ABSTRACT
Recurrent respiratory papillomatosis (RRP) is a rare disease, characterized by recurrent proliferation of benign squamous cell papillomas in the larynx as well as in the other parts of the aerodigestive tract. We have compared different treatment options for RRP of the aerodigestive tract including surgical, conservative and combined approaches. A total of 43 patients with papillomatosis that received a combined therapy were followed in the period from 2009 to 2013. The treatment included electrosurgery and CO2 laser surgery alongside with either immunotherapy with Bacillus Calmette-Guerin (BCG) (Calgevax) or α-interferon. In the control group without immunotherapy (n = 16) we used conventional microlaryngeal surgery. During the follow-up, relapse occurred in two patients for the CO2 laser surgery with Calgevax immunotherapy group (n = 16). In the group treated with α-interferon preceded by CO2 laser surgery (n = 9) and electrosurgery (n = 2), relapse had occurred in three patients. Among the control group, recurrence was observed in six patients. This required re-operation. Our data showed a three times more frequent relapses among patients who were operated with conventional surgery as compared to those operated with CO2 laser surgery and Calgevax immunotherapy, and two times more often relapses in patients operated with conventional surgery as compared to those with electrosurgery and CO2 laser surgery and application of α-interferon therapy. Conventional and laser surgeries have a palliative effect, though playing an important role in ensuring the airway patency. While specific antivirus treatment for human papilloma viruses does not exist, the immune modulation with Calgevax considerably reduces the frequency of relapses, by stimulating cellular immune effector mechanisms. The combined protocol allows rarefication of relapses and improvement of patients' quality of life, but not complete healing.
ABSTRACT
BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a rare manifestation of human papilloma virus (HPV) infection with extremely high relapse frequency, poorly understood immunopathogenesis, and lack of efficient treatment. Immunotherapy with Calgevax (BCG) in combination with CO2 surgery significantly improves the outcome of RRP. The present study investigates cellular immunity parameters in RRP patients, and the effects of 20-month Calgevax immunomodulation. MATERIALS AND METHODS: RRP patients (n = 15) subjected to combined therapy were tested before, 6, 12 and 20 months after the start of immunomodulation. Absolute counts and percentage of T, B and NK cells, effector T1 (CD8 + IFNgamma+); Th1 (CD4+IFNgamma+), Th17 (CD4+IL-17+) and regulatory (CD4+FoxP3+) T lymphocytes, as well as the in vitro stimulated secretion of IL-2, IL-4, IL-5, IL-10, IFNgamma and TNFalpha were determined by flow cytometry (FACSCanto II, BD). RESULTS: While no significant changes were detected in the circulating T, B and NK subsets, RRP patients presented increased proportions of Tc1, Th1 and Th17 cells, and significantly reduced IFNgamma/IL-4 and IFNgamma/IL-10 ratios as compared to healthy controls (15% vs. 8%), (58 vs. 139 and 15 vs. 26, respectively), p < 0.05 for all comparisons. Increased Treg (9% vs. 4%), and decreased Th17 effectors share (0.7% vs. 0.4%) were observed at 12 months, while IFNgamma/IL-4 and IFNgamma/IL-10 ratios were restored after 20 months of Calgevax application. CONCLUSIONS: Antiviral response closely depends on cytokine background. Calgevax potentiates Treg differentiation at the expense of proinflammatory Th17, limits hyperactivation and virus-specific T cell clones depletion, and restores a Th1 cytokine background.
