Post-marketing Surveillance Studies on the Paediatric population Associated with Vaccination

N.K. Hada* and Ashawat M.S.

Laureate Institute of Pharmacy, Kathog, Hamirpur, Himachal Pradesh

*Corresponding Author E-mail: nh.pharma11@gmail.com

ABSTRACT:

The aim of this text is to grasp the requirement of observance and coverage of the adverse events (AEs) related to vaccination throughout the post-marketing surveillance studies (PMS) and analysis of the protection, efficaciousness and adverse events of vaccination data from PMS studies. The data obtained through numerous specialists with moral pointers of medicine vaccination by knowing the severity of AEs. Literature review and survey form were key aspects for the achieving the objectives. The approval for the survey form obtained from ICRI (India). The analysis work would be helpful for the scholars UN agency area unit wanting to recognize the particular state of affairs of vaccination associated adverse events and additionally knowledgeable to induce some necessary facts regarding AEs observance in children’s once vaccination. For the health professionals it'd create them tuned in to their role and responsibilities in surveillance system. Parents of such subjects were also informing the way to beware of their children’s vaccination schedules and management of delicate adverse drug reaction and events.

AIM and OBJECTIVE: The aim of the research is to identify the importance of monitoring and reporting of AEs associated with vaccination during the PMS studies and evaluation of the safety, efficacy and adverse events of vaccination by comparing data from PMS studies obtained through various paediatricians with ethical guidelines on paediatric in different countries across the worldwide.

METHODOLOGY: Research work has been conducted after an extensive review of literature. With help of questionnaire, a survey among various paediatricians has been conducted. Then data collection on the basis of obtained by these paediatricians has been done. Analysis and compiling of obtained data is done. Results obtained with the help of statistical methods.

RESULTS: Obtained results from the questionnaires survey demonstrate that 70% of paediatricians reported vaccines available for paediatrics are essential, while remaining 30% are not in the favour of all vaccines use and only recommend vaccines according to their experience and NIS (National Immunization Schedule). 60% of paediatricians reported AEs associated with vaccination are mild, 32% reported these AEs moderate, and 8% reported these AEs are severe. Hospitalization is not recommended by any of above paediatricians. 76% of paediatricians prefer treatment for AEs at home only, while 66% are not aware of the any AEs monitoring and reporting system.

CONCLUSION: Awareness of the AEs monitoring, reporting and management is necessary among the health professionals and parents. Awareness campaign should be conducted to report and management of AEs associated with vaccination in paediatrics. The passive system needs to be getting active so the short comings of passive system will overcome. Common case definitions and guidelines are required globally so uniformity in reporting the ADRs and AEs will be achieved.

KEYWORDS:

1. INTRODUCTION:

Vaccines are necessary for children to prevent vaccine preventable disease. Bacteria and virus which causes the disease are still exist. Infection of the viruses or bacteria can occur any time. If immunization for these diseases stopped then the incidence rate of vaccine preventable diseases will increase. In US during 1989s rate of measles vaccines is dropped by various reasons after that incidence of measles increased during 1989-1991. More than 43,000 cases of measles were reported with 100 deaths. Due to decrease in vaccination this outbreak occurred in unvaccinated children.

2. REVIEW OF LITERATURES:

Vaccines are the biological product which act on immune system of body and enhances it to work against foreign agents. The foreign agents are mostly infectious organism and their toxins. Vaccines enhance active immunity and works as antigens. The antigen begins production of specific antibodies against infectious organisms in the body. Types of vaccines are described below; (Table 1)

Table 1: Types of Vaccine

Killed (inactivated) vaccines	Live attenuated vaccine
*BACTERIAL*
Typhoid-paratyphoid (TAB)	BCG
Cholera	Typhoid- Ty 21 a
Whooping cough (Pertussis)
Meningococcal
Haemophilus influenzae type b
Plague
*VIRAL*
Poliomyelitis inactivated (IPV/Salk)	Poliomyelitis oral live (OPV/Sabin)
Rabies (Neural Tissue)	Mumps
Rabies (Chick embryo cell, PCEV)	Measles
Rabies (Human diploid cell, HDCV)	Rubella
Rabies (Vero cell, PVRV)	Varicella
Influenzae
Hep. B
Hep. A
*TOXOIDS*
Tetanus ( fluid / adsorbed)
Diphtheria ( adsorbed)
*COMBINED VACCINES*
Double antigen (DT-DA)
Triple antigen (DPT)
Typhoid- paratyphoid- cholera (TABC)
Measles, Mumps, rubella (MMR)

