Efficacy and Safety Profile of Tuberculin Protein Purified Derivative Injection As Immunotherapy For the Treatment of Cutaneous and Anogenital Warts: A Review Article

Figures & data

Table 1 Clinical Trials Using PPD Immunotherapy in Cutaneous and Anogenital Warts

Authors, Years, Country	Study Design	Treatment Arms(s)	Participants	Type of Warts	Follow-up Duration (Months)	Protocols	Complete Response (%)	Recurrences (%)	Side Effects
Abd- Elazeim et al^Citation16 2014 (Egypt)	RCT	PPD (A) Saline (B)	A: 20 B: 20	Recalcitrant; common	Group A: Test dose: 0.1 mL PPD, intradermal on forearm Treatment: volume injected determined by the size of skin test reactivity according to Johnson et al^Citation20 0.3; 0.2; and 0.1 mL if the reaction diameter was 5–20, 21–40, and >40 mm (intralesion on largest wart) Group B: 0.3 mL normal saline, intralesion on largest wart Weekly interval, max. 6 sessions	Target warts: A: 75 B: 0 Distant warts: A: 25 B: 0	10	6	Pain, mild erythema, swelling, transient post-hypopigmentation
Abou-Taleb et al^Citation18 2019 (Egypt)	RCT	PPD (A) Vitamin D3 (B)	A: 22 B: 23	Simple, recalcitrant; common, plantar	Group A: Test dose: 0.1 mL PPD-5TU, intradermal Treatment: volume injected determined by the size of skin test reactivity according to Kus et al^Citation13 0.3; 0.2; and 0.1 mL if the reaction diameter was 5–9, 10–15, and >15 mm (intralesion, max. 3 lesions) Group B: Injection of 0.1 mL lignocaine (20 mg/mL) followed by injection of 0.6 mL vitamin D3 (intralesion on max. 3 lesions) 3 weeks interval, max. 3 sessions	Target warts: A: 72.7 B: 43.5 Distant warts: A: 59.1 B: 21.7	0	3	A: tolerable pain, erythema, edema B: severe pain (needed anesthesia), erythema, edema, itching
Ahmed et al^Citation21 2020 (India)	RCT	Vitamin D3 (A) MR (B) PPD (C)	A: 15 B: 15 C: 15	Simple; common, plane, palmo-plantar, filiform	Group A: 2 units of vitamin D3 600.000 (15 mg/mL) Group B: 2 units of MR vaccine (0.5 mL/dose) Group C: 2 units of PPD-5TU (0.1 mL/dose) Injected into 2 largest warts 2-weeks interval, min. 3 injections	A: 25.5 B: 9.3 C: 23.2	A: 6.66 B: 0 C: 6.66	6	A: mild pain, persistent swelling, necrosis at injection site C: mild swelling, fever, erythema, itching
Alajlan,^Citation22 2020 (Saudi Arabia)	Open label study	PPD (A) Saline (B)	A: 62 B: 20	Recalcitrant; common	Test dose: Group A: 0.1 mL PPD-5TU, intradermal on forearm Group B: 0.1 mL normal saline, intradermal on forearm Treatment: Group A: 0.1 mL PPD-5TU, intradermal on 1 or 2 warts Group B: 0.1 mL normal saline, intradermal on 1 wart 3 weeks interval, max. 3 sessions	A: 79 B: 10	0	3	Pain at injection sites
Amirnia et al^Citation11 2015 (Iran)	RCT	PPD (A) Saline (B) Cryo-therapy (C)	A: 35 B: 34 C: 33	Recalcitrant; common, plantar, anogenital/mucous membrane	Group A: Test dose: 0.1 mL PPD, intradermal on forearm Treatment: volume injected determined by the size of skin test reactivity according to Johnson et al^Citation20 (intralesion on largest wart) Group B: 0.3 mL of saline, intralesion on largest wart Group C: liquid nitrogen spray applied perpendicularly to the largest wart at a distance of 2 cm, 2 mm margin (3 freeze-thaw cycles) 2-weeks interval, max. 6 sessions	Target warts: A: 77.1 B: 0 C: 18.2 Distant warts: A: 85.7	A: 8.6 B: 5.9 C: 24.2	6	C: pain, blister, erythema, swelling, hyperpigmented scar None observed on PPD and placebo group
