eMedicine Specialties > Dermatology > Mycobacterial Infections
Papulonecrotic Tuberculids
Updated: Jul 9, 2009
Introduction
Background
The tuberculids, first described by Darier in 1896, represent a form of cutaneous hypersensitivity reaction to tuberculosis (TB) antigens.1 Although many types of tuberculids have been described, most are now understood to not be uniquely caused by tuberculosis. However, papulonecrotic tuberculids (PNTs) and lichen scrofulosorum are still widely accepted as true tuberculids.
The entity papulonecrotic tuberculid was first established by Pautrier in 1936 as a distinct tuberculosis-associated disorder, when he described the characteristic clinical and histopathologic features. Papulonecrotic tuberculid is a chronic, recurrent, and symmetric eruption of necrotizing skin papules arising in crops, involving primarily the arms and the legs. A hallmark of this condition is that lesions heal with varioliform scarring. The eruption is believed to represent a hypersensitivity reaction to tuberculosis antigens released from a distant focus of infection. Most patients react markedly to the Mantoux skin test (purified protein derivative, PPD) and may exhibit other evidence of current or past tuberculosis infection.
Pathophysiology
The pathophysiology of papulonecrotic tuberculid is controversial. Most authors believe this disease entity is triggered by an initial Arthus reaction to mycobacterial antigens. This is then followed by a hypersensitivity reaction in which antigens undergo opsonization by antibodies, followed by immune complex deposition in small cutaneous blood vessels. The ensuing complement cascade triggers a leukocytoclastic vasculitis, leading to destruction of vessel walls with ensuing tissue necrosis. However, other authors dispute this mechanism, citing the lack of leukocytoclastic vasculitis in some cases. Instead, they propose that the primary lesion is the result of subacute lymphohistiocytic vasculitis that leads to thrombosis and subsequent tissue necrosis.
Whatever underlies the pathophysiology, a consensus has been reached that papulonecrotic tuberculid represents a true hypersensitivity reaction rather than the result of a local cutaneous tuberculosis infection. This is based on the observation that papulonecrotic tuberculid lesions have consistently failed to either stain positive for, or culture out, mycobacterial organisms. Although the organisms are absent, mycobacterial DNA have been detected in approximately half of the biopsy specimens subjected to polymerase chain reaction. These observations support the idea that lesions of papulonecrotic tuberculid are the result of released mycobacterial antigens in the setting of a concurrent but distant infection.
Frequency
United States
A decreasing incidence of papulonecrotic tuberculid began in the second half of the 1900s and the decline continues to this day. This phenomenon is attributed to aggressive tuberculosis control now found in wide practice. Currently, almost all cases come from areas outside of North America with high endemic rates of tuberculosis. However, a rare US case, involving a previously healthy 9-year-old girl from Chicago, Ill, was reported in 1990.2 Historically, reports indicate that young women and children are especially susceptible to this disorder.
Papulonecrotic tuberculid–like lesions have also been associated with other mycobacterial infections, including Mycobacterium bovis and Mycobacterium kansasii, and from BCG vaccination.3 With the increased incidence of tuberculosis infection in patients with HIV,4 the frequency of papulonecrotic tuberculid may increase, although this has not yet occurred, due possibly to effective public health measures to identify, isolate, and treat active cases of tuberculosis.
International
Papulonecrotic tuberculid is an uncommon disorder even in populations with a high prevalence of tuberculosis, occurring in less than 5% of active tuberculosis cases. In the literature, 91 cases were reported during a 17-year period in South Africa in 1974. In addition, 12 cases from a period of longer than 30 years in England were reported in 1986. In the latter study, most patients were immigrants and had presumably acquired the infection outside of England. Freiman et al reported a case in a 25-year-old woman from the Philippines who had immigrated to Canada 8 years previously.5
Mortality/Morbidity
The condition typically follows a prolonged and relapsing course lasting years, although spontaneous resolution has been reported. Significant varioliform scarring is a sequela, and progression to lupus vulgaris has been observed.6,7 An association with Takayasu arteritis of the aortic arch has also been documented.
