A Systematic Review of the Literature of Delayed Inflammatory Reactions After Hyaluronic Acid Filler Injection to Estimate the Incidence of Delayed Type Hypersensitivity Reaction

Abstract

Background

Hyaluronic acid (HA) dermal filler injection is believed to be a safe procedure. However, with the increase in the number of performed procedures and indications, the number of product-related complications, especially delayed inflammatory reactions, has also increased. Delayed-type hypersensitivity (DTH) reaction is one of these delayed inflammatory reactions, which is preventable by performing a pretreatment skin test.

Objectives

The authors sought to find the incidence of delayed inflammatory reactions and DTH reaction after HA injection and to determine whether a pretreatment skin test is worthwhile to be performed.

Methods

The authors conducted a systematic literature review of all the relevant prospective studies, retrospective studies, and case reports on delayed inflammatory reactions and DTH reaction after HA filler injection.

Results

The incidence of delayed inflammatory reactions calculated from the prospective studies was 1.1% per year, and that of possible DTH reaction was 0.06% per year. Most retrospective studies estimated a percentage of delayed inflammatory reactions of less than 1% in 1 to 5.5 years. The incidence of DTH reaction would be lower than that. Among all the DTH cases reported, only about 5% of them were proven to be genuine DTH reactions.

Conclusions

The incidence of both delayed inflammatory reactions and DTH reaction is low. There is evidence that genuine DTH reactions caused by HA fillers approved by the Food and Drug Administration do exist. This adverse event can be prevented by performing a pretreatment skin test. However, the incidence of DTH reaction is so low that the pretreatment skin test is not mandatory if Food and Drug Administration-approved HA fillers are used.

Level of Evidence: 4

The demand for nonsurgical esthetic treatment is ever increasing. Among all nonsurgical procedures, hyaluronic acid (HA) dermal filler injection ranks second after toxin injection.¹ This technique is safe and serious complications are uncommon. However, with the increase in the number of procedures performed and indications, the number of product-related complications, especially delayed inflammatory reactions, has also increased. Delayed-type hypersensitivity (DTH) reaction is one of these delayed inflammatory reactions. There are many case reports and retrospective studies on DTH reaction after HA filler injection. Luckily, DTH reaction is preventable by performing a pretreatment skin test.^2-4

Aims and Objectives

We sought to find the incidence of delayed inflammatory reactions and DTH reactions after HA filler injection and to determine whether a pretreatment skin test is worthwhile to be performed before an HA dermal filler is administered.

Important Concepts

The causes of delayed inflammatory reactions include (1) DTH reactions, (2) foreign-body granuloma reactions, (3) biofilms, and (4) atypical infections. DTH reaction is also known as type IV hypersensitivity reaction, which is a delayed cell-mediated inflammatory immune response to antigens. There are 3 types of DTH reactions: contact, tuberculin, and granulomatous.^2-4

In granulomatous DTH reactions, there is a balance between protective immunity and T-cell-mediated tissue damage to insoluble antigen. A good example of this is seen in tuberculoid leprosy. Persistence of antigens leads to the differentiation of macrophages to epithelioid cells, followed by fusion to form giant cells. The whole pathological response is called “granulomatous reaction,” and it results in tissue damage. Granuloma formation is driven by T-cell activation of macrophages and is dependent on tumor necrosis factor.

Contact hypersensitivity and tuberculin-type hypersensitivity both occur within 72 hours of antigen challenge. Granulomatous hypersensitivity reactions develop over a period of 21 to 28 days; the granulomas are formed by the aggregation and proliferation of macrophages and may persist for weeks. In terms of its clinical consequences, this is by far the most serious type of type IV hypersensitivity response.^2-4

Nonimmunologic granulomas, such as foreign-body granuloma formation due to inorganic matter (eg, talc and silica), can be distinguished by the absence of lymphocytes in the lesion. The histology of a typical immunological granuloma is a macrophage/epithelioid core surrounded by a cuff of lymphocytes, and there may also be considerable fibrosis.^3,4 Please refer to Table 1 for the 3 types of DTH reactions.³

A DTH reaction is, by definition, preventable and can be diagnosed by a skin test. It will be worthwhile to perform such a pretreatment skin test even though the waiting time needed to interpret the test is not short (ie, 21-28 days). This is especially true when the patient has previous adverse reactions. If the patient tests positive, he/she should not receive further treatment with the same HA dermal filler.

