The vaccines-associated Arthus reaction

ABSTRACT

The Arthus reaction is a rare adverse reaction that usually occurs after vaccination with large and more severe local reactions, belonging to type Ⅲ hypersensitivity reaction. This reaction is characterized by pain, swelling, induration (Tissue that becomes firm) and edema, even accompanied by severe necrosis or ulceration at the injection sites. However, most of mild cases generally can be cured without treatment, and only severe cases need to be treated with anti-allergy. Therefore, this adverse reaction is often ignored by people.

We searched PubMed, Web of Science and Chinese database (CNKI database and Wan Fang database) for published studies using the terms “Arthus reaction” or “Arthus phenomenon”, combined with “vaccine”, with no date or language restrictions for all publications before January 28, 2019. Only 30 cases of Arthus reaction were found, of which only one case died.4 cases of Arthus reaction post-dose-1 were reported in the review. The proportion of Arthus reaction occurred after the first, second and third injections in those case reports was 13.3%, 50.0%, and 23.3%, respectively. Arthus reaction was determined according to the clinical symptoms (The symptoms which were observed by the researchers, such as red, swelling and painful with itching at or around the injection sites). The specific causes of Arthus reaction after one dose of vaccination are not described in detail in literatures. Therefore, it could be hypothesized that the case has a pre-existing specific IgG (Such as pre-existing antibody, etc.) to cause the Arthus reaction.

And 17 reported cases were observed in children younger than 6 y. In addition, we collected only 18 cases of bacterial vaccine-induced Arthus reaction and 12 cases of viral vaccines. However, there are no other data (Such as the total number and incidence rate of vaccination) in literatures, so we cannot compare statistically significant differences. At presents, no previous reviews of vaccine-induced Arthus reaction have been found. Thus, a systematic review about vaccine-associated Arthus reaction is urgently needed to deepen people‘s understanding and concern of this phenomenon. In this manuscript, we retrospectively reviewed the description of the discovery process and mechanisms of Arthus reaction, a description of the characteristics of Arthus reaction cases, reporting the Arthus reaction cases in China during 2010–2015, diagnostic criteria and general treatment, preventive measures of Arthus reaction, and challenges remaining to be investigated in the future.

KEYWORDS:

• Arthus reaction; vaccination

Introduction

In the past century, the vaccine-preventable infectious diseases have been completely eradicated (Smallpox) or hugely reduced (Such as, polio, measles, pertussis, and diphtheria) with the widespread use of vaccines. Since the threats of these infectious diseases are no longer feared, the public and mass media pay more attention to vaccine safety in current era. The Adverse Events Following Immunization (AEFI) surveillance system mainly reports adverse reactions or events, which include fever, local redness and swelling, induration, Arthus reaction, and other symptoms.¹ Yet the Arthus reactions have been infrequently and rare reported after vaccinations.^2,3

The Arthus phenomenon was first noted in rabbits; subsequently, similar reactions were observed in a variety of animal species, such as, guinea pigs, rats, and dogs, as well as in humans.^4,5 This phenomenon can be elicited by vaccines, drugs (Insulin injection), insect bites, and so on.⁶ Repeated injections of certain vaccines is prone to occurred Arthus reaction, and this phenomenon is usually characterized by localized acute small-vessel inflammation at the injection site.⁷ The most common clinical manifestations of Arthus reaction are local tissue hardening, accompanied by obvious redness, swelling, and pain, diameter less than 5.0 cm at or around the site following the injection in mild cases, but in some severe cases the diameter of the redness or swelling can spread to the entire upper arm or extend to the injected upper arm from shoulder to elbow.⁸ Those clinical manifestations usually can persist for one week, or even persisting for few months, without scar left after healing. However, the mild necrosis at the injection site, sclerosis in the deep tissue, and even severe necrosis and ulceration in local tissues, skin, and muscles can be found in severe cases. Nevertheless, the relatively low incidence of the Arthus reaction is often leading to a neglection in the vaccine clinical studies and routine vaccination practice. Here, we briefly describe the discovery process and mechanisms of the Arthus reaction, and summarize the Arthus reaction reported to deepen people‘s understanding and concern of this phenomenon.

