Abstract
An 80-year-old man had a secondary prevention defibrillator in place for
treatment of sustained ventricular tachycardia. After a generator
replacement several years later, he developed a series of apparent pulse
generator infections requiring extraction. Each purulent appearing
pocket eruption was culture negative. Eventually, he was diagnosed with
a delayed hypersensitivity reaction to triclosan, an antibacterial that
is commonly impregnated in surgical sutures. The evaluation for this is
difficult and can be misleading. This entity should be considered in the
differential diagnosis of patients with culture negative CIED
infections.
.
An 80-year-old man with mitral valve disease and ischemic cardiomyopathy
underwent placement of a dual chamber implantable cardiac defibrillator
(ICD) in 2004 with an upgrade to a cardiac resynchronization therapy
defibrillator (CRT-D) in 2008. He required infrequent therapy for
monomorphic ventricular tachycardia (VT) and he had a generator
replacement in 2013. He lost a great deal of weight and had a pocket
revision for threatened generator erosion in 2014. The pulse generator
was repositioned into the subpectoral plane at that
time.
The patient underwent another pulse generator replacement in April 2019.
Several weeks later, he developed erythema and tenderness overlying the
new generator (Figure 1). He denied fever or chills, had no leukocytosis
(white blood cell count 7.6 x 103/mcL), and blood
cultures prior to initiation of empiric antibiotics were no growth. A
pulse generator infection was suspected, and a complete system
extraction was performed in July 2019. Frank purulence was noted within
the pocket. Bacterial cultures and gram stain obtained intraoperatively
remained negative. The patient was intermittently febrile following the
procedure without developing leukocytosis, positive culture data, or
evidence of vegetation by TEE. He completed a 14-day course of combined
intravenous and oral empiric antibiotics, receiving linezolid upon
discharge at the recommendation of the infectious disease consult team.
Repeat outpatient blood cultures remained negative and a right sided
pre-pectoral CRT-D system was implanted in October 2019. He was out of
state in December 2019, at which time his pocket again became inflamed.
After failing a 10-day course of outpatient clindamycin, the system was
extracted at another tertiary care facility and the patient completed a
course of antibiotics. Three months later, given his recent extractions
from both pre-pectoral regions, a dual chamber ICD was implanted using a
right femoral vein approach with lead tunneling to the right lower
quadrant for abdominal device placement.
He was readmitted to our facility two months later with erythema and
ulceration of the abdominal pocket despite a seven-day trial of
cephalexin. TTE was negative for lead or valvular vegetation. CT imaging
revealed reactive right inguinal lymph nodes and a fluid collection
surrounding the pulse generator and at the site of the lead suture
sleeves in the right groin. Once again, he underwent extraction. Blood
cultures, gram stains and tissue samples taken from the femoral and
abdominal pocket sites were cultured for bacteria, fungi, and
mycobacteria. All cultures remained negative. Broad range sequencing for
fungal 18S rRNA and bacterial 16S rRNA studies were negative. Serologies
for Q fever and Bartonella were also negative. A CT venogram revealed
patent vascular access through a right subclavian collateral network. A
defibrillator vest was applied and a peripherally inserted central
catheter was placed. The patient completed a 14-day course of
ceftriaxone and vancomycin at the recommendation of the infectious
disease team.
After recurrent culture negative infections, an alternative diagnosis
such as a contact hypersensitivity reaction was suspected, and he was
referred to Allergy & Immunology. Patch testing was negative out to 12
days for components of the previously utilized CRT-D system,
intraoperative antibiotics, and material comprising a commercially
available antibacterial envelope: Cobalt 1%, Cobalt Sulfate 2.5%,
Titanium Oxide 0.1%, Minocycline 10%, Doxycycline 5%, Rifampin 10 %,
Rifampin 30%, and Adhesives. Given his history of sustained VT, he
underwent re-implantation of a gold-plated dual chamber ICD system via
right axillary venous access in November 2020 and was discharged with a
90-day course of prophylactic doxycycline 100mg daily.
Approximately six weeks later the patient developed erythema and
tenderness over the new device pocket. After a decision was made to
extract the system, an aspirate of purulent material (Figure 2) was
obtained for standard gram and AFB stains and was cultured for bacteria,
fungi, and mycobacteria. A PET CT was also performed demonstrating
findings consistent with inflammation around the ICD with extension to
the superior vena cava.
The patient was taken for a fourth extraction. During the procedure,
three commonly utilized surgical sutures (Silk, Vicryl and Ethibond)
were placed as single interrupted sutures in the right upper chest
(Figure 3) to further evaluate for a hypersensitivity reaction. We also
tested a sample of the antibacterial envelope by placing a small wedge
of envelope subcutaneously and approximating the fascia by our standard
technique (Figure 3). Results of the incubated aspirate and peripheral
blood cultures remained negative. Given the low suspicion for an
infectious process, the patient was discharged without antibiotics.
Approximately 14 days after placement of interrupted test sutures, the
patient presented with erythema and induration at the test site for the
antibacterial envelope with standard pocket closure (Figure 4). After
another week, the site developed fluctuance and pustular drainage. A
similar reaction was not noted at the other suture sites. We also we
noted four discrete healing deep ulcerations at the sites of the
interrupted fascial sutures placed by the operator during the previously
implanted gold-plated ICD. At this point, we realized that our standard
technique for fascial closure utilized triclosan-coated antimicrobial
sutures (Vicryl Plus). Epidermal patch testing was repeated, this time
adding a patch test to triclosan to the same panel of antibiotics,
metals, and adhesives. Patch testing was again negative. Intradermal
testing for a hypersensitivity reaction to triclosan-coated suture was
then performed by placing a single-interrupted Vicryl Plus suture in the
right pre-pectoral area. Fourteen days later, the patient presented with
erythema and pustular drainage from the suture site (Figure 5). After
another week, the site developed superficial erosion.
Upon identifying triclosan-coated suture as the culprit allergen, our
team contacted the other two device implanting facilities. They both
confirmed employing triclosan-coated suture for fascial closure at the
device system