METHODS

We conducted a systematic literature review of all the relevant prospective studies, retrospective studies, and case reports on delayed inflammatory reactions and DTH reactions after HA filler injection. A comprehensive search of the literature on this subject was performed on PubMed. The strategy was to find all relevant articles using MeSH terms combined with keywords. Boolean operators (“AND”, “OR”, “NOT”) were used to expand or limit the search areas. Different constructs of search terms were created using truncation, quotations, parentheses, and Boolean operators.

The keywords used were as follows: hyaluronic acid, dermal filler, filler, Restylane, Juvederm, Belotero, Prevelle, Elevess, Captique, Revanesse, Teoxane, safety, adverse events, complications, adverse reaction, delayed hypersensitivity, delayed-type hypersensitivity, delayed-type hypersensitivity reaction, inflammatory, inflammation. Search in PubMed search engine with a combination of the keywords: ((((hyaluronic acid) AND (filler* OR dermal filler* OR facial OR cosmetic OR aesthetic)) OR Restylane OR Juvederm OR Belotero OR Prevelle OR hylaform OR captique OR Revanesse OR Elevess OR Teoxane) AND (complication* OR safety OR reaction* OR event* OR granuloma*)). Articles found: 990 (including prospective studies, retrospective studies, and case reports).

The formula was created in early May 2018, and the search results were obtained in the same month. The first author created the formula, reviewed the search results, and performed the data analysis. The guiding principles used were the MSc Aesthetic Medicine Dissertation Guidelines, Queen Mary University of London.

Selection Process: Inclusion and Exclusion Criteria

Only HA dermal fillers were included. Poly-L-lactic acid, calcium hydroxyapatite, carboxymethylcellulose, and polycaprolactone were all excluded. Permanent and semipermanent materials (eg, acrylic hydrogels) were excluded. Mixtures of HA with these materials were also excluded.

There are many HA dermal fillers available, and many of them are not United States Food and Drug Administration (FDA) approved and are of unproven quality. They may contain high levels of impurities and thus will have a high chance of eliciting various acute and delayed inflammatory reactions. Illegitimate HA products may also be contaminated by pathogenic bacteria during the manufacturing process. Studies on non-FDA-approved HA products were excluded.

Treatment of facial lipoatrophy in patients positive for human immunodeficiency virus was excluded because of the altered immune response in these patients. The injection technique is also very important. HA products injected by nonphysicians were excluded, and journals that were not peer-reviewed were also excluded. Articles on the injection of HA and another product at the same time in the same areas (eg, Botulinum toxin, autologous fat graft, or platelet-rich plasma) were also excluded. However, comparison studies or trials of HA vs another filler (eg, poly L-lactic acid) were included, but the information on the non-HA products was excluded. Also excluded were non-English articles, in vitro studies, and articles on nonhuman patients. Prospective studies with a follow-up period shorter than 1 month were not suitable for the systematic analysis of the delayed-onset long-term complications and were thus excluded. Review articles, teaching materials, how-we-do-it articles, clinical experience, injection techniques, consensus based on expert opinions, treatment algorithms of complications, vascular complications (blindness and stroke), and commentaries as well as treatments of joint problems (eg, intraarticular injections for the management of osteoarthritis) were also excluded.

Prospective Studies

Ninety-two prospective articles were selected from the above 990 articles after screening the titles and abstracts of these 92 articles. After all the abstracts were analyzed, 42 of them were selected and full texts of these titles were obtained. The full texts of all the 42 articles were read, and finally 33 of them were included in this study. The references of these articles were also reviewed, and 2 more articles^5,6 were found and included in this study. Therefore, 35 articles were included in this study.