What are the discovery process and mechanisms of Arthus reaction?

The Arthus reaction is a localized inflammatory response, belonging to a typical local subacute type III hypersensitivity reaction. The Arthus reaction was discovered by Nicolas Maurice Arthus in 1903^9–11”: Arthus subcutaneously injected 5 cc. of horse serum into rabbits per 6 d. After the third injection, the slight infiltration was observed at the injection site, persisting 2 or 3 d. After the fourth injection, he noted that a local oedematous reaction occurred and the absorption of serum became slow. After the fifth injection, the infiltration became more severe, and edematous did not disappear until after 5 or 6 d. After the sixth injection a white (not containing pus and absolutely sterile), solid, compact and thick mass was produced in the subcutaneous cellular tissue, lasting for several weeks. After the seventh injection the skin became rapidly red, then blanched and dried, and even leading to a gangrenous plaque. The general condition of the rest of the animal (Without the injection of 5 cc. horse serum) is good.” This phenomenon was soon repeated in many laboratories, and was entitled the Arthus phenomenon (Or Arthus reaction) by Nicolle in 1907.¹²

The mechanism of this phenomenon has been investigated in many studies.^13–18 This reaction is mediated by intradermal injections of antigen into a local skin site of an animal subject preexisting large amounts of immunoglobulin G (IgG) antibodies specific to the antigen. The antigen will diffuse into the walls of local blood vessels and the immune complexes which are comprised of antigen, antibody, and complement in vessels precipitating close to the injection site. Subsequently, the C3a, C4a, and C5a complements are activated by the immune complexes, and the activation of FcγRIII (Binding immune complexes) on the localized mast-cells induces their degranulation with an increase in local vascular permeability, resulting in an inflammatory response. Besides the chemotactic factors C3a, C5a, and C5b67 attract large numbers of neutrophils to immune-complexes followed by lytic enzymes release, which can lead to the injury of vessel walls with the development of hemorrhage, edema, thrombi, local ischemia, and necrosis. Eventually, the series actions can lead to localized tissue and vascular damage, which are characterized by redness, swelling, pain, erythema, central blanching, induration, petechiae, and occasionally by tissue necrosis.” These signs and symptoms usually begin 2–12 h after exposure to the antigen, develop gradually in the next few hours and most of them resolve within one week without sequelae.¹⁹

Case of vaccine-related arthus reaction

Literature search

We searched PubMed and Web of Science databases for published studies using the terms (MeSH terms, title terms, and abstract terms) “Arthus reaction” or “Arthus phenomenon”, combined with “vaccine” in English language, with no date or language restrictions for all publications before January 28, 2019. Published Chinese studies or reports on Arthus reactions post-vaccination were also identified from the CNKI database and Wan Fang database using the same search terms and strategy.

Inclusion and exclusion criteria

We included the published literatures on Arthus reactions in this reviews by following inclusion criteria: (1) studies provided sufficient data to describe the Arthus reaction/phenomenon; (2) Arthus reaction following the vaccination or immunization; (3) Original case reports or clinical studies. The exclusion criteria were as follows: (1) for duplicate publications; (2) irrelevant papers; (3) Arthus reaction in animal experiments; (4) Arthus reaction/phenomenon not caused by vaccination/immunization.

A total of 146 relevant literatures were found in English language database (Pubmed and Web of Science), and 87 of them were included after excluding duplicate documents (Figure 1). Then, a total of 84 literatures were excluded due to the reports of irrelevant papers (n = 29), Arthus reaction in animals (n = 17), non-vaccine studies (n = 15) and Arthus reaction/phenomenon not caused by vaccination/immunization (n = 23). 3 studies were included after reviewing the full texts of the remaining literatures. Secondary searching of reference lists yielded an additional three references. On the other hand, 69 relevant Chinese literatures were found in CNKI database and Wan Fang database. Then, 44 duplicate literatures and 8 literatures were excluded for some reasons. The main reasons for exclusion of studies are provided in Figure 1. Secondary searching of reference lists yielded an additional two references. There were 6 studies in English database and 19 studies in Chinese database. Finally, 25 literatures met the inclusion criteria, and only 30 cases were found in the 25 literatures to the case reports of vaccine-related Arthus reaction in human beings (1 of the 25 literatures reported six cases of Arthus reaction²⁰) (Figure 1).

