An open labelled prospective clinical study to evaluate the ef icacy , safety and cost analysis of Pidotimod as add-on drug for maintenance therapy in Paediatric Recurrent Acute Respiratory tract Infections

Nagaraju K*1, Karthik N2, Porchelvan S3, Rishi Jain4, Snehal Muchhala5 1Division of Allergy & Clinical immunology, Saveetha Medical college, Chennai602105, India 2VN Allergy & Asthma Research Centre, Chennai-60045, India 3Department of Biostatistics, Saveetha medical college, Chennai-602105, India 4Medico marketing, Wockhardt Limited, Mumbai 40005, India 5Medical Operations, Wockhardt Limited, Mumbai 40005, India


INTRODUCTION
Acute respiratory tract infection (ARTI) forms the most common infection af licting children worldwide. Irrespective of the socioeconomic and geographical conditions, children get at least 3-6 episodes of ARTI per year (Kamath et al., 1969;Monto, 1974). In India, the incidence peaks in winter and autumn (Kumar et al., 2015). The prevalence rate of ARTI was reported to be high (59%) among children less than 5 years in rural and urban areas of South India (Kumar et al., 2015). There is a higher incidence of ARTI in South East Asian countries when compared to global statistics (Selvaraj et al., 2014). It is well known that smoke, pollution, dampness and passive smoking predispose children to ARTI (de Martino and Ballotti, 2007;Karevold, 2006;Zhang et al., 2014). ARTI results in not only morbidity, but also considerable expenditure for medical consultations, treatments, emergency care and hospital admissions (Wheeler, 1995). Often indiscriminate use of routine antibiotics coupled with easy OTC availability in India complicates the issue further by inducing antibiotic resistance (van de Pol et al., 2013;Del-Rio-Navarro et al., 2006). In fact, 75% of prescriptions in ARTI contain antibiotics. The cost of management escalates as we consider the impact of loss of school days and loss of man-days for the working parents (McCutcheon and Fitzgerald, 2001). RRTI is facilitated by a decreased immune response in early life, both innate and adaptive. Various approaches have been tried to reduce the recurrence of ARTI (Dharnidharka et al., 2014). Immaturity of immune response involving neutrophils, NK cells, T and B cells, in early childhood, is often cited as a reason for this RRTI (Raniszewska et al., 2015).
Nonspeci ic enhancement of immune response is one among the functional approaches tried to prevent the recurrent ARTI (Zuccotti and Mameli, 2013). Both synthetic and natural sources of immune stimulant have been tried to prevent ARTI (Zuccotti and Mameli, 2013). One such synthetic immune stimulant-Pidotimod (3-lpyroglutamyl-1-thiazolidine-4-carboxylic acid) has both biological and immunological activity over adaptive and innate immune responses, and is authorised for use in children more than three years of age (Mameli et al., 2015). However, in India, Drug Controller General of India has approved its use for children 2 years and above. Pidotimod is known to effect immune stimulatory activity via T cells and granulocytes (Zuccotti and Mameli, 2013). Mameli et al and Licari et al showed that Pidotimod may prevent recurrence of ARTI (Caramia et al., 1994;Licari et al., 2014). The safety pro ile and ef icacy of Pidotimod was upheld by a recent meta-analysis of 29 clinical trials on ARTI in children. It has been shown to be superior to conventional treatment in terms of reduction in recurrence, duration of symptoms and antibiotic usage (Niu et al., 2019). It was shown to decrease the duration of cough and fever in ARTI. There was a signi icant increase in serum immune globulins (IgG,IgA,IgM) and T lympocyte subtypes (CD3+,CD4+) in children who used pidotimod (Niu et al., 2019).

MATERIALS AND METHODS
This is a prospective, open label, non-comparative, single arm exploratory and interventional study conducted at Saveetha Medical college Hospital, Chennai between May 2018 to April 2019. The trial was initiated after prior approval from the Institutional Ethical Committee (013/05/2016/IEC/SU) and it was registered under the Clinical Trial registration No: CTRI/2018/02/011898. All children from 2 to 12 years of age of both sexes with recurrent ARTI (de ined as ≥ 3 episodes per year or ≥ 15 days of respiratory illness in the past three months), (Paramesh et al., 2017) were followed up for two months before inclusion in the study. Those patients who were allergic to the drug under study or had been vaccinated in the last three months for respiratory illness or diagnosed with congenital or acquired immune de iciency like HIV, or who were on antibiotic or steroids or any immune modulatory drugs or those with other co-morbid illness which could interfere with successful participation were excluded. 65 patients were enrolled after obtaining informed written consent. The uses, side effects, possibility of withdrawal from the study at any point of time were explained to the parents following the declaration of Helsinki (Figure 1).
All eligible children received Pidotimod 400 mg twice daily before meals for 15 days (800 mg/day) followed by 400 mg once daily for 45 days in addition to the standard therapy as per institutional protocol. Pidotimod was made available as liquid Immulina TM 200 mL (strength of 400 mg/7 mL) and as tablets Immulina (400 mg).
Each child was assessed at the beginning of the study (baseline data) with a medical history, physical examination, number and duration of ARTI episodes, episodes requiring antibiotics usage, average duration of antibiotic usage, rescue medications, number and duration of hospitalization, concomitant medications administered and adverse effects of Pidotimod. This was monitored at 2 months and at 6 months from the date of inclusion (Figure 1). Expenditure incurred prior to treatment with Pidotimod was analyzed from data obtained by parental recall and verifying the actual bills. The same was assessed during the trial also. As part of the exploratory approach, absolute count of CD markers (CD 45,3,4,8), Lymphocyte and total leucocyte count (TLC) were measured at baseline and after completion of therapy (at 6 months).
Statistical analysis: the number and duration of ARTI episodes, episodes requiring antibiotics along with their average duration, number and duration of episodes of hospitalizations were analysed by   paired t-test /Wilcoxson signed Rank test. The analysis of safety data and exploratory analysis was done using descriptive statistics. P-value<0.05 was considered as statistically signi icant.