Awad et el.^Citation23 2022 (Egypt)	RCT	PPD (A) Cryo-therapy + PPD (B)	A: 25 B: 25	Simple, recalcitrant; common	Group A: Test dose: 0.1 mL PPD-5TU, intradermal on forearm Treatment: volume injected determined by the size of skin test reactivity according to Kus et al^Citation13 (intralesion on largest wart) Group B: cryotherapy applied for all lesions using liquid nitrogen spray at a distance of 1 cm, margin 1–2 mm (single freezing cycle) followed by intralesional PPD injection into the largest wart 2-weeks interval, max. 4 sessions	A: 48 B: 44	A: 20 B: 0	2	Both groups: pain, redness, edema B: blistering, hypopigmentation
Awad et al^Citation24 2022 (Egypt)	RCT	PPD (1) Zinc sulfate 2% (2)	1: 60 2: 60 (pediatric)	Simple, recalcitrant; common, plantar, anogenital	Group 1: 0.1 mL PPD, intralesion on largest wart Group 2: Zinc sulfate 2%, intralesion on largest wart 2-weeks interval, max. 5 sessions	Target warts: 1: 83.3 2: 93.4 Distant warts: 1: 81.7 2: 81.7	1: 1.7 2: 10	6	1: pain, itching, fever, acute urticaria 2: pain, inflammation, necrosis, ulceration, necrosis, scar, itching, fever, scarring alopecia
Azab et al^Citation15 2022 (Egypt)	RCT	PPD (1) Control (2)	1: 63 2: 50	Simple, recalcitrant; ano-genital	Test dose: 0.1 mL PPD, intradermal on forearm Group 1: PPD-10TU, intralesion on largest wart, 2-weeks interval for 6 sessions Group 2: included healthy individuals, no treatment given Measurements of IL-17 in all patients before and after PPD injection in group 1, and to all control subjects in group 2	Target warts: 1: 58.7 Distant warts: 2: 66.7	1: 23.3	3	Pain, edema, systemic symptoms, erythema, swelling, hypo or hyper-pigmentation
Bhalala et al^Citation25 2022 (India)	RCT	PPD (A) MMR (B) Saline (C)	A: 27 B: 25 C: 21	Simple, recalcitrant; common, plane, palmoplantar, periungual, anogenital	Group A: 0.1 mL PPD, intralesion on largest wart Group B: 0.1 mL MMR, intralesion on largest wart Group C: 0.1 mL normal saline, intralesion on largest wart 2-weeks interval, max. 4 sessions	A: 51.85 B: 56 C: 0	A: 1 patient	6	All groups: pain A: scarring, swelling B: flu-like symptoms
Bharga-va et al^Citation26 2021 (India)	RCT	PPD	40	Simple, recalcitrant; common, plantar, palmar, plane, periungual	0.01 mL PPD 5-TU, intralesion on the largest wart Weekly interval for 4 weeks	65	N/A	N/A	N/A
Chandra et al^Citation27 2019 (India)	RCT	PPD (A) Mw (B)	A: 32 B: 32	Simple, recalcitrant; common, plane, palmo-plantar, periungual	Test dose on all patients: 0.1 mL PPD-10TU, intradermal on forearm Group A: 0.1 mL PPD-10TU, intradermal on deltoid region Group B: 0.1 mL Mw vaccine, intradermal on deltoid region 2-weeks interval, max. 6 sessions	A: 50 B: 68.8	0	3	A: hyper-pigmentation, erythema, scaling, pruritus B: indurated nodule after every injection that healed with scarring, ulceration, erythema, scaling, pruritus
Chou-dhary et al^Citation12 2018 (Nepal)	Open label study	PPD	52	Simple, recalcitrant; common, plantar, plane, periungual	PPD-2.5TU into each wart until lesions blanched, max. 25 TU in 1 session 2-weeks interval, max. 5 sessions	78.8	0	6	Erythema, pain, edema, low-grade fever
Diab et al^Citation4 2021 (Egypt)	RCT	PPD	20	Simple, recalcitrant; common	0.01 mL PPD-5TU, intralesion on largest wart 2-weeks interval, max. 6 sessions	35	0	6	Pain, myalgias, fever, erythema, edema, skin pigmentation
Diab et al^Citation28 2021 (Egypt)	RCT	PPD (A) PPD + iso-tretinoin (B)	A: 20 B: 20	Simple, recalcitrant; common, plantar	Group A: 0.1 mL PPD, intralesion on largest wart, 2-weeks interval, max. 6 sessions Group B: PPD as given in group A + low dose isotretinoin (0.2–0.4 mg/kg/day) for 3 months	A: 35 B: 55	A: 0 B: 9.1	3	All groups: erythema, edema, pain, dis-pigmentation, fever, myalgias B: cheilitis, dry skin
