Aquamid Comps

Delayed Immune-Mediated Adverse Effects Related toPolyacrylamide Dermal Fillers: Clinical Findings, Management,and Follow-Up

JAUME ALIJOTAS-REIG, MD, PHD,�y VICTOR GARCIA-GIMENEZ, MD,yz FRANCESC MIRO-MUR, PHD,z AND

MIQUEL VILARDELL-TARRES, MD, PHD�y

BACKGROUND It has been thought that polyacrylamide (PA) injections do not have inflammatory sideeffects. Recent evidence shows that local and regional delayed adverse effects may appear with its use.

OBJECTIVE To evaluate the clinical complaints and follow-up of patients with delayed immune-medi-ated adverse effects related to PA injections.

METHODS Prospective, case-series study of 10 patients with delayed adverse effects related to PAinjections. Only patients with intermediate or delayed adverse effects related to polyacrylamide injectionwere included. Patients with immediate side effects were excluded. Patients underwent clinical man-agement, follow-up, and when possible, blood tests and biopsy.

RESULTS Average latency period to onset of symptoms was 10 months (range 2–36). Tender, inflam-matory nodulesFgranulomasFwith pseudo-abscesses were commonly seen. Laboratory abnormalitieswere found in all analyzed cases. After 20.1 months average follow-up, five patients were in remission,two had recurrent bouts, and three were lost to follow-up, one of them in remission.

CONCLUSION Although it happens infrequently, local and regional delayed and recurrent granuloma-tous reactions may complicate PA gel injections.

The authors have indicated no significant interest with commercial supporters.

More and more people are seeking medical

solutions for their aging skin or for purely

esthetic and cosmetic indications. Currently, physi-

cians have many different types of dermal and sub-

dermal fillers, including nonpermanent, permanent,

reversible, and nonreversible materials.1,2 Different

classes of fillers have been proposed, according to

their origin and longevity (duration).1,2 Although

manufacturers and different publications claim that

the fillers are nontoxic and nonimmunogenic and

that complications are uncommon,3,4 unwanted side

effects occur with all compounds used.1,5–7 Thus,

two notions are lacking in the usual classes of dermal

fillers used: long-term safety and the reversibility of

side effects. At present, acrylamide compounds,

mainly polyacrylamide (PA), are increasingly used in

Europe. PA gel (Aquamid Contura International,

Soeborg, Denmark) is a gel polymer made of PA

(2.5%) and water (97.5%).8 Although in the early

reports on PA injections for cosmetic purposes no

significant signs of bio-incompatibility were

reported,9–12 more recent evidence refutes these state-

ments, and the complete safety of PA gels can therefore

no longer be corroborated.1,7,13–16 We communicate

herein our experience with a cohort of 10 patients who

were referred to our immunology unit presenting with

delayed adverse reactions related to PA implant fillers.

Patients and Methods

In recent years, a prospective protocol has been es-

tablished to manage patients with intermediate and

& 2009 by the American Society for Dermatologic Surgery, Inc. � Published by Wiley Periodicals, Inc. �ISSN: 1076-0512 � Dermatol Surg 2009;35:360–366 � DOI: 10.1111/j.1524-4725.2008.01041.x

3 6 0

�Department of Internal Medicine I and zLaboratory Unit, Aging Research and Systemic Autoimmune Diseases Unit,Vall d’Hebron University Hospital, Barcelona, Spain; yDepartment of Medicine, Autonomous University of Barcelona,Barcelona, Spain; yEuropa Medical Centre, Barcelona, Spain, Spain; and zSpanish Society of Medicine and CosmeticSurgery, Barcelona, Spain

long-term side effects related to implant fillers, PA

gel included. In all cases, physicians who work in

esthetic and plastic clinics in different cities of Spain

injected the fillers. Our Clinical Immunology Unit

and members of the scientific committee of the

Sociedad Espanola de Medicina y Cirugıa Cosmetica

(Spanish Society of Cosmetic Medicine & Surgery)

jointly designed this study protocol. Members of this

society were invited to voluntarily send us all

patients with intermediate or delayed side effects

related to cosmetic and esthetic implant fillers.

In accordance with the habitual protocol related to

injection fillers, strictly sterile techniques were used

in all cases. In all 10 analyzed cases, PA was injected

accurately and in the recommended facial areas.

