Diagnosing and Treating Hansen's Disease

According to data from the World Health Organization (WHO), the number of new cases of Hansen’s disease (HD, or leprosy) identified worldwide declined by about 20% from 2003 to 2004. At least 116 of 122 countries once considered leprosy—endemic have achieved a prevalence rate of less than one case per 10,000 population.^1,2

Meanwhile, the number of active HD infections in the United States catalogued through the CDC and the National Hansen’s Disease Program (NHDP) rose from 76 cases in 2000 to 166 in 2005, with an additional 137 cases in 2006 (the most recent year for which complete figures are available).^3,4 Currently, 6,500 US residents are known to have HD, of whom 3,300 require care for active disease.³

Accurate diagnosis and straightforward, aggressive treatment can mean certain cure for this dreaded disease, as it is responsive to a combination of available drugs. For primary care providers in the US, familiarity with this condition can play a role in eliminating it altogether.

Background and Etiology
HD is believed to have originated in East Africa with the pseudonym of leprosy, from the Greek lepi, meaning “fish scales.” Although HD is one of the oldest known human infections, it is not well understood by many Western health care providers. Once considered highly contagious and easily transmissible, HD has proven to be neither: 95% of the human population is not susceptible to the responsible pathogen.³ HD retains its reputation as a devastating illness when left untreated, however, with sequelae often including significant sensory and motor dysfunction.⁵

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Mycobacterium is the same rod-shaped, acid-fast bacillus (AFB) implicated in pulmonary tuberculosis, cutaneous tuberculosis, and numerous cutaneous nontuberculoid infections^.6,7

HD transmission is believed to occur almost exclusively by nasal droplet, inhaled by way of others’ nares or lungs. Research continues in possible transmission by skin-to-skin contact.^8,9

Leprosy is particularly challenging for immunocompromised persons, such as those with HIV/AIDS or tuberculosis. According to data from the NHDP, HD in the US is found primarily among undocumented immigrants who live in close quarters. Cases considered “home-grown” rather than “imported”⁵ are most commonly diagnosed in Hawaii and in a swath from Texas to Georgia and south toward Florida. Pockets of HD incidence are also found in California, New York, and Massachusetts.⁴

Clinicians’ lack of familiarity with HD and its relative rarity in the US help explain why diagnosis and treatment are commonly delayed. As a patient’s disease progresses from an insidious, gradual, and relatively painless onset, the primary care provider may be grappling with an extensive differential diagnosis (see “Differential Diagnosis for Hansen’s Disease [Leprosy],”^10,11 below). Even after confirming a diagnosis of HD, the provider must contend with a lack of information and misinformation about HD among staff members, the patient’s family, and society at large, as well as the associated stigma. Patient education and effective treatment are of comparable importance.

Patient Presentation and History
A 40-year-old Latino man presented to a primary care provider with a well-demarcated, erythematous patch on his right upper back that had raised outer edging and faint flaking. The patch was surrounded by several smaller but similar asymmetrical macules. The patient denied pruritus but stated that the area “felt funny.” He said the lesion might have been spreading during the previous several months, but he could not be certain because of its location.

The man denied any medication use except for a topical antibiotic ointment he had applied to the affected area with no improvement. His provider made a diagnosis of tinea corporis and prescribed an antifungal cream, naftifine. After two weeks without results, the patient was referred to a dermatologist.

During the assessment, it became apparent that the patient was experiencing numbness in his fingertips and general muscle weakness in his arms. A KOH prep was difficult to obtain, as the lesion site was somewhat smooth. Any dermatophytes that may have been present had been eliminated by the naftifine, and KOH results were negative.

A 5.0-mm punch biopsy from the largest lesion was ordered. A preliminary diagnosis of sarcoidosis (chronic inflammation with an unusual skin manifestation) was made, with serious consideration given to early cutaneous T-cell lymphoma (mycosis fungoides). A high-potency steroid was prescribed for five days’ use, twice daily.

On his return to the dermatologist, the patient reported that the site was no better. He was informed that the dermatologist and the pathologist, both with considerable experience, had detected no bacilli or dermal nerve infiltration in the tissue sample but had observed abundant lymphocytic infiltration. This finding, coupled with the patient’s decreased sensation, muscle fatigue, and status as a recent immigrant from a South American country, led to an initial diagnosis of borderline leprosy (BB).

Physical Examination and Disease Progression
If the first provider suspected a fungal infection during the initial examination, he should have completed a KOH scraping to confirm that suspicion. While superficial fungal infections are extremely common, particularly in the southeastern US, a sampling of scale with KOH 5% to 20% and the absence of dermatophytes under the microscope might have permitted a quick rule-out.¹² Additionally, dermatophytic infections are very responsive to current medications within days, not weeks.

Thus, the key to an accurate diagnosis of leprosy begins with a physical examination that takes into account both chronic unresolved cutaneous lesions and neurologic changes in sensitivity.

A great majority of patients with HD have no noteworthy clinical symptoms until the first skin manifestations. While sensory neuropathy is prominent in all patients, additional findings (depending on the type of leprosy involved) may include plantar ulcers, chronic nasal congestion with early evidence of cartilage loss over the nasal bridge, chronic nosebleeds, cranial nerve palsies, and eye paralysis.¹² In rare cases, hypogonadism may develop, or the clinical team may discover amyloidosis, an accumulation of insoluble proteins in the tissues that impairs function in various organs; this condition is usually detected by skin biopsy. If early or indeterminate leprosy is identified, neither form persists; rather, the condition will progress to one of the following:

• Borderline lepromatous leprosy (BL) and lepromatous leprosy (LL) offer very high resistance to treatment and are considered malignant forms of HD. Findings in patients with BL or LL include multiple lesions in various crazy-quilt presentations: macules, papules, plaques, nodules, masses, and patches of deep, erythematous infiltration across the extremities, face, and trunk.¹² Loss of all hair except on the scalp is possible. Ulcers may form on the palms of the hands and soles of the feet.