(Source: K D Tripathi, Essentials of Medical Pharmacology)

Oral Polio Vaccine/ OPV ( Sabin)

Poliomyelitis a contagious disease causative organism is poliovirus. Poliomyelitis caused through intestinal virus, this virus can attack spinal cord and nerve cells of brain. Commonly occurred ADRs are diarrhoea, headache and fever. Paralytic poliomyelitis occurs very rarely (Figure 1 and 2).

Figure 1: Polio Vaccination: Adverse Reactions and Serious Adverse Reactions in mid 1990 through VAERs in US. (Source: Snapshot from Neil Z. Miller)

Figure 2: Polio Death Rates before and After Introduction of Vaccine in US and England , X Axis- Years, Y Axis- Decreasing Percentages (Source: Snapshot from Neil Z. Miller)

DPT (Diphtheria, Tetanus, Pertussis)

The causative organism for diphtheria is corny bacterium diptheriae. This can be form in cutaneous and nasal form. Toxins cause neuropathy and cardiomyopathy. This rate has higher rates of deaths in young’s. Bordello pertussis is causative organism for pertussis. This is very communicable disease of respiratory tract. Cough which is whoop in the origin is called as whooping cough. It can cause seizures, pneumonia and encephalopathy. Less than six months of age infants dies, ratio is 1 in every 200 cases. The Causative organism for tetanus is Clostridium tetani, severe muscles contraction occurs. First it starts with jaw and neck then it progress towards trunk muscles. Because of pertussis content of the vaccine pain, oedema, erythma occur which are common. Serious events like convulsions collapse may occur. High fever in the 1 per 330 doses occurs.

MMR (Measles, Mumps, Rubella)

Measles is an acute and highly contagious disease and causative organism is measles virus mainly occurring in developing countries. Mortality rate in developing countries is 1-5%. Red rashes with special characters, coryza, conjunctivitis and cough occur. In the period of Dec. 2003 to Jan.2004 immunization campaign for measles and rubella was conducted across the worldwide where AEs associated with combined vaccines monitored in 4000 children (See Table 2). 25.4% recipient of vaccine shows AEs due to this vaccine. No death was occurred during campaign. Fever is common AE in children in 5-10 Yrs age(s). The Causative organism for mumps is mumps virus. In this infection encephalopathy develops in children. Swelling of salivary gland develops in about 2/3 of cases. The Causative organism for rubella is rubella virus causes mild fever with rashes. Congenital infection of this disease occurs in 90% of infants which are infected during first trimester of pregnancy. These infants are at risk of congenital malformations as mental retardation, deafness, heart defects etc. Rashes, fever are commonly occurs. Nearly 5% of cases with pain in joints, stiff neck occurs. Anaphylaxis is rare events in the case of this vaccine.

Table 3: Subjects Reporting Local Reactions 30 Days Following Vaccination

High risk children					Healthy children
	2 injections(A1)		1 injections (A2)		2 injections (B)
	n Subject	%	n Subject	%	n Subject	%
After 1^st Vaccination
Any reaction	11	13.8	8	15.4	9	12.0
Pain	6	7.5	3	5.8	3	4
Redness	6	7.5	2	3.8	3	4
Indurations	2	2.5	2	3.8	2	2.7
Oedema	3	3.8			2	2.7
Ecchymosed	2	2.5	1	1.9	2	2.7
Purities	1	1.3		1		1.3
After 2^nd vaccination
Any reaction	7	9.5			7	9.7
Pain	3	4.1			2	2.8
Redness	4	5.4			1	1.4
Indurations	3	4.1			1	1.4
Oedema	3	4.1			2	2.8
Ecchymosed	2	2.7			5	6.9
Purities	1	1.4			1	1.4

(Source: Snapshot from Maria Luisa Avila Aguero, Sabine Arnoux)