Figure 1. Flow diagram of the process of literature selection on vaccine-induced Arthus reaction.

English database only includes Pubmed and Web of Science, and Chinese database includes Wanfang database and CNKI database.

Table 1 shows the details of the cases of vaccine-related Arthus reaction are recorded, including type of vaccines, author/reference/year of reporting, country, age, gender, schedule (injection times), dosage, inoculation sites or (and) routes, main manifestation of local skin and outcome. The Arthus reactions reported in English literatures were mainly before 1980, while in Chinese literatures were after 1980. One possible reason for this is that the China Ministry of Health (MOH) issued guidance for handling vaccine adverse reactions in 1980, while Arthus reaction has been discovered and studied in Western a long time ago (before 1980).²¹ The most common clinical symptoms were redness, swelling, and induration around the injection site. Among these reported Arthus reaction cases, 29 cases recovered, and only 1 death case was reported (Table 1).^3,10,22–26 In 1934, Ross FE reported that a 4.5-y-old boy suffered from local necrosis after multiple subcutaneous injections of tetanus antitoxin. He described the occurrence of a characteristic set of typical symptoms. These symptoms appear to be due to an allergic reaction between antibodies and specific antigens, resulting in the formation of toxic substances that cause local necrosis in the tissues. A few days later, the boy died of sepsis that night.²² Most case reports of vaccine-related Arthus reactions mainly caused by Toxin-antitoxin (12, 40.0%), HepB (8, 26.7%), and DTaP (4, 13.3%). While the proportion of the case reports which caused by other vaccines is much lower, such as Rabies Vaccine (RabV, 2[6.7%]), 23-valent Pneumococcal Polysaccharide Vaccine (PPV23, 2[6.7%]), attenuated measles vaccine (MV, 2[6.7%]; Figure 2). The majority of reported cases were observed in children younger than 6 y (17, 56.7%), which may be associated with the situation that most recommended immunizations are administrated in children under 6 y of age.²⁷ In addition, 2 (6.7%) Arthus reaction cases were reported in children 6–18 y of age, and 6(20.0%) were found in adults age over 18 y (Figure 2). Besides, we found that most of the Arthus phenomenon cases followed the booster injections (Which add up to 76.6%).

Table 1. Case reports of vaccine-related Arthus reaction.