Prospective Studies With Histological Examinations

Two prospective studies with a detailed histological examination of the implantation sites were found from the above search. These articles were analyzed in this study.

Retrospective Studies

A total 125 articles were selected and reviewed from the above 990 articles after screening the titles and abstracts of these 125 articles. An abstract review was then carried out to allow the selection of those papers relevant to the aims and objectives of this study. This yielded 23 articles, which were read in full to determine their relevance. After considering the inclusion and exclusion criteria, 7 of these articles were finally included in this study.

Case Studies

A total 125 articles were selected and reviewed from the 990 articles after screening the titles and then the abstracts of these 125 articles. After all the abstracts were analyzed, 20 of them were selected and the full texts of these titles were obtained and read. Thirteen of the papers were deemed relevant and were therefore included. The references of these articles were also reviewed, and 2 more articles^7,8 were found and included in this study. In total, 15 articles were included in this study.

RESULTS

Prospective Study

Thirty-five relevant prospective studies were found after the systematic search of the literature. The HA dermal fillers under study were Restylane (Q-Med AB, Galderma, Uppsala, Sweden) (26 articles), Juvéderm (Allergen, Irvine, CA) (12 articles), and Belotero (Merz, Greensboro, NC) (1 article). They were all FDA-approved, 1,4-butanediol diglycidyl ether–linked HA dermal fillers.

The number of patients involved in these prospective studies was low, with an average per article of 116. The number of participants in most of the articles was less than 150. There were only 2 articles that had more than 300 participants. These 2 articles had an exceptionally high number of participants (n = 423 and n = 433).^9,10 However, their follow-up periods were only 6 months.

The majority (46%, n = 16) of the studies had a follow-up period of 6 months. Eleven studies had follow-up periods that varied from 7 months to 1 year, and 4 studies had follow-up periods lasting from 13 to 18 months. The number dropped to 3 in studies with follow-up periods from 19 months to 2 years, and only 1 study had a follow-up period longer than 2 years.

Among the 35 articles included in the study, 21 clearly stated that there were no delayed inflammatory reactions or did not mention any of the delayed inflammatory complications. Most of them were common injection site-related reactions, such as bleeding, erythema, swelling, bruising, itching, and pain. They resolved without treatment after a few days to a few weeks and were related to the injection skills/techniques rather than to the product itself. Occasionally, these reactions might be erroneously reported by the authors as delayed inflammatory reactions. These were excluded from our analysis.

Fourteen articles were studied in detail because they reported delayed inflammatory complications after HA dermal filler injection. Thirty-eight cases of delayed inflammatory reactions were found, among which 2 were possible DTH reactions.^11,12

These 2 “possible” DTH reactions presented with recurrence of similar symptoms of delayed inflammatory reactions at subsequent HA filler injections. This was highly suggested as a DTH reaction.^11,12 However, the appearance of similar symptoms at subsequent injections does not mean that the patient suffers from a DTH reaction. To confirm the diagnosis of DTH reaction, an intradermal skin test is needed. This is the reason why these 2 cases were termed “possible” DTH reactions but not confirmed DTH reactions (Tables 2-4).^5,6,9,11-41

The total number of patients included in this analysis was 4043. The total patient-months at risk were 43,006. The incidence rate is the total number of new cases divided by the patients at risk during the observation period (patient-month at risk). Therefore, the incidence rate was 38 cases per 43,006 patient-months at risk (= 38/43,006 = 0.00088 cases per patient-month at risk; or 0.011 cases per patient-year at risk [0.00088 × 12] or 1.1 patients per 100 patient-years at risk), that is, 1.1% per year.

After combining all the studies, the incidence of delayed inflammatory adverse reactions after FDA-approved HA dermal filler injection was about 1.1% per year. Two cases were possible DTH reactions. The incidence of a possible DTH reaction was 0.06% per year. The incidence of delayed inflammatory reactions after HA filler injection was 1.1% per year, and the incidence of possible DTH reaction after HA filler injection was 0.06% per year.