Durga-devi et al^Citation29 2018 (India)	Open label study	PPD (1) Topical 5% 5-fluorouracil (2)	1: 25 2: 25	Simple, recalcitrant; peri-ungual, warts in other areas (not mentioned in detail)	Group 1: PPD-1TU, volume injected determined by size of skin test reactivity according to Johnson et al^Citation20 intralesion on one randomly selected lesion, 3-weeks interval, max. 6 sessions Group 2: topical 5% 5-FU applied on the lesion(s) selected by investigator, under occlusion daily during the night and left for 12 hours, for 3 months	1: 88 2: 20	0	3	1: none 2: paronychia, edema, pain, erythema
Eassa et al^Citation30 2011 (Egypt)	RCT	PPD (A) Distilled water (B)	A: 20 B: 20 (preg-nant)	Recalcitrant; ano-genital	Tuberculin test on all patients: 0.1 mL PPD-2TU, intradermal on forearm Group A: 0.1 mL PPD, intradermal on middle third of ventral aspect of both forearm, repeated weekly for 12 weeks Group B: 0.1 mL distilled water at similar site as in Group A, repeated weekly for 4 weeks then shifted to 0.1 mL PPD weekly for 12 weeks	A: 50 B: 45	0	>6	Pain, erythema, tenderness
Elela et al^Citation31 2011 (Egypt)	RCT	PPD intra-lesion (1) PPD intra-dermal (2) Saline (3)	1: 40 2: 50 3: 20	Simple, recalcitrant; common, plantar, plane	Group 1: 0.1 mL PPD, intralesion Group 2: 0.1 mL PPD, intradermal into the right forearm Group 3: 0.1 mL normal saline, intralesion 2-weeks interval, max. 10 injections	1: 94.1 2: 96 3: 15	N/A	N/A	N/A
Farhana et al^Citation32 2018 (India)	RCT	Vitamin D3 (A) PPD (B)	A: 10 B: 10	Simple, recalcitrant; common, plantar, periungual	Group A: 0.2 mL (15 mg/mL) vitamin D3, intralesion per wart Group B: 0.2 mL PPD-5TU, intralesion per wart 2-weeks interval until complete clearance	A: 70 B: 80	A: 10 B: 0	3	Pain, erythema, swelling, itching
Fatima et al^Citation33 2019 (Pakistan)	Quasi experi-mental	PPD (A) Cryo-therapy (B)	A: 30 B: 30	Cutaneous warts	Group A: 0.1 mL PPD-5TU, intralesion on largest wart Group B: cryotherapy using liquid nitrogen by direct application using orange stick with cotton tip for (2 freeze-thaw cycles) 2-weeks interval, max. 6 sessions	A: 70 B: 30	N/A	3	N/A
Fawzy et al^Citation34 2020 (Egypt)	RCT	PPD (1) Candida (2) MMR (3)	1: 40 2: 40 3: 40	Simple, recalcitrant; plane	Group 1: 0.1 mL PPD, intralesion on largest wart Group 2: 0.1 mL of 1/1000 solution of Candida antigen, intralesion on largest wart Group 3: 0.1 mL MMR vaccine, intralesion on largest wart 2-weeks interval, max. 5 sessions	1: 55 2: 70 3: 62.5	1: 7.5 2: 0 3: 0	6	All groups: pain, erythema, edema, flu-like symptoms
Ghaly et al^Citation35 2020 (Egypt)	RCT	PPD (1) Vitamin D3 (2) Saline (3)	1: 20 2: 20 3: 20	Simple; plantar	Group 1: PPD-5TU, volume injected determined by the size of skin test reactivity according to Kus et al^Citation13 intralesion on largest wart, 2-weeks interval, max. 3 sessions Group 2: 0.2 mL (300.000 IU 7.5 mg/mL) vitamin D3, intralesion on largest wart after prilocaine injection, 4-weeks interval, max. 3 sessions Group 3: 0.3 mL normal saline, intralesion on largest wart, 2-weeks interval, max. 3 sessions	Target wart: 1: 50 2: 70 3: 0 Distant wart: 1: 37.5 2: 25 3: 0	0 in all groups	6	1: pain, hyper-pigmentation, flu-like symptoms, erythematous edema 2: hyper-pigmentation, pain 3: none
