Papulonecrotic tuberculid

Papulonecrotic tuberculid (PNT) is an uncommon form of id eruption, which occurs in association with tuberculosis infections in patients with a high degree of immunity and allergic sensitivity to mycobacterial organisms. It commonly presents as recurrent crops of papulonecrotic lesions that crust or ulcerate, and heal with atrophic varioliform scars over time. The differential diagnoses of PTN are wide and varying. Tuberculin test is usually strongly positive. Histology shows tuberculoid histology with endarteritis and thrombosis of dermal blood vessels. One of the hallmarks of PNT is its prompt response to antituberculous therapy. The purpose of this article is to increase awareness of this condition among dermatologists.


Introduction
Cutaneous tuberculosis (TB; including tuberculids) is a rare entity, constituting 0.15% of all reported cases of TB and only 1% of all extrapulmonary TB cases. 1,2 Tuberculids are a heterogeneous group of skin lesions that occur in association with TB infections elsewhere in the body, including the skin, in patients with a high degree of immunity and allergic sensitivity to the mycobacterial organism. Tuberculids comprise papulonecrotic tuberculid (PNT), lichen scrofulosorum, erythema induratum-nodular vasculitis, nodular tuberculid and granulomatous phlebitis (phlebitic tuberculid). 3 In this review, the pathogenesis, clinical features, differential diagnosis and management of PNT are discussed.

History
The concept of tuberculid was introduced in 1896 by Darier, as representing a form of cutaneous hypersensitivity reaction to TB antigens. Later in 1936, Pautrier established PNT as a distinct TB-associated skin entity, and described its characteristic clinical and histopathological features. 4 Epidemiology Until a few decades ago, the incidence of tuberculids had been declining in western countries; however, a recent upsurge has been noted all over the world. It has been attributed to socioeconomic factors such as overcrowding, poverty, refugee movement, increases in HIV infections and the emergence of drug-resistant Mycobacterium tuberculosis strains. Tuberculids are more common in areas with an increased prevalence of TB such as India, South Africa and Hong Kong. 2 The incidence of PNT is uncommon, accounting for approximately 4% of patients with cutaneous TB. PNT chiefly affects children and young adults, with a slight female preponderance. 1,2,5 tissue from occult or inapparent TB elsewhere in the body. 5 Apart from M. tuberculosis, PNT-like lesions have also been associated with Mycobacterium kansasii, Mycobacterium bovis and Mycobacterium avium complex, and have also been reported following bacillus Calmette-Gu erin (BCG) vaccination. The pathogenesis of PNT represents an Arthus reaction (Type III) accompanied by delayed-type hypersensitivity (Type IV) reaction, as illustrated in Fig. 1. 1,5 Clinical features PNT indicates good immunological status, as it is usually seen in patients with a moderate or high degree of immunity. 6 It presents as recurrent crops of asymptomatic, symmetrical, hard, painless, dusky-red or violaceous, inflammatory papulonodular, papulopustular or pustular lesions, measuring 1-5 mm in diameter, which eventually crust or ulcerate and heal spontaneously over time, with residual pigmentary changes and atrophic varioliform scars. 1,2,7,8 The lesions are initially seen on the extensor aspects of the limbs and gluteal region (Fig. 2a), and eventually become widespread. 9 Other sites that can be involved include the face, ears, penis, vulva, perineum and scalp 5 ( Fig. 2bg). In Japan, PNT of the penis is considered a distinct entity; Nishigori et al. 10 reported a series of 121 Japanese patients in whom the penis was principally involved. PNT commonly manifests as ulceration or scars. 11 Constitutional symptoms such as pyrexia and asthenia may precede the eruption of PNT lesions. 12 Without treatment, spontaneous resolution of individual lesions can occur in a few weeks, with simultaneous occurrence of new lesions. 9 Vesicular, pustular, lichenoid and umbilicated lesions, as well as verrucous variants resembling acquired perforating dermatosis, have been described. 13,14 Koebnerization of PNT lesions has been reported, 15 as has the appearance of PNT lesions at the tuberculin testing site on the arm. 16 In patients with HIV, PNT can occur after the initiation of antiretroviral therapy, due to the improvement in immunity. 17