Table 4: Expected Number of Adverse Events per Million primary Vaccines

Type of AEs	Patient Age At Vaccination
Type of AEs	Younger than 1 Yr	1-4 Yrs Old	5-19Yrs Old	20Yrs or Old
No. of deaths (all causes)	5	0.5	0.5	1
No. of cases of post vaccinial encephalitis	6	2	3	4
No. of progressive vaccinia	1	0.5	1	7
No. of eczema vaccinatum	14	44	35	30
No. of generalized rashes	400	9,600	140	250
No. of accidental implantations	507	577	371	606

(Source: Snapshot from J. Michael Lane)

Table 5: Adverse Events Associated with Vaccines

Type of AEFI	Definition	Example
Vaccine reaction	An event caused or precipitated by the active component or one of the other components of the vaccine. This is due to the Inherent properties of vaccine.	Anaphylaxis due to measles vaccine
Programme error	An event caused by an error in vaccine preparations, handling or administration.	Bacterial abscess due to unsterile injection
Coincidental	An event that occurs after immunization but is not caused By the vaccine. This is due to chance of association.	Pneumonia 4 days after polio oral vaccine
Injection reaction	Event from anxiety about, or pain from the injection itself rather than the vaccine	fainting spell in a teenager after immunization
Unknown	Event’s cause cannot be determined	-

Source: Snapshot from Department of Family Welfare GoI

Table 6: Frequency of common mild vaccine reactions

Vaccine	Local reaction (pain, fever, swelling)	Fever	Irritability, malaise and non-specific symptoms
BCG	Common	-	-
Hepatitis B	up to 5%	1-6%	-
Measles	up to 10%	up to 5%	up to 5%
OPV	None	Less than 1%	Less than 1%
Tetanus	up to 10%	up to 10%	up to 25%
DPT	up to 50%	up to 10%	up to 60%
Treatment	Cold cloth at injection site Paracetamol	Extra oral fluids Cool clothing	-

Source: Snapshot from Department of Family welfare GoI

Table 7: Serious AEs with onset time and rate

Vaccine Doses	AE	Time b/w vaccination and onset	No. of events per million
BCG	BCG Ostetis Suppurative Lymphadenitis Disseminated BCG infection	1-2 month 2-6 month 1-12 month	1-700 100-1000 2
Measles	Anaphylaxis Febrile seizures Thrombocytopenia	0-4 hour 5-12 days 15-35 days	1-50 333 33
Hepatitis B	Guillain-barre Syndrome Anaphylaxis	1-6 weeks 0-1 hour	1-2 1.4-3.4
OPV	Vaccine associated Paralytic polio	4-30	1.4-3.4
DPT	Encephalopathy Anaphylaxis Seizures Hypotonic hypo responsive episode	0-3 days 0-1 Hour 0-3 days 0-24 hours	0-1 20 570 570

Source: Snapshot from Department of Family Welfare GoI

Reporting of Adverse Event Following Immunization (AEFI) in India

There is system according to Health Ministry of India to monitor and report AEs following immunization (See Table 8). This system works on various levels from where it can monitor and report AEFI to the central authority.

Table 8: Immunization Schedule in India

Vaccine	Age(s) group
	Birth	6 weeks	10 weeks	14 weeks	9-12months
Primary vaccination
BCG	x
Oral polio	x	x	x	x
DPT		x	x	x
Hepatitis B		x	x	x
Measles					x
Booster Doses
DPT + Oral polio vaccine	16 to 24 months
DT	5 Years
Tetanus toxoid (TT)	At 10 yrs and again at 16 years
Vitamin A	9, 18, 24, 30, and 36 months

(Source: Department of Family Welfare GoI).

At field level: Medical officers of PHC (Primary Health Center), health professionals are responsible for follow up to children’s which they have vaccinated. During the vaccination they inform about risk of AEFI so they can voluntarily report any AEs occurred after vaccination. Parents informed about mild events and management of AEs at home. In cases of serious events MO (Medical Officer) should be informed immediately by field worker. All the AEFI monitored entered in to the monthly report form. This monthly report forms are to be submitted to DIO (District Immunization officer).

At PHC level: Once the any AEFI reported by parents then it is responsibility of MO to initiate investigation. After that, filling of first information report is done by MO. Serious events reporting form should be sent within 24 hours of report and other reports on monthly basis to DIO. If death occurs in that case used syringes, bottles for vaccine need to send to DIO.

At medical institution level: In admitted children for the various treatments they need MO is concern person to report all AEFIs. In cases where further investigations needed it is duty of MO to inform it to DIO immediately by phone. Work at medical institution level conducts in manner of at PHC level.

