumonia
• Eye problems (cataracts, glaucoma, and blindness)
• Kidney failure
• Neurosarcoidosis (bilateral facial palsy)
• Hypercalcemia

Complications of Crohn Disease

• Obstruction of the small intestine or colon
• Intestine perforation
• Intestinal abscesses and fistulae
• Intestinal bleeding

Other diseases that can involve delayed hypersensitivity reactions

In all of them, Th1 cells play a role in responding to autologous antigens leading to autoimmune disease and inflammation.

• Autoimmune myocarditis 
• Type 1 diabetes mellitus 
• Peripheral neuropathies  
• Hashimoto thyroiditis   
• Multiple sclerosis  
• Rheumatoid arthritis

Some drugs can also cause type IV hypersensitivity reactions. Allopurinol and lamotrigine have a risk of developing delayed hypersensitivity reactions at higher doses.

an interprofessional team evaluates the patient with a delayed hypersensitivity disorder. The family doctor monitors the patient in the community and transfers the patient to an allergist, infectious disease specialist, or immunologist when the essential treatment does not help. In some cases, psychological support is needed. Nurses play a critical role in the management of a patient with delayed hypersensitivity disorder. they are involved in patient education, supervising treatment, and relating changes in patient status to the team. Pharmacists review medication choices and doses, monitor compliance, and provide patient education. When there is an emergency, e.g., penicillin allergy reaction the entire professional team including physicians and nurses must be involved in care. [Level 5]