Intermediate side effects were defined as the onset,

between 1 and 12 months after bioimplants were

filled, of one or more of the following clinical signs:

edema, angioedema, skin induration, and swelling or

tender nodules with or without fistulization or dis-

charge of pus or filler material. Systemic complaints

included fever, arthralgia, arthritis, skin lesions, dry

eyes and mouth, and any other sign or clinical

complaint, depending on the organ involved.

Delayed side effects were defined as onset 12 months

or longer after the filler injection, with the same local

or systemic complaints referred to above.

Up to July 2007, more than 150 cases of interme-

diate or delayed implant filler-related adverse effects

had sought medical attention in our unit. Ten cases

of adverse effects related to PA were recruited ac-

cording to the above-mentioned criteria. Five cases

were evaluated only through the review of their

medical records, sent to us by their attending phy-

sician. Some of the cases were attended once in

our outpatient clinic. Recommended clinical study

protocol included standard blood test, C-reactive

protein (CRP), fibrinogen, calcium, lactic dehydro-

genase (LDH), angiotensin-converting enzyme

(ACE), serum protein electrophoresis, antinuclear

antibodies, and CH50. Biopsy of lesions was not

mandatory but warranted. Treatment was based on

antibiotics; nonsteroidal anti-inflammatory drugs

(NSAIDs), especially ibuprofen; local steroids; and

oral prednisone; and in some cases, hydroxychlor-

oquine or allopurinol.

Results

Medical records of 10 patients were sent to us be-

cause nonimmediate side effects were suspected to be

related to PA. Five cases were evaluated only through

a revision of their medical histories sent to us by their

attending physician. Five cases were also referred to

our unit to undergo a complete study and follow-up.

Nine of the ten cases were filled with PA alone. The

age, sex, time lapse, previous implants, and main

location of fillers may be seen in Table 1. All patients

were evaluated during the active phase (while the

side effect was clinically apparent). In all cases, a

physician had filled PA. All of the cases were women.

The average latency time between the PA filler im-

plant and the onset of symptoms was 10 months

(range 2–36). One case (number 2) had probably

been previously filled with hyaluronic acid 36

months earlier, with no side effects detected. In all

cases, PA had been injected in various zones of the

facial area (Table 1). Predisposing conditions and

triggering events in this series of patients may be seen

in Table 2. Main complications can be seen in Table

3. In brief, painful inflammatory nodules of different

sizes (0.5–4 cm in diameter) were seen. In cases 2, 3,

5, and 8, pseudo-abscesses appeared. Drainage and

irrigation was performed repeatedly, and the mate-

rial obtained was cultured, generally with negative

results. Microorganisms were yielded in only one

case (case 3) after multiple cultures. It was positive

for gram-positive cocci. Polymerase chain reaction–

DNA analysis was performed in cases 3 and 5, with

negative results. Severe localized or generalized fa-

cial edema was present in two cases (cases 2 and 4).

No systemic or distant manifestations were observed

in any of the 10 cases.

Laboratory Results

Laboratory tests were done on four of the 10 cases

(cases 2, 3, 5, and 9) (40%). Six patients refused.

3 5 : S 1 : F E B R U A RY 2 0 0 9 3 6 1

A L I J O TA S - R E I G E T A L

Abnormalities in acute phase reactantsFCRP,

fibrinogen, hypera-2, or gammaglobulinemia or

a combination of some or all of theseFwere present

in all four (100% of analyzed cases), high levels of

ACE in three (75%: cases 1, 3 and 8), and LDH in

one (25%: case 3). Complement proteins also

showed low levels in one case (case 3), and antinu-

clear antibodies were negative in all cases. Serum

calcium levels were within the normal range in all

cases. Punch biopsy was performed on three patients

(cases 2, 3, and 5). Histopathologic examination was

similar in these three cases, showing a foreign-body-

type granuloma. No microorganisms were observed.

Therapeutic Schedule

Although there was no bacterial growth, initial

antibiotic treatment was assayed, as suggested

by Christensen and colleagues.8,16 The antibiotics

and doses used are shown in Table 3. Briefly, seven

cases (70%) were placed on antibiotic treatment.

