Recalcitrant warts can accurately be defined as warts that remain after six months of conventional treatment (Figures 1-4). Up to one-third of non-genital warts, especially plantar and periungual warts, become recalcitrant. Given that malignant skin disorders, such as squamous cell carcinoma and verrucous carcinoma, can present with characteristics similar to warts, the dermatologist should do a punch biopsy to confirm the diagnosis of any lesions that fail to respond to treatment regimens [4].

Treatment modalities available for recalcitrant warts include topical treatments like imiquimod, topical 5FU, topical formic acid, intralesional immunotherapy (bleomycin, candida antigen, interferon alfa), and oral therapies like oral retinoids and zinc sulfate. Laser treatments such as the CO₂ laser, pulsed dye laser, and Nd: YAG, were used as a last resort of treatment [5] - [11] (Table 1).

Intralesional immunotherapy stimulates the immune system to grow a delayed-type hypersensitivity response to various antigens and the wart tissue. This modality is associated with the production of Th1 cytokines, which activate cytotoxic and natural killer cells to eradicate HPV infection. This option clears not only local warts but also distant warts, unlike traditional wart therapies [12].

Different immunotherapeutic agents have been used for intralesional injection. These include autogenous vaccine, Candida antigen, mumps antigen, trichophytin skin test antigen, MMR vaccine, BCG vaccine, Mycobacterium w vaccine, tuberculin and interferon alpha, and gamma injection. This procedure utilizes the fact that there is a high prevalence of immunity to these antigens in the general population. Most children well tolerated the dose of the antigen [12]. Intralesional immunotherapy can give significant results with few sessions. It can also eradicate distant warts with mild or insignificant adverse events at the site of injection.

BCG stands for Bacille Calmette Guerin. BCG is a weakened (attenuated) version of bacteria called Mycobacterium bovis, which is closely related to Mycobacterium tuberculosis, the agent responsible for tuberculosis.

Several BCG vaccines, based on different strains, are available worldwide. BCG vaccines are usually administered by intradermal injection on the deltoid area. The correct administration technique by a well-trained health worker is essential to ensure proper dosage and optimal BCG efficacy and safety. A scar usually develops at the site of BCG injection due to local inflammatory

processes. However, scar formation is not a marker for protection, and approximately 10% of vaccine recipients do not develop a scar. BCG vaccine has been standardized in a dose of 0.05 mL for infants and 0.1 mL for children and older, and it is not available in combination with other vaccines [13]. The protective immunity after primary infant BCG vaccination could last for up to 15 years in some populations [13].

Who should have the BCG vaccine?

1) BCG is recommended when immunization with it has not previously been carried out, and they are negative for tuberculo protein hypersensitivity.

2) Neonates with a family history of tuberculosis in the last five years.

3) Neonates, infants, and children below 16 years old were born or whose parents were born in a country with an incidence of TB higher than 40 per 100,000 [13].

4) New immigrants aged 16 - 35 years from Sub-Saharan Africa or a country with an incidence of tuberculosis greater than 500 per 100,000 [13].

5) Contacts under 36 years old with active respiratory tuberculosis (for healthcare or laboratory workers who have a history of contact with clinical materials or patients with a disease, age limit does not apply).

6) Healthcare workers and laboratory staff (irrespective of age) who are likely to have contact with patients, clinical materials, or derived isolates. (There is inadequate evidence of protection by the BCG vaccine in adults aged over 35 years; however, vaccination is recommended for healthcare workers irrespective of age because of the increased risk to them or their patients) [13] [14] (Table 2).

Who should not have the BCG vaccination?

The BCG vaccine is not recommended for:

1) People who have already had a BCG vaccination and those with a history of TB.

2) People with a positive tuberculin skin test (Mantoux).

3) People who have had a previous anaphylactic reaction (severe allergic reaction) to any of the substances used in the vaccine.

4) Newborn babies in a household where a case of TB is suspected or confirmed.

5) Immunocompromised people, either as a result of health conditions such as HIV, leukemia, and lymphoma or treatments such as chemotherapy and systemic steroids.

6) People who are seriously unwell (vaccination should be delayed until they recover) or have a septic skin condition at the site of injection.

7) Pregnant women.

Because the vaccine doesn’t work well for adults, BCG vaccinations are not usually given to people over 16 years old and never over the age of 35, with exception to people who have an occupational risk for TB [15] (Table 2).

