Clinical Notes

Tuberculin Skin Testing in Nursing Homes: Taking the Mystery Out of the Two-Step PPD

Jolene F. Siple Amy Hecht Carol Joseph D.L. Thompson

Objective: To present an overview of tuberculosis (TB) in elderly nursing home (NH) residents with a focus on the purified protein derivative (PPD) skin test and the two-step technique used on admission.

Data Sources: MEDLINE search, tertiary literature sources, and a bibliographic review of other pertinent articles and reports in the English language addressing human studies.

Data Extraction: Information on epidemiology, pathogenesis, diagnosis, and management of TB was extracted manually from selected published articles and reports.

Data Synthesis: Elderly residents and health care workers in NHs have an increased incidence of contracting TB compared with the general population. Tuberculin skin testing using PPD is a screening method to identify those infected with Mycobacterium tuberculosis, the acid-fast bacillus that causes TB. Because of decreased immune function in elderly persons, a two-step PPD technique is recommended for screening NH residents to help the immune system "recall" previous TB exposure. By using this technique, the prevalence of false-negative PPD skin tests is reduced. The two-step technique also diminishes the likelihood that periodic retesting will produce an apparent new positive reaction, or "recent conversion," through the booster effect. The latter is an important distinction because therapy differs; a person with a conversion is evaluated for active disease (treatment with at least two anti-TB drugs) while a person with a long-standing positive skin test is at much lower risk.

Conclusion: By using the two-step PPD technique on NH admission an accurate baseline is established and the number of false-negative skin tests and the likelihood of confusing old and new TB infections is reduced. During drug-regimen reviews, the consultant pharmacist should be knowledgeable on usual pharmacologic therapies and monitor the use of anti-TB medications.

Key Words: Tuberculosis; Skin testing; Tuberculin purified protein derivative.

Abbreviations Used: TB = Tuberculosis; HIV = Human immunodefiency virus; NH = Nursing home; PPD = Tuberculin purified protein derivative; TU = Tuberculin unit.

Consult Pharm 1996; 11: 263-69.

The incidence of tuberculosis (TB) in developed countries is higher in those 65 years and older than in any other group other than human immunodeficiency virus (HIV)-infected persons.¹ Among the elderly, nursing home (NH) residents have the highest TB case rate, 39.2 per 100,000, an incidence three times greater than the elderly population in general.²

TB is caused by a tubercle bacillus (Mycobacterium tuberculosis) that is primarily spread by respiratory transmission such as coughing or sneezing from an infectious source.¹ Tuberculous infection (infection with M. tuberculosis without clinical disease) is not to be confused with tuberculosis (active or clinical disease caused by M. tuberculosis). In the closed NH environment, residents and staff are vulnerable to new infection (primary tuberculous infection in naive hosts), exogenous reinfection (previously infected persons acquire tuberculosis from infectious individuals), or reactivation tuberculosis (recrudescence of old disease, which accounts for 90% of TB in the elderly).^3,4

Most persons who become infected do not experience clinical illness. The risk of newly infected persons developing active TB is approximately 10% over a lifetime, particularly during the first one to two years; in persons coinfected with HIV this risk increases to 8% per year.^4,5 Infected persons are usually asymptomatic and do not transmit disease.¹ The bacilli persist for years, and hosts contract clinically apparent disease only when the immune system becomes impaired. Risk factors such as declining health, poor nutrition, insulin-dependent diabetes mellitus, and medications that compromise the immune system, including steroids and chemotherapeutic agents, may contribute to recrudescence of dormant disease. Impairment in cell-mediated (T-cell) immunity increases vulnerability to mycobacterial diseases and therefore increases the risk of mortality.

TB may not be considered in the NH population resulting in delays in diagnosis, which in some cases is only made at autopsy.⁶ Specific signs and symptoms of TB can be absent or atypical in the elderly, especially those with multiple concomitant diseases. Diagnosis is often difficult in NH residents who have cognitive impairment or communication limitations. Chest x-ray signs of TB in this population are often attributed to bronchitis, bronchopneumonia, or cancer.

