The use of biologics has prevailed over a considerable period. The first biologic to be used therapeutically was vaccines and they were developed from animals. Medical science has witnessed the development of the smallpox vaccine and subsequently, other vaccines like rabies and diphtheria followed [1,2]. The implementation of the Biologics Control Act of 1902 mandated the regulations for producing and licensing of vaccines as this was preceded by the deaths of 22 children involving contaminated diphtheria antitoxin and smallpox vaccine [2]. Good quality health care is now considered the universal right of every human being. The advent of fast-paced lifestyles in modern times has led to an increase in the development of co-morbid conditions which directly and indirectly lead to the development of a wide array of diseases. To combat this, scientists are constantly trying to develop drugs to treat emerging diseases more effectively. Better-quality biologics were developed using recombinant technology and thus widened the spectrum of uses for biologics [3,4]. Infectious diseases, malignancies, rheumatoid arthritis, and other autoimmune conditions became amenable to treatment.  However, this has led to the ever-present problem of the development of adverse drug reactions (ADR). The development of ADRs not only poses a risk to the use of a drug, but inadequate reporting of an ADR is a dent in the safety of the patients. This is of significance not only in adults but of particular importance to the vulnerable pediatric population. The rising count of auto-immune, rheumatological, hematological, and inflammatory diseases among children, is a serious challenge that pediatricians face today. The use of biologicals has become the linchpin in treating malignancies, rheumatological disorders, etc. Though biologicals warranted therapeutic advantages, their mechanism of action did not completely rule out the risk of significant immune-mediated side effects. Biological agents are structurally high molecular weight autologous proteins weighing more than one kDa (KiloDalton) in contrast to most drugs which have molecular weights less than one kDa [5]. While drugs are synthetic compounds, biological agents are produced via molecular genetic techniques and purified from engineered cells [5]. Drugs can be administered either through oral or parenteral routes and undergo metabolism [6]. On the other hand, biological agents are subject to degradation within the gastrointestinal (GI) tract, and hence they require parenteral routes of administration. They undergo various processing mechanisms within the body but are not metabolized. Biologic agents have innate immune-mediated effects as they originate from foreign non-self-proteins, which are not expected to be seen with drugs as they are smaller compounds [7,5].

The proper reporting and evaluation of adverse drug reactions require monitoring diligent monitoring. This is where pharmacovigilance exerts its prowess. Pharmacovigilance is the science related to compiling, monitoring, researching, qualifying, and evaluating the data obtained from healthcare professionals and patients about the adverse effects of drugs, biological and botanical products, as well as those agents used in traditional medicine [8]. The pediatric population is a whole lot more vulnerable, concerning the impact of ADRs. Hence there are stringent guidelines put in place for prescribing new drugs since many of them are marketed without adequate safety data from clinical trials, thereby increasing the threat of drug toxicity [9]. Also, the ADR data in an adult cannot be relied upon to match and justify ADRs in children. Although the diagnosis of malignancies, rheumatoid arthritis, and other autoimmune conditions occurred in the pediatric age group, research in this population was rudimentary. There are very few published data regarding adverse drug reactions in children using biologicals. Hence, we attempt in this study to investigate the ADRs occurring due to biologicals in the pediatric age group.