At district level: After receiving FIR, DIO initiates investigations by filling PIR and DIR. This FIR forwarded to AC (UIP) within 24 hrs, PIR within 7 days, and DIR within 90 days. DIO assist RTI in investigation after completion DIO provides the feedback to MO (PHC) and HA.

Vaccinovigilance System in Europe

The entire adverse event reporting programs are done according to FDA guidelines. In 1990, FDA has started VAERS (Vaccine Associated Adverse Events Reporting System). FDA has introduces VAERS, which is jointly conducted by FDA and Centre for Disease Control and Prevention. In the data base of FDA yearly 11000 to 15000 adverse events reported which include mild to serious events reported by professionals, manufacturer companies and people who reports to AE reporting centre. WHO also give preference to immunization safety assessment to improve national surveillance system. AE in case of vaccines are acceptable in the ratio of 1: 100000. Scientific and Technical Evaluation of Vaccination Programme in European Union (EUVAX) is project performed to work of vaccine safety. Aim of EUVAX project is to maintain database on all immunization related aspect which will be interactive for health professionals. Long term objectives of the EUVAX project are comparison b/w countries and provide data on different countries which is useful to identify strengths and weakness of surveillance system. France, Sweden and Spain manage vigilance regionally while Switzerland acts both regionally and centrally.

Table 9: The Recommended Immunization Schedule for Age Group (0-6 Years) of paediatrics in US

	Age group (s) of child in months (M) and years (Yr)
Vaccine	Birth	1M	2 M	4 M	6 M	12 M	15 M	18 M	19-23M	2-3 Yr	4-6Yr
Hep. B (1)	Hep. B	Hep. B*			Hep. B^*
Rotavirus (2)			RV	RV	RV
Diptheria, Tetanus, Pertussis (3)			DTaP	DTaP	DTaP		DTaP^*				DTaP^*
Haemophilus influenza type b (4)			Hib	Hib	Hib	Hi b^*
Pneumococcal (5)			PCV	PCV	PCV	PCV^*				PPSV^**
Inactivated Poliovirus (6)			IPV	IPV	IPV^*						IPV^*
Influenza (7)					Influenza (Yearly)^*
Measles, Mumps, Rubella (8)						MMR^*					MMR^*
Varicella (9)						Varicella^*					Varicela
Hepatitis A (10)						Hep A (2doses)^*				HepA (2doses)^**
Meningococcal (11)										MCV**

(* indicates the range of recommended ages for all children except certain high risk groups, ** indicates the ranges of recommended ages for certain high risk groups). Source: Snapshot from American academy of paediatrics (http://www.aap.org, http://www.aafp.org)

Meningococcal, pneumococcal, Hib, Influenza, Hep.A vaccines are included which are not in the Indian schedule. This difference indicates the change in need of the vaccination in different countries, while deciding immunization policies for any country many factors influences it e.g. incidence of disease, geographical differences, availability of vaccines and most important cost effectiveness of that vaccination programme.

Fle

Fre

NoC

AEFI covered bylaw/regulation

Passive reporting (suspected AEFI)

Reporting is voluntary (local level)

Reporting is voluntary(regional level)

Medical qualified staff

Full time staff

Expert group of vaccine specialist

Expert group on vaccine safety

(ISO 3166 Country codes; Australia (AT), Belgium Flemish (BE-Fle), Belgium French (BE-Fre), Switzerland (CH), Germany (DE), Denmark (DK), Spain (ES), Finland (FI), France (FR), Great Britain (GB), Greece (GR), Ireland (IE), Italy (IT), Luxembourg (LU), Netherlands (NL), Norway (NO), Portugal (PT), Sweden (SE). NOC- Number of countries, AEFI-Adverse events following immunization, X indicates positive answer). (Source: Snapshot from Kari S. Lankinen, Satu Pastila)

In Sweden and UK, all AEs associated with vaccines are compulsory to report. Reactions reported are classified in the six countries. (AT, ES, BE, GB, FR). During the vaccine related injuries, compensations vary from no fault to compensation through legal action. In 1989-99 some regulatory actions were taken when concern about vaccine safety increased. Specific withdrawal of batches took place in these five countries (BE, GR, PT, AT, DE).