Ibrahim et al^Citation36 2021 (Egypt)	RCT	Cryo-therapy (A) PPD (B) Cryo-therapy + PPD (C)	A: 25 B: 25 C: 25	Simple, recalcitrant; common	Group A: cryogun sprayed at distance of 1 cm, margin 1–5 mm (single freeze-thaw cycle) Group B: 0.1 mL PPD-10TU, intralesion on largest wart Group C: 0.1 mL PPD-10TU, intralesion on largest wart followed by spraying all warts with cryogun 2-weeks interval, max. 4 sessions	A: 24 B: 48 C: 84	N/A	2 weeks	A: pain, edema, hypopigmentation, bullae formation B: pain, erythema, edema, flu-like symptoms C: pain, edema, bullae, hypo-pigmentation, erythema, flu-like symptoms
Jain et al^Citation37 2021 (India)	Open label study	Vitamin D3 (1) MMR (2) PPD (3)	1: 20 2: 20 3: 20	Recalcitrant; common, plane, palmoplantar, periungual, subungual	Group 1: 0.2 mL (15 mg/mL) vitamin D3, intralesion on largest wart or 2 warts after lignocaine injection Group 2: 0.5 mL MMR vaccine, intralesion on largest wart or 2 warts Group 3: 0.1 mL PPD-10TU, intralesion on largest wart or 2 warts 2-weeks interval, max. 4 sessions	Target wart: 1: 80 2: 90 3: 85 Distant wart: 1: 70 2: 85 3: 75	1: 8.3 None in other groups	3	1: itching, swelling with itching, swelling with pain, dys-pigmentation 2: acute urticaria exacerbation, itching, swelling, swelling with pain, dyspigmentation 3: itching, swelling with exfoliation, swelling with itching, swelling with pain, dyspigmentation
Jaiswal et al^Citation38 2019 (India)	RCT	PPD	51	Simple, recalcitrant; common, palmoplantar, plane, periungual, anogenital	0.01 mL PPD-5TU, intralesion on largest wart Weekly interval, max. 6 sessions	68.6	N/A	3	Pain, swelling, erythema
Kaimal et al^Citation39 2020 (India)	Open label study	PPD	28	Cryotherapy- resistant; common, palmo-plantar, periungual	0.01 mL PPD-2TU, intralesion into index wart (oldest and/or largest wart) 2-weeks interval, max. 6 sessions	50	0	3	Pain, edema
Milante et al^Citation40 2019 (Philip-pines)	Randomized, open-label, superiority trial	Single injection PPD (1) Multiple injection PPD (2)	1: 29 2: 29	Simple, recalcitrant; common	Test dose: 0.1 mL PPD-5TU, intradermal on forearm Group 1: PPD-5TU, volume injected determined by by the size of skin test reactivity according to Kus et al^Citation13 intralesion on largest wart Group 2: PPD–5TU, intralesion on all lesions, volume injected determined as maximum 88 TU or 1.76 mL 2-weeks interval, max. 6 sessions	1: 58.6 2: 79.3	0 in all groups	6	1: pain, fever, malaise, edema, pain 2: fever, malaise, edema, vesiculation, more painful than group 1
Mishra et al^Citation14 2022 (Nepal)	Open label study	PPD	54	Simple, recalcitrant; palmo-plantar, periungual	0.01 mL PPD, intralesion on the largest wart 2-weeks interval, max. 6 sessions	66.7	11	3	2 cases of local site reaction: intense swelling, pain, and edema requiring therapy discon-tinuation Other: mild erythema, edema, pain
Moham-med et al^Citation41 2020 (Egypt)	RCT	PPD (A) MMR (B) Saline (C)	A: 30 B: 30 C: 30	Recalcitrant; common, plane, plantar, periungual, ano-genital	Test dose: PPD 0.1 mL or MMR 0.1 mL, intradermal on forearm Group A: 0.2 mL PPD (10 TU), intralesion on largest wart Group B: 0.2 mL MMR (20 IU), intralesion on largest wart Group C: 0.2 mL saline, intralesion on largest wart 2-weeks interval, max. 5 sessions	Target warts: A: 60 B: 80 C: 0 Distant warts: A: 60 B: 40 C: 0	N/A	N/A	All groups: minimal pain B: minimal erythema, transient induration