In both BL and LL, results on AFB smears will reflect moderately high or very high concentrations of the pathogen in the patient’s system. Thus, these forms of HD are defined as multibacillary. If either is left untreated, the accumulation of proteins attributed to amyloidosis and secondary infections that develop eventually lead to death.

• Borderline leprosy (BB) has already been described in the case patient, with five or six ill-defined lesions and mild impairment of the peripheral nervous system. Aggressive treatment of this form of HD is important. A strong immune system provides no guarantee of successful treatment, and therapy must forestall a likely continuum to more serious forms.¹³

• Borderline tuberculoid leprosy (BT) and tuberculoid leprosy (TT) are both forms of paucibacillary HD. They offer little resistance to treatment in the patient with a healthy immune system. Lesions are generally scant (fewer than five; see figure), and the AFB smear reveals 0 to 10 bacteria in 100 fields.¹²

For the primary care provider, a thorough physical examination also requires familiarity with reasonable differentials. Hallmarks of conditions less likely to be leprosy include nausea, vomiting, or diarrhea, fever and chills, rectal bleeding and unexplained weight loss, headaches, and shortness of breath.

Diagnostic Testing
To help gauge progression of the disease and assess effectiveness of therapy, it is common practice to conduct a neurosensory test at each office visit. This is performed by touching the patient’s extremities and the periphery of lesions with a simple nylon monofilament.¹³ The patient’s response or lack of response is documented and changes are noted for future therapeutic decision making.

In patients with suspected HD, the NHDP recommends that a full-thickness 4.0-mm elliptical or punch biopsy be performed at the periphery of the largest or most active lesion and that slides be sent to the NHDP in formalin or paraffin for review.¹⁴ Experienced NHDP pathologists may order additional stains. A detailed protocol can be found at www.hrsa.gov/hansens/clinical/diagnostics/biopsy.htm.

Proficiency in performing slit smears, a technique to obtain tissue fluid, is also helpful.¹⁵ Measurement of the number of bacteria in a set number of fields allows for calculation of the host’s bacterial index, making it possible to determine an appropriate treatment level.

The preferred sites for the slit smear are active lesions, if possible from both ear lobes plus two additional locations. After alcohol swabbing, a tight, bloodless pinch is made, with a 3.0-mm incision that yields blood and fluid. The resulting culture is examined for AFB, which are found abundantly in lepromatous leprosy (whereas tuberculoid leprosy, by definition, should yield none or few). This smear may be repeated at three- to six-month intervals to determine effectiveness of therapy. It is considered superior to a nasal culture, which often yields false-negative results.¹⁶

After the Diagnosis
In the US, HD is a nationally notifiable disease: Health care providers are required by law to inform the CDC of the known particulars while complying with HIPAA requirements.¹⁷

That the case patient was a recent immigrant from a country with a high incidence of HD, coupled with a loss of sensation in his extremities, led to the correct diagnosis. His lack of response to antifungals or anti-inflammatory agents, though frustrating to both patient and provider, was helpful in excluding two common conditions in the differential diagnosis. Other possibilites that were considered ultimately did not ring true:

Vitiligo, a loss of pigment that produces white patches resembling borderline leprosy but lacks the raised edging¹⁸;

Granuloma annulare, a lightly raised, ring-shaped lesion that is usually found on the extremities¹⁹; and

Lupus erythematosus, in which patients almost universally experience pruritus and burning, whereas lack of sensation is key to a diagnosis of leprosy.²⁰

Treatment and Management
Health care providers must appear confident to instill confidence in their patients. Any provider with the knowledge and acuity to make a diagnosis of leprosy should be adequately equipped to manage the patient’s care. However, the hesitant or uncertain provider should consider referral to dermatology or to infectious disease for continued management.

The NHDP recognizes the WHO classification of leprosy as multibacillary or paucibacillary (observing a “simple clinical rule” of six or more lesions representing multibacillary HD and five or fewer, paucibacillary HD1), with additional consideration to the three major disease subtypes mentioned earlier: TT, which is treatable; BB, which is considered unstable; and LL, which is resistant to treatment. NHDP and WHO recommendations for treatment differ slightly but address the same goals: complete elimination of the pathogen, preservation of muscle and nerve function, prevention of secondary infections, and management of the adverse effects of medication.^1,21 Adhering to universal precautions is important.

In the US, the multidrug treatment regimen for paucibacillary (TT or BT) leprosy comprises one year of oral rifampin 600 mg/d and oral dapsone 100 mg/d²¹; WHO, in deference to cost containment in developing countries, recommends a six-month regimen of these agents (ie, rifampin 600 mg/mo and dapsone 100 mg/d).¹ A third drug sometimes given to allay active neuritis is oral clofazimine 50 mg/d for one year²¹ (per WHO recommendations, a monthly dose of 300 mg, plus 50 mg/d¹). In patients with preexisting or subsequent anemia, dapsone dosing should be lowered to 50 mg, the minimally effective level. Of note, clofazimine is no longer commercially available in the US and is held by the NHDP as an investigational new drug for treatment of US patients.²¹

According to US recommendations,²¹ use of this three-agent regimen is extended to two years for patients with multibacillary (LL, BL, BB) leprosy. For these patients, WHO recommends its regimen for 12 months.¹

Rifampin is a powerful antibiotic used for effective treatment of tuberculosis, methicillin-resistant Staphylococcus aureus, gonorrhea, Listeria, and Haemophilus influenzae. However, its use has been shown to reduce the efficacy of anticoagulants, oral contraceptives, and prednisone, possibly requiring therapeutic adjustments.²² Recommended alternatives for rifampin include (in the order of preference) minocycline 100 mg/d, ofloxacin 400 mg/d, levofloxacin 500 mg/d, or twice-daily clarithromycin 500 mg.¹³

Patient compliance with the regimen is facilitated by convenient blister packs that contain standard weekly and monthly doses of these medications, all clearly marked. Many local health departments make these medications available at no cost to patients.