Amoxicillin–clavulanic acid 875/125 mg three times

a day and ciprofloxacin 500 mg twice a day were the

antibiotics used in our cases. The length of treatment

was 4 weeks. A response was obtained in only one

case and was temporary. Nine of the ten patients

were treated with NSAIDs, generally ibuprofen

TABLE 2. Predisposing Conditions and Triggering Events in This Series of Patients

Patient Smoking

Autoimmune Background Setting Triggering Events

Personal Familial Trauma Infection

1 No No� No Physician Yes No

2 No No No Physician No no

3 Yes No No Physician ND ND

4 No No No Physician No No

5 No No No Physician No Yes

6 No Type 1

diabetes mellitus

No Physician No No

7 Yes No No Physician ND ND

8 No No ND Physician ND ND

9 No No No Physician No Yes

10 Yes No ND Physician ND ND

�Atopy. ND = no data.

TABLE 1. Gender, Time Elapsed, Previous Implants and Location of Fillers in This Series

Patient Age/Sex Latency Previous Fillers Main Location

1 35/F 36 No Glabella nasolabial folds

2 42/F 6 Probably hyaluronic

acid 3 years before

polyacrylamide was injected

Lips and cheeks

3 49/F 3 No Peri-ocular lines

4 50/F 2 No Lips and nasolabial folds

5 55/F 2 No Lips, cheeks, and nasolabial folds

6 49/F 2 No Glabella and lips

7 54/F 24 No Nasolabial folds and lips

8 34/F 12 No Glabella and peri-ocular line

9 51/F 12 No Cheek bones and nasolabial folds

10 43/F 3 No Cheek bones

F = female.

D E R M AT O L O G I C S U R G E RY3 6 2

P O LYA C RY L A M I D E A D V E R S E E F F E C T S

1,800 to 2,400 mg/d and intralesional steroids

(betamethasone). Each vial contained 3 mg of beta-

methasone phosphate and 3 mg of betamethasone

acetate in a total volume of 2 mL. According to the

size and inflammatory aspect of the nodules, we in-

jected betamethasone, 0.1 to 0.5 cm3 per nodule,

usually with no dilution. Oral prednisone (0.2–

0.4 mg/kg per day) was administered in eight cases

(80%), hydroxychloroquine (6 mg/kg per day) in

four cases (40%), and allopurinol (up to 400 mg/d)

in one case (10%) (Table 3). One patient was treated

with NSAIDs only (case 10).

Follow-Up

Follow-up of the 10 patients can be seen in Table 3.

Average clinical follow-up was 20.1 months (range

6–48). In brief, at the time of writing this article, five

patients (Cases 1, 3, 4, 6, and 10) were in remission.

Patient 5 was in remission but was lost to follow-up

at 6 months. Patients 2 and 9 were lost to follow-up.

Cases 7 and 8 had recurrent inflammatory bouts.

Case 7 was not placed on antibiotic treatment. Her

inflammatory flares were controlled with intralesio-

nal steroids and small doses of oral prednisone. Case

8 was treated with ciprofloxacin 500 mg twice a day

for 4 weeks. No response was obtained. Previously,

she had been placed on amoxicillin–clavulanic acid

875/125 mg three times a day for 3 weeks, with no

clinical response.

No systemic complaints have appeared in any pa-

tients in this series. High serum ACE levels persisted

in cases 1 and 3, although they were asymptomatic.

No granulomatous disorders or other systemic im-

mune-mediated diseases appeared in this subgroup

of patients with high ACE levels.