Mohta et al^Citation8 2022 (India)	Randomized, open-label study	Mw (A) PPD (B)	A: 55 B: 47	Simple, recalcitrant; extra-genital	Group A: 0.1–0.2 mL Mw vaccine, intralesion on the largest wart Group B: 0.1–0.2 mL PPD-5TU, intralesion on the largest wart 4-weeks interval, max. 3 sessions	A: 76.3 B: 65.9	0	6	Most common: pain, erythema Rare: fever, nodule formation, transient urticaria
Mohta et al^Citation42 2022 (India)	RCT	PPD (A) Mw (B)	A: 46 B: 51	Recalcitrant; extra-genital	Group A: 0.1 mL PPD, intralesion on largest wart Group B: 0.1 mL Mw vaccine, intralesion on largest wart 4-weeks interval, max. 5 sessions	Target wart: A: 63 B: 76.5 All warts: A: 52.17 B: 62.75	0 in all groups	3	A: erythema, swelling, pruritus, mild fever, generalized urticaria B: mild fever, painful nodule, ulceration, erythema, pruritus
Mou-basher et al^Citation43 2021 (Egypt)	RCT	PPD (A) Cryo-therapy (B) PPD + cryo-therapy (C)	A: 15 B: 15 B: 15	Simple, recalcitrant; anogenital	Group A: PPD, volume injected determined by the size of skin test reactivity according to Johnson et al^Citation20 intralesion, evaluation was done at 2 weeks Group B: liquid nitrogen using cryogun at a distance of 2 cm, margin 2 mm (3 freeze-thaw cycle), 2-weeks interval for 4 sessions	A: 13.3 B: 26.7 C: 46.7	N/A	N/A	A: pain, flu-like symptoms, erythema B: pain, erosion, hypopigmentation C: pain, flu-like symptoms, erythema, hypopigmentation
Nada et al^Citation44 2020 (Egypt)	RCT	PPD	59	Simple, recalcitrant; anogenital	Tuberculin test: 0.1 mL PPD-5TU, intradermal on forearm Treatment: 0.2 mL PPD-5TU, intralesion on the largest wart 2-weeks interval, max. 6 sessions	69.5	32.6	3	Pain, mild erythema, swelling, hypopigmentation
Nimbal-kar et al^Citation45 2022 (India)	RCT	PPD	45	Simple, recalcitrant; common, palmoplantar, filiform, periungual	PPD 10 TU, intralesion on the largest wart 2-weeks interval, max 6 sessions	62.2	0	4	Localized hair loss around injected wart over the scalp, pain and abscess at injection site, hyperpigmentation, urticaria
Nofal et al^Citation46 2020 (Egypt)	RCT	PPD (1) Candida antigen (2) PPD / Candida antigen alternate (3) Saline (4)	1: 36 2: 38 3: 34 4: 35	Simple, recalcitrant; common, plantar, filiform, periungual	Group 1: 0.1 mL PPD, intralesion on largest wart Group 2: 0.1 mL of 1/1000 solution of Candida antigen, intralesion on largest wart Group 3: alternating therapy of intralesional PPD and intralesional Candida antigen on largest wart Group 4: 0.1 mL normal saline, intralesion on largest wart 2-weeks interval, max. 6 sessions	1: 61.1 2: 36.8 3: 70.6 4: 8.6	1: 9.1 4: 33.3	N/A	N/A
Nofal et al^Citation47 2021 (Egypt)	RCT	PPD (1) Candida antigen (2) MMR (3)	1: 50 2: 50 3: 50	Simple, recalcitrant; periungual	Test dose: 0.1 mL of each antigen, intradermal on forearm Group 1: 0.1 mL PPD, intralesion on largest wart Group 2: 0.1 mL of 1/100 solution of Candida antigen, intralesion on largest wart Group 3: 0.1 mL MMR 2-weeks interval, max. 5 sessions	Target warts: 1: 70 2: 80 3: 74 Distant warts: 1: 70 2: 86.7 3: 83.3	0 in all groups	6	All groups: pain, erythema, edema, flu-like symptoms
Nofal et al^Citation48 2022 (Egypt)	RCT	PPD (A) Candida antigen (B) MMR (C) PPD + Candida antigen + MMR (D)	A: 40 B: 40 C: 40 D: 40	Recalcitrant; common, palmar, plantar, plane, filiform, subungual	Group A: 0.3 mL PPD 0.3 mL, intralesion on largest wart Group B: 0.3 mL of 1/100 solution of Candida antigen, intralesion on largest wart Group C: 0.3 mL MMR, intralesion on largest wart Group D: 0.1 mL PPD + Candida antigen 0.1 mL + MMR 0.1 mL (combined in the same syringe), intralesion on largest wart 2-weeks interval, max. 5 sessions	Target warts: A: 57.5 B: 72.5 C: 62.5 D: 77.5 Distant warts: A: 48 B: 61.5 C: 55.5 D: 65	A: 8.7 B: 13.8 C: 12 D: 6.45	6	All groups: pain, erythema and desquamation, blister, edema, flu-like symptoms, hypopigmentation