Vaccine	Reference	country	Age	Gender	Vaccine dose			Main manifestation of local skin	Outcome
					Schedule(Injection times)	Dosage	Inoculation sites or (and) routes
Toxin-antitoxin	Gatewood W.E.^Citation20 (1927)	America	25 y	F	0–8 d	20,000units, 40,000units	intramuscularly to the right and left hip	The hip and arm were greatly swollen. There was an area of blanching 12 cm. in diameter over the summit of the swelling in the thigh, and a similar but smaller area on the arm. The surrounding tissues were also much swollen but were soft, red and tender.	Recovered
	Gatewood W.E.^Citation20(1927)	America	NA	NA	3th^#	50,000 units	NA	The same blanching, swelling and evidence of extravascular blood were present.	Recovered
	Gatewood W.E.^Citation20(1927)	America	NA	F	3th^#	NA	NA	A marked serum sickness coincident with pain, redness and great swelling at the site of injection	Recovered
	Gatewood W.E.^Citation20(1927)	America	NA	F	3th^#	NA	the left arm	The arm became red, swollen and hard. The swelling was somewhat painful, and there was a moderate febrile reaction.	Recovered
	Gatewood W.E.^Citation20(1927)	America	NA	F	3th^#	NA	NA	Because a severe local reaction with some necrosis followed the second dose of toxin-antitoxin. Induration and discoloration followed the subcutaneous anti-scarlet fever serum.	Recovered
	Gatewood W.E.^Citation20(1927)	America	NA	F	NA	10,000 units	NA	The serum sickness was severe.	Recovered
	Tumpeer, I H.^Citation47 (1931)	Chicago	25 y	F	0–9 d	20,000 units, 40,000units	intramuscularly to the right and left hip	A blanched area, 12 cm. in diameter, appeared over the swelling of the thigh and a similar area appeared over the arm. These regions were swollen, soft, red and tender.	Recovered
	Tumpeer, I H.^Citation47(1931)	Chicago	5 y	F	0–3 d	1,000 units, 15,000units	intramuscularly to the left and right buttock	A redness and swelling at the site, and the next day there were urticarial wheals locally, becoming scattered the following day while the local swelling subsided.	Recovered
	John A.M.^Citation11(1934)	Worcester	21 y	F	0–7 d	10,000units	intramuscularly to the left buttock	The left buttock was enlarged to twice its normal size, was tense and shiny with purplish mottling peripherally and fluctuation centrally.	Recovered
	Ross F E.^Citation22(1934)	NA	4.5 y	M	NA	NA	NA	A generalized erythematous rash, subsequent the skin and subcutaneous tissues of the entire thigh, hip and abdomen were involved in a huge necrotic sloughing mass	Died
	Li JL.^Citation48(2004)	China	50 y	F	1th	NA	intramuscularly to the deltoid muscle	Skin tests for twenty-minutes were negative. Red swelling were observed at the injection sites, with a diameter of 10 cm or more.	Recovered
	Li CF, et al.^Citation49(2006)	China	17 y	M	1th	NA	intramuscularly to the left buttock	In the third day, swelling appeared on the upper right chest, about 10 cm × 12 cm red swollen.	Recovered
DTaP	Liu ZT.^Citation50 (1985)	China	18 m	F	1th	0.2 mL	Right upper arm	In the 9th day, the red swelling and induration were observed on the injected site, which during the following a few days become necrotic.	Recovered
	Hao MY.^Citation51(2005)	China	15 y	M	4th^#	0.5 mL	Right upper arm	The redness and itching were observed on the right upper arm. The edema appeared on the entire arm at the sites of injection in the afternoon. In the 3th day, 4 cm swelling appear on the right arm, then become a slightly red and bright.	Recovered
	Duan XY, et al.^Citation23(2013)	China	2 y	M	NA	0.5 mL	Left upper arm	The next day, there was a fever, swelling of the inoculation site, bruising and bruising	Recovered
	Na M, et al.^Citation26(2016)	China	7 m	M	2th^#	NA	NA	In the 2nd day, erythema appeared on the skin, about 2 cm in diameter, with no exudate, induration, suppuration, After more than 10 days, the scope of the rash increased, and it exuded and erosion.	Recovered
MV	Buser F.^Citation24 (1967)	Tokyo	1.5 y	M	2th^#	1.0 ml	Subcutaneously to the upper part of the arm	A red swelling was observed on the sixth to eighth day at the site of the upper arm, lasting for several days.	Recovered
	Dong CG.^Citation25(2008)	Sichuan, China	5 y	M	8 month,1.5 y and 5 y	0.2 ml, 0.5 ml	Left upper arm	In the 2th day, the itching appeared on the site of injection, in the 4th day, 1.5-cm × 1.0-cm red swollen and 0.3 cm~0.5 cm blister appeared on the left upper arm,	Recovered
RabV	Zhang H, et al.^Citation52(1996)	China	60 y	F	0–3-7–14–30 d^￡	1 ml or 2 ml	intramuscularly to the buttock	5 hours after the third injection, local reaction appeared on the buttocks. Red swollen with a diameter of 10 cm or more occurred at the site.	Recovered
	Wei M.^Citation53 (1997)	China	12 y	M	0-3-7–14–30 d	NA	intramuscularly to the deltoid muscle	1 hour after the third dose of injection, a large 10-cm × 10-cm red swollen and indurate appear on the site injection.	Recovered
HepB	Hervey F, et al.^Citation3(2001)	Fresno, California	73 d	F	16–73 d	0.5 ml	intramuscularly to the deltoid muscle	A large 1.5 cm × 1.0 cm eschar appear on the left deltoid muscle.	Recovered
	NA.^Citation54(2001)	China	2 m	M	0–1 month^﹡	NA	Right upper arm	In the 8th day, bruising purple, 2 cm × 2 cm indurate and tenderness were observed on the upper arm, the symptoms gradually aggravated at the sites of injection.	Recovered
	Zhu XJ, et al.^Citation55(2002)	Tianjin, China	1 m	M	0–1 month^﹡	NA	Right upper arm	In the 10th day, cyanosis of skin, 2 cm × 2 cm indurate, and tenderness were observed on the site of injection. A month later, the right upper arm deltoid inoculation site has a 5.5 cm × 6.5 cm nearly circular plaque with blue, irregular edges, touches hard, rough skin surface was a cord-like.	Recovered
	Xu ZC.^Citation56 (2007)	Jiangxi, China	1 m	F	0–1 month^﹡	5 μg	Right deltoid muscle	In the 8th day, 2 cm × 2 cm red swelling and indurate, were observed on the site of injection, with tenderness. Half a month later, Right upper arm deltoid inoculation site has a 5 cm × 5 cm round red mass, shiny color, irregular edges, significantly higher than the skin, injection of local mild necrosis, deep tissue harder.	Recovered
	Zheng ZG, et al.^Citation57(2007)	Guangxi, China	1 m	M	0–1 month^﹡	5 μg	Right upper arm	In the 7th day, red swelling and indurate were observed on the site of injection, with 10 cm × 10 cm bruising purple, 3 cm × 4 cm subcutaneous cord-like induration on the right upper arm deltoid skin.	Recovered
	Yan DM, et al^Citation58(2009)	Beijing, China	20 y	M	2th^#	NA	Left deltoid muscle	After 1 week, the region of the left arm deltoid was significantly inflamed	Recovered
	NA.^Citation59(2009)	China	2 m	M	2th^#	5 μg	Right upper arm	In the 10th day, red swelling with diameter of 5 cm or more appeared on the Right upper arm. The areas were firm, not tender.	Recovered
	Xiao JH.^Citation60(2012)	Fujian, China	2 m	F	0–2 month^﹡	5 μg	Right upper arm	In the 10th day, swelling with diameter of 5 cm or more appeared on the Right upper arm, the local tissue harder, with no obvious tenderness.	Recovered
PPV23	Shao HX, et al.^Citation61(2006)	China	33 m	M	0–87 d	0.5 ml	intramuscularly to the deltoid muscle	In the evening, body temperature was 39.3℃. The red swelling from the shoulder to the elbow appeared on the Right upper arm following the second dose of vaccination.	Recovered
	Long YH, et al.^Citation62(2014)	China	49 y	F	1th	NA	intramuscularly to the deltoid muscle	In the afternoon, 5 × 6 cm red swelling and indurate, were observed on the site of vaccination.	Recovered

