+
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Travel Medicine and Infectious Disease (2014) xx, 1e8
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
Adverse events following rabies postexposure prophylaxis: A comparative study of two different schedules and two vaccines* Tugba Sari a,*,1, Necla Tulek a,1, Cemal Bulut a,1, Behic Oral b,2, Gunay Tuncer Ertem a,1 a Ankara Training and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Ankara, Turkey b Guven Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Ankara, Turkey
Received 30 December 2013; received in revised form 17 February 2014; accepted 11 March 2014
KEYWORDS Rabies; Rabies vaccines; Rabies immunoglobulin; Side effects; Post-exposure prophylaxis
Summary Objective: Due to lack of effective treatment for rabies, post-exposure prophylaxis becomes very important. In this study, we investigated side effects developed in patients following administration of rabies post-exposure prophylaxis. Methods: A total of 1685 patients were vaccinated. 265 patients (15.7%) administered the Essen regimen with equine rabies immunoglobulin and 1420 patients (84.2%) administered Zagreb regimen. 761 (45.2%) patients were vaccinated with a verocell vaccine; Verorab and 924 patients (54.8%) were vaccinated with Abhayrab. Results: All side effects were higher in female patients than those of males. The patients with chronic illness also had significantly, increased side effects; headache (12.4%), pain at site of administration (11.3%), and arthralgia (10.5%) compared to the patients without chronic illness. We grouped the patients in three as; 0e15years, 15e60 years, and 60 years and above. In the first group; fever (21.2%), vomiting (2.4%) and coughing (2.1%); in the second group (15 e60 years), headache (8.8%), arthralgia (6.7%) were significantly increased compared to the other groups.
*
Abstract from the manuscript have been presented at 22th ECCMID 2012, abstract book page: 107. * Corresponding author. Present address: Buldan Chest Disease Hospital, Department of Infectious Diseases and Clinical Microbiology, Buldan, Denizli, Turkey. Tel.: þ90 258 4313057; fax: þ90 258 4313579. E-mail addresses: [email protected], [email protected] (T. Sari), [email protected] (N. Tulek), [email protected] (C. Bulut), [email protected] (B. Oral), [email protected] (G. Tuncer Ertem). 1
Tel.: þ90 312 595 3000; fax: þ90 312 363 3396.
2
Tel.: þ90 312 457 2525; fax: þ90 312 468 8030.
http://dx.doi.org/10.1016/j.tmaid.2014.03.004 1477-8939/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sari T, et al., Adverse events following rabies post-exposure prophylaxis: A comparative study of two different schedules and two vaccines, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.03.004
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2
T. Sari et al. Side effects are significantly higher with schema of 2-1-1 and Abhayrab trade mark vaccine, particularly following the first doses. Discussion: Second generation rabies vaccines are safe, effective and cheaper than HDCV. When fatality of rabies disease is considered, occurring side effects can be tolerated. ª 2014 Elsevier Ltd. All rights reserved.
Introduction Rabies is an acute viral zoonotic disease that causes fatal encephalomyelitis in humans and many other mammals [1]. Although highly effective prophylaxis is available, this viral infection remains a cause of death in almost all countries, with the exception of Antarctica and some island nations [1e3]. Due to a lack of effective treatment for rabies, postexposure prophylaxis for prevention of disease has taken priority. Rabies prophylaxis is primarily applied following exposure, but it can also be applied pre-exposure [4,5]. According to the World Health Organization (WHO); over 10 million people per year, mostly from Asia, are vaccinated following contact with the disease [6]. Rabies post-exposure prophylaxis is almost 100% successful when it is applied using vaccines prepared in modern tissue culture concomitantly with rabies immunoglobulin (RIG) at the correct dose and time [4]. A variety of post-exposure prophylaxis schedules are currently being used, including the Essen regimen, which is recommended by the WHO. It consists of five doses of human diploid cell vaccine (HDCV), administered intramuscularly on days 0, 3, 7, 14 and 28, plus rabies RIG at initial. In 2009, the Centre for Diseases Control and Prevention (CDC) modified this schedule by omitting the vaccine on day 28 [3,4]. Primarily cell-culture or embryonatedegg-based rabies vaccines are also used worldwide. Two types of RIG preparations are in use: RIG of human (HRIG), at a recommended dose of 20 IU/kg, and RIG of equine (ERIG) origin, at a recommended 40 IU/kg for ERIG. According to recent WHO and CDC recommendations, full RIG dosage should be administered around the wound, if anatomically appropriate [4,7e10]. Although human rabies cases have obviously decreased in Turkey in recent years, animal rabies remains a problem, and over 100.000 people per year receive prophylaxis due to the rabies risk from exposure to infected animals [1]. Rabies prophylaxis is implemented according to the Turkish Republic Ministry of Health General Directorate of Basic Health Services Directive of Prevention and Control of Rabies, and all the vaccines and immunoglobulins are provided by the government [8]. Monthly 250 to 350, and annually an average of 3000e4000, people with suspected contact with rabies are admitted to our clinic from Ankara and its nearby districts. Prophylaxis is initiated in approximately 50% of these individuals. The high fatality rate of rabies, means that the numbers of people receiving prophylaxis may be in excess of what is actually required. Therefore, in addition to the efficiency of the vaccine, its safety must be also considered. Nowadays, less serious and fewer frequent reactions are observed with cell cultures or embryonated-eggs-based
vaccines. However, the side effects of vaccine and immunoglobulins may change, according to their manufacturer and origin [8,10]. In this study, we investigated the side effects that developed in patients following administration of rabies prophylaxis. We aimed to determine the differences in the side effects of vaccines according to trade marks and to different vaccination schedules.