Podder et al^Citation49 2016 (India)	RCT	BCG (A) PPD (B)	A: 33 B: 27	Simple, recalcitrant; common, plane, palmo-plantar	Group A: 0.1 mL BCGl, intradermal on right arm Group B: 0.1 mL PPD-5TU, intradermal on right arm 4-weeks interval, max. 3 sessions	A: 48.5 B: 18.5	0 in both groups	1	More adverse events in group A: pain, abscess, scar B: pain, scar
Pundir et al^Citation50 2018 (India)	RCT	PPD	40	Simple, recalcitrant; plane warts on face	PPD-2TU, intralesion on each wart, max. 10 TU each session 2-weeks interval, total 4 sessions	65.75	10	6	Erythema, swelling, pain, fever, body ache
Puri,^Citation51 2019 (India)	RCT	PPD	25	Recalcitrant; common, plane, palmoplantar, ano-genital	PPD-2.5TU, intralesion on each wart, max 25 TU each session 3-weeks interval, total 3 sessions	72	8	6	Erythema, edema, pain, fever
Raveen-dra et al^Citation52 2021 (India)	RCT	PPD (A) Vitamin D3 (B)	A: 50 B: 50	Simple, recalcitrant; common, plane, palmo-plantar, periungual, facial	Group A: PPD-2.5TU, intralesion on each lesion, max. 10 lesions or 25 TU each session Group B: 0.1 mL vitamin D3, intralesion on each lesion, max. 10 lesions or 1 mL each session 2-weeks interval for 4 sessions	A: 76 B: 84	A: 4 B: 8	− 1 –6 via tele-phone	Minimal-moderate pain
Saoji et al^Citation53 2016 (India)	Open uncontrolled trial	PPD	55	Simple, recalcitrant; common, plane, plantar	PPD-2.5TU intralesion on each wart, max 10 lesions and 25 TU each session 2 weeks interval, total 4 sessions	76	1.8	6	Erythema, edema, pain, low grade fever, body ache
Sha-heen et al^Citation17 2015 (Egypt)	RCT	MMR (1) PPD (2) Saline (3)	1: 10 2: 10 3: 10	Simple, recalcitrant; common, plane, plantar, periungual, ano-genital	Test dose: 0.1 mL MMR or PPD-5TU, intradermal on forearm Group 1: volume of MMR injected determined by the size of skin test reactivity: 0.3; 0.2; and 0.1 mm of intralesional if the reaction diameter was 5–20 mm, 21–40 mm, and >40 mm (intralesion on largest wart) Group 2: volume of PPD injected determined by the size of skin test reactivity according to Kus et al^Citation13 (intralesion on largest wart only) Group 3: 0.3 mL normal saline, intralesion on largest wart 3-weeks interval, max. 3 sessions	Target wart: 1: 80 2: 60 3: 0 Distant wart: 1: 40 2: 60 3: 0	0	3	All groups: pain 1: erythema, swelling, vasovagal attack 3: vasovagal attack
Shar-quie et al^Citation54 2016 (Iraq)	RCT	PPD (A) Distilled water (B)	30	Simple, recalcitrant; common, plane, plantar	Test dose: 0.1 mL PPD-2TU, intradermal on forearm Group A: PPD-2TU, intralesion on each wart located in the right side of the body until the lesion gets blanched Group B: Distilled water, intralesion on each wart located in the left side of the body until the lesion gets blanched 2-weeks interval, max. 3 sessions	- A: 23.33 - B: 0	0	2	Mild pain
Sil et al^Citation19 2020 (India)	Co-hort	PPD (A) Mw (B) MMR (C)	A: 9 B: 11 C: 12	Simple, recalcitrant; non-genital	Group A: 0.1 mL PPD, intradermal on deltoid region Group B: 0.1 mL Mw vaccine, intradermal on deltoid region Group C: 0.3 mL MMR vaccine, intradermal on deltoid region 2-weeks interval, max. 6 sessions	A: 44.44 B: 45.45 C: 41.66	N/A	N/A	N/A