Sex
Females seem to be at a slightly increased risk for developing this disorder.
Age
Children and young adults are more susceptible to this condition than other people. In the 1974 study from South Africa, two thirds of the patients were younger than 30 years.
Clinical
History
- The characteristic lesions are small, erythematous, inflammatory papules that undergo central ulceration and heal spontaneously within weeks, leaving a varioliform scar.
- Lesions arise in symmetric crops, typically with an acral predilection. Characteristically, lesions develop over the extensor surfaces, particularly the knees, the elbows, and the dorsum of the hands and the feet, although widespread involvement may be present.
- New lesions form as older lesions resolve, giving the eruption a polymorphous appearance.
- Oral lesions have not been reported to date.
- Papulonecrotic tuberculids have been reported to coexist with lesions of erythema induratum,8 as well as lichen scrofulosorum.9 In several reports, cutaneous lesions resolved with appropriate antituberculosis therapy.
Physical
- Primary lesion: The characteristic initial lesions are 2- to 8-mm, erythematous papules that become pustules and undergo central ulceration forming hemorrhagic-crusted papules.
Bilaterally symmetric papulonecrotic lesions on the lower extremities.
- Distribution: Lesions arise in symmetric crops, typically with an acral predilection. Characteristically, lesions develop over the extensor surfaces, particularly the knees, the elbows, and the dorsum of the hands and the feet, although widespread involvement may occur. Involvement of the glans penis has also been reported.
- Color: Hyperpigmented to erythematous papules with central crusting are seen early, and the lesions generally heal with scarring.
- Lymph nodes: In one study, as many as one third of the cases were associated with cervical lymphadenopathy, and some patients developed scrofuloderma.
Causes
The eruption is a form of an exaggerated host immunologic response to a mycobacterial infection involving the cutaneous vessels. Active tuberculosis is reported in as many as 40% of patients.
Differential Diagnoses
Lymphomatoid Papulosis
Papular Urticaria
Pityriasis Lichenoides
Other Problems to Be Considered
Pityriasis lichenoides et varioliformis acuta (PLEVA)
Septicemia
Perforating granuloma annulare
Miliary tuberculosis (patients are ill and lesions are culture-positive for tuberculosis)
Suppurative folliculitis
Pustular syphilide
Drug eruption
Sarcoidosis10
Workup
Laboratory Studies
- Patients should be evaluated for evidence of active tuberculosis or other forms of mycobacterial infection. Tuberculous involvement of the female genital tract may account for the increased incidence in females, and a culture of menstrual fluid and endometrial biopsy may be of value in excluding occult disease.
- CBC count, chemistry panel, and urinalysis should be performed.
- The erythrocyte sedimentation rate is often very high and can be used to monitor treatment. It decreases 4-6 weeks after treatment is started.
Imaging Studies
- Chest radiography is needed to rule out active or past pulmonary tuberculosis.
- Abdominal radiographs may show lymph node calcifications typical of tuberculosis.
Other Tests
- Mantoux (PPD) intradermal skin tests are usually strongly positive. Some authors require this result for diagnosis. However, false-negative negative results can occur in the setting of immunosuppression. Hence, clinical correlation in such cases is prudent.
Histologic Findings
The histologic features vary with the timing of the biopsy. In an early lesion, evidence of a vasculitis, which is typically leukocytoclastic with fibrinoid necrosis of the vessel wall and karyorrhectic debris, should be present. However, some authors have found that the primary lesion consists of lymphohistiocytic, rather than leukocytoclastic, vasculitis.
Characteristic of the disorder is the presence of perivascular spongy edema. Later, because of the obliterative vascular changes, a wedge-shaped area of focal dermal necrosis develops, surrounded by a granulomatous inflammatory infiltrate with giant cells and epithelioid histiocytes. Well-formed tuberculoid granulomas with Langerhans giant cells are not usually present in the lesions. Special stains for mycobacteria are typically negative.