Materials and methods Type of trial This was a prospective trial.
Selection of cases We conducted this study between February 2010 and December 2010 at the Infectious Diseases and Clinical Microbiology Outpatient Clinic of the Ministry of Health Ankara Training and Research Hospital, Turkey. We randomly included patients of all age groups who were given post-exposure rabies prophylaxis. In our clinic, rabies prophylaxis is performed according to the Turkish Republic Ministry of Health General Directorate of Basic Health Services Directive of Prevention and Control of Rabies. As post-exposure prophylaxis, we intramuscularly applied two schedules (vaccination at days 0, 3, 7, 14 and 28 plus immunoglobulin at initiation or vaccine schedule of 2-1-1 at days 0, 7 and 21.) after wound care, according to risk. We administered five doses of vaccine þ ERIG more frequently than a schedule of 2-1-1 in patients from rural areas, patients with lesions in the headeneck region, patients with multiple lesions, patients having contact via bite, and in cases of bites from wild animals and stray dogs. We completed a record form for each patient enrolled in the study and recorded data that included gender; age; place and time of bite or mucosal exposure; exposure type; causative animal type; whether or not the individual is an animal owner; whether or not the animal has been immunised and the immunisation record is available; location and number of lesions; presence of chronic diseases and medicines; previous exposure, vaccine history; previous antiserum administration; applied vaccine schedule; administered vaccine doses; type and trade name of rabies vaccine; and, if used, type and trade name of rabies immunoglobulin. We followed patients up for a month and completed questionnaires with regard to all possible side effects related to rabies prophylaxis and complaints of patients. We excluded from the study those patients who could not be regularly followed up to monitor side effects.
Please cite this article in press as: Sari T, et al., Adverse events following rabies post-exposure prophylaxis: A comparative study of two different schedules and two vaccines, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.03.004
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Adverse events following rabies post-exposure prophylaxis
Administered vaccine and immunoglobulin We used two licensed vaccines for active immunisation: 1) Abhayrab vaccine (Human Biologicals Institute, India): Composition; Wistar rabies PM/WI 38-1503-3M strain form Vero cell culture; 2.5 IU/dose; excipients; human serum albumin, maltose, thiomersal, phosphate tampon, solvent; 0.5 mL sodium chloride; and 2) Verorab vaccine (Pasteur Merieux, France): Composition; Wistar rabies PM/WI 381503-3M strain form Vero cell culture; 2.5 IU/dose; excipients; human serum albumin, maltose solvent; 0.5 mL sodium chloride. We administered each dose of vaccine as 0.5 mL into the deltoid muscle. We used Equirab (Bharat serums and vaccines ltd. India) as RIG for passive immunisation. This contains 1000 IU/5 mL equine origin rabies antiserum; excipients; xerol, sodium chloride, glycine, water for injection. We administered 40 IU/kg to each patient.
Monitoring side effects We interviewed and informed each patient who underwent prophylaxis with regard to possible side effects. We administered questionnaires addressing possible side effects listed on the form to each patient visit during prophylaxis; in addition, we asked the patients to inform us of any unexpected conditions in the following month. The side effects that we recorded as being related to the vaccine were as follows: Local side effects; pain, swelling, redness, itching, paraesthesia at site of vaccine administration, and systemic side effects; headache, dizziness, fever, itching, weakness, abdominal pain, lymphadenopathy (LAP), nausea, vomiting, myalgia, cough, insomnia, numbness, irregular menstruation, decreased libido, rash, sore throat, arthralgia, encephalopathy and other (with explanation). We evaluated the side effects of the vaccine with regard to age, gender, chronic disease, each dose of vaccine, different vaccine schedules, with administration of RIG and trade name of vaccine used.
Statistical analysis We compared all side effects according to age, gender, vaccination schedule, and trade name, and used the X-test and Fisher’s exact X-test with the SPSS (Version 15.0; SPSS, Inc. Chicago, IL) programme for testing statistical significance. During analysis, we considered p values of less than 0.05 as significant.