RESULTS AND DISCUSSION
Out of the 65 children who enrolled after valid consent, 14 discontinued (n=5 logistical reasons, 7 shifted residence and 2 for unknown reasons) and 51 completed the study. (Figure 1. Follow-up). 61.4% were males with a mean age of 4.6 ± 2.09 years. There was a signi icant reduction in the mean number of episodes of ARTI in the 6 months followup period ( The number of ARTI episodes requiring antibiotics (7.07± 1.88 vs 1.85± 1,2; p<0.001) and mean duration of antibiotic usage (6.59± 1.76 vs 2.28 ± 0.98; p< 0.01) were signi icantly reduced during follow-up period of 6 months following Pidotimod use. The mean school days lost for children due to ARTI also reduced signi icantly (p<0.001) ( Table 1). Changes in Absolute lymphocyte count and CD markers (CD45,3,4,8) were found to be statistically signi icant though TLC showed an insignificant reduction after Pidotimod use (Table 2; Figure 2). 14% reported adverse reactions though most of them were mild and self-limiting. (Figure 3).
The present study clearly demonstrates that Pidotimod has good ef icacy in the management of recurrent ARTI in children of 2 to 12 years of age. Das et. Al. in their study had also concluded that Pidotimod signi icantly decreases the RRTI (Das et al., 2017). This study reports that Pidotimod is cost effective in the management of recurrent ARTI since the intervention demonstrates a reduction in average treatment cost, number and duration of ARTI episodes, hospitalizations, antibiotic use and days lost due to illness, which is similar to other studies reported. 20. Present study also reports that there is a signi icant reduction in antibiotic use following Pidotimod treatment, reducing the possibility of antibiotic resistance. All these indings are similar to some studies reported recently. One study involving 100 children with a mean of 4.9 years with history of at least 6 episodes in 1 year found that Pidotimod treatment improved symptoms of ARTI along with concomitant reduction of use of medication including antibiotics and loss of school days (Caramia et al., 1994).
It was also observed that in the present study, that 60-day Pidotimod therapy resulted in, signi icantly decreased antibiotic usage and gave a 2-fold reduction rate of ARTI recurrence within a 3-month period. They also had milder ARTI with early recovery as found in similar study (Namazova-Baranova et al., 2014).
Current study also shows an increase in absolute CD count and lymphocyte count at completion of 2 months of treatment, suggesting that Pidotimod might signi icantly increase the activity of immune system. This enhancement of immune response may be the reason for better reduction in RRTI which was also corroborated in another study (Zhang et al., 2014).
Signi icant reduction in health care expenditure in the present study after Pidotimod therapy is similar to the indings of Asha Goyal et .al., although it was performed in adults (Goyal, 2018). Current study is the irst of its kind showing cost effectiveness of using Pidotimod in ARTI in children.
The adverse events reported were mild and selflimiting and were within reasonable limits (14%). This is congruent with a recent meta-analysis which shows only 5% mild and transient adverse reactions while using Pidotimod. There was no statistically signi icant increase in adverse effects with the use of Pidotimod (Namazova- Baranova et al., 2014). This is also the irst Indian study which gauges the use and effects of Pidotimod for 6 months and also evaluates the immune stimulant nature through an objective measurement of immune markers.
Though the absence of use of a placebo or randomization can be explained by the fact that it is a study done on an experimental drug on compassionate grounds, and being a non-blinded study by itself may be considered as limitations of the present study. Further we are not ruling out the possibility of a recall bias. Hence there is a need for a randomized controlled trial to generate con irmatory data on ef icacy, cost bene its and safety of Pidotimod therapy.

CONCLUSIONS
The role of Pidotimod in prevention and treatment of recurrent ARTI in children is reinforced by the present study with opportunities for signi icant health care cost bene its in developing nations. The immune stimulant activity further supports the potential use of Pidotimod along with the current standard care in the management of ARTI in children.