Prospective Studies With Histological Examinations

Prospective studies are the gold standard for detecting the safety issues of a product. This can be seen from the fact that the FDA accepts prospective studies from manufacturers of dermal fillers to demonstrate efficacy and safety before they are launched into the market. However, most prospective studies do not investigate delayed inflammatory reactions with a challenge test or/and biopsy with histological examination. From the above prospective studies, 2 articles were found to have conducted both an intradermal skin test and a histological examination on the patients after HA implantation.

Hamilton et al¹⁰ examined the immunogenicity of Restylane and Restylane Perlane by performing intradermal skin tests and histological examinations on the patients who had been treated with the HA implants. The patients were followed up for 24 weeks, and an intradermal skin test was performed on all the patients at week 24. Biopsy and histological examination were performed 3 days after the intradermal skin test. No patient developed clinical signs of DTH reaction.

The histological examination of all the biopsies showed no evidence of a DTH reaction. Among the 565 biopsies, most of them were classified as nonspecific inflammation or normal on the basis of the complete absence of lymphocytes. Others showed foreign-body reaction and folliculitis, among others. Some showed sparse lymphocytes that were not diagnostic of a DTH reaction.

From the above study, we could not estimate the incidence of a DTH reaction. The result interpretation was invalid. The problem is the short observation time before the results were interpreted. Biopsy and histological examination should be performed after 3 to 4 weeks, not after 3 days. This is because the reaction time until the clinical presentation develops for a granulomatous-type DTH reaction is 3 to 4 weeks.

Duranti et al¹³ performed a prospective study on the effect of Restylane on human tissue by a histological examination of biopsies of the implant test sites of 5 patients. At the start of the study, several small aliquots of HA were implanted on the forearms of the 5 patients, who received Restylane implantation for esthetic reasons. Biopsy and histological examination were performed on the fourth, 12th, 24th, and 52nd weeks after the HA dermal filler implantation. None of the patients developed any clinical signs of a DTH reaction. For the histological examination, 1 of 5 patients developed a foreign-body reaction and none developed a DTH reaction. This study had a 1-year follow-up period. However, the number of patients participating in the study was very small, only 5 patients. None of the patients in either of the prospective studies developed clinical signs or histological signs of a DTH reaction. The first study involved 433 patients and had a follow-up period of 6 months. However, the result interpretation was flawed. If the observation period had been long enough, the authors might have been able to find cases of DTH reactions. The second one involved 5 patients and had a follow-up period of 12 months. The drawback in this study was the small participant population.

Retrospective Studies

Seven retrospective studies were found. In 6 of these 7 studies, the authors claimed that the cases they reported were DTH reactions. One did not provide an etiology on the delayed inflammatory reactions. The sizes of the studied populations varied from 320 to 406,000. These studies had a lower level of evidence, were prone to bias, and were affected heavily by many confounding factors. Reviewing records cannot provide the true incidence of a complication. Some authors of the retrospective studies claimed that they calculated the incidence of a delayed inflammatory reaction of HA dermal filler injection, but these were very inaccurate and sometimes misleading.

Friedman et al⁴² reported a trend in the reduction of localized hypersensitivity reaction from 0.07% in 1999 to 0.02% in 2000. A decrease in the overall adverse events from 0.15% in 1999 to 0.05% in 2000 was also reported. The total number of patients treated with a Restylane HA filler was 406,000. This was calculated from the number of syringes of Restylane sold during that period of time. The data of adverse events were based on worldwide data (database of Q-Med Esthetics) gathered by the manufacturer of the Restylane HA dermal filler. The extremely low incidence of delayed complications might be due to the fact that the adverse events were very much underreported because this reporting system relied on the voluntariness of the physicians using Restylane. The authors did not even send out questionnaires to the physicians.