3 and vaccinated 924 (54.8%) patients, admitted between July 2010 and December 2010, with Abhayrab. In the Abhayrab group, we vaccinated 813 (88%) patients with a 2-1-1 vaccine schedule and 111 (12%) patients with five doses of vaccine þ ERIG, while in the Verorab group, we vaccinated 607 (79.8%) patients with a vaccine schedule of 2-1-1 and 154 (20.2%) patients with five doses of vaccine þ ERIG. The demographical features of the patients are shown in Table 1. We observed no side effects in 74.9% of all patients, while observing a variety of side effects in the remaining 25.1%. The most frequently reported side effects were fever (15.8%), weakness (10.6%), headache (7.2%), local pain and swelling (6.5%), arthralgia (4.9%), nausea (4.2%), myalgia (3.8%), dizziness (2.8%) and abdominal pain (2.6%). As we used vaccine and immunoglobulin concomitantly in a treatment regime of five doses of vaccine þ ERIG, we could not separately evaluate side effects related to immunoglobulin. When we evaluated the side effects with regard to the gender of the study participants, pain (p < 0.001), swelling and redness at site of administration (p Z 0.01), headache (p < 0.001), dizziness (p < 0.001), fever (p Z 0.002), weakness (p < 0.001), abdominal pain (p Z 0.001), nausea (p < 0.001), myalgia (p < 0.001), cough (p Z 0.002) and arthralgia (p < 0.001) were significantly higher in females than in males. The most frequently observed side effects in males and females are compared in Fig. 1. When we evaluated the side effects according to age groups, Group 1 included patients under the age of 15 years Table 1 Characteristics of patients (n Z 1685) submitting to our immunization center. Category
Subcategory
N (%)
Gender
Male Female Group 1 (0e15 years) Group 2 (15e60 years) Group 3 (60 years and over) Yes No Headeneck Upper extremity Lower extremity Body Multiple sites One More than one Bite Scratch Lick Other Dog Cat Wild animal Rodent/Other 2þ1þ1 5 doses vaccine þ Ig Yes No
1089 596 532 1030 123
Age
Previous rabies vaccine Place of bite
Number of bite Contact type
Results We enrolled a total of 1685 patients (1089 males, 596 females; 64.6% and 35.4%, respectively) with a mean age of 28.7 (range 1e98) years in the study. We had given 1420 (84.3%; 910 males and 510 females) patients the vaccine schedule of 2-1-1, while 265 (15.7%; 179 males and 86 females) received the classical five doses of vaccine plus rabies RIG. Age and gender distribution among groups were similar. We vaccinated 761 (45.2%) patients, admitted to our centre between February 2010 and June 2010, with Verorab
Type of animal
Treatment schema Chronic disease
(64.6) (35.4) (31.6) (61.1) (7.3)
51 (3.1) 1634 (96.9) 103 (6.1) 896 (53.2) 531 (31.5) 119 (7.1) 36 (2.1) 1443(85.7) 242 (14.3) 1380 (81.9) 298 (17.7) 1 (0.1) 6 (0.4) 1133 (67.2) 531 (31.5) 15 (0.9) 3 (0.2) 1420 (84.3) 265 (15.7) 124 (7.3) 1561 (92.7)
Please cite this article in press as: Sari T, et al., Adverse events following rabies post-exposure prophylaxis: A comparative study of two different schedules and two vaccines, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.03.004
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T. Sari et al. 20 % 18 % 16 %
Fever Weakness
14 %
Headache Pain
12 %
Arthralgia 10 %
Nausea Myalgia
8%
Dizziness Abdominal pain
6%
Enduration and redness 4%
Cough
2% 0% 1
Figure 1
2
Evaluation of side effects according to gender, 1: Female, 2: Male%: For 100 individuals.
(532 patients; 31.6%); Group 2 included patients aged 15e60 years (1030 patients; 61.1%); and Group 3 included patients age over 60 years (123 patients; 7.3%). In general, we found a significantly higher number of complaints in Group 1 (patients aged under 15 years). In particular, complaints of fever (p < 0.001), vomiting (p Z 0.001) and cough (p Z 0.01) were significantly higher in children, while arthralgia was significantly higher in those aged between 15 and 60 years (p < 0.001). Side effects according to age groups are compared in Fig. 2. In addition, there were significantly higher side effects of pain at site of administration (14 patients; 11.3%), headache (15 patients; 12.1%) and arthralgia (13 patients; 10.5%) among patients with chronic disease requiring continuous drug administration compared to the others; p Z 0.03, p Z 0.04 and p Z 0.008, respectively. The most frequent chronic diseases were hypertension, diabetes and hyperlipidemia. When we evaluated vaccine side effects on the basis of vaccination schedule, they were most frequent in the 2-1-1 schedule group. Fever (16.7% vs. 11.3%; p Z 0.02), weakness (11.6% vs. 4.9%, p Z 0.001), headache (8% vs. 3%, p Z 0.003), local pain (7.3% vs. 2.6%, p Z 0.004), arthralgia (5.5% vs. 1.9%, p Z 0.01) and myalgia (4.2% vs. 1.5%, p Z 0.03) were significantly higher with a vaccine schedule of 2-1-1 than with a five dose vaccine þ ERIG, respectively. Significant side effects compared by vaccine schedule are given in Fig. 3. Side effects following first doses were higher 0-15 years n:532 (31,6%) 15-60 years, n:1030 (61,1%) 60 years and over, n:123 (7,3%)
25% 20% 15% 10% 5% 0% Cough
Figure 2
Vomiting
Headache
Arthralgia
Fever
Side effects according to age%: For 100 individuals.
