History
Delayed-type hypersensitivity (DTH) skin testing is usually performed to detect exposure to tuberculosis and, occasionally, when unusually extensive Candida infection has occurred. In these settings, the patient often has no prior history of unusually severe or opportunistic infections. In developing countries, ruling out confounding clinical malnutrition and rubeola infection that negate DTH skin test reactivity is crucial. HIV infection, sarcoidosis, and malignancies, such as Hodgkin lymphoma , also cause negate DTH responses.
Overwhelming infection such as sepsis is also known to cause suppresed DTH responses. One study indicated that this is mediated by CD8+ Treg cells through a TRAIL-dependent mechanisms and these cells are induced by apoptotic cells. [19]
The presence of any cause for immunosuppression modifies the interpretation of tuberculin DTH skin tests; in an immunosuppressive condition, 5-mm induration is interpreted as a positive response.
DTH skin reactions are absent in patients with lepromatous leprosy (M leprae), sarcoidosis, coccidioidomycosis, schistosomiasis, rheumatological diseases, severe viral infections (eg, influenza, mononucleosis, mumps), and those given the measles, mumps, rubella (MMR) vaccine recently (≤3 wk). Systemic steroid therapy can cause anergy; however, inhaled steroids with high bioavailability could also decrease DTH reactions and less frequently produce anergy when administered in large doses. Longer duration (>2 wk) and higher doses of oral steroids increase the risk for anergy, but no exact doses or duration predict induction of anergy in a given individual.
Other immunosuppressive agents that cause anergy include cancer chemotherapy agents, calcineurin inhibitors, and monoclonal antibodies against the immune system such as anti-TNF and anti-CD20 agents.
Usually, a patient with anergy caused by a T-cell immunodeficiency can be identified before wasting sets in. A pattern of unusually frequent or severe common infections, extensive mucocutaneous candidiasis, or dermatitis together with lymphopenia raises the suspicion of severe combined immunodeficiency (SCID) or other severe T-cell immunodeficiencies.
A patient with disseminated BCG or NTM infection may have a history of consanguinity or familial infection, indicating autosomal recessive genetic disorders. It is necessary to evaluate these patients for IFNGR1, IFNGR2, STAT-1, IL12P40, and IL12RB1 mutations. Patients with BCG infection usually present in early infancy after administration of the BCG vaccine. NTM infection develops more typically in mid childhood when community exposure to these mycobacteria occurs. A patient with one of the above mutations responds poorly to appropriate anti-mycobacterial therapy and often has a fulminant fatal infection.
Nontyphus Salmonella infections are more frequently observed in patients with the above-described disorders. Asthma, atopy, and immune complex disease (eg, glomerulonephritis, vasculitis, positive rheumatoid factors) are sometimes present.
Repetitive DTH skin testing does not change the parameters used to define a positive test result.
DTH antigens for coccidioidomycosis are no longer available. Diagnosis depends on identifying the organism or serology. Negative skin test reactivity to coccidioidin does correlate with a less favorable clinical outcome. However, the positive skin test result usually persists following an initial infection so that recurrence cannot be determined by the DTH skin testing.
DTH skin test reactivities for histoplasmosis and blastomycosis cross-react. In addition, positive DTH skin reactions in exposed but not infected individuals living in endemic areas confound interpretation. Both fungal infections have increased in incidence in HIV patients; these patients are frequently anergic. Diagnosis now requires culturing the organism, antigen/DNA detection, and/or serologic confirmation.
Physical
The DTH response in the skin is determined by the extent of induration. Erythema indicates an immediate hypersensitivity reaction and begins earlier than induration but often persists even after induration has developed.
DTH skn test to most antigens is read as positive when induration is 5 mm or more at 48 hours and 72 hours following inoculation. For tuberculin, 15 mm is considered a positive response for persons aged 4 years or older without risk factors; 10 mm is considered a positive response for younger children and those in populations with increased exposure or in whom immunosuppression is likely. A tuberculin reaction of 5 mm is considered positive when clinical evidence of tuberculosis, HIV infection, or close contact with people with infectious tuberculosis is noted.
Disseminated BCG and NTM infection are characterized by fever, wasting, lymphadenopathy, and hepatosplenomegaly.
Causes
A positive DTH response to the purified protein derivative (PPD) of M tuberculosis is elicited 4-6 weeks after exposure to M. tuberculosis. Populations at increased risk for tuberculosis include immigrants from countries with a high incidence of tuberculosis, such as African, Asian, and South American countries, and those with HIV infection. High-risk populations in the United States include those who are incarcerated, those who are homeless, migrant workers, and those who use illicit drugs. Individuals who are exposed to these populations are also at increased risk.
Anergy is discussed under History and Pathophysiology.
A single functional mature T cell can transfer DTH reactions; thus, a patient who received hematopoietic stem cell transplant from a donor with positive DTH responses to the specific antigen could reveal positive DTH responses to the same antigen.
Contact DTH reactions (contact hypersensitivity [CH]) occur in patients with poison ivy and nickel hypersensitivity
DTH to sulfonamides, phenytoin, and carbamazepine has been described. Reactions to penicillin-type antibiotics may be cell-mediated, but immunoglobulin G (IgG)-mediated responses are much more common. [20]
Genetic factors in CH are not well understood but studies targeting candidate genes revealed association of single nucleotide polymorphisms of some candidate genes in development of CH. These genes include NAT1, NAT2, GSTT, ACE, TNF, and IL-16. [21]