NA: not available. F = female; M = male.

^#aAmong child and young adult occurred in the Arthus phenomenon, but there is no exact schedule immunization in the literature to received killed-virus & attenuated measles vaccine.

^﹡bAfter the second dose, the child appeared Arthus reaction. The literature did not show that the child received other doses of the vaccine.

^＋cThe AEFI surveillance system in China monitor these data. Nevertheless, these data are not described in detail that the subjects received the vaccine.

^￡dThe article show that subject delay the second dose of Rab-V.

&^eThe data show that these cases received different HepB vaccine type.

Figure 2. Distribution of Arthur‘s reaction Cases by vaccine (A), age (B) and the number of vaccination (C).

The Arthus reaction in China‘s AEFI system during 2010–2015

The AEFI is a surveillance system to record medical incidents that take place after the immunizations, causes concern, and is believed to be caused by immunizations.²⁸ In China, the National surveillance program of AEFI was issued in 2010. During 2010–2015, a total of 103 cases of Arthus reactions were reported to the AEFI^29–33(Table 2). The highest annual reporting rate was 0.02 per million doses in 2010, while the lowest one was 0.0002 per million doses in 2013^29,32 (Table 2). Moreover, cases of Arthus phenomenon were more prone to occur in DTaP, DTP, DT, HepB, and Rab-V (Table 2). Besides, the other vaccines were rarely reported, such as killed-virus & attenuated measles vaccine, Rabies Vaccine (Rab-V), 23-valent pneumococcal polysaccharide vaccine (PPV23), and influenza A (H1N1) vaccine, and so on.^{24,25,29–39} The overall incidence of Arthus reactions was very low compared with other common vaccine-related injection-site reactions. However, we should be aware that the AEFI is a passive surveillance system, and it is possible that some Arthus reaction cases may not be captured, and the incidence of Arthus reaction may be biased by underreporting.