in patients having a 2-1-1 schedule than in those receiving five doses þ ERIG. This difference was decreased by following doses. When we evaluated side effects according to vaccine trade name, we observed a higher number in patients who received the Abhayrab vaccine, compared to those who received the Verorab vaccine (p < 0.001 for local pain, headache, weakness, insomnia and arthralgia; p Z 0.002 for local swelling and redness; p Z 0.001 for nausea; p Z 0.01 for local numbness; p Z 0.03 for nasal discharge), as shown in Fig. 4. In a subanalysis, we compared the Verorab and Abhayrab vaccines according to vaccine schedule and all side effects were higher in patients receiving the Abhayrab vaccine in a schedule of 2-1-1. Nasal discharge, abdominal pain, nausea and itching were higher among patients receiving the five doses vaccine and ERIG with Verorab than among those vaccinated with Abhayrab, but we detected no significant difference. Side effects with regard to vaccine schedules with two different vaccine trade marks are shown in Table 2. Among the 1685 vaccinated patients, we observed persistent fever at 39 C, crying attacks, irritability and minimal body rash following the first two doses of vaccination of Abhayrab in a 2-1-1 schedule in a girl aged 9 years 18% 16% 14% 12% 10% 8% 6% 4% 2% 0%
Zagreb regimen Essen regimen
Pain
Fever
Myalgia
Figure 3 Side effects according to vaccine schema%: For 100 individuals.
Please cite this article in press as: Sari T, et al., Adverse events following rabies post-exposure prophylaxis: A comparative study of two different schedules and two vaccines, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.03.004
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Adverse events following rabies post-exposure prophylaxis
5
25%
20%
15%
Abhayrab Verorab
10%
5%
0%
Figure 4
Comparison of side effects according to vaccine trademarks%: For 100 individuals.
old. In addition, serum sickness developed in one patient aged 32 years, following administration of Verorab with a programme of five doses þ ERIG. This patient remained in hospital and was discharged one week later, completely cured. With the exception of these two cases, we observed no very serious side effects related to vaccine or immunoglobulin. In total, 17 patients had to consult a physician, due primarily to fever (n Z 12), cough (n Z 2), sore throat (n Z 2) and rash (n Z 1) and they were treated with antipyretics and antihistamines.
Discussion Since rabies is a fatal disease and can be prevented through prophylaxis, even after exposure to virus, rabies vaccines have being administered to millions of people worldwide. However, all of the vaccines must be safe. Although current rabies vaccines are indeed safe, side effects may vary between vaccine types and even between brands. In the present study, we evaluated early and late side effects in patients who received rabies prophylaxis post-exposure with regard to vaccine administration schedule and trade mark of vaccine. Most of our study population (61.1%) were aged between 15 and 60 years, and were male; this might be due to the fact that this group was more active and spent more time outside. The most frequently encountered lesions were on the extremities, as expected. Unfortunately, domestic animal bites were the most frequent reason for rabies prohylaxis in our study. Systemic side effects due to rabies vaccines have previously been reported as headache, cough, abdominal pain, myalgia, weakness, and, less frequently, urticaria, angioedema, fever and anaphylaxis [4,11]. In the present study, the side effects we most frequently observed were fever
(15.8%), weakness (10.6%), headache (7.2%), local pain (6.5%), arthralgia (4.9%), nausea (4.2%), myalgia (3.8%), dizziness (2.8%) and abdominal pain (2.6%). In a comparative study, local side effects were reported in 64% of patients vaccinated by vero cell vaccine, 79% of whom were in the Verorab group vaccinated by HDCV, and the most frequently observed systemic side effects were headache and fever [12]. Although local side effects were similar, even a lower rate of local pain, fever and headache were observed at a higher frequency than in other studies [12e19]. All complaints due to rabies vaccine were higher in females. As indicated in some studies, autoimmune diseases are more frequent in woman [20,21]. Wilde at al [22]. found that serum sickness was more frequently reported in women following ERIG, and Shohat and colleagues [23] observed side effects due to MMR vaccine most frequently in woman. Some publications have reported the difference of the immune response in male and female animals [24,25]. In addition, some authors have indicated that atopy, as well as allergic reactions to antibiotics and anaesthetics, are higher in woman [26,27]. This remains an issue for research. While fever, vomiting and cough were significantly higher in the group of patients age 15 years and under, headache and arthralgia were significantly higher in patients aged between 15 and 60 years than those of different ages in our study. In their study, Thongcharoen and colleagues [28] did not observe serious side effects among 27 vaccinated children, and in Thailand, headache and fever were observed in
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Travel Medicine and Infectious Disease (2014) xx, 1e8
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevierhealth.com/journals/tmid
Adverse events following rabies postexposure prophylaxis: A comparative study of two different schedules and two vaccines* Tugba Sari a,*,1, Necla Tulek a,1, Cemal Bulut a,1, Behic Oral b,2, Gunay Tuncer Ertem a,1 a Ankara Training and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Ankara, Turkey b Guven Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Ankara, Turkey