Andre⁴³ reported 18 cases of suspected DTH reaction after Restylane injection. The author claimed that the global risk of hypersensitivity was 0.8% in the period from 1997 to 2001. After 2000, the percentage of hypersensitivity reactions dropped to 0.6% because of a reduction in the protein content in the raw material of Restylane. The number of patients treated with Restylane was 4320. This was calculated from the number of syringes of Restylane sold during that period of time. The adverse events were reported via questionnaires returned by the physicians. Because no challenge tests or histological examinations were performed, none of the cases from the above 2 studies could be proven to be a DTH reaction.

Beleznay et al⁴⁴ reported 23 cases of late-onset immune-mediated nodule formation after HA filler injection in 2342 patients. The authors argued that all of these were immune-mediated because the complications occurred most commonly during the cold and flu season (fall and winter). The authors pointed out that 9 of 23 of these patients had an immunologic stimulus, such as flu-like sickness, dental surgery, or teeth cleaning immediately before the appearance of the complication. However, no case could be diagnosed to suffer from a DTH reaction because no biopsies or challenge tests were performed in any of the patients. We could only conclude that 0.5% of the patients who had HA filler injection developed a delayed inflammatory reaction in a period of 5.5 years.

Bae et al⁴⁵ reported 3 cases of delayed inflammatory reaction after HA filler treatment of 320 patients. No cultures, biopsies, or challenge tests were performed. Therefore, all 3 cases were classified as delayed inflammatory reaction instead of a DTH reaction. In this study, it was reported that 0.9% of the patients from the period from March 2010 to February 2012 (24 months) developed delayed inflammatory reactions after HA dermal filler injection.

Artzi et al⁴⁶ found that an exceptionally high percentage (4.25%) of their patients developed DTH reactions. However, the authors did not perform detailed investigations on all of their patients who complained of delayed inflammatory reactions. Most importantly, they did not perform intradermal skin tests. They performed a culture for bacteria, fungus, and mycobacteria and polymerase chain reaction on only 1 of these patients, and the results were negative. However, generalization of the result based on only 1 patient was very difficult. Most importantly, the absence of microorganisms does not mean that the reaction they saw was a DTH reaction. The histological examination of a biopsy taken from that patient revealed a dermal nodular granuloma that was composed of an epithelioid histiocytic granuloma with numerous multinucleated foreign body-type giant cells surrounding an amorphous material. This description is very typical of a foreign-body granuloma instead of a DTH reaction, which should consist mainly of lymphocytes and has no or very few giant cells. It could be concluded that the incidence of genuine DTH reactions would be lower than the figure provided by the authors.

Lowe et al⁴⁷ reported 3 cases of suspected DTH reaction after HA treatment of 709 patients. One of these patients had both a positive intradermal skin test and histological examination consistent with DTH. The other 2 had a positive intradermal test, but no histological examination was performed. Therefore, the authors concluded there was 1 confirmed DTH reaction and the other 2 were possible DTH cases. Lowe et al reported that 3 of 709 patients (0.42%) developed delayed inflammatory reactions in a period of 4 years. One of the 709 patients (0.14%) developed a DTH reaction in the same period.

Micheels⁴⁸ reported 8 cases (3.5%) of suspected DTH reactions. He performed intradermal tests on 5 of the patients who had delayed inflammatory reactions. However, for unknown reasons, the author digested the HA fillers with hyaluronidase before injecting them into the dermis. Therefore, the result of the intradermal skin test became meaningless. A histological examination of most of the implantation treatment sites or the intradermal skin test site showed a strong foreign-body reaction to the fillers. The other histological examination results were inconclusive. In conclusion, the author reported a 3.5% delayed inflammatory reaction in a period of 4 years. None of these cases could be proven to be a DTH reaction (Tables 2-4).^42-48

The above studies were all retrospective. The follow-up periods of the patients in each study were different. In some of the studies, the population at risk was just an estimation made from the number of syringes of HA fillers sold. Thus, the true incidence rate could not be calculated. Most of the above studies, except the 2 studies that had major flaws in their interpretation of the results, estimated a percentage of delayed complications of less than 1% in 1 to 5.5 years. Because DTH reaction is just 1 of these delayed complications, its incidence should be much lower than the above figure. Only 1 person from the above studies developed a confirmed DTH reaction. All the other delayed inflammatory reactions could not be proven as a DTH reaction, and thus it was predicted that the actual incidence rate of DTH reactions was very low.