Discussion

Delayed granulomatous reactions have been related

to collagen, silicone, polylactic acid, polyalkylimide,

hyaluronic acid, Gore-Tex, and methacrylate im-

plants.1,5,15–17 The same types of adverse reactions

have been described with the use of combinations

of methacrylate–collagen and ethyl–methacrylate–

hyaluronic acid.16,18 Some different delayed adverse

reactions to PA have also been reported, mainly

TABLE 3. Main Complications, Type of Treatment and Follow-Up

Patient Main Complication Treatment� Follow-Up/Timey

1 Inflammatory nodules skin induration,

cyst

Antibioticsz/Allopurinol

betamethasonez/HCQ

Residual nodules/24

2 Inflammatory nodules, pseudo-ab-

scesses, facial edema

Antibioticsz/prednisone HCQ Lost to follow-up

3 Inflammatory nodules, giant pseudo-

abscesses

Antibioticsz/prednisone HCQ In remission/48

4 Inflammatory nodules, facial angio-

edema

Antibioticsz/betamethasone

prednisone

In remission/18


scesses

Antibioticsz/prednisone HCQ Remission/lost 6

6 Inflammatory nodules Prednisone In remission/15

7 Inflammatory nodules Prednisone Mild bouts/41


scesses

Antibioticsz/prednisone Recurrent bouts/15

9 Inflammatory nodules Antibioticsz/prednisone Lost/14

10 Mild inflammatory nodules NSAIDs only In remission/6

�Nonsteroidal anti-inflammatory drugs (NSAIDs) were given in all cases.yTotal follow-up until November 2007 (in months).zLocal injection of betamethasone (3 mg/mL).zAmoxicillin-clavulanic acid 875/125 mg three times a day for 4 weeks; ciprofloxacin 500 mg twice a day for 4 weeks.

HCQ = hydroxychloroquine (6 mg/kg per day).

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skin induration, inflammatory nodules, and pseudo-

abscesses.1,7–11,13–16,19 Since becoming available, PA is

an increasingly commonly used filler in Europe. PA is

a homogeneous gel consisting of a backbone of 97.5%

sterile, pyrogen-free water and 2.5% cross-linked PA,

which is nonresorbable.8,16 It is distributed in a pre-

filled syringe (Contura Inc., Soeborg, Denmark).

The product has been thoroughly tested and cleared

for toxicity and antigenicity,9–11 but adverse events

occur,1,7–11,13–16,19 as they do with all types of fillers.

Nevertheless, in a prospective multicenter study of

101 patients monitored over 24 months, von Buelow

found only two cases of late, adverse effects related

to PA.12 In an extensive, prospective study of case

reports volunteered by injecting physicians over

a 28-month period, Christensen and colleagues16

reported 55 adverse effects out of 40,000 people

injected. Only eight cases (8/55) had a delay of more

than 31 days (range 2–364 days; median 12 days).

In two of these cases, the filler was badly positioned,

and in another two, the only adverse effect was

herpes labialis. Thus, only four patients in the

Christensen series had true intermediate or delayed

granulomas related to PA. Our series showed 10

cases of extensive facial inflammatory nodulesF

granulomasFin patients injected only with PA. In

this series, all patients who agreed to blood analysis

had high levels of acute-phase reactants (CRP and

fibrinogen), so underlying inflammatory processes in

different stages had to be present. High LDH levels

(1/4; 25%) can also indicate different conditions,

for instance, liver disease, hemolytic anemia, or

lymphoproliferative diseases. They may also be

related to lymphocyte or macrophage activation,

which is the most probable explanation in our cases.

Likewise, high ACE levels (3/4; 75%) may be sec-

ondary to macrophage and granulomatous immune

responses. Similar results were reported for other

granulomatous immune-mediated diseases such as

sarcoidosis and sarcoidosis-related disorders20 and

sarcoidosis related to implant fillers.21,22 Plasma

ACE values remained high in two patients (cases 1

and 3), although they remain asymptomatic. All

bioimplants can, in vitro, elicit a primary immune-

mediated foreign-body-type reaction based on mac-

rophage activation and the induction of T-cell re-

sponse.10,17,18,23–25 In theory, gradual development

of network collagen fibers around the particles ap-

pears to coincide with a decrease in the inflammatory

reaction, but so-called stable granulomas26 may

evolve into a progressive abnormal granulomatous

response to fillers. Sometimes, undesirable effects ap-

pear during minor trauma or after infection.1,8,17 In

some cases in our series, certain bouts were related to

facial trauma or infectious processes. This clinical

correlation highlights the possible role of infectious

agents as a triggering factor for the development of

pathologic immune-mediated reactions.8,16,17 In the-

ory, two or more different antigenic stimuli may in-

crease the risk of abnormal immune response and

produce immune-mediated adverse effects.27 In this

series, one patient (case 2) had probably previously

filled with HA. Although no adverse effects were re-

corded in relation to these previous fillers, they may

have contributed to the current clinical problems.