Received 30 December 2013; received in revised form 17 February 2014; accepted 11 March 2014
KEYWORDS Rabies; Rabies vaccines; Rabies immunoglobulin; Side effects; Post-exposure prophylaxis
Summary Objective: Due to lack of effective treatment for rabies, post-exposure prophylaxis becomes very important. In this study, we investigated side effects developed in patients following administration of rabies post-exposure prophylaxis. Methods: A total of 1685 patients were vaccinated. 265 patients (15.7%) administered the Essen regimen with equine rabies immunoglobulin and 1420 patients (84.2%) administered Zagreb regimen. 761 (45.2%) patients were vaccinated with a verocell vaccine; Verorab and 924 patients (54.8%) were vaccinated with Abhayrab. Results: All side effects were higher in female patients than those of males. The patients with chronic illness also had significantly, increased side effects; headache (12.4%), pain at site of administration (11.3%), and arthralgia (10.5%) compared to the patients without chronic illness. We grouped the patients in three as; 0e15years, 15e60 years, and 60 years and above. In the first group; fever (21.2%), vomiting (2.4%) and coughing (2.1%); in the second group (15 e60 years), headache (8.8%), arthralgia (6.7%) were significantly increased compared to the other groups.
*
Abstract from the manuscript have been presented at 22th ECCMID 2012, abstract book page: 107. * Corresponding author. Present address: Buldan Chest Disease Hospital, Department of Infectious Diseases and Clinical Microbiology, Buldan, Denizli, Turkey. Tel.: þ90 258 4313057; fax: þ90 258 4313579. E-mail addresses: [email protected], [email protected] (T. Sari), [email protected] (N. Tulek), [email protected] (C. Bulut), [email protected] (B. Oral), [email protected] (G. Tuncer Ertem). 1
Tel.: þ90 312 595 3000; fax: þ90 312 363 3396.
2
Tel.: þ90 312 457 2525; fax: þ90 312 468 8030.
http://dx.doi.org/10.1016/j.tmaid.2014.03.004 1477-8939/ª 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sari T, et al., Adverse events following rabies post-exposure prophylaxis: A comparative study of two different schedules and two vaccines, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.03.004
+
MODEL
2
T. Sari et al. Side effects are significantly higher with schema of 2-1-1 and Abhayrab trade mark vaccine, particularly following the first doses. Discussion: Second generation rabies vaccines are safe, effective and cheaper than HDCV. When fatality of rabies disease is considered, occurring side effects can be tolerated. ª 2014 Elsevier Ltd. All rights reserved.
Introduction Rabies is an acute viral zoonotic disease that causes fatal encephalomyelitis in humans and many other mammals [1]. Although highly effective prophylaxis is available, this viral infection remains a cause of death in almost all countries, with the exception of Antarctica and some island nations [1e3]. Due to a lack of effective treatment for rabies, postexposure prophylaxis for prevention of disease has taken priority. Rabies prophylaxis is primarily applied following exposure, but it can also be applied pre-exposure [4,5]. According to the World Health Organization (WHO); over 10 million people per year, mostly from Asia, are vaccinated following contact with the disease [6]. Rabies post-exposure prophylaxis is almost 100% successful when it is applied using vaccines prepared in modern tissue culture concomitantly with rabies immunoglobulin (RIG) at the correct dose and time [4]. A variety of post-exposure prophylaxis schedules are currently being used, including the Essen regimen, which is recommended by the WHO. It consists of five doses of human diploid cell vaccine (HDCV), administered intramuscularly on days 0, 3, 7, 14 and 28, plus rabies RIG at initial. In 2009, the Centre for Diseases Control and Prevention (CDC) modified this schedule by omitting the vaccine on day 28 [3,4]. Primarily cell-culture or embryonatedegg-based rabies vaccines are also used worldwide. Two types of RIG preparations are in use: RIG of human (HRIG), at a recommended dose of 20 IU/kg, and RIG of equine (ERIG) origin, at a recommended 40 IU/kg for ERIG. According to recent WHO and CDC recommendations, full RIG dosage should be administered around the wound, if anatomically appropriate [4,7e10]. Although human rabies cases have obviously decreased in Turkey in recent years, animal rabies remains a problem, and over 100.000 people per year receive prophylaxis due to the rabies risk from exposure to infected animals [1]. Rabies prophylaxis is implemented according to the Turkish Republic Ministry of Health General Directorate of Basic Health Services Directive of Prevention and Control of Rabies, and all the vaccines and immunoglobulins are provided by the government [8]. Monthly 250 to 350, and annually an average of 3000e4000, people with suspected contact with rabies are admitted to our clinic from Ankara and its nearby districts. Prophylaxis is initiated in approximately 50% of these individuals. The high fatality rate of rabies, means that the numbers of people receiving prophylaxis may be in excess of what is actually required. Therefore, in addition to the efficiency of the vaccine, its safety must be also considered. Nowadays, less serious and fewer frequent reactions are observed with cell cultures or embryonated-eggs-based
vaccines. However, the side effects of vaccine and immunoglobulins may change, according to their manufacturer and origin [8,10]. In this study, we investigated the side effects that developed in patients following administration of rabies prophylaxis. We aimed to determine the differences in the side effects of vaccines according to trade marks and to different vaccination schedules.