Reaction or event	Yes	No	Countries
SAVR	16	2	BE-Fle, BE-Fre
UAVR	16	2	BE-Fle, BE-Fre
All AVR	8	10	AT, BE-Fle, BE-Fre, DE, DK,GB,IE,S
SAE	10	8	AT, BE-Fle, BE-Fre, DE, DK, GB, IE, S
UAE	10	8	AT, BE-Fle, BE-Fre, DE, DK, GB, IE, S
All AEs	5	13	BE-Fle, BE-Fre, ES, GR, LU

AVR- Adverse vaccine reaction, SAVR- Serious adverse vaccine reaction, UAVR- Unexpected adverse vaccine reaction, AE- Adverse event, SAE- Serious adverse event, UAE-Unexpected adverse event. (ISO 3166 Country codes; Australia (AT), Belgium Flemish (BE-Fle), Belgium French (BE-Fre), Switzerland (CH), Germany (DE), Denmark (DK), Spain (ES), Finland (FI), France (FR), Great Britain (GB), Greece (GR), Ireland (IE), Italy (IT), Luxembourg (LU), Netherlands (NL), Norway (NO), Portugal (PT), Sweden (SE). (Source: Snapshot from Kari S. Lankinen, Satu Pastila)

MATERIAL AND METHODS

Extensive literature reviews has been done for the better understanding of the vaccinovigillance and study is designed as survey by using questionnaire form. The approval was obtained from ICRI (Mumbai). The list of 50 Paediatricians was prepared who are practicing paediatric vaccinations. With their consent questionnaires were given to them and asked to give feedback. The collected data from survey were used in proceeding with study. Various graphs and tables are used for interpretation of collected data. Frequency and percentage of collected data from questionnaire were obtained. Then descriptive analysis of data was presented with help of statistics.

RESULTS

35 (70%) Paediatricians state that all vaccines available are necessary for children. All vaccines means vaccines which are included in the NIS and that are not included in to NIS also. 15 (30%) state all vaccines are not necessary. NIS is competent enough to protect against vaccine preventable diseases (See Figure 8).

Figure 8: Vaccine those are needed according to Paediatricians

30% of Paediatricians who are against the optional vaccines gives the some vaccines name which are according to them does not play important role in paediatric health. Some of these vaccines are used in National Immunization of some western countries, depending upon disease prevalence, availability, cost effectiveness and experience in the field paediatricians suggest for some of the above stated vaccines are not necessary in India (See Figure 9).

Figure 9: Vaccines are not useful in Paediatrics

Risk associated with vaccines 45 (90%) of Paediatricians state that vaccines which are used in India are not causing any health problems in children, that means vaccines are safe for use. While 5 (10%) reported the relation b/w vaccines and other health problems. That means most of the paediatricians are supporting the use of vaccines in children (See Figure 10). No. of Vaccination carried out in a month is given in Table 13, Figure 11).

Figure 10: Risks Associated with Vaccination

Figure 11: No. of Vaccination carried out in a month (A: 30-50, B: 50-70, C: 70-90, D: 90-100, E > 100)

Table 13: No. of Vaccination carried out in a month

No. of vaccines in a month	Frequency	Percentage
A	18	36
B	12	24
C	10	20
D	6	12
E	4	8

Figure 12: Vaccines used other than NIS (National Immunization Schedule)

Paediatricians who support vaccines other than NIS are 8 (16%). Hep. B vaccine reported by 4 (8%). Yellow fever is not reported by any of paediatricians. 42 (84%) reported NIS is enough for any child (See Figure 12).

Figure 13: Type of AEs occurred due to vaccines (1. Programmatic Error 2. Vaccine reaction 3. Coincidence, 4. Injection reaction, 5. Unknown)

Out of five types of AE occurred due to vaccination most of the time Programmatic error 14 (28%) and coincidence 14 (28%) is the type of AE observed by paediatricians. 10 (20%) experienced that AE may be occurred due to vaccines. 6 (12%) report AEs are of unknown reason, they cannot be explained. Injection reaction is reported by 6 (12%) of paediatricians (See Figure 13).

Figure 14: Severity of AEs associated with vaccination in paediatrics

AEs occurred due to vaccination are mostly mild. 30 (60%) of Paediatricians encountered mild AEs. Moderate AEs are observed by 16 (32%). Only 4 (8%) reported connects AEs with vaccination (See Figure 14).