Patient Education
Informing patients what to expect regarding their medications, necessary lab work, and avoiding transmission of HD can ease worry, protect others from illness, and increase the likelihood of an excellent prognosis. Patients with lepromatous (multibacillary) HD should be urged to limit their interactions with others at work or school (particularly preventing exposure to their nasal excretions) until a low bacterial index is achieved. For close contacts of patients recently diagnosed with HD, single-dose rifampin has been shown to provide effective prevention for two years.²³

Emphasizing adherence to daily multidrug therapy minimizes the chance that bacterial resistance will develop. Patients should be given complete information about the individual agents used:

Rifampin 600 mg is the maximum daily dose for an adult. Hepatotoxicity is a concern, and liver enzyme levels (ie, aspartate aminotransferase, alanine aminotransferase) should be measured at three-month intervals. It is important to obtain a history of previous liver disease, exposure to hepatitis, and drug and alcohol use. In otherwise healthy adults, rifampin has the curious effect of turning bodily fluids such as urine and tears bright red. Forewarning patients of this benign development may prevent anxious reactions. Contact lenses may be irreversibly stained.²⁴

Dapsone, for many years the first-line monotherapy for leprosy, is a bacteriostatic, sulfa-based antibiotic that only prevents the multiplication of bacteria, but it is still worthy of respect. Before dapsone is initiated, a screening test for glucose-6-phosphate dehydrogenase deficiency should be performed to determine the risk for dapsone-associated hemolysis.²⁴ Dapsone use is contraindicated in women who are breastfeeding. In patients with severe heart conditions, dapsone can reduce oxygen flow, as evidenced by a bluish discoloration of the lips and fingertips. Mild anemia, headache, gastrointestinal upset and nausea are all common adverse effects.

Clofazimine, a soft gelatin capsule, may cause gray-blue or red hyperpigmentation in individuals who are light-skinned; this effect reverses once the drug is discontinued. Nausea, vomiting, and abdominal pain have been reported. This slow-release bactericidal drug has an extremely long half-life of 70 days. It provides anti-inflammatory action similar to that of prednisone without the latter agent’s long-term adverse effects.²⁴

The Patient’s Outcome
The case patient was the second with HD seen in this dermatology practice. A man who presented on an earlier occasion, possibly an undocumented worker in fear of deportation, seemed concerned about the reporting process, even though he was assured that no personal information would be released. He did not return for follow-up, and attempts to reach him proved fruitless.

The case patient, by contrast, was pleasant and cooperative. He appeared to understand his condition, the required treatment and its possible adverse effects, and the need for continued lab work and regular follow-up appointments. A day laborer in a large factory, he was particularly careful to avoid transmission of his illness to his family or co-workers.

Within two months of beginning multidrug therapy, he experienced quick clearance of the lesions on his back. His bacterial index approached 0 by the time he underwent the second smear. Although he complained of loose stools and classic orange-red bodily fluid throughout the entire year of treatment, he resisted the temptation to discontinue the regimen.

He has experienced no relapses in six years and is considered cured.

Conclusion
Only one in every 20 people is susceptible to infection with M leprae, but cases of leprosy continue to be reported in the US, and illness is of particular concern among immunocompromised individuals. Treatment delay is common because of the condition’s relative rarity in the US, but therapy with standard antibiotics is extremely effective. Lengthy isolation from family and community is not often needed, and relapses are rare. Fully restored health is the rule rather than the exception for patients treated for Hansen’s disease.

According to data from the World Health Organization (WHO), the number of new cases of Hansen’s disease (HD, or leprosy) identified worldwide declined by about 20% from 2003 to 2004. At least 116 of 122 countries once considered leprosy—endemic have achieved a prevalence rate of less than one case per 10,000 population.^1,2

Meanwhile, the number of active HD infections in the United States catalogued through the CDC and the National Hansen’s Disease Program (NHDP) rose from 76 cases in 2000 to 166 in 2005, with an additional 137 cases in 2006 (the most recent year for which complete figures are available).^3,4 Currently, 6,500 US residents are known to have HD, of whom 3,300 require care for active disease.³

Accurate diagnosis and straightforward, aggressive treatment can mean certain cure for this dreaded disease, as it is responsive to a combination of available drugs. For primary care providers in the US, familiarity with this condition can play a role in eliminating it altogether.

Background and Etiology
HD is believed to have originated in East Africa with the pseudonym of leprosy, from the Greek lepi, meaning “fish scales.” Although HD is one of the oldest known human infections, it is not well understood by many Western health care providers. Once considered highly contagious and easily transmissible, HD has proven to be neither: 95% of the human population is not susceptible to the responsible pathogen.³ HD retains its reputation as a devastating illness when left untreated, however, with sequelae often including significant sensory and motor dysfunction.⁵

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Mycobacterium is the same rod-shaped, acid-fast bacillus (AFB) implicated in pulmonary tuberculosis, cutaneous tuberculosis, and numerous cutaneous nontuberculoid infections^.6,7

HD transmission is believed to occur almost exclusively by nasal droplet, inhaled by way of others’ nares or lungs. Research continues in possible transmission by skin-to-skin contact.^8,9

Leprosy is particularly challenging for immunocompromised persons, such as those with HIV/AIDS or tuberculosis. According to data from the NHDP, HD in the US is found primarily among undocumented immigrants who live in close quarters. Cases considered “home-grown” rather than “imported”⁵ are most commonly diagnosed in Hawaii and in a swath from Texas to Georgia and south toward Florida. Pockets of HD incidence are also found in California, New York, and Massachusetts.⁴

Clinicians’ lack of familiarity with HD and its relative rarity in the US help explain why diagnosis and treatment are commonly delayed. As a patient’s disease progresses from an insidious, gradual, and relatively painless onset, the primary care provider may be grappling with an extensive differential diagnosis (see “Differential Diagnosis for Hansen’s Disease [Leprosy],”^10,11 below). Even after confirming a diagnosis of HD, the provider must contend with a lack of information and misinformation about HD among staff members, the patient’s family, and society at large, as well as the associated stigma. Patient education and effective treatment are of comparable importance.