Table 2. Number and Estimated Incidence Rate (Per million Doses) of Arthus reaction by vaccine and diagnosis in China, 2010–2015.

Vaccine	No. of Arthus’s reaction cases [Incidence Rate (Per million Doses)]												Total, n(%)
	2010^Citation63		2011^Citation64		2012^Citation19		2013^Citation2		2014^Citation65		2015^Citation66
HepB	6	0.10	4	0.010	2	0.002	2	0.003	4	0.006	4	0.01	22(21.36%)
DTP	10	0.14	0	0.000	0	0.000	0	0.000	0	0.000	0	0.00	10(9.70%)
JEV-L	1	0.03	1	0.003	0	0.000	0	0.000	1	0.003	0	0.00	3(2.91%)
MPV-A	1	0.03	1	0.003	0	0.000	0	0.000	0	0.000	0	0.00	2(1.94%)
BCG	0	0.00	0	0.000	1	0.010	0	0.000	0	0.000	2	0.01	3(2.91%)
DTaP	0	0.00	3	0.004	7	0.010	5	0.010	7	0.010	6	0.01	28(27.18%)
DT	0	0.00	1	0.010	1	0.010	1	0.010	3	0.020	1	0.24	7(6.80%)
Hib	3	0.26	0	0.000	1	0.010	0	0.000	0	0.000	1	0.01	5(4.85%)
OPV	0	0.00	0	0.000	0	0.000	0	0.000	1	0.001	0	0.00	1(0.97%)
MPV-AC	1	0.04	1	0.004	0	0.000	1	0.003	1	0.003	0	0.00	4(3.88%)
Rab-V	0	0.00	4	0.020	0	0.000	1	0.010	2	0.010	0	0.00	7(6.80%)
MR	0	0.00	0	0.000	1	0.010	1	0.004	0	0.000	0	0.00	2(1.94%)
HepA-L	0	0.00	0	0.000	0	0.000	1	0.005	0	0.000	0	0.00	1(0.97%)
MMR	0	0.00	0	0.000	1	0.000	0	0.000	0	0.000	0	0.00	1(0.97%)
PPV23	1	0.46	0	0.000	2	0.060	0	0.000	0	0.000	0	0.00	3(2.91%)
PPCV7	0	0.00	0	0.000	1	0.170	0	0.000	0	0.000	0	0.00	1(0.97%)
InfV	0	0.00	0	0.000	1	0.010	0	0.000	0	0.000	0	0.00	1(0.97%)
VarV	2	0.33	0	0.000	0	0.000	0	0.000	0	0.000	0	0.00	2(1.94%)
Total	25	0.02	15	0.003	18	0.004	12	0.002	19	0.004	14	0.003

Baseline twenty-first century annual monitor data.

Source: the CDC of China.

What are the diagnostic criteria, general treatment, and preventive measures of arthus reaction?

Nowadays, the diagnostic criteria and principles of management of the Arthus reaction caused by vaccines have not been clearly defined. In general, the cases of Arthus reaction were diagnosed by physicians or expert panel according to the subject‘s vaccination status (e.g., immunization program, dose, injection site), main clinical manifestations (e.g., limb local swelling, induration, and other symptoms), and other relevant information. Besides, they also conducted an individual causality assessment-to comprehensive determine whether it belongs to the Arthus reaction.