Case Studies

Fifteen articles were found after a systematic search of the literature. The authors of the studies claimed explicitly, in the title, in the abstract, or in the text, that the complication(s) they reported was/were DTH reaction(s). Twenty cases were extracted from these 15 articles. All cases had clinical presentations consistent with a delayed inflammatory reaction. All the culture results were either negative or not available. Three of them had 1 previous uneventful HA filler injection. The rest did not have any previous HA injections. A history of many previous uneventful HA injections is strong proof against DTH reaction. However, a single previous uneventful HA filler injection was less strong evidence against this. Four studies had positive skin challenge tests. In 8 of them, histological examinations were performed. One of these results supported a DTH reaction, 5 of these results supported a foreign-body reaction, and 2 of them were inconclusive.

One of the studies by Perez-Perez et al⁴⁹ had both a challenge test and histological examination consistent with DTH reactions. Culture results, previous exposure to HA, and treatment responses were all consistent with those of a DTH reaction. Therefore, we concluded that Perez-Perez et al⁴⁹ reported a genuine DTH reaction after HA dermal filler injection. Alsaad et al⁵⁰ and Raulin et al⁵¹ both reported a case of possible DTH reaction. They demonstrated a positive intradermal skin test. Their histological examination results neither proved nor disproved a DTH reaction. The case reported by Goodman⁵² also had a positive challenge test but had no other supporting evidence. This 1 was a possible DTH reaction.

In all the other reports, no challenge tests were performed on the patients. Most of the biopsies had a histological feature of a foreign-body reaction instead of a DTH reaction. The remaining 2 had inconclusive histological results (Tables 2-4).^7,8,49-61 It seemed that the incidence of DTH reactions was high because of the large amount of literature reporting cases of DTH reactions following HA filler injection. However, most of these articles did not have enough evidence to support the notion that the cases reported were genuine DTH reactions. Some of the evidence, such as the presence of foreign-body giant cells, absence of lymphocytes in the histological examination, multiple uneventful previous HA dermal filler injections, and negative intradermal skin tests, was even against or disproving of a DTH reaction. Very few of them had enough evidence to support their claims of being a DTH reaction. Of 20 cases reported, only 1 case confirmed a DTH reaction. This was only about 5% of all the suspected DTH reaction cases. Three cases were possible DTH.

DISCUSSION

If the patient has any previous adverse reactions to HA implants, it is suggested, though not mandatory, to perform a pretreatment skin test to prevent a future DTH reaction. If a non-FDA-approved HA filler is used, a pretreatment skin test is also suggested. All the relevant investigations (biopsies, intradermal skin tests, and cultures) play a role in diagnosing, treating, and preventing delayed inflammatory reactions (infection-related, immune-related, or foreign-body reaction).

Biofilms and atypical infections can be diagnosed by culture/polymerase chain reaction/fluorescence in situ hybridization. Foreign-body reactions have negative culture/polymerase chain reaction/fluorescence in situ hybridization results and negative skin tests. They can, however, be diagnosed via histological examinations. The histological appearance of a DTH granuloma can be similar to that of a foreign-body granuloma in some cases, but DTH granulomas have positive intradermal skin tests, whereas foreign-body granulomas do not.

The culture of discharge and histological appearance of a biopsy cannot exclude DTH reactions. This is because DTH reactions may coexist with other types of delayed inflammatory reactions (eg, infections and foreign-body reactions). This is why skin tests are important for these patients.

Guidance to esthetic physicians/surgeons on course of action when presented with an inflammatory nodule after HA filler injection is proposed. Please refer to Figures 1 and 2 for the algorithm. If this is followed properly, we will be able to find out the causes of the delayed reactions, and thus the patients will be able to be treated more effectively and future occurrences of adverse events (whatever the cause may be) can be prevented.