Elderly residents and health care workers in long-term care facilities, including consultant pharmacists, are at increased risk for infection with TB. For residents, the chance of infection increases with length of stay in the facility. On average, one NH resident will develop TB every one to two years, infecting about six others.⁷ Since NH staff generally work 40 out of 168 hours per week, their case rate is about one fourth that of residents.⁷ NH employees have been found to have a threefold higher observed case rate of TB than that expected for other employed adults of similar age, race, and sex.²

PPD Skin Testing and the Two-Step Technique

Tuberculin skin testing is a screening method to identify persons infected with M. tuberculosis, the acid-fast bacillus that causes TB.⁸ TB skin testing is performed using Tuberculin Purified Protein Derivative, and hence is often referred to as PPD testing. PPD is available in three strengths, but only the 5-tuberculin unit (TU) is recommended by the American Thoracic Society and Centers for Disease Control and Prevention, since the other strengths are not biologically standardized (Table 1). A small amount of Tween-80 is added by the manufacturer to reduce adsorption of the tuberculoprotein to glass and plastic.⁸ PPD skin testing is particularly important for residents of NHs in whom the risk of developing clinically active TB is higher than that of the general population.

Table 1. Tuberculin Purified Protein Derivative (PPD) Products Available

Strength	Tuberculin Unit (TU) in 0.1 mL PPD	Comments
First	1 TU	Originally used in those areas where TB was very likely or in those who could be hypersensitive to a stronger solution. Not ade-quately standardized to allow accurate interpretation.8
Intermediate	5 TU	Standardized for use in humans by Bureau of Biologics; only strength that can be accurately interpreted.
Second	250 TU	Not recommended for 5-TU nonresponders (e.g., anergic patients). Not adequately standardized to allow accurate interpretation and results may be misleading.8,9 Small risk of severe hypersensitivity reaction.

The goals of TB screening in NHs are to: (1) detect persons harboring tubercle bacilli who are at risk of developing active TB, (2) establish a baseline PPD status, either positive or negative, (3) identify persons who have recently converted their PPD test from negative to positive and thus qualify for preventive therapy or treatment, and (4) identify transmission or spread of TB in a facility.^{1, 4}

The PPD skin test is based on a delayed hypersensitivity reaction to the tubercle bacillus, which usually develops in the host with- in 2-10 weeks after the initial infection.^3,5,8 When a PPD test is administered to a person harboring tubercle bacilli, the host's immune system responds with a characteristic inflammatory reaction at the site.^4,10 Although sensitivity to TB, once acquired, tends to persist, it can diminish with time or with a decline in immune competence.⁸ Older persons may experience a specific waning of T-cell mediated immunity for TB antigen.^11,12 The purpose of the two-step technique is to increase the sensitivity of the PPD test by stimulating the immune system to recall previous exposure to tubercle bacilli.

All new NH residents and employees are required to have a PPD test, unless they are known to have had a prior positive test result. The PPD skin test is given by the Mantoux technique in which 0.1 mL of PPD (5 TU) is injected intradermally into the volar surface of the forearm with a 26- or 27-gauge needle and tuberculin syringe, creating an elevation of the skin or wheal.^1,8 Characteristically, reactions begin in five to six hours, are maximal at 72 hours, and subside over a period of days.⁸ Induration of 10 mm or more is generally considered to indicate a positive reaction; however, it is recommended that a lower threshold (> 5 mm) be used in severely immunocompromised persons (e.g., HIV infection), those with recent close contact to infectious TB cases, and those with chest x-rays consistent with old healed TB who never received treatment.⁴ Persons with a documented change in their PPD reaction from negative to positive within the previous two years are designated recent converters. Recent converters are considered to be at high risk for developing active TB. Criteria for recent conversion requires >10 mm of induration for persons under 35 years of age, and >15 mm of induration for those 35 and older, because of the increased risk of isoniazid-associated hepatotoxicity if therapy is instituted in the older age group.²