Patient Presentation and History
A 40-year-old Latino man presented to a primary care provider with a well-demarcated, erythematous patch on his right upper back that had raised outer edging and faint flaking. The patch was surrounded by several smaller but similar asymmetrical macules. The patient denied pruritus but stated that the area “felt funny.” He said the lesion might have been spreading during the previous several months, but he could not be certain because of its location.

The man denied any medication use except for a topical antibiotic ointment he had applied to the affected area with no improvement. His provider made a diagnosis of tinea corporis and prescribed an antifungal cream, naftifine. After two weeks without results, the patient was referred to a dermatologist.

During the assessment, it became apparent that the patient was experiencing numbness in his fingertips and general muscle weakness in his arms. A KOH prep was difficult to obtain, as the lesion site was somewhat smooth. Any dermatophytes that may have been present had been eliminated by the naftifine, and KOH results were negative.

A 5.0-mm punch biopsy from the largest lesion was ordered. A preliminary diagnosis of sarcoidosis (chronic inflammation with an unusual skin manifestation) was made, with serious consideration given to early cutaneous T-cell lymphoma (mycosis fungoides). A high-potency steroid was prescribed for five days’ use, twice daily.

On his return to the dermatologist, the patient reported that the site was no better. He was informed that the dermatologist and the pathologist, both with considerable experience, had detected no bacilli or dermal nerve infiltration in the tissue sample but had observed abundant lymphocytic infiltration. This finding, coupled with the patient’s decreased sensation, muscle fatigue, and status as a recent immigrant from a South American country, led to an initial diagnosis of borderline leprosy (BB).

Physical Examination and Disease Progression
If the first provider suspected a fungal infection during the initial examination, he should have completed a KOH scraping to confirm that suspicion. While superficial fungal infections are extremely common, particularly in the southeastern US, a sampling of scale with KOH 5% to 20% and the absence of dermatophytes under the microscope might have permitted a quick rule-out.¹² Additionally, dermatophytic infections are very responsive to current medications within days, not weeks.

Thus, the key to an accurate diagnosis of leprosy begins with a physical examination that takes into account both chronic unresolved cutaneous lesions and neurologic changes in sensitivity.

A great majority of patients with HD have no noteworthy clinical symptoms until the first skin manifestations. While sensory neuropathy is prominent in all patients, additional findings (depending on the type of leprosy involved) may include plantar ulcers, chronic nasal congestion with early evidence of cartilage loss over the nasal bridge, chronic nosebleeds, cranial nerve palsies, and eye paralysis.¹² In rare cases, hypogonadism may develop, or the clinical team may discover amyloidosis, an accumulation of insoluble proteins in the tissues that impairs function in various organs; this condition is usually detected by skin biopsy. If early or indeterminate leprosy is identified, neither form persists; rather, the condition will progress to one of the following:

• Borderline lepromatous leprosy (BL) and lepromatous leprosy (LL) offer very high resistance to treatment and are considered malignant forms of HD. Findings in patients with BL or LL include multiple lesions in various crazy-quilt presentations: macules, papules, plaques, nodules, masses, and patches of deep, erythematous infiltration across the extremities, face, and trunk.¹² Loss of all hair except on the scalp is possible. Ulcers may form on the palms of the hands and soles of the feet.

In both BL and LL, results on AFB smears will reflect moderately high or very high concentrations of the pathogen in the patient’s system. Thus, these forms of HD are defined as multibacillary. If either is left untreated, the accumulation of proteins attributed to amyloidosis and secondary infections that develop eventually lead to death.

• Borderline leprosy (BB) has already been described in the case patient, with five or six ill-defined lesions and mild impairment of the peripheral nervous system. Aggressive treatment of this form of HD is important. A strong immune system provides no guarantee of successful treatment, and therapy must forestall a likely continuum to more serious forms.¹³

• Borderline tuberculoid leprosy (BT) and tuberculoid leprosy (TT) are both forms of paucibacillary HD. They offer little resistance to treatment in the patient with a healthy immune system. Lesions are generally scant (fewer than five; see figure), and the AFB smear reveals 0 to 10 bacteria in 100 fields.¹²

For the primary care provider, a thorough physical examination also requires familiarity with reasonable differentials. Hallmarks of conditions less likely to be leprosy include nausea, vomiting, or diarrhea, fever and chills, rectal bleeding and unexplained weight loss, headaches, and shortness of breath.

Diagnostic Testing
To help gauge progression of the disease and assess effectiveness of therapy, it is common practice to conduct a neurosensory test at each office visit. This is performed by touching the patient’s extremities and the periphery of lesions with a simple nylon monofilament.¹³ The patient’s response or lack of response is documented and changes are noted for future therapeutic decision making.

In patients with suspected HD, the NHDP recommends that a full-thickness 4.0-mm elliptical or punch biopsy be performed at the periphery of the largest or most active lesion and that slides be sent to the NHDP in formalin or paraffin for review.¹⁴ Experienced NHDP pathologists may order additional stains. A detailed protocol can be found at www.hrsa.gov/hansens/clinical/diagnostics/biopsy.htm.