The histologic differential diagnosis depends on the timing of the biopsy as well as the histologic appearance. In particular, inflammatory palisading granulomas (ie, granuloma annulare and infectious granulomas) may look similar as compared to those found occasionally in papulonecrotic tuberculid. However, the ability to exclude mucin and infectious organisms in effect rules out granuloma annulare and infectious granulomas, respectively.
Treatment
Medical Care
Treatment is directed at eradicating the underlying mycobacterial infection. Tuberculosis treatment guidelines may vary from region to region and from different authorities (ie, the World Health Organization [WHO] and the Centers for Disease Control and Prevention [CDC]). Currently, for patients with active tuberculosis, a 4-drug therapy with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) is recommended to avoid the development of resistance. Papulonecrotic tuberculids respond promptly to appropriate antituberculosis therapy. New lesions cease forming within days to weeks after therapy is initiated, and existing lesions heal rapidly, usually within several months. A minimum of 6 months of anti-tuberculosis therapy is recommended. Recurrences rarely occur after appropriate therapy.
Also see the following guidelines:
- Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America.11
- Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC.12
Medication
The goal of pharmacotherapy is to eradicate the underlying mycobacterial infection that causes papulonecrotic tuberculid.
Antitubercular agents
These agents are effective in the treatment of mycobacterial infections. Therapy with a 4-drug combination of rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) is recommended to avoid the development of resistance.
Isoniazid (Laniazid, Nydrazid)
Best combination of effectiveness, low cost, and minor adverse effects. First-line drug unless resistance or another contraindication is known. Therapeutic regimens of <6 mo demonstrate an unacceptably high relapse rate. Coadministration of pyridoxine is recommended to minimize risk of peripheral neuropathy secondary to isoniazid therapy. Prophylactic doses of 6-50 mg of pyridoxine daily are recommended. Twice-weekly dosing not recommended in HIV patients with CD4 lymphocyte counts <100 cells/µL
Dosing
Adult
5 mg/kg PO qd (usually 300 mg/d); 10 mg/kg PO qd or divided bid in patients with disseminated disease; not to exceed 300 mg/d
Directly observed therapy: 15 mg/kg twice weekly; not to exceed 900 mg/d; twice-weekly dosing not recommended in HIV patients with CD4 lymphocyte counts <100 cells/µL
Pediatric
10-20 mg/kg PO qd; not to exceed 300 mg/d
Interactions
Higher incidence of isoniazid-related hepatitis can occur with daily alcohol consumption; aluminum salts may decrease serum levels (administer 1-2 h before taking aluminum salts); may increase effects of anticoagulants with coadministration; may inhibit metabolic clearance of benzodiazepines; carbamazepine toxicity or isoniazid hepatotoxicity may result from concurrent use (monitor carbamazepine concentrations and liver function); coadministration with cycloserine may increase CNS adverse effects (eg, dizziness); acute behavioral and coordination changes may occur with coadministration of disulfiram; coadministration with rifampin after halothane anesthesia may result in hepatotoxicity and hepatic encephalopathy; may inhibit hepatic microsomal enzymes and increase toxicity of hydantoin
Contraindications
Documented hypersensitivity; previous isoniazid-associated hepatic injury or other severe adverse reactions
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Monitor patients with active chronic liver disease or severe renal dysfunction; periodic ophthalmologic examinations during isoniazid therapy are recommended even when visual symptoms do not occur
Adverse effects include anemia, seizure, systemic lupus erythematosus, thrombocytopenia, and hepatitis (severe and sometimes fatal); adverse effects following isoniazid therapy may include toxic encephalopathy, nystagmus, dizziness, and tinnitus
Rifampin (Rifadin, Rimactane)
For use in combination with at least 1 other anti-TB drug. Inhibits DNA-dependent bacterial RNA polymerase but not mammalian RNA polymerase. Cross-resistance may occur. Treat for 6-9 mo or until 6 mo have elapsed from conversion to sputum culture negativity.