The study was a prospective observational study conducted during a 1-year period from 2020 to 2021. Children in the age group of one month up to 18 years of age of either gender whose condition required the administration of Biologicals were included in the study. Patients with poor general health conditions, and Glasgow Coma Scale (GCS) less than 15 were excluded from the study. The study was conducted by ethical standards. The study protocol was approved by the Institutional Ethics Committee (IEC). Assent was obtained from the children who were below seven years of age and informed consent was taken from the legal guardian of the child. The children and their families were assured of all confidentiality from the side of the medical practitioners and the institution. Children in the age group of one month up to 18 years of age of either gender, were administered Biologicals and were admitted to the wards under the Department of Pediatrics during the study period. The administration of the biologicals was done by trained nurses. The disease condition of the child determined the type of biological used and the dose administered was calculated depending on the weight of the child. All the healthcare professionals were sensitized about the reporting of adverse drug reactions. The institute where the study was undertaken is a Regional Training Centre (RTC) and an Adverse Drug Reaction Monitoring Centre (AMC) under the Pharmacovigilance Program of India (PvPI). After the administration of biologicals, they were monitored for the development of any ADRs until their discharge from the hospital. Monitoring for adverse effects was done by using a questionnaire that had a list of ADRs reported in standard textbooks and from other data gathered from clinical trials. Using this questionnaire, regular inquiry of the primary caregiver was done and of the health care workers for the occurrences of any ADRs. This was corroborated with laboratory investigations if clinically indicated. Pediatric inpatient and intensive care units were provided with ADR notification forms. The direct reporting of ADR to the pharmacovigilance center through telephone conversation was encouraged. The inpatients included those who were admitted because of an ADR or those who encountered an ADR during the treatment period. The collected reports were documented and analyzed for the demographic profile causality, severity, and preventability. ADRs were classified based on the Anatomical and Therapeutic Classification System 1999 (ATC 1999) [11,12]. Causality of ADRs was assessed by Naranjo’s algorithmic scale which is a questionnaire that classified the suspected ADRs as definite, probable, possible, or doubtful by a scoring method [13]. The severity of the ADRs was assessed by using the Modified Hartwig and Siegel Scale which gives an overview of the severity of the ADR [14]. The preventability of the ADRs was assessed by the Modified Schumock and Thorton scale [15,16]. Based on the proportion of adverse drug reactions in children using biological drugs that were observed in an earlier publication by Mrutunjay D (2015), the minimum sample size calculated was 282 cases. But due to the present COVID-19 (Corona Virus Disease – 19) pandemic situation, a total of 100 cases were included in the study. The percentage of adverse drug reactions, their severity, and causality were computed with a 95% confidence level. The frequency rate of ADRs on exposure to biologicals among children was presented using percentages.  Follow-up and outcome were not within the scope of this study.

A total of 100 children were administered biologicals and the total number of patients with ADRs in the study was 100. A gender-wise distribution (Figure 1: Pie diagram representing the gender-wise distribution of ADR) of ADRs showed a male preponderance with 56% of them being males and 44% being females. The study also revealed that ADRs mainly occurred in the age group between 1 and 5 years of age (Figure 2: Pie diagram representing the age-wise distribution of ADR). The most common route of administration that caused an ADR was when the drugs were administered via the intravenous route (55%), followed by the oral (20%) and intramuscular route (15%). The subcutaneous route (10%) was the least commonly reported. (Figure 3: Pie diagram representing various routes of administration of Biologicals).

Based on the type of ADR- The study pointed out that, the most common ADR reported was thrombophlebitis (26%) followed by vomiting (20%), constipation (1%), headache (13%), and abdominal pain (10%).

Figure 1: Gender-wise distribution of Adverse Drug Reactions.

Figure 2: Age-wise distribution of Adverse Drug Reactions.

Figure 3: Various routes of administration of biologicals.

Based on System Involvement- The ADRs (Figure 4) that were reported were found to impact the hematological system (42%) the most, followed by the cardiovascular system (18%) and the rheumatological system (10%).

Figure 4: Various types of adverse drug reactions caused by biologicals.

Figure 5: Bar diagram representing the frequency of ADRs associated with each system.

Figure 6: Bar diagram representing the Biologicals Causing the ADRs.

Figure 7: Bar diagram showing the various diagnosis associated with ADR.

Based on the drug involved- Among all the drugs causing ADRs, the highest incidence reported was due to intravenous immunoglobulins (IV-IG) (28%), Granulocyte -Colony Stimulating Factor (G-CSF) (18%), enoxaparin (8%), cyclophosphamide (7%) and cytarabine (6%).

Based on the Diagnosis Associated with ADR- The ADRs that were reported were found to be most associated with patients diagnosed with leukemia (30%) followed by Multisystem Inflammatory Syndrome in Children – Covid-19 (MISC-Covid 19) (16%) and encephalitis (7%).

Based on the drug and the ADR associated with it - An observation was made that among all the reported adverse drug reactions, constipation caused by G-CSF (18%) was the common reaction. This was succeeded by IV-IG causing both thrombophlebitis (15%) and headache (13%). Enoxaparin and cyclophosphamide were reported to have caused thrombophlebitis (8%) and vomiting (7%) (Figure 8).

Figure 8: Bar diagram showing the top 5 drugs causing ADRs.

Figure 9: Bar diagram showing the causality of an ADR assessed using Naranjo’s Scale.

Figure 10: Bar diagram showing the severity of ADR assessed using the Modified Hartwig Seigel Scale.

Figure 11: Bar diagram showing the preventability of ADR assessed using the Modified Schumok Thorton Scale.