Proficiency in performing slit smears, a technique to obtain tissue fluid, is also helpful.¹⁵ Measurement of the number of bacteria in a set number of fields allows for calculation of the host’s bacterial index, making it possible to determine an appropriate treatment level.

The preferred sites for the slit smear are active lesions, if possible from both ear lobes plus two additional locations. After alcohol swabbing, a tight, bloodless pinch is made, with a 3.0-mm incision that yields blood and fluid. The resulting culture is examined for AFB, which are found abundantly in lepromatous leprosy (whereas tuberculoid leprosy, by definition, should yield none or few). This smear may be repeated at three- to six-month intervals to determine effectiveness of therapy. It is considered superior to a nasal culture, which often yields false-negative results.¹⁶

After the Diagnosis
In the US, HD is a nationally notifiable disease: Health care providers are required by law to inform the CDC of the known particulars while complying with HIPAA requirements.¹⁷

That the case patient was a recent immigrant from a country with a high incidence of HD, coupled with a loss of sensation in his extremities, led to the correct diagnosis. His lack of response to antifungals or anti-inflammatory agents, though frustrating to both patient and provider, was helpful in excluding two common conditions in the differential diagnosis. Other possibilites that were considered ultimately did not ring true:

Vitiligo, a loss of pigment that produces white patches resembling borderline leprosy but lacks the raised edging¹⁸;

Granuloma annulare, a lightly raised, ring-shaped lesion that is usually found on the extremities¹⁹; and

Lupus erythematosus, in which patients almost universally experience pruritus and burning, whereas lack of sensation is key to a diagnosis of leprosy.²⁰

Treatment and Management
Health care providers must appear confident to instill confidence in their patients. Any provider with the knowledge and acuity to make a diagnosis of leprosy should be adequately equipped to manage the patient’s care. However, the hesitant or uncertain provider should consider referral to dermatology or to infectious disease for continued management.

The NHDP recognizes the WHO classification of leprosy as multibacillary or paucibacillary (observing a “simple clinical rule” of six or more lesions representing multibacillary HD and five or fewer, paucibacillary HD1), with additional consideration to the three major disease subtypes mentioned earlier: TT, which is treatable; BB, which is considered unstable; and LL, which is resistant to treatment. NHDP and WHO recommendations for treatment differ slightly but address the same goals: complete elimination of the pathogen, preservation of muscle and nerve function, prevention of secondary infections, and management of the adverse effects of medication.^1,21 Adhering to universal precautions is important.

In the US, the multidrug treatment regimen for paucibacillary (TT or BT) leprosy comprises one year of oral rifampin 600 mg/d and oral dapsone 100 mg/d²¹; WHO, in deference to cost containment in developing countries, recommends a six-month regimen of these agents (ie, rifampin 600 mg/mo and dapsone 100 mg/d).¹ A third drug sometimes given to allay active neuritis is oral clofazimine 50 mg/d for one year²¹ (per WHO recommendations, a monthly dose of 300 mg, plus 50 mg/d¹). In patients with preexisting or subsequent anemia, dapsone dosing should be lowered to 50 mg, the minimally effective level. Of note, clofazimine is no longer commercially available in the US and is held by the NHDP as an investigational new drug for treatment of US patients.²¹

According to US recommendations,²¹ use of this three-agent regimen is extended to two years for patients with multibacillary (LL, BL, BB) leprosy. For these patients, WHO recommends its regimen for 12 months.¹

Rifampin is a powerful antibiotic used for effective treatment of tuberculosis, methicillin-resistant Staphylococcus aureus, gonorrhea, Listeria, and Haemophilus influenzae. However, its use has been shown to reduce the efficacy of anticoagulants, oral contraceptives, and prednisone, possibly requiring therapeutic adjustments.²² Recommended alternatives for rifampin include (in the order of preference) minocycline 100 mg/d, ofloxacin 400 mg/d, levofloxacin 500 mg/d, or twice-daily clarithromycin 500 mg.¹³

Patient compliance with the regimen is facilitated by convenient blister packs that contain standard weekly and monthly doses of these medications, all clearly marked. Many local health departments make these medications available at no cost to patients.

Patient Education
Informing patients what to expect regarding their medications, necessary lab work, and avoiding transmission of HD can ease worry, protect others from illness, and increase the likelihood of an excellent prognosis. Patients with lepromatous (multibacillary) HD should be urged to limit their interactions with others at work or school (particularly preventing exposure to their nasal excretions) until a low bacterial index is achieved. For close contacts of patients recently diagnosed with HD, single-dose rifampin has been shown to provide effective prevention for two years.²³

Emphasizing adherence to daily multidrug therapy minimizes the chance that bacterial resistance will develop. Patients should be given complete information about the individual agents used:

Rifampin 600 mg is the maximum daily dose for an adult. Hepatotoxicity is a concern, and liver enzyme levels (ie, aspartate aminotransferase, alanine aminotransferase) should be measured at three-month intervals. It is important to obtain a history of previous liver disease, exposure to hepatitis, and drug and alcohol use. In otherwise healthy adults, rifampin has the curious effect of turning bodily fluids such as urine and tears bright red. Forewarning patients of this benign development may prevent anxious reactions. Contact lenses may be irreversibly stained.²⁴

Dapsone, for many years the first-line monotherapy for leprosy, is a bacteriostatic, sulfa-based antibiotic that only prevents the multiplication of bacteria, but it is still worthy of respect. Before dapsone is initiated, a screening test for glucose-6-phosphate dehydrogenase deficiency should be performed to determine the risk for dapsone-associated hemolysis.²⁴ Dapsone use is contraindicated in women who are breastfeeding. In patients with severe heart conditions, dapsone can reduce oxygen flow, as evidenced by a bluish discoloration of the lips and fingertips. Mild anemia, headache, gastrointestinal upset and nausea are all common adverse effects.