Materials and methods Type of trial This was a prospective trial.
Selection of cases We conducted this study between February 2010 and December 2010 at the Infectious Diseases and Clinical Microbiology Outpatient Clinic of the Ministry of Health Ankara Training and Research Hospital, Turkey. We randomly included patients of all age groups who were given post-exposure rabies prophylaxis. In our clinic, rabies prophylaxis is performed according to the Turkish Republic Ministry of Health General Directorate of Basic Health Services Directive of Prevention and Control of Rabies. As post-exposure prophylaxis, we intramuscularly applied two schedules (vaccination at days 0, 3, 7, 14 and 28 plus immunoglobulin at initiation or vaccine schedule of 2-1-1 at days 0, 7 and 21.) after wound care, according to risk. We administered five doses of vaccine þ ERIG more frequently than a schedule of 2-1-1 in patients from rural areas, patients with lesions in the headeneck region, patients with multiple lesions, patients having contact via bite, and in cases of bites from wild animals and stray dogs. We completed a record form for each patient enrolled in the study and recorded data that included gender; age; place and time of bite or mucosal exposure; exposure type; causative animal type; whether or not the individual is an animal owner; whether or not the animal has been immunised and the immunisation record is available; location and number of lesions; presence of chronic diseases and medicines; previous exposure, vaccine history; previous antiserum administration; applied vaccine schedule; administered vaccine doses; type and trade name of rabies vaccine; and, if used, type and trade name of rabies immunoglobulin. We followed patients up for a month and completed questionnaires with regard to all possible side effects related to rabies prophylaxis and complaints of patients. We excluded from the study those patients who could not be regularly followed up to monitor side effects.
Please cite this article in press as: Sari T, et al., Adverse events following rabies post-exposure prophylaxis: A comparative study of two different schedules and two vaccines, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.03.004
+
MODEL
Adverse events following rabies post-exposure prophylaxis
Administered vaccine and immunoglobulin We used two licensed vaccines for active immunisation: 1) Abhayrab vaccine (Human Biologicals Institute, India): Composition; Wistar rabies PM/WI 38-1503-3M strain form Vero cell culture; 2.5 IU/dose; excipients; human serum albumin, maltose, thiomersal, phosphate tampon, solvent; 0.5 mL sodium chloride; and 2) Verorab vaccine (Pasteur Merieux, France): Composition; Wistar rabies PM/WI 381503-3M strain form Vero cell culture; 2.5 IU/dose; excipients; human serum albumin, maltose solvent; 0.5 mL sodium chloride. We administered each dose of vaccine as 0.5 mL into the deltoid muscle. We used Equirab (Bharat serums and vaccines ltd. India) as RIG for passive immunisation. This contains 1000 IU/5 mL equine origin rabies antiserum; excipients; xerol, sodium chloride, glycine, water for injection. We administered 40 IU/kg to each patient.
Monitoring side effects We interviewed and informed each patient who underwent prophylaxis with regard to possible side effects. We administered questionnaires addressing possible side effects listed on the form to each patient visit during prophylaxis; in addition, we asked the patients to inform us of any unexpected conditions in the following month. The side effects that we recorded as being related to the vaccine were as follows: Local side effects; pain, swelling, redness, itching, paraesthesia at site of vaccine administration, and systemic side effects; headache, dizziness, fever, itching, weakness, abdominal pain, lymphadenopathy (LAP), nausea, vomiting, myalgia, cough, insomnia, numbness, irregular menstruation, decreased libido, rash, sore throat, arthralgia, encephalopathy and other (with explanation). We evaluated the side effects of the vaccine with regard to age, gender, chronic disease, each dose of vaccine, different vaccine schedules, with administration of RIG and trade name of vaccine used.
Statistical analysis We compared all side effects according to age, gender, vaccination schedule, and trade name, and used the X-test and Fisher’s exact X-test with the SPSS (Version 15.0; SPSS, Inc. Chicago, IL) programme for testing statistical significance. During analysis, we considered p values of less than 0.05 as significant.