Sukanya et al^Citation55 2020 (India)	RCT	PPD	25	Simple, recalcitrant; common	PPD-2.5TU, intralesion into into all warts, max. 5 lesions 2-weeks interval, max. 6 sessions	56	N/A	6	Pain, erythema, inflammation, itching
Tawfik et al^Citation56 2022 (Egypt)	RCT	PPD (A) Candida antigen (B)	A: 40 B: 40	Simple; anogenital	Test dose: 0.1 mL PPD and 0.1 mL Candida antigen, intradermal on forearm Group A: PPD-5TU, volume injected determined by the size of skin test reactivity according to Kus et al^Citation13 intralesion on largest wart Group B: Candida antigen 1/1000, volume injected determined by the size of skin test reactivity: 0.3; 0.2; and 0.1 mL if the reaction diameter was 5–20 mm, 21–40 mm, and >40 mm, intralesion on largest wart 2-weeks interval, max. 4 sessions	A: 72.5 B: 85	A: 3.4 B: 2.9	6	All groups: mild pain, burning sensation after injection A: itching, erythema B: erythema, edema
Wan Ahmad Kammal et al^Citation57 2021 (Malay-sia)	RCT	Cryo-therapy (1) PPD (2)	1: 15 2: 15	Simple, recalcitrant; common,	Group 1: liquid nitrogen sprayed perpendicularly at a distance of 2 cm to all warts, margin 2 mm (2 freeze-thaw cycle) Group 2: PPD-2.5TU, intralesion on largest wart 2-weeks interval, max. 6 sessions	1: 73.3 2: 86.7	1: 27.3 2: 13.4	4	1: blister, hypo-pigmentation, hyperpigmentation, compartment-like syndrome-like symptoms and sign with swelling, cyanosis, and hypoaesthesia at the tip of the finger 2: pain, edema, erythema

Table 2 Case Reports Using PPD Immunotherapy in Cutaneous and Anogenital Warts

Authors, Years, Country	Study Design	Treatment Arms(s)	Partici-Pants	Type of Warts	Follow-up Duration (Months)	Protocols	Complete Response (%)	Recurrences (%)	Side Effects
Achdiat et al^Citation58 2022 (Indo-nesia)	Case report	PPD	1	Simple; anogenital	Tuberculin skin test revealed 15 mm induration Treatment: 0.2 mL PPD-2TU, intralesion on one lesion Weekly interval, 3 sessions	Complete clearance on day 46^th	0	24	Pain
Alha-shimi et al^Citation59 2021 (Egypt)	Case report	PPD	1	Simple, anogenital	0.2–0.3 mL PPD, intralesion on 2–3 different lesions at least 2 cm apart 2-weeks interval, 7 sessions	98% clearance after 7 sessions	0	10	Mild discomfort
Manoj et al^Citation60 2019 (India)	Case series	PPD	5	Simple, cutaneous	PPD, intradermal (not mentioned in detail) 2-weeks interval, max. 6 sessions	80	N/A	3–6	Mild pain
Nofal et al^Citation61 2020 (Egypt)	Case series	Candida antigen MMR PPD	2	Recalcitrant; cutaneous	Case 1: 0.3 mL MMR, intralesion on largest wart, 2-weeks interval, for 5 sessions then switched to 0.3 mL Candida antigen solution 1/1000, intralesion on largest wart, 2-weeks interval Case 2: 0.3 mL PPD, intralesion, 2-weeks interval, for 5 sessions then switched to 0.3 mL Candida antigen solution 1/1000, intralesion on largest wart, 2-weeks interval	Both cases: complete clearance after 2^nd session	1: 0 2: 0	1: 24 2: 6	Case 1: pain, erythema, edema, exfoliation, influenza-like symptoms

Figure 1 Flowchart of the article selection process.

Figure 2 Efficacy of Purified Protein Derivative in all studies.

Figure 3 Local adverse events following Purified Protein Derivative injection.

Figure 4 Systemic adverse events following Purified Protein Derivative injection.

Figure 5 Purified Protein Derivative dosage among fixed-dose studies using single injection.

Figure 6 Different treatment intervals between studies.

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