Based on Naranjo Scale- Naranjo’s Adverse Drug Reaction Probability scale inferred that an adverse reaction attributed to a particular drug would “definitely” occur if it was used in 60% of the patients. The “possibility” and “probability” of an ADR to a particular drug were reported to be 23% and 17% respectively. There was no “doubtful” category of ADRs reported.

Based on the Modified Hartwig Scale- Based on the Hartwig scale, the severity of the ADRs that were reported was assessed. It alluded that 55% of the ADRs were mild and 45% were found to be of moderate severity. None of the ADRs was reported in the severe category of reactions.

Based on the Modified Schumock Thorton Scale - It was implied that 64% of the ADRs reported were “probably preventable” and 36% were “definitely preventable”, though, none were in the “not preventable” category. The most used biologicals in this study were IV-IG and G-CSF. The diseases that frequently required intervention with biological therapy were leukemias and Multisystem Inflammatory Syndrome in Children (MIS-C) secondary to Covid-19. The adverse reactions were all easily manageable and did not endanger the life of any of the subjected vulnerable children. With the ever-increasing incidence of leukemia, auto-inflammatory, and, auto-immune diseases, etc., the use of biologicals is warranted at a greater intensity without being associated with adverse reactions.

This study explored the frequency of ADRs in biologicals consumed by children. A total of 100 cases were included in the study, of which 56% were males and 44% were females (Figure 1). The male-to-female ratio among the participants was 14:11. In comparison to the study conducted by Sindhu AR (2019), a total of 15 cases were included, out of which 53% were male and 45% were female. In another study conducted by Mrutunjay Dash (2015), a total of 127 cases were included of which 37% were males and 62% were females. The present study showed that most of the ADRs occurred in the age group between 1 to 5 years (Figure 2). In the study by Chiara Nasso (2020), the median age of children was found to be 2.5 years. The study conducted by T.V.S. Divyalasya (2003) showed that most ADRs occur in children below the age of 1 year. The most common ADR in the current study associated with the use of a biological was thrombophlebitis (26%) (Figure 4).  A study done by R. Priyadarshini (2011) found that the most common ADRs were rashes and urticaria. It was noted that 42% of ADRs occurred due to diseases involving the hematological system followed by cardiovascular (18%) and rheumatological system (10%) (Figure 5). This finding contrasts with the study conducted by Sindhu AR et al (2019) in which the maximum number of ADRs (46%) was found in the skin and subcutaneous tissue. The most common biological cause of ADR in the present study was IV-IG (28%) (Figure 6). As per the study by Sindhu AR (2019), children developed more ADRs due to the rising use of antibiotics. In another study by T.V.S. Divyalasya (2003), it was observed that vaccines were the commonest agents causing ADRs. The current study revealed that the most common diagnosis associated with an ADR was seen in leukemia (30%) (Figure 7). In contrast, in the study conducted by Olga Morales-Rios, neoplasms were the most common diagnosis associated with ADR. The causality of the ADR assessed by Naranjo’s probability scale brought out the maximum number of ADRs under the “definite” category (60%) and none in the “doubtful” category (Figure 9). When compared to the study results of Mrutunjay Dash (2015), the ADRs mostly were observed to be under the “probable” category and no ADRs were under the “definite” category. The modified Hartwig scale was used to study the severity of ADR which revealed that most of the ADRs were in the mild (55%) category, 45% were in the moderate category of reactions and no “severe” cases of ADR were reported in our study (Figure 10). This was like the results of the study conducted by Mrutunjay Dash (2015) in which most of the ADRs were reported to be mild. This observation contrasted with another study by Kishor Kumar Digra (2015), in which most of the ADRs were moderate reactions. According to the Modified Schumock Thorton Scale, 64% of the ADRs in our study were “probably preventable”. (Figure 11) These observations are in stark contrast with the findings published by Reeja R (2021), where most of the ADRs were categorized under the “not preventable” category.

The effective treatment of the pediatric age group with minimal adverse effects is a challenge. The emergence and use of newly developed drugs that could provide effective treatment and improve the quality of life in these patients, often lure and tempt clinicians to use these drugs. However, underreporting of adverse drug reactions in adults is a huge hurdle that is yet to be overcome, and in the pediatric age group, this problem is magnified. The rampant use of biologicals in pediatric practice has brought forth the need to quantify its adverse reactions. This study reported that ADRs due to biologicals were uncommon. Thus, it has reinforced the safety of biologicals used in the pediatric age group allowing them to prevail as an important aid in therapy.