3 and vaccinated 924 (54.8%) patients, admitted between July 2010 and December 2010, with Abhayrab. In the Abhayrab group, we vaccinated 813 (88%) patients with a 2-1-1 vaccine schedule and 111 (12%) patients with five doses of vaccine þ ERIG, while in the Verorab group, we vaccinated 607 (79.8%) patients with a vaccine schedule of 2-1-1 and 154 (20.2%) patients with five doses of vaccine þ ERIG. The demographical features of the patients are shown in Table 1. We observed no side effects in 74.9% of all patients, while observing a variety of side effects in the remaining 25.1%. The most frequently reported side effects were fever (15.8%), weakness (10.6%), headache (7.2%), local pain and swelling (6.5%), arthralgia (4.9%), nausea (4.2%), myalgia (3.8%), dizziness (2.8%) and abdominal pain (2.6%). As we used vaccine and immunoglobulin concomitantly in a treatment regime of five doses of vaccine þ ERIG, we could not separately evaluate side effects related to immunoglobulin. When we evaluated the side effects with regard to the gender of the study participants, pain (p < 0.001), swelling and redness at site of administration (p Z 0.01), headache (p < 0.001), dizziness (p < 0.001), fever (p Z 0.002), weakness (p < 0.001), abdominal pain (p Z 0.001), nausea (p < 0.001), myalgia (p < 0.001), cough (p Z 0.002) and arthralgia (p < 0.001) were significantly higher in females than in males. The most frequently observed side effects in males and females are compared in Fig. 1. When we evaluated the side effects according to age groups, Group 1 included patients under the age of 15 years Table 1 Characteristics of patients (n Z 1685) submitting to our immunization center. Category
Subcategory
N (%)
Gender
Male Female Group 1 (0e15 years) Group 2 (15e60 years) Group 3 (60 years and over) Yes No Headeneck Upper extremity Lower extremity Body Multiple sites One More than one Bite Scratch Lick Other Dog Cat Wild animal Rodent/Other 2þ1þ1 5 doses vaccine þ Ig Yes No
1089 596 532 1030 123
Age
Previous rabies vaccine Place of bite
Number of bite Contact type
Results We enrolled a total of 1685 patients (1089 males, 596 females; 64.6% and 35.4%, respectively) with a mean age of 28.7 (range 1e98) years in the study. We had given 1420 (84.3%; 910 males and 510 females) patients the vaccine schedule of 2-1-1, while 265 (15.7%; 179 males and 86 females) received the classical five doses of vaccine plus rabies RIG. Age and gender distribution among groups were similar. We vaccinated 761 (45.2%) patients, admitted to our centre between February 2010 and June 2010, with Verorab
Type of animal
Treatment schema Chronic disease
(64.6) (35.4) (31.6) (61.1) (7.3)
51 (3.1) 1634 (96.9) 103 (6.1) 896 (53.2) 531 (31.5) 119 (7.1) 36 (2.1) 1443(85.7) 242 (14.3) 1380 (81.9) 298 (17.7) 1 (0.1) 6 (0.4) 1133 (67.2) 531 (31.5) 15 (0.9) 3 (0.2) 1420 (84.3) 265 (15.7) 124 (7.3) 1561 (92.7)
Please cite this article in press as: Sari T, et al., Adverse events following rabies post-exposure prophylaxis: A comparative study of two different schedules and two vaccines, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.03.004
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MODEL
4
T. Sari et al. 20 % 18 % 16 %
Fever Weakness
14 %
Headache Pain
12 %
Arthralgia 10 %
Nausea Myalgia
8%
Dizziness Abdominal pain
6%
Enduration and redness 4%
Cough
2% 0% 1
Figure 1
2
Evaluation of side effects according to gender, 1: Female, 2: Male%: For 100 individuals.
(532 patients; 31.6%); Group 2 included patients aged 15e60 years (1030 patients; 61.1%); and Group 3 included patients age over 60 years (123 patients; 7.3%). In general, we found a significantly higher number of complaints in Group 1 (patients aged under 15 years). In particular, complaints of fever (p < 0.001), vomiting (p Z 0.001) and cough (p Z 0.01) were significantly higher in children, while arthralgia was significantly higher in those aged between 15 and 60 years (p < 0.001). Side effects according to age groups are compared in Fig. 2. In addition, there were significantly higher side effects of pain at site of administration (14 patients; 11.3%), headache (15 patients; 12.1%) and arthralgia (13 patients; 10.5%) among patients with chronic disease requiring continuous drug administration compared to the others; p Z 0.03, p Z 0.04 and p Z 0.008, respectively. The most frequent chronic diseases were hypertension, diabetes and hyperlipidemia. When we evaluated vaccine side effects on the basis of vaccination schedule, they were most frequent in the 2-1-1 schedule group. Fever (16.7% vs. 11.3%; p Z 0.02), weakness (11.6% vs. 4.9%, p Z 0.001), headache (8% vs. 3%, p Z 0.003), local pain (7.3% vs. 2.6%, p Z 0.004), arthralgia (5.5% vs. 1.9%, p Z 0.01) and myalgia (4.2% vs. 1.5%, p Z 0.03) were significantly higher with a vaccine schedule of 2-1-1 than with a five dose vaccine þ ERIG, respectively. Significant side effects compared by vaccine schedule are given in Fig. 3. Side effects following first doses were higher 0-15 years n:532 (31,6%) 15-60 years, n:1030 (61,1%) 60 years and over, n:123 (7,3%)
25% 20% 15% 10% 5% 0% Cough
Figure 2
Vomiting
Headache
Arthralgia
Fever
Side effects according to age%: For 100 individuals.