Clofazimine, a soft gelatin capsule, may cause gray-blue or red hyperpigmentation in individuals who are light-skinned; this effect reverses once the drug is discontinued. Nausea, vomiting, and abdominal pain have been reported. This slow-release bactericidal drug has an extremely long half-life of 70 days. It provides anti-inflammatory action similar to that of prednisone without the latter agent’s long-term adverse effects.²⁴

The Patient’s Outcome
The case patient was the second with HD seen in this dermatology practice. A man who presented on an earlier occasion, possibly an undocumented worker in fear of deportation, seemed concerned about the reporting process, even though he was assured that no personal information would be released. He did not return for follow-up, and attempts to reach him proved fruitless.

The case patient, by contrast, was pleasant and cooperative. He appeared to understand his condition, the required treatment and its possible adverse effects, and the need for continued lab work and regular follow-up appointments. A day laborer in a large factory, he was particularly careful to avoid transmission of his illness to his family or co-workers.

Within two months of beginning multidrug therapy, he experienced quick clearance of the lesions on his back. His bacterial index approached 0 by the time he underwent the second smear. Although he complained of loose stools and classic orange-red bodily fluid throughout the entire year of treatment, he resisted the temptation to discontinue the regimen.

He has experienced no relapses in six years and is considered cured.

Conclusion
Only one in every 20 people is susceptible to infection with M leprae, but cases of leprosy continue to be reported in the US, and illness is of particular concern among immunocompromised individuals. Treatment delay is common because of the condition’s relative rarity in the US, but therapy with standard antibiotics is extremely effective. Lengthy isolation from family and community is not often needed, and relapses are rare. Fully restored health is the rule rather than the exception for patients treated for Hansen’s disease.

According to data from the World Health Organization (WHO), the number of new cases of Hansen’s disease (HD, or leprosy) identified worldwide declined by about 20% from 2003 to 2004. At least 116 of 122 countries once considered leprosy—endemic have achieved a prevalence rate of less than one case per 10,000 population.^1,2

Meanwhile, the number of active HD infections in the United States catalogued through the CDC and the National Hansen’s Disease Program (NHDP) rose from 76 cases in 2000 to 166 in 2005, with an additional 137 cases in 2006 (the most recent year for which complete figures are available).^3,4 Currently, 6,500 US residents are known to have HD, of whom 3,300 require care for active disease.³

Accurate diagnosis and straightforward, aggressive treatment can mean certain cure for this dreaded disease, as it is responsive to a combination of available drugs. For primary care providers in the US, familiarity with this condition can play a role in eliminating it altogether.

Background and Etiology
HD is believed to have originated in East Africa with the pseudonym of leprosy, from the Greek lepi, meaning “fish scales.” Although HD is one of the oldest known human infections, it is not well understood by many Western health care providers. Once considered highly contagious and easily transmissible, HD has proven to be neither: 95% of the human population is not susceptible to the responsible pathogen.³ HD retains its reputation as a devastating illness when left untreated, however, with sequelae often including significant sensory and motor dysfunction.⁵

Leprosy is a chronic bacterial disease caused by Mycobacterium leprae. Mycobacterium is the same rod-shaped, acid-fast bacillus (AFB) implicated in pulmonary tuberculosis, cutaneous tuberculosis, and numerous cutaneous nontuberculoid infections^.6,7

HD transmission is believed to occur almost exclusively by nasal droplet, inhaled by way of others’ nares or lungs. Research continues in possible transmission by skin-to-skin contact.^8,9

Leprosy is particularly challenging for immunocompromised persons, such as those with HIV/AIDS or tuberculosis. According to data from the NHDP, HD in the US is found primarily among undocumented immigrants who live in close quarters. Cases considered “home-grown” rather than “imported”⁵ are most commonly diagnosed in Hawaii and in a swath from Texas to Georgia and south toward Florida. Pockets of HD incidence are also found in California, New York, and Massachusetts.⁴

Clinicians’ lack of familiarity with HD and its relative rarity in the US help explain why diagnosis and treatment are commonly delayed. As a patient’s disease progresses from an insidious, gradual, and relatively painless onset, the primary care provider may be grappling with an extensive differential diagnosis (see “Differential Diagnosis for Hansen’s Disease [Leprosy],”^10,11 below). Even after confirming a diagnosis of HD, the provider must contend with a lack of information and misinformation about HD among staff members, the patient’s family, and society at large, as well as the associated stigma. Patient education and effective treatment are of comparable importance.

Patient Presentation and History
A 40-year-old Latino man presented to a primary care provider with a well-demarcated, erythematous patch on his right upper back that had raised outer edging and faint flaking. The patch was surrounded by several smaller but similar asymmetrical macules. The patient denied pruritus but stated that the area “felt funny.” He said the lesion might have been spreading during the previous several months, but he could not be certain because of its location.

The man denied any medication use except for a topical antibiotic ointment he had applied to the affected area with no improvement. His provider made a diagnosis of tinea corporis and prescribed an antifungal cream, naftifine. After two weeks without results, the patient was referred to a dermatologist.

During the assessment, it became apparent that the patient was experiencing numbness in his fingertips and general muscle weakness in his arms. A KOH prep was difficult to obtain, as the lesion site was somewhat smooth. Any dermatophytes that may have been present had been eliminated by the naftifine, and KOH results were negative.

A 5.0-mm punch biopsy from the largest lesion was ordered. A preliminary diagnosis of sarcoidosis (chronic inflammation with an unusual skin manifestation) was made, with serious consideration given to early cutaneous T-cell lymphoma (mycosis fungoides). A high-potency steroid was prescribed for five days’ use, twice daily.