Funding: None

Conflict of Interest: None

Ethics Approval: Approved

Informed Consent: Obtained.

1. Barquet N, Domingo P. Smallpox: the triumph over the most terrible of the ministers of death. Ann Intern Med. 1997; 127: 635-642.
2. Junod SW. Update from the Food and Drug Law Institute. Silver Spring, MD: Food and Drug Administration. 2002.
3. Roque AC, Lowe CR, Taipa MA. Antibodies and genetically engineered related molecules: production and purification. Biotechnol Prog. 2004; 20: 639-654.
4. Burnouf T. Recombinant plasma proteins. Vox Sang. 2011; 100: 68-83.
5. Aubin F, Carbonnel F, Wendling D. The complexity of adverse side-effects to biological agents. J Crohns Colitis. 2013; 7: 257-262.
6. Patel SV, Khan DA. Adverse Reactions to Biologic Therapy. Immuno-Allergy Clin N Am. 2017; 37: 397-412.
7. Pichler WJ. Adverse side-effects to biological agents. Allergy. 2006; 61: 912-920.
8. Sindhu AR, Sebastian M, Panicker PR, Muthusamy S, Nallasamy V, Ramanathan R, et al. A study on adverse drug reactions in hospitalized pediatric patients in a Tertiary Care Hospital. J Appl Pharm Sci. 2019; 9: 072-076.
9. Mrutunjay D, Jena M, Mishra S, Panda M, Patro N. Monitoring of Adverse Drug Reactions in Paediatric Department of a Tertiary Care Teaching Hospital: A Hospital Based Observational Study. IJPRAS. 2015; 4: 69-76.
10. Jha K, Larizgoitia I, Audra-Lopez C, Prasopa-Plaizier N, Waters H, Bates DW. The global burden of unsafe medical care: analytic modeling of observational studies. BMJ. 2013; 22: 809-815.
11. Skrbo A, Zulic I, Hadzic S, Gaon ID. Anatomic-therapeutic-chemical classification of drugs. Med Arh. 1999; 53: 57-60.
12. Skrbo A, Begovic B, Skrbo S. Classification of drugs using the ATC system Anatomic, Therapeutic, Chemical Classification and the latest changes. Med Arh. 2004; 58: 138-141.
13. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30: 239-245.
14. Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm. 1992; 49: 2229-2232.
15. Schumock GT, Seeger JD, Kong SX. Control charts to monitor rates of adverse drug reactions. Hosp Pharm. 1995; 30: 1088, 1091-2, 1095-6.
16. Schumock GT, Thornton JP. Focusing on the preventability of adverse drug reactions. Hosp Pharm. 1992; 27: 538.
17. Priyadarshini R. Surendiran A, Adithan C, Sreenivasan S, Sahoo FK. A study of adverse drug reactions in pediatric patients J Pharmacol Pharmacother. 2011; 2: 277-280.
18. Morales-Rios O, Cicero-Oneto C, GarciaRuiz C, Villanueva-Garcia D, Hernandez-Hernandez M, Olivar-Lopez V, et al. Descriptive study of adverse drug reactions in a tertiary care pediatric hospital in Mexico from 2014 to 2017. PLoS ONE. 2020; 15: e0230576.
19. Nasso C, Mecchio A, Rottura M, Valenzise M, Menniti-Ippolito F, Cutroneo PM, et al. A 7- Years Active Pharmacovigilance Study of Adverse Drug Reactions Causing Children Admission to a Pediatric Emergency Department in Sicily. Front Pharmacol. 2020; 11: 1090.
20. Divyalasya TVS, Krishnaiah V, Yashoda HT, Pundarikaksha H. Adverse drug reactions in pediatric patients in a tertiary care hospital in India: a prospective observational single center study. Int J Basic and Clinical Pharmacology. 2003.
21. Pattern of Adverse Drug Reactions in Children Attending the Department of Pediatrics in a Tertiary Care Center: A Prospective Observational Study. Clinical Medicine Insights: Pediatrics. 2015: 9: 73-78.
22. Reeja R, Beena JS, Ajith Krishnan AS, Bindulatha NAIR R. Adverse drug reactions in pediatric patients in a tertiary care hospital. Asian J Pharmaceutical and Clinical Research. 2021; 14: 113-115.