In addition to local steroid treatment, we used

antibiotics, NSAIDs, and prednisone (Table 3).

Antimalarials (hydroxychloroquine) were used in the

same way as in other granulomatous or immune-

mediated diseases.20 Antimalarials also have many

anti-inflammatory, anti-aggregant, and immune-

regulatory properties.28,29 Cases of granulomatous

reactions secondary to implant fillers have been

treated with hydroxychloroquine.17,29,30 Allopurinol

was administered to one patient (case 1). Allopurinol

has also been used as a treatment for cutaneous

sarcoidosis and granuloma related to implant fill-

ers.31,32 Although in our series there was evidence of

bacterial infection in only one case, as suggested by

Christensen,8,16 antibiotics were used in seven pa-

tients (70%) but with no improvement; therefore,

the relevance of antibiotic treatment is questioned. In

the Christensen report,16 only 10 cases (10/55) were

cured with antibiotics alone or in combination with

other drugs. The treatment of similar clinical con-

ditions associated with other implant fillers, PA in-

cluded, has produced conflicting results regarding

antibiotic treatment.1,15,17,30 As commented earlier,

some cases of adverse effects related to fillers have



been related to infections, such as bronchitis, phar-

yngitis, influenza, or pneumonia, suggesting that

bacteria or viruses may play some role.8,16 Thus, the

exact value of the bacterial presence as a primary

causative factor of idiopathic granulomatous, im-

mune-mediated disorders or related to bioimplants is

not truly known.33 We think that this type of delayed

complication related to implant fillers, according to

histopathologic data and considering the few cases

of bacteria recovered in the samples, may be due to a

delayed type of hypersensitivity (type 4) reaction.34

In this series and in previous experiences, antibiotic

treatment showed no effectiveness.17,29 The disparity

between our results and those of Christensen and

colleagues16 may be due to, among other factors, the

time when antibiotics were administered. Christen-

sen reported better results if antibiotics were

begun immediately after granulomas appear.

In cases in which antibiotics seem to be useful,

it is unclear whether this is because of bactericidal

properties, or their anti-inflammatory or immune-

modulating effects.35,36 In this series of patients, the

long-term follow-up showed better outcomes than

those obtained in similar series of patients with

delayed-onset side effects related to other bioim-

plants.17,19 We had 5 cases with sustained remission,

and another case was lost to follow-up in clinical

remission. Two cases persist with recurrent inflam-

matory nodules, is spite of the treatment used. Ac-

cording to our own experience in severe, recurrent

cases related to other fillers, other drugs, such as

calcineurin inhibitors, should be offered to these

patients if recurrence occurs (Alijotas-Reig J,

unpublished data).

What is the prevalence of the delayed immune-

mediated adverse effects related to PA compounds?

Based on current information, it is difficult to answer

this question. On the one hand, we do not know the

real number of cases that have developed delayed

adverse effects, because of the tendency of many

doctors not to report negative events. On the other

hand, we do not have information about the total

number of cases treated with PA and the volume

or number of times that PA was injected into

each patient. However, we do know that almost

16,000 mL was sold in Spain from January 2001 to

June 2005 (Real Lasting Group, the dealer of

Aquamid in Spain).

Although infrequent, perhaps in predisposed hosts,

PA injections may cause delayed, moderate to severe

immune-mediated adverse effects. Considering the

increased use of PA in Europe and probably in the

future in the United States, doctors should be aware

that intermediate or delayed adverse effects can

occur with PA dermal injections.

Acknowledgments The authors would like to ac-

knowledge all members of the Sociedad Espanola de

Medicina y Cirugıa Cosmetica for sending us the

medical records and all of the patients who permit-

ted us to perform this study.

We also give thanks to Mrs. Maureen Shaughnessy

(USA), who holds a Masters in Technical Transla-

tion, Rovira i Virgili University, Tarragona, Spain,

for her help in revising the English style and gram-

mar of the manuscript.

This study was partially supported by a grant

from the Sociedad Espanola de Medicina y Cirugıa

Cosmetica.

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Address correspondence and reprint requests to:Jaume Alijotas-Reig, MD, PhD, Josep Ma de Segarra,2-F, 08190-Sant Cugat del Valles, Barcelona, Spain, ore-mail: [email protected], e-mail: [email protected]



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