On his return to the dermatologist, the patient reported that the site was no better. He was informed that the dermatologist and the pathologist, both with considerable experience, had detected no bacilli or dermal nerve infiltration in the tissue sample but had observed abundant lymphocytic infiltration. This finding, coupled with the patient’s decreased sensation, muscle fatigue, and status as a recent immigrant from a South American country, led to an initial diagnosis of borderline leprosy (BB).

Physical Examination and Disease Progression
If the first provider suspected a fungal infection during the initial examination, he should have completed a KOH scraping to confirm that suspicion. While superficial fungal infections are extremely common, particularly in the southeastern US, a sampling of scale with KOH 5% to 20% and the absence of dermatophytes under the microscope might have permitted a quick rule-out.¹² Additionally, dermatophytic infections are very responsive to current medications within days, not weeks.

Thus, the key to an accurate diagnosis of leprosy begins with a physical examination that takes into account both chronic unresolved cutaneous lesions and neurologic changes in sensitivity.

A great majority of patients with HD have no noteworthy clinical symptoms until the first skin manifestations. While sensory neuropathy is prominent in all patients, additional findings (depending on the type of leprosy involved) may include plantar ulcers, chronic nasal congestion with early evidence of cartilage loss over the nasal bridge, chronic nosebleeds, cranial nerve palsies, and eye paralysis.¹² In rare cases, hypogonadism may develop, or the clinical team may discover amyloidosis, an accumulation of insoluble proteins in the tissues that impairs function in various organs; this condition is usually detected by skin biopsy. If early or indeterminate leprosy is identified, neither form persists; rather, the condition will progress to one of the following:

• Borderline lepromatous leprosy (BL) and lepromatous leprosy (LL) offer very high resistance to treatment and are considered malignant forms of HD. Findings in patients with BL or LL include multiple lesions in various crazy-quilt presentations: macules, papules, plaques, nodules, masses, and patches of deep, erythematous infiltration across the extremities, face, and trunk.¹² Loss of all hair except on the scalp is possible. Ulcers may form on the palms of the hands and soles of the feet.

In both BL and LL, results on AFB smears will reflect moderately high or very high concentrations of the pathogen in the patient’s system. Thus, these forms of HD are defined as multibacillary. If either is left untreated, the accumulation of proteins attributed to amyloidosis and secondary infections that develop eventually lead to death.

• Borderline leprosy (BB) has already been described in the case patient, with five or six ill-defined lesions and mild impairment of the peripheral nervous system. Aggressive treatment of this form of HD is important. A strong immune system provides no guarantee of successful treatment, and therapy must forestall a likely continuum to more serious forms.¹³

• Borderline tuberculoid leprosy (BT) and tuberculoid leprosy (TT) are both forms of paucibacillary HD. They offer little resistance to treatment in the patient with a healthy immune system. Lesions are generally scant (fewer than five; see figure), and the AFB smear reveals 0 to 10 bacteria in 100 fields.¹²

For the primary care provider, a thorough physical examination also requires familiarity with reasonable differentials. Hallmarks of conditions less likely to be leprosy include nausea, vomiting, or diarrhea, fever and chills, rectal bleeding and unexplained weight loss, headaches, and shortness of breath.

Diagnostic Testing
To help gauge progression of the disease and assess effectiveness of therapy, it is common practice to conduct a neurosensory test at each office visit. This is performed by touching the patient’s extremities and the periphery of lesions with a simple nylon monofilament.¹³ The patient’s response or lack of response is documented and changes are noted for future therapeutic decision making.

In patients with suspected HD, the NHDP recommends that a full-thickness 4.0-mm elliptical or punch biopsy be performed at the periphery of the largest or most active lesion and that slides be sent to the NHDP in formalin or paraffin for review.¹⁴ Experienced NHDP pathologists may order additional stains. A detailed protocol can be found at www.hrsa.gov/hansens/clinical/diagnostics/biopsy.htm.

Proficiency in performing slit smears, a technique to obtain tissue fluid, is also helpful.¹⁵ Measurement of the number of bacteria in a set number of fields allows for calculation of the host’s bacterial index, making it possible to determine an appropriate treatment level.

The preferred sites for the slit smear are active lesions, if possible from both ear lobes plus two additional locations. After alcohol swabbing, a tight, bloodless pinch is made, with a 3.0-mm incision that yields blood and fluid. The resulting culture is examined for AFB, which are found abundantly in lepromatous leprosy (whereas tuberculoid leprosy, by definition, should yield none or few). This smear may be repeated at three- to six-month intervals to determine effectiveness of therapy. It is considered superior to a nasal culture, which often yields false-negative results.¹⁶

After the Diagnosis
In the US, HD is a nationally notifiable disease: Health care providers are required by law to inform the CDC of the known particulars while complying with HIPAA requirements.¹⁷

That the case patient was a recent immigrant from a country with a high incidence of HD, coupled with a loss of sensation in his extremities, led to the correct diagnosis. His lack of response to antifungals or anti-inflammatory agents, though frustrating to both patient and provider, was helpful in excluding two common conditions in the differential diagnosis. Other possibilites that were considered ultimately did not ring true:

Vitiligo, a loss of pigment that produces white patches resembling borderline leprosy but lacks the raised edging¹⁸;

Granuloma annulare, a lightly raised, ring-shaped lesion that is usually found on the extremities¹⁹; and

Lupus erythematosus, in which patients almost universally experience pruritus and burning, whereas lack of sensation is key to a diagnosis of leprosy.²⁰

Treatment and Management
Health care providers must appear confident to instill confidence in their patients. Any provider with the knowledge and acuity to make a diagnosis of leprosy should be adequately equipped to manage the patient’s care. However, the hesitant or uncertain provider should consider referral to dermatology or to infectious disease for continued management.