Mycobacterium indicuspranii (MIP), earlier known as Mw, is a non-pathogenic, rapidly growing, atypical mycobacterium. It shares many common Band T cell determinants with Mycobacterium leprae and Mycobacterium tuberculosis, [33] based on its growth characteristics and metabolic properties [34] [35]. It is validly classified as a member of the Mycobacterium avium complex [35]. The new concept of this bacterium is due to its translational application as an immunotherapeutic. The origin of this nomenclature is the combination of isolating bacterial species from India (indicus) and the name of the discoverer PranTalwar (pranii) and studied at the National Institute of Immunology, India [36]. Mw vaccine consists of 0.5 × 10⁹ heat-killed bacilli per 0.1 ml that used as an adjunct in patients with multibacillary leprosy. The vaccine induces strong cytokine responses including IL-2, IL-4, IL-5, and interferon gamma [37].

Mw vaccination by both the parenteral route and aerosol administration gives greater immunity than BCG administered parenterally in the mouse model of tuberculosis [38]. The vaccine is primarily used as adjuvant immunotherapy for multibacillary leprosy. Its immunomodulatory effects have also been shown in other disorders such as pulmonary TB, HIV infection, and malignant neoplasms of the head, bladder, and lung [39].

As an adjunct to chemotherapy, the vaccine accelerates bacterial elimination and hastens clinical improvement. A significant number of patients vaccinated with MWv showed histopathological upgrading and, eventually, attainment of a state of nonspecific infiltration without dermal granulomas [40]. Published studies used Mw vaccine for multiple warts, anogenital warts, extensive extragenital cutaneous warts, and periungual or subungual warts with no prior history of treatment for the same. The mean dose of Mw vaccine used to clear one wart is equal to that required to remove >10 warts.

The route of administration was intralesional to 3 - 5 lesions at a time, intralesional injections in <3 warts, intralesional in a single wart, or the largest in case of multiple warts. A maximum of 10 injections (12 weeks) was given, whichever was earlier, until either complete clearance of wart [41] [42] [43].

The side effects of Mwv include tender erythematous papules healed with a scar, erythema at the site of warts in (70%) of patients, swelling in (16%), and superficial ulceration in one patient. Two patients had a low-grade fever, and two patients had tenderness and swelling of the submandibular lymph node.

The recurrence rate varied from zero in some studies to 14.28% in one study (Table 4).

A skin test composed of a purified protein derivative (PPD) of mycobacterium antigens which elicit immune response in the classic example of delayed hypersensitivity reaction. T lymphocytes that are sensitized due to a previous infection are recruited to the site of injection, where they release lymphokines. Lymphokines cause the induration through vasodilatation, edema, fibrin deposition, and attraction of other inflammatory cells to the site. The Mantoux method is the only technique that has been standardized and extensively validated to do TST testing. PPD-S (0.1 mL = 5 tuberculin units) (TU) is injected into the volar aspect of the forearm using a 27-gauge needle. PPD-RT23 of 2(TU) is alternative to PPD-S. The diameter of the induration is measured after 48 - 72 h. The tuberculin skin test (TST) has a sensitivity ranging between 33% and 96% and specificity of 62.5%. QuantiFeron and Elispot are FDA-approved tests that assess sensitizations to MTB by measuring the amount of interferon-gamma release (IGRA) secreted from lymphocytes. QuantiFeron has 89% and 99% sensitivity and specificity, respectively, while Elispot has 98.8% and 100% sensitivity and specificity. Thus, these tests can determine TB even in patients who have received previous BCG and active disease, too [44] [45] [46] [47] [48].

The proportion of BCG-vaccinated people who had a positive TST has been reported to vary from 0% to 90% [45]. Apart from children under six years, any person considered for BCG immunization must first be given a skin test for hypersensitivity to tuberculo protein. The skin test is not necessary for a child under 6 years provided the child has not stayed for longer than three months in a country with an incidence of tuberculosis greater than 40 per 100,000, the child has not had contact with a person with tuberculosis, and there is no family history of tuberculosis during the last five years [14].

A positive test can result from clinical or latent infection due to M. tuberculosis, from BCG vaccination, and from environmental mycobacteria [47] [49].

Rare cases of anaphylactic reactions and foreign body reactions involving a Mantoux test site have been reported. There is no chance of TB development from this test, as live bacteria are not used in it. Rare occurrences of local reactions, such as regional lymphangitis and adenitis, were also reported [46].

Inactive cases of TB, immunosuppression, and old age are considered to be a contraindication to PPD. It should be used with caution in pregnant women as it is pregnancy category C.