A two-step PPD is recommended for NH residents since some persons with prior TB exposure will have negative PPD reactions on initial testing (false negatives).¹³ The two-step technique is simply a repetition of PPD testing for individuals with a negative test (< 10 mm) using 5 TU one to two weeks after initial testing (Figure 1). The repeat antigenic challenge may have a booster or recall effect, revealing true positive reactions. By definition, the second skin test is positive if there is 10-mm induration or if there has been an increase in size of induration of at least 6 mm (from < 10 mm on the initial test). The booster effect can usually be demonstrated within one week of an initial skin test and will persist for at least one year.⁸ The booster effect becomes more important with increasing age (> 55 years) and rarely occurs in children.⁸ The boosting effect can also serve as a double check, since it can also be the result of an error in administering or reading the initial PPD skin test.^8,9

Using the two-step PPD skin test technique at NH admission prevents confusion between "conversion" and "boosted" reactions. A conversion is a negative skin test that converts to a positive test within two years and represents a newly acquired infection. Converters have an increased risk of developing active TB; 7% of women and 12% of men in NHs develop clinical TB within two years of conversion if not treated preventively with isoniazid.^3,14,15 New infections can only be detected if an accurate baseline is established at NH admission using the two-step technique. The booster effect identifies "reactors," persons who have long harbored TB but have a small chance of developing active TB. Elderly reactors are not routinely given preventive therapy. This is an important distinction because if only a one-step method is used for initial testing and a resident has a negative PPD result (false negative), then a booster effect on a yearly retest may be misinterpreted as a recent conversion. Misclassifying a NH resident with a booster effect as a recent convertor may cause that resident as well as other facility residents and staff to undergo unnecessary diagnostic tests and treatments.

Another problem in interpreting PPD tests in NHs are false-negative reactions. False-negative PPD tests, even with the two-step technique, may occur in up to 20% of NH residents with active TB and result from generalized anergy and diminished cutaneous reactivity.¹⁴ Conditions commonly found among NH residents-such as malnutrition, immunosuppression, and diabetes mellitus-can all result in false-negative PPDs.⁵ Anergy testing is used to determine a resident's ability to mount an immune response to skin testing (immunocompetence). Anergy testing is not routinely recommended for NH residents, unless they are also HIV-infected. Creditor and colleagues16 found elderly patients may fail to react to PPD, Candida, and trichophyton during screening and still develop obvious PPD skin reactions after exposure to TB. Other factors such as testing error, protein malnutrition, and general illness may result in false-negative PPD tests.^1,8,17,18

NH residents may also manifest false-positive reactions caused by infection with other mycobacteria. A positive TB skin test also results from prior vaccination with BCG (bacillus of Calmette and Guerin), a live-attenuated mycobacterial strain derived from M. bovis routinely used in many countries for prevention of TB.⁴

Monitoring and Treatment

Since the PPD test does not distinguish between active and latent disease, residents with positive PPD results should be further evaluated by careful history and chest x-ray for evidence of active TB. A chest x-ray is also recommended for NH residents with anergy and those with negative skin test results displaying clinical symptoms consistent with active TB.¹⁹ Since 75% of all TB cases in older persons occur in the respiratory tract, sputum smear and culture for M. tuberculosis are also recommended if the chest x-ray is abnormal.^1,4