in patients having a 2-1-1 schedule than in those receiving five doses þ ERIG. This difference was decreased by following doses. When we evaluated side effects according to vaccine trade name, we observed a higher number in patients who received the Abhayrab vaccine, compared to those who received the Verorab vaccine (p < 0.001 for local pain, headache, weakness, insomnia and arthralgia; p Z 0.002 for local swelling and redness; p Z 0.001 for nausea; p Z 0.01 for local numbness; p Z 0.03 for nasal discharge), as shown in Fig. 4. In a subanalysis, we compared the Verorab and Abhayrab vaccines according to vaccine schedule and all side effects were higher in patients receiving the Abhayrab vaccine in a schedule of 2-1-1. Nasal discharge, abdominal pain, nausea and itching were higher among patients receiving the five doses vaccine and ERIG with Verorab than among those vaccinated with Abhayrab, but we detected no significant difference. Side effects with regard to vaccine schedules with two different vaccine trade marks are shown in Table 2. Among the 1685 vaccinated patients, we observed persistent fever at 39 C, crying attacks, irritability and minimal body rash following the first two doses of vaccination of Abhayrab in a 2-1-1 schedule in a girl aged 9 years 18% 16% 14% 12% 10% 8% 6% 4% 2% 0%
Zagreb regimen Essen regimen
Pain
Fever
Myalgia
Figure 3 Side effects according to vaccine schema%: For 100 individuals.
Please cite this article in press as: Sari T, et al., Adverse events following rabies post-exposure prophylaxis: A comparative study of two different schedules and two vaccines, Travel Medicine and Infectious Disease (2014), http://dx.doi.org/10.1016/j.tmaid.2014.03.004
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MODEL
Adverse events following rabies post-exposure prophylaxis
5
25%
20%
15%
Abhayrab Verorab
10%
5%
0%
Figure 4
Comparison of side effects according to vaccine trademarks%: For 100 individuals.
old. In addition, serum sickness developed in one patient aged 32 years, following administration of Verorab with a programme of five doses þ ERIG. This patient remained in hospital and was discharged one week later, completely cured. With the exception of these two cases, we observed no very serious side effects related to vaccine or immunoglobulin. In total, 17 patients had to consult a physician, due primarily to fever (n Z 12), cough (n Z 2), sore throat (n Z 2) and rash (n Z 1) and they were treated with antipyretics and antihistamines.
Discussion Since rabies is a fatal disease and can be prevented through prophylaxis, even after exposure to virus, rabies vaccines have being administered to millions of people worldwide. However, all of the vaccines must be safe. Although current rabies vaccines are indeed safe, side effects may vary between vaccine types and even between brands. In the present study, we evaluated early and late side effects in patients who received rabies prophylaxis post-exposure with regard to vaccine administration schedule and trade mark of vaccine. Most of our study population (61.1%) were aged between 15 and 60 years, and were male; this might be due to the fact that this group was more active and spent more time outside. The most frequently encountered lesions were on the extremities, as expected. Unfortunately, domestic animal bites were the most frequent reason for rabies prohylaxis in our study. Systemic side effects due to rabies vaccines have previously been reported as headache, cough, abdominal pain, myalgia, weakness, and, less frequently, urticaria, angioedema, fever and anaphylaxis [4,11]. In the present study, the side effects we most frequently observed were fever
(15.8%), weakness (10.6%), headache (7.2%), local pain (6.5%), arthralgia (4.9%), nausea (4.2%), myalgia (3.8%), dizziness (2.8%) and abdominal pain (2.6%). In a comparative study, local side effects were reported in 64% of patients vaccinated by vero cell vaccine, 79% of whom were in the Verorab group vaccinated by HDCV, and the most frequently observed systemic side effects were headache and fever [12]. Although local side effects were similar, even a lower rate of local pain, fever and headache were observed at a higher frequency than in other studies [12e19]. All complaints due to rabies vaccine were higher in females. As indicated in some studies, autoimmune diseases are more frequent in woman [20,21]. Wilde at al [22]. found that serum sickness was more frequently reported in women following ERIG, and Shohat and colleagues [23] observed side effects due to MMR vaccine most frequently in woman. Some publications have reported the difference of the immune response in male and female animals [24,25]. In addition, some authors have indicated that atopy, as well as allergic reactions to antibiotics and anaesthetics, are higher in woman [26,27]. This remains an issue for research. While fever, vomiting and cough were significantly higher in the group of patients age 15 years and under, headache and arthralgia were significantly higher in patients aged between 15 and 60 years than those of different ages in our study. In their study, Thongcharoen and colleagues [28] did not observe serious side effects among 27 vaccinated children, and in Thailand, headache and fever were observed in