Most Arthus reactions reported were mild and usually self-limited and generally did not need treatment. However, for some moderate cases, they could be treated with anti-allergy drugs as required, such as diphenhydramine, 25 to 50 mg per adult, 0.5 to 1.0 mg/kg per child, 3 times per day, or promethazine, 25 to 50 mg per adult, 1.0 mg/kg per child, 3 times per day. For severe cases with tissue necrosis could be taken cortisone 2 times a day, each 50 mg, intramuscular injection, once a week.^9,10 Meanwhile, keeping the injected site clean to prevent secondary infection and promote the regeneration of necrotic tissue. Some treatments also could relieve symptoms (swelling or pain), such as cold compresses cold the affected limb around the injection site, acetaminophen and limb elevation.¹⁹

Some studies found that the pre-antibody level of individual, dosage of vaccine, and booster immunization may be related to the occurrence of the vaccine-induced Arthus reaction.³ Theoretically, we could prevent this phenomenon by controlling these risk factors for individuals. Although we invested a lot of manpower, material resources and money to implement these preventive measures, the benefits may be extremely low due to the Arthus reaction is a rare adverse reaction. Thus, it is an economical and practical way to take precautions for vaccinator who developed Arthus reaction. In order to prevent this phenomenon, it may need to be spaced at longer intervals and antibody levels should be monitored to determine when boosting is needed for those individuals. For example, Advisory Committee on Immunization Practices (ACIP) has recommended that persons who experienced an Arthus reaction after a dose of tetanus toxoid–containing vaccine should not receive Td more frequently than every 10 y, even for tetanus prophylaxis as part of wound management.² Besides, if persons experienced an Arthus reaction after diphtheria toxoid-containing vaccine, they should use tetanus toxoid for booster to reduce the occurrence of Arthus reaction rather than Tdap.⁴⁰ Moreover, some experts recommend that if Arthus reaction occurs at the initial dose in the primary infant series in a child under 6 months, the next doses need to be postponed for several months until the reduction of sero-antibodies. If the child is younger than 6 months when the second dose expires, this should be deferred until the child is 6 months of age; the third dose should be given 2 months apart. If the following dose is at the age of 6 months, there is no need to delay because circulating maternal antibodies will be significantly reduced.⁴¹

Challenges and future work

The vaccine-induced Arthus reactions as a relatively rare adverse reaction are frequently overlooked. In this review, we have documented the discovery process, mechanism, diagnostic criteria of Arthus phenomenon, summarized the previous reported Arthus reaction cases after the vaccination, and discussed the general treatment and preventive measures. We hope this review could refresh the awareness and recognition of people about the complexity of the Arthus phenomenon in order to better prevent the Arthus reaction.

Indeed, we found in the Chinese database the number and incidence rate of Arthus reaction induced by various vaccines in China, but during the sample period of the English database, we did not find the relevant surveillance data. Thus, we cannot compare whether there is a difference in the incidence rate of Arthus reaction between the China and the rest of the world. On the other hand, the cases in English literature mainly occurred before 1980. The Arthus case has indeed declined since 1980. We have not yet found out why the Arthus reaction has decreased. It can be assumed that the vaccine is improved (updated) or the Arthus reaction is underreported.

So far, there is still no unified definition and diagnostic standard for Arthus reaction; thus, we recommend the public health sector experts to accurate and unify the definition and the diagnostic criteria for Arthus reaction. Notably, the incidence of reported Arthus reaction within the context of the total immunized population is often extremely low.^2,3 Then in order to overcome challenges of the Arthus reaction reporting rate following vaccination, some physicians of expert panels maybe have advised the inclusion of rare Arthus reaction into national and provincial-level hospitals owned a local Hospital Information System (HIS).⁴² Meanwhile, the improvements of reporting rate related to Arthus reaction will ensure a better understanding and awareness of this phenomenon. Mechanistic studies have been valuable in better understanding Arthus reaction action but currently, mechanisms of Arthus reaction are less well understood.⁴³ Hence, researcher in the scientific research institutions is still needed into the mechanisms underlying potential vaccine-associated Arthus reaction in an immunized population. The general public is difficult to accurately and scientifically understand the Arthus reaction if not carefully researched. It is important to note that Arthus reactions usually occur at and around the injection site,^3,24 and in order to better prevent this phenomenon, vaccinators are advised to regularly care and clean the same injection site.