Positive PPD tests should be posted prominently in the resident's medical record. Since an old infection may become active TB, it serves to remind staff to collect sputum for mycobacterial examination when a chronic cough (> three weeks), unexplained weight loss, fever (low grade and persistent), or chronic chills and night sweats are observed.²⁰ Those with symptoms of pulmonary TB, such as chronic cough or hemoptysis, should receive a chest x-ray regardless of skin test results.⁴ All uninfected residents (nonreactors) should be scheduled for annual one-step skin tests.⁴ Any time an active case of TB is discovered in the NH or conversions are noted on mandatory annual skin test of staff and residents, closely associated residents and personnel should be retested immediately and after three months to detect new infections.^3,5

Not all those with positive PPD skin tests are routinely given isoniazid preventive therapy since the risk of developing hepatotoxicity must be weighed against the risk of developing TB.¹⁹ The usual dose of isoniazid recommended for preventive therapy is 300 mg orally per day for adults and is routinely used for 6-12 months depending on clinical conditions (e.g., poor compliance, drug resistance, HIV infection).¹ Vitamin B6 (pyridoxine) 50 mg orally per day should be administered with isoniazid for prevention of peripheral neuropathy.²¹

Treatment options for TB disease include a variety of agents and lengths of therapy. Treatments vary depending on such factors as the presence of extrapulmonary TB, immunosuppression, and renal function.^18,20,22 Multiple-drug-resistant M. tuberculosis (MDR-TB) is becoming more prevalent and is defined as resistant to more than two drugs (at least isoniazid and rifampin).^1,21 Recent reviews of anti-TB therapy are listed in the references.^1,17,23

Consultant pharmacists should monitor for side effects of anti-TB medications, and adverse drug events should be documented (Table 2). NH residents may already be on complex drug regimens and drug interactions must be evaluated. The pharmacist should also provide residents with education about the actions and side effects of anti-TB medications, such as rifampin-induced orange discoloration of body fluid. NH residents must be observed to ensure that they actually ingest their anti-TB medications. The consultant pharmacist should check the medication administration records for documentation that anti-TB doses were administered by nursing staff and taken by residents. The start and stop dates of anti-TB agents should be clearly documented. Careful clinical monitoring is important since elderly residents may not be able to report or recognize signs and symptoms of drug toxicity. Residents and staff need to recognize the need for compliance and completion of a full course of therapy even when the patient is asymptomatic. To avoid further drug resistance from developing, a single drug is never added on to an existing failing regimen.²⁴