Dosing
Adult
600 mg PO/IV qd
Pediatric
10-20 mg/kg PO/IV; not to exceed 600 mg/d
Interactions
Induces microsomal enzymes (especially P450 CYP3A4-mediated metabolism), which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, digoxin, and other medications metabolized by this system; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue 1 or both agents if alterations in LFTs occur)
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur
Pyrazinamide
Pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M tuberculosis, depending on concentration of drug attained at site of infection; mechanism of action is unknown. Administer for initial 2 months of a 6-mo or longer treatment regimen for drug-susceptible patients. Treat drug-resistant patients with individualized regimens.
Dosing
Adult
15-30 mg/kg PO qd; not to exceed 2 g/d
Indirectly observed therapy: 50-70 mg/kg PO 2 times/wk, not to exceed 4 g/d; or 50-70 mg/kg 3 times/wk, not to exceed 3 g/d
Pediatric
Administer as in adults
Interactions
None reported
Contraindications
Documented hypersensitivity; severe hepatic damage; acute gout
Precautions
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Use only in combination with other effective anti-TB agents; inhibits renal excretion of urates; may result in hyperuricemia (usually asymptomatic); perform baseline serum uric acid determinations; discontinue drug if signs of hyperuricemia with acute gouty arthritis; perform baseline LFTs (closely monitor in liver disease); discontinue if signs of hepatocellular damage appear; caution in history of diabetes mellitus; coadministration of ethionamide may potentiate hepatotoxicity
Ethambutol (Myambutol)
Diffuses into actively growing mycobacterial cells, such as tubercle bacilli. Impairs cell metabolism by inhibiting synthesis of one or more metabolites, which, in turn, causes cell death. No cross-resistance demonstrated. Mycobacterial resistance is frequent with previous therapy. Use in these patients in combination with second-line drugs that have not been previously administered. Administer qd until permanent bacteriologic conversion and maximal clinical improvement is seen. Absorption is not significantly altered by food.
Dosing
Adult
No previous anti-TB therapy: 15 mg/kg (7 mg/lb) PO qd
Previous anti-TB therapy: 25 mg/kg (11 mg/lb) PO qd
Pediatric
<13 years: Not recommended
>13 years: Administer as in adults
Interactions
Aluminum salts may delay and reduce absorption (give several hours before or after ethambutol dose)
Contraindications
Documented hypersensitivity; optic neuritis (unless clinically indicated)
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Reduce dose in impaired renal function; may have reversible visual adverse effects if promptly discontinued
Follow-up
Complications
- Complications include significant varioliform scarring and those of tuberculosis infections, including progression to lupus vulgaris.
Prognosis
- Patients typically follow a waxing and waning course lasting many years, although spontaneous resolution has been reported.
- Papulonecrotic tuberculids respond promptly to appropriate antituberculosis therapy. New lesions cease forming within days to weeks after therapy is initiated, and existing lesions heal rapidly, usually within several months. Recurrences are rare after appropriate therapy.
- Unfortunately, despite even the most aggressive efforts, mortality is high in those infected with multidrug resistant tuberculosis.
Multimedia
Media file 1: Bilaterally symmetric papulonecrotic lesions on the lower extremities.
References
Darier MJ. Des "tuberculides" cutanees. Ann Dermatol Syph. 1896;7:1431-36.
Sloan JB, Medenica M. Papulonecrotic tuberculid in a 9-year-old American girl: case report and review of the literature. Pediatr Dermatol. Sep 1990;7(3):191-5. [Medline].
Iden DL, Rogers RS 3rd, Schroeter AL. Papulonecrotic tuberculid secondary to Mycobacterium bovis. Arch Dermatol. Apr 1978;114(4):564-6. [Medline].
Fernandes C, Maltez F, Lourenco S, Morgado A, Proenca R. Papulonecrotic tuberculid in a human immunodeficiency virus type-1 patient with multidrug-resistant tuberculosis. J Eur Acad Dermatol Venereol. May 2004;18(3):369-70. [Medline].