Figure 15: Commonly observed AEs. (1.Fever, Swelling, Irritability 2.Fatigue, Rash 3.Abcess 4.Anaphylaxis)

Common AEs due to vaccination Fever, Swelling and irritability are reported by 38 (76%). Fatigue and rash is reported by 10 (20%), where abscess and anaphylaxis shock are rare AEs. Abscess is reported by 2 (4%) of paediatricians (See Figure 15).

Figure 16: Treatment for AEs (A- Paracetamol, B- Paracetamol and Fluids, C- Advice only rest, D- tapid sponge, E- Advise hospitalization)

Treatment for AEs is given by 38 (76%) of paediatricians and 12 (24%) did not reported that no any special treatment is necessary. For mild reactions paracetamol, fluids and rest is advised by 25 (65.78%), tapid sponge is advised by 13 (13.21%) while no any paediatricians suggest that there is need of hospitalization for AEs associated to vaccine (See Figure 16).

Figure 17: Record Archiving for AEs (C- Computerized, M- Manual)

Record of AES is archived by 42 (82%) of paediatricians with the schedule of immunization, while 8 (16%) did not keep any record for AEs. Out of these 25 (59.52%) of keep computerized record and 17 (40.47%) keep manual (paper record) (See Figure 17).

Figure 18: Awareness and Reporting of AEs (Y- Yes, N-No, R-Report, P-PHC, D-DIO)

17 (34%) paediatricians are aware of the AEs reporting system and 33 (66%) are not aware. Centre wise 6 (35.29%) report at PHC, 3 (17.64%) report to DIO, while 8 (47.05%) did not report at any centre (See Figure 18).

DISCUSSION:

Initially at ground level, primary investigations are conducted by MO and DIO if there is further requirement then regional and state expert committee needed. All the countries have their own systems to report adverse event with special committees working on work assigned to them, but having a common aim to establish safety and efficacy of the vaccines used in paediatrics. All the reported data is centrally collected at Uppsala monitoring centre (UMC) Sweden, which is established by WHO. In most of countries reporting system is passive process like India. Individual case reporting is more in EU than in India. There is feedback system also available in some countries on reported events which is lacking in India. While reporting AEs that common terminology is not available all over, makes difficulty while comparing data of different countries. But efforts to make common case definitions and guidelines to report adverse events are being initiated by Brighton Collaboration.

CONCLUSION;

Many paediatricians reported that vaccines did not cause any serious AEs. The common factors which resist concern about ADRs or AEs monitoring in paediatric population:

· When any drug used in children it may affect growth of children which has long term effect on the health of children’s

· Where ethnic and social diversity is more the influence of this diversity contribute in ADR frequency

· Irrational use drugs and vaccines in paediatric groups may lead to ADR which are not possible to detect during clinical trials

· Children like elder people cannot complain about their health issues and because of this ADR may go without notice.

· Children when vaccinated are more prone to skin reactions

· There are some diseases which are common in Indian children. E.g. Typhoid, Malaria. While in treatment of taking preventive measures through vaccines for this disease there is necessary to detect ADRs, and Additive in drugs and vaccines can lead to ADR. In India is not common practice to give detailed description of these “inactive ingredient”.

For ADR monitoring in paediatric practice different methods are used like spontaneous reporting system, institutional surveillance system. Epidemiological studies, Case control and Cohort studies are more useful for safety evaluation use of these methods should be increased. Combination of different methods should be used in evaluating the safety of vaccines to overcome the shortcoming of individual system.

ACKNOWLEDGEMENT:

Author is thankful to the Principal and H.O.D. of Pharmacology, ICRI (Mumbai) India, for providing their approval for survey and valuable suggestions.

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Received on 11.12.2013 Modified on 20.12.2013

Res. J. Pharmacology & P’dynamics. 6(1): Jan.-Mar. 2014; Page 50-58

WHO region	Number of Countries/Areas	One dose vaccine	Two dose vaccine	No. of using any Mumps vaccine
Africa	48	0	0	0
America	47	15	6	21(45)
Europe	51	25	18	43(84)
Eastern Mediterranean	23	6	5	11(48)
South East Asia	10	0	0	0
Western Pacific	36	6	1	7(19)
Total	215	52	30	82(38)