Table 2: Precautions and Monitoring Parameters of Selected Anti-TB Agents.^a,b

Agent	Precautions	Monitoring Parameters
Isoniazid	Hepatic enzyme elevation: 10-20% patients have mild transient elevation of serum aminotransferases within first six months that in most patients will normalize while on therapy. Hepatitis: risk factors include increased age, daily alcohol ingestion, concomitant rifampin therapy. Elevation of serum transminases to three to five times normal requires discontinuation of INH. May rechallenge at lower dose (e.g., 50 mg/day) after symptoms and levels normalize and gradually increase to full dose over two to three weeks. Neurotoxicity: peripheral neuropathy; usually preceded by parathesias of the feet and hands. CNS effects: hyperexcitability (may be prevented by dividing dose, for example 100 mg po t.i.d.), mental status changes, ataxia, psychosis (rare), seizures. Drug interactions: increased serum concentration of phenytoin and carbamazepine, decreased absorption with aluminum antacids, possible decreased metabolism of oral anticoagulants. Food interactions: tyramine (cheese, wine)-hypertension, tachycardia, flush, chills; fish (tuna, skipjack, and tropical species)-histamine like symptoms including headache, nausea, vomiting, flush, palpitations. Other: hematologic (thrombocytopenia, agranulocytosis), gastrointestinal upset (nausea, vomiting), hypersensitivity reaction or lupus-like syndrome (fever, rash, arthralgias). Contraindications: previous INH-associated hepatic injury, history of severe adverse reaction (e.g., drug fever, rash, arthritis), and acute or unstable liver disease of any etiology.	Baseline liver-function tests (LTF) then monthly serum transaminase levels. Clinical assessment for hepatitis (anorexia, nausea, vomiting, malaise, abdominal tenderness-especially right upper quadrant, persistantly dark urine, jaundice, unexplained fever for ³ 3 days). Pyridoxine 50 mg po/day to decrease risk of INH neurotoxicity.
Rifampin	GI upset: most common adverse reaction. Nausea, vomiting, abdominal cramps, diarrhea including antibiotic-associated Clostridium difficile. Hepatitis: additive hepatotoxic effect if combined with INH. Body fluid color: harmless red-orange coloring of urine, saliva, sweat, tears-contact lenses may be permanently stained. Hematologic: thrombocytopenia (bleeding tendency, easy bruising, blood in urine), hemolytic anemia, cytopenias. Drug interactions: rifampin may induce liver microsomal enzymes causing accelerated clearance of digoxin, oral hypoglycemics, warfarin, theophylline, anticonvulsants, steroids, cyclosporine, ketoconazole, fluconazole, oral contraceptives, methadone (by as much as 50%), estrogens. Influenza-like syndrome: more common with intermittent administration of larger doses (>10 mg/kg); fever, chills, headache, arthralgias, acute renal failure. Other: rash, allergic reactions, drowsiness.	LFTs (see above), education on orange-red dicoloration of body fluid, complete blood count, and platelets.
Ethambutol	Optic neuritis: risk factors include duration of therapy and higher doses (accumulates in those with renal insufficiency-dose is based on renal function). Changes in color discrimination (red/green) and visual acuity. Other: hyperuricemia, gastrointestinal upset (nausea, vomiting, abdominal pain, anorexia), anaphylactoid reaction (rare), dermatitis, pruritus, headache, mental confusion, hepatotoxicity, neutropenia, thrombocytopenia. Tablet may be crushed and mixed with apple juice or applesauce to mask bitter taste (refrigerate, stable 24 hours).	Any unilateral or bilateral change in visual acuity or color discrimination, renal function.
Pyrazinamide	Hepatitis: dose related (15% with 2 g/day). Hyperuricemia: acute gout uncommon. May be associated with arthralgias-treatment with salicylates for symptomatic relief. Gastrointestinal upset: nausea, vomiting, anorexia, photosensitivity. Other: skin rash, thrombocytopenia, flushing. Contraindications: acute gout, severe hepatic damage.	LFTs (see above), uric acid, dose adjustment in renal failure.

a Baseline measurements of hepatic enzymes, bilirubin, serum creatinine ,and blood urea nitrogen, as well as complete blood and platelet count to detect any abnormality that could complicate therapy.
INH = isoniazid; serum transminase = AST (SGOT), ALT (SGPT).
b Adapted from reference 1,17, 18, 21, 23.

Conclusion

The two-step PPD is recommended for admission screening of NH residents. When a two-step PPD technique is used, a positive dermal reaction is found in up to 50% of residents on admission.^4,14 The booster response rate is reported to be between 2-6% for residents of NHs.^14,25 Despite the increased cost and possible logistic and practical problems of implementing the two-step PPD, this method decreases the number of false-negative skin tests and reduces the likelihood of confusing old and new TB infections, thus saving residents and staff from unnecessary testing and treatment.

References

1. Centers for Disease Control and Prevention. Core curriculum on tuberculosis. 3rd ed. U.S. Department of Health & Human Services. Atlanta, GA: Centers for Disease Control and Prevention, 1994.

2. Centers for Disease Control. Prevention and control of tuberculosis in facilities providing long-term care to the elderly. MMWR 1990:39 (No. RR-10):7-20.

3. Daniel T, Cauthen GM, Collins FM et al. Improving methods for detecting infected persons at risk of developing disease. Am Rev Respir Dis 1986;134:409-13.

4. American Thoracic Society/Centers for Disease Control. Joint statement: control of tuberculosis in the United States. Am Rev Respir Dis 1992;146:1623-33.