Diagnostic methods
The tuberculin test is usually positive in patients with PNT, frequently with a severe and even necrotic reaction within 8-12 h (Fig. 3a). 1 However, tuberculin skin testing has disadvantages such as false-positive results in patients with prior BCG vaccination or infection with nontuberculous mycobacteria. 28 Thus, a lesional biopsy should be carried out to confirm the diagnosis (Fig. 3b,c). In early lesions, vascular involvement consisting of leucocytoclastic vasculitis or lymphocytic vasculitis associated with fibrinoid necrosis and thrombotic occlusion of individual vessels are seen. Later, a wedge-shaped infarct-like lesion starts in the dermis with a large central zone of coagulation necrosis surrounded by inflammatory cells. As the wedge casts off, the epitheloid cells and giant cells collect around its periphery, even though focal granuloma formation is poor. In approximately 20% of cases, follicular necrosis or suppuration is present. Immunohistochemistry shows a predominance of T lymphocytes, along with macrophages, scanty antigen-presenting cells and an absence of B lymphocytes. 1,3,5 Dermoscopy of PNT is described in Fig. 3d.
The smaller numbers of bacilli, along with the local delayed hypersensitivity reaction, the killing of bacilli upon arrival to the skin and the robust inflammation associated with PNT make it difficult to isolate acidfast bacilli from skin biopsy specimens. 4 However, Jun et al. reported finding small numbers of acid-fast bacillus in a pathological section of PNT lesion. 6 The reliability of PCR as a diagnostic technique in PNT tissue samples is controversial. 28 The sensitivity varies from 0 to 80% in PNT lesions. 29,30 For M. tuberculosis complex, an amplified 123-bp sequence is considered specific. 16 PCR-negative PNT cases have been reported as papulonecrotic TB in the literature, and such cases call into question the categorization of this entity as a tuberculid. 5 Interferon-c release assay can detect latent tuberculous infection where PCR is negative. 28 A recommended approach to a patient with clinical suspicion of PNT is outlined in Table 3.

Treatment
The treatment of tuberculids involves antituberculous therapy (ATT) with a 2-month intensive phase followed by a 4-month maintenance phase. One of the hallmarks of PNT is its prompt response to ATT. The lesions usually start to clear within 3-12 weeks of initiating ATT. 1 Owing to a high degree of immunity, reports of spontaneous rapid resolution of skin lesions without any ATT have been reported. 31 In doubtful cases, a therapeutic trial of ATT is decisive. The use of a single drug should be avoided as it can result in recurrence. 1 In instances where treatment was provided for a shorter duration and fewer drugs were used, a higher incidence of recurrence was noted. Resistant cases require antituberculous treatment for a prolonged period of time. 5

Conclusion
The diagnosis of PNT is often delayed due to its rarity, lack of awareness among dermatologists, wide differential diagnosis and lack of evident TB foci in patients. However, the following diagnostic criteria may help: (i) presence of characteristic skin lesions, (ii) evidence of current or past TB infection, (iii) strongly positive Mantoux test, (iv) tuberculoid histology with endarteritis and thrombosis of dermal blood vessels, and (v) good response to ATT. With the increasing trend of TB all over the world, a high suspicion of PNT should be kept in mind in any patient with papulonecrotic lesions.

Learning points
• PNT represents immunological reaction to degenerated M. tuberculosis bacilli or their antigenic fragments, which are deposited in the skin and subcutaneous tissue.
• PNT is usually seen in individuals with moderate or high degree of immunity.
• Clinically, PNT presents as symmetrical crops of recurrent inflammatory papulonodular, papulopustular or pustules, which ulcerate and heal with residual atrophic varioliform scars. • Initially, the lesions are seen on the extensor aspects of the limbs and gluteal region, eventually becoming widespread.
• Tuberculin test is usually strongly positive.
• Leucocytoclastic vasculitis or lymphocytic vasculitis associated with fibrinoid necrosis is the early histological finding.
• PNT shows prompt response to ATT.

Conflict of interest
The authors declare that they have no conflict of interest.

Funding
None.

Ethics statement
Ethics approval not applicable. The patients have provided informed consent for publication of their case details and images.

Data availability
Data are available on request from the corresponding author. Data openly available in a public repository that issues datasets with DOIs.