The NHDP recognizes the WHO classification of leprosy as multibacillary or paucibacillary (observing a “simple clinical rule” of six or more lesions representing multibacillary HD and five or fewer, paucibacillary HD1), with additional consideration to the three major disease subtypes mentioned earlier: TT, which is treatable; BB, which is considered unstable; and LL, which is resistant to treatment. NHDP and WHO recommendations for treatment differ slightly but address the same goals: complete elimination of the pathogen, preservation of muscle and nerve function, prevention of secondary infections, and management of the adverse effects of medication.^1,21 Adhering to universal precautions is important.

In the US, the multidrug treatment regimen for paucibacillary (TT or BT) leprosy comprises one year of oral rifampin 600 mg/d and oral dapsone 100 mg/d²¹; WHO, in deference to cost containment in developing countries, recommends a six-month regimen of these agents (ie, rifampin 600 mg/mo and dapsone 100 mg/d).¹ A third drug sometimes given to allay active neuritis is oral clofazimine 50 mg/d for one year²¹ (per WHO recommendations, a monthly dose of 300 mg, plus 50 mg/d¹). In patients with preexisting or subsequent anemia, dapsone dosing should be lowered to 50 mg, the minimally effective level. Of note, clofazimine is no longer commercially available in the US and is held by the NHDP as an investigational new drug for treatment of US patients.²¹

According to US recommendations,²¹ use of this three-agent regimen is extended to two years for patients with multibacillary (LL, BL, BB) leprosy. For these patients, WHO recommends its regimen for 12 months.¹

Rifampin is a powerful antibiotic used for effective treatment of tuberculosis, methicillin-resistant Staphylococcus aureus, gonorrhea, Listeria, and Haemophilus influenzae. However, its use has been shown to reduce the efficacy of anticoagulants, oral contraceptives, and prednisone, possibly requiring therapeutic adjustments.²² Recommended alternatives for rifampin include (in the order of preference) minocycline 100 mg/d, ofloxacin 400 mg/d, levofloxacin 500 mg/d, or twice-daily clarithromycin 500 mg.¹³

Patient compliance with the regimen is facilitated by convenient blister packs that contain standard weekly and monthly doses of these medications, all clearly marked. Many local health departments make these medications available at no cost to patients.

Patient Education
Informing patients what to expect regarding their medications, necessary lab work, and avoiding transmission of HD can ease worry, protect others from illness, and increase the likelihood of an excellent prognosis. Patients with lepromatous (multibacillary) HD should be urged to limit their interactions with others at work or school (particularly preventing exposure to their nasal excretions) until a low bacterial index is achieved. For close contacts of patients recently diagnosed with HD, single-dose rifampin has been shown to provide effective prevention for two years.²³

Emphasizing adherence to daily multidrug therapy minimizes the chance that bacterial resistance will develop. Patients should be given complete information about the individual agents used:

Rifampin 600 mg is the maximum daily dose for an adult. Hepatotoxicity is a concern, and liver enzyme levels (ie, aspartate aminotransferase, alanine aminotransferase) should be measured at three-month intervals. It is important to obtain a history of previous liver disease, exposure to hepatitis, and drug and alcohol use. In otherwise healthy adults, rifampin has the curious effect of turning bodily fluids such as urine and tears bright red. Forewarning patients of this benign development may prevent anxious reactions. Contact lenses may be irreversibly stained.²⁴

Dapsone, for many years the first-line monotherapy for leprosy, is a bacteriostatic, sulfa-based antibiotic that only prevents the multiplication of bacteria, but it is still worthy of respect. Before dapsone is initiated, a screening test for glucose-6-phosphate dehydrogenase deficiency should be performed to determine the risk for dapsone-associated hemolysis.²⁴ Dapsone use is contraindicated in women who are breastfeeding. In patients with severe heart conditions, dapsone can reduce oxygen flow, as evidenced by a bluish discoloration of the lips and fingertips. Mild anemia, headache, gastrointestinal upset and nausea are all common adverse effects.

Clofazimine, a soft gelatin capsule, may cause gray-blue or red hyperpigmentation in individuals who are light-skinned; this effect reverses once the drug is discontinued. Nausea, vomiting, and abdominal pain have been reported. This slow-release bactericidal drug has an extremely long half-life of 70 days. It provides anti-inflammatory action similar to that of prednisone without the latter agent’s long-term adverse effects.²⁴

The Patient’s Outcome
The case patient was the second with HD seen in this dermatology practice. A man who presented on an earlier occasion, possibly an undocumented worker in fear of deportation, seemed concerned about the reporting process, even though he was assured that no personal information would be released. He did not return for follow-up, and attempts to reach him proved fruitless.

The case patient, by contrast, was pleasant and cooperative. He appeared to understand his condition, the required treatment and its possible adverse effects, and the need for continued lab work and regular follow-up appointments. A day laborer in a large factory, he was particularly careful to avoid transmission of his illness to his family or co-workers.

Within two months of beginning multidrug therapy, he experienced quick clearance of the lesions on his back. His bacterial index approached 0 by the time he underwent the second smear. Although he complained of loose stools and classic orange-red bodily fluid throughout the entire year of treatment, he resisted the temptation to discontinue the regimen.

He has experienced no relapses in six years and is considered cured.

Conclusion
Only one in every 20 people is susceptible to infection with M leprae, but cases of leprosy continue to be reported in the US, and illness is of particular concern among immunocompromised individuals. Treatment delay is common because of the condition’s relative rarity in the US, but therapy with standard antibiotics is extremely effective. Lengthy isolation from family and community is not often needed, and relapses are rare. Fully restored health is the rule rather than the exception for patients treated for Hansen’s disease.