5. Centers for Disease Control and Prevention. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 1994. MMWR 1994;43(No.RR-13):1-32.

6. Rieder HL, Kelly GD, Bloch AB et al. Tuberculosis diagnosis at death in the United States. Chest 1991;100:678-81.

7. Dutt AK, Stead WW. Tuberculosis. Clin Geriatr Med 1992;8:761-75.

8. American Thoracic Society/American Academy of Pediatrics/Centers for Disease Control/Infectious Disease Society of America. Joint statement: diagnostic standards and classification of tuberculosis. Am Rev Respir Dis 1990;142:725-35.

9. Snider DE Jr. The tuberculin skin test. Am Rev Respir Dis 1982;125(No 3, Pt 2):108-18.

10. Sokal JE. Measurement of delayed skin-test responses. N Engl J Med 1975;293:501-2.

11. Couser JI, Glassroth J. Tuberculosis-an epidemic in older adults. Clin Chest Med 1993;14:491-9.

12. Ben-Yehuda A, Weksler ME. Host resistance and the immune system. Clin Geriatr Med 1992;8:701-11.

13. Finucane TE. The American Geriatrics Society statement on two-step PPD testing for nursing home patients on admission. J Am Geriatr Soc 1988;36:77-8.

14. Stead WW, Lofgren JP, Warren EW et al. Tuberculosis as an endemic and nosocomial infection among the elderly in nursing homes. N Engl J Med 1985;321:1483-7.

15. Stead WW, To T, Harrison RW et al. Benefit-risk considerations in preventive treatment for tuberculosis in elderly persons. Ann Intern Med 1987;107:843-45.

16. Creditor MC, Smith EC, Gaalai JB et al. Tuberculosis, tuberculin reactivity, and delayed cutaneous hypersensitivity in nursing home residents. J Gerontol 1988;43:M97-100.

17. Mallet L, Strozyk WR. Tuberculosis in the elderly: incidence, manifestations, PPD skin tests, and preventive therapy. DICP Ann Pharmacother 1991;25:650-5.

18. Peloquin CA, Berning SE. Infection caused by Mycobacterium tuberculosis. Ann Pharmacother 1994;28:72-84.

19. Yoshikawa TT. Tuberculosis in the nursing home. Nurs Home Med 1995;3(9):207-13.

20. Stead WW, Lofgren JP. Does the risk of tuberculosis increase in old age? J Infect Dis 1983;147:951-5.

21. American Thoracic Society/Centers for Disease Control. Joint statement: treatment of tuberculosis and infection in adults and children. Am J Respir Crit Care Med 1994;149:1359-74.

22. Anonymous. Four-drug initial therapy advised for tuberculosis patients. J Crit Illness 1993;8:1259-60.

23. Houston S, Fanning A. Current and potential treatment of tuberculosis. Drugs 1994;48:689-708.

24. Mahmoudi A, Iseman MD. Pitfalls in the care of patients with tuberculosis: common errors and their association with the acquisition of drug resistance. JAMA 1993;270:65-8.

25. Barry MA, Regan AM, Kunches LM et al. Two-stage tuberculin testing with control antigens in patients residing in two chronic disease hospitals. J Am Geriatr Soc 1987;35:147-53.

Jolene F. Siple, Pharm.D., is Clinical Pharmacist, VA Medical Center, Portland, Oregon. Amy Hecht R.N., M.S.N., F.N.P.,is Nurse Practitioner, VA Medical Center, Portland, Oregon. Carol Joseph, M.D., is Director, Extended Care Services, VA Medical Center, Portland, Oregon. D.L. Thompson, Pharm.D., is Clinical Pharmacist, Salem Hospital, Salem, Oregon.

Address for reprints: Jolene Siple, VA Medical Center (119-V), P.O. Box 1035, Portland, OR 97207.

Copyright © 1996, American Society of Consultant Pharmacists, Inc. All rights reserved.