Freiman A, Ting P, Miller M, Greenaway C. Papulonecrotic tuberculid: a rare form of cutaneous tuberculosis. Cutis. Jun 2005;75(6):341-6. [Medline].
Morrison JG, Fourie ED. The papulonecrotic tuberculide. From Arthus reaction to lupus vulgaris. Br J Dermatol. Sep 1974;91(3):263-70. [Medline].
Senol M, Ozcan A, Aydin A, Karincaoglu Y, Sasmaz S, Sener S. Disseminated lupus vulgaris and papulonecrotic tuberculid: case report. Pediatr Dermatol. Mar-Apr 2000;17(2):133-5. [Medline].
Milligan A, Chen K, Graham-Brown RA. Two tuberculides in one patient--a case report of papulonecrotic tuberculide and erythema induratum occurring together. Clin Exp Dermatol. Jan 1990;15(1):21-3. [Medline].
Thappa DM, Karthikeyan K, Jayanthi S. Tuberculid in a child: transformation from papulonecrotic to lichen scrofulosorum. Pediatr Dermatol. Jan-Feb 2003;20(1):91-3. [Medline].
Chalermdamrichai P, Puavilai S, Jerasutus S, Boonsarngsuk V, Kiattboonsri S, Suwatanapongched T. Sarcoidosis presenting as papulonecrotic tuberculid-like lesions: report of a case. J Med Assoc Thai. Jul 2004;87(7):839-44. [Medline].
[Guideline] Taylor Z, Nolan CM, Blumberg HM. Controlling tuberculosis in the United States. Recommendations from the American Thoracic Society, CDC, and the Infectious Diseases Society of America. MMWR Recomm Rep. Nov 4 2005;54:1-81. [Medline].
[Guideline] Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep. Dec 16 2005;54:1-47. [Medline].
Barbagallo J, Tager P, Ingleton R, Hirsch RJ, Weinberg JM. Cutaneous tuberculosis: diagnosis and treatment. Am J Clin Dermatol. 2002;3(5):319-28. [Medline].
Jordaan HF, Van Niekerk DJ, Louw M. Papulonecrotic tuberculid. A clinical, histopathological, and immunohistochemical study of 15 patients. Am J Dermatopathol. Oct 1994;16(5):474-85. [Medline].
Pautrier L-M. Darier J, ed. Tuberculose nodulare dermique á petits nodules. Nouvelle Pratique. Paris: Masson Editeur; 1936.
Victor T, Jordaan HF, Van Niekerk DJ, Louw M, Jordaan A, Van Helden PD. Papulonecrotic tuberculid. Identification of Mycobacterium tuberculosis DNA by polymerase chain reaction. Am J Dermatopathol. Dec 1992;14(6):491-5. [Medline].
Wilson-Jones E, Winkelmann RK. Papulonecrotic tuberculid: a neglected disease in Western countries. J Am Acad Dermatol. May 1986;14(5 Pt 1):815-26. [Medline].
Keywords
papulonecrotic tuberculid, PNT, necrotizing skin papules, tuberculosis hypersensitivity, TB antigens
Contributor Information and Disclosures
Author
Robert L Chen, MD, PhD, Instructor, Department of Medicine, Section of Dermatology, University of Chicago Medical Center
Robert L Chen, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Dermatology Foundation, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.
Coauthor(s)
David Barnette, Jr, MD, Chief of Dermatopathology, Departments of Internal Medicine and Dermatology, Naval Medical Center at San Diego
David Barnette, Jr, MD is a member of the following medical societies: American Academy of Dermatology and American Society of Dermatopathology
Disclosure: Nothing to disclose.
Medical Editor
Terry L Barrett, MD, Clinical Professor of Dermatology and Pathology, University of Texas Southwestern School of Medicine; Director, ProPath Dermatopathology, Dallas, Texas
Terry L Barrett, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Medical Association, American Society of Dermatopathology, College of American Pathologists, and United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.
Pharmacy Editor
Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.
Managing Editor
Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory
Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association
Disclosure: Nothing to disclose.
CME Editor
Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire Consulting
Chief Editor
Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.