In general, potential factors (such as type of vaccine, the dosage and doses of vaccine, time interval, and pre-antibody level) were carefully considered and well controlled in order to prevent of Arthus reaction. We collected only 18 cases of bacterial vaccine-induced Arthus reaction and 12 cases of viral vaccines. However, there are no other data (such as total number and incidence of vaccinations) in literatures, so we cannot compare statistically significant differences. Studies have shown that the higher dosages of vaccine can cause Arthus reaction.⁴⁴ Retrospective studies, especially case reports, may not be able to describe the relationship between the case with Arthus reaction and the dosage of vaccine in a comprehensive and detailed. This indicates an urgent need for more research between the dosage of vaccine and Arthus reaction. On the other hand, of the 30 reported cases of Arthus reaction, 22 occurred after the second and third doses of the vaccine. Therefore, it could be hypothesized that cases who receive multiple revaccinations do have a sufficient concentration of type-specific antibody to cause an Arthus reaction in the published literature.⁴⁵ Arthus reactions are more likely to occur after frequently repeated injections of the same vaccine.⁴⁶ Thus, appropriate spacing at longer intervals between injections may be an effective measure to avoid or reduce this phenomenon. Other possibilities are primary prevention of Arthus reaction in sensitized or at-risk children (the majority of reported cases were observed in children younger than 6 y). This may be due to poor immunization in children compared to adults, and multiple or intensive revaccination campaigns under 6 y of age, which are consistent with the above the doses of vaccine.

This study has three limitations worthy of mention. First, we obtained vaccine-related Arthus reaction cases mainly from the CNKI database, Wan Fang database, PubMed and Web of Science databases. However, we exclude the other non-English published literature. Therefore, there may be selective bias in our review. Second, we collected only 18 cases of bacterial vaccine-induced Arthus reaction and 12 cases of viral vaccines. The cases of Arthus reaction are descriptive studies or case reports. These cases may not be Arthus reaction. Thus, there is ascertainment bias because observers might expect more bacterial cases, and viral cases are under-reported. Finally, the number and incidence rate of Arthus reaction in Table 2 are derived from the China‘s AEFI System. There may be ascertainment bias and reporting bias. In summary, the public health scholars and related personnel are encouraged to standardize the definition of Arthus reaction and to establish diagnostic criteria for Arthus reaction in the future. And then it is recommended that the health sector experts and their staff will closely observe and monitor the early symptoms of Arthus reaction following vaccination and reduce its severity and harmfulness. The national health sector has the right and responsibility to observe and improve the AEFI surveillance system so as to early detection. Importantly, the National Institutes of Health further improve the prevention and treatment of Arthus reaction in the future. And researchers in the scientific research institutions are needed into the mechanisms underlying potential vaccine-associated Arthus reaction in an immunized population. On the positive side, the above recommendations and measures may contribute to early detection, accurate diagnosis, and effective treatment of Arthus reaction.

Abbreviations

ACIP	=	Advisory Committee on Immunization;
AEFI	=	adverse events following immunization;
BCG	=	Bacilli Calmette-Guérin Vaccine;
DTaP	=	Diphtheria Tetanus and Acellular Pertussis Combined Vaccine;
DT	=	Diphtheria and Tetanus Combined Vaccine;
DTP	=	Diphtheria, Tetanus, Pertussis Combined Vaccine;
HepA-L	=	Hepatitis A Attenuated Live Vaccine;
HepB	=	Hepatitis B Vaccine;
Hib	=	Haemophilus Influenzae Type b Polysaccharide Conjugate Vaccine;
InfV	=	Influenza Vaccine;
JEV-L	=	Japanese Encephalitis Attenuated Live Vaccine;
MPV-A	=	Group A meningococcal polysaccharide Vaccine;
MPV-AC	=	Group A and C meningococcal polysaccharide Vaccine;
MR	=	Measles and Rubella Combined Attenuated Live Vaccine;
MMR	=	Measles, Mumps and Rubella Combined Attenuated Live Vaccine;
OPV	=	Oral Poliomyelitis Attenuated Live Vaccine;
PPV23	=	23-valent Pneumococcal Polysaccharide Vaccine;
PPCV7	=	7-valent Pneumococcal Polysaccharide Conjugate Vaccine;
Rab-V	=	Rabies Vaccine;
VarV	=	Varicella attenuated live Vaccine

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Additional information

Funding

This study was supported by Vaccine Clinical Evaluation Platform Construction Project under China National Science and Technology Major Projects (2018ZX09734004). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.