Some authors doubt the value of pretreatment skin tests. They argue that some delayed reactions can occur as long as 3 to 6 months after the initial filler injection. However, one important point they may have overlooked is that the result of a pretreatment skin test for a granulomatous-type DTH reaction is obtained in 21 to 28 days’ time, not 3 to 6 months. It is not impractical to perform such a test, because it does not take too long to obtain the result in a patient who may suffer from a DTH reaction. If the patient tests positive, he/she should not be further treated with the same HA.

Clinicians should pay close attention to patients who experienced previous adverse reactions to HA implants, especially delayed inflammatory reactions. Pretreatment skin tests are useful for preventing potential DTH reactions. There has yet been no proof on the hypothesis that flu or bacteremia due to dental procedures may cause inflammatory reactions in HA implants.

There are many fake and counterfeit HA products produced in Asian countries every year. The China Association of Plastics and Aesthetics revealed that 70% of the country’s Botox and HA dermal fillers are either counterfeit or smuggled into China illegally.⁶²

According to a news report in December 2018, the Chinese police uncovered a supply network of unlicensed and fake beauty products sold to beauty parlors in at least 10 provinces. Nearly 30 million yuan (£3.4 million) worth of counterfeit Botox, vitamin C injections, HA fillers, and unlicensed equipment have been sold to patients over a 6-month period according to Xinhua News Agency.^63,64

The adverse events after the injection of these products may be much higher than those seen after utilizing the FDA-approved products. This is worth studying in-depth. However, we do not have access to the data.

Limitations

Most of the prospective studies aimed to investigate the efficacy of HA fillers instead of the adverse reactions. This is why the documentation of these adverse events, especially the delayed-type reactions, was not optimal. This might affect our estimation of the incidence of DTH reactions. In addition, the follow-up periods were short, 6 month in most studies (46%). Although a positive skin test appears in 21 to 28 days’ time, the symptoms after cosmetic treatments may not appear until a few months, especially when this is the first time the patient receives this kind of treatment. Thus, some of the DTH reactions might be missed.

In the retrospective studies, the incidence of DTH reactions and delayed inflammatory reactions could be severely biased/affected by many confounding factors. For example, the number of patients treated was not exact but was loosely estimated from the number of syringes of HA fillers sold. Moreover, the number of adverse reactions might be severely underestimated because this depended on the “voluntary” reporting by the physicians who utilized that particular HA product. In addition, the clinical presentations and the investigations were not clearly documented.

In the case report section, we found that many of the authors were unwilling to perform any investigations, not to mention a skin test. Some of them cultured the discharge/pus and then made a diagnosis of DTH reaction on the basis of just the aseptic nature of the discharge/pus. As a matter of fact, the allergic nature of a reaction cannot be made by culture alone.

In addition, it was noted that many physicians/surgeons treated the adverse reactions with combination treatments (systemic antibiotics, systemic steroids, intralesional steroids, etc.) before any investigation was performed. As a result, making an accurate diagnosis became even more difficult because of these combination treatments.

CONCLUSIONS

The incidence of delayed inflammatory reactions calculated from the prospective studies was 1.1% per year, and that of possible DTH reactions was 0.06% per year. Most of the retrospective studies estimated a percentage of delayed inflammatory reactions of less than 1% in 1 to 5.5 years. Among all the DTH cases reported, only about 5% of them were proved to be genuine DTH reactions.

DTH reaction is 1 of the causes of delayed inflammatory reactions after HA filler injection. This is preventable by performing pretreatment intradermal skin tests. Its incidence is much lower than that of a bovine collagen filler, which is estimated to be around 3% to 10%.⁶⁵ Hence, we conclude that pretreatment intradermal skin tests are not mandatory before HA implantation if the practitioner utilizes an FDA-approved HA filler.

Disclosures

Dr Convery works as a Country Expert for Teoxane UK. The other authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article.

Funding

The authors received no financial support for the research, authorship, and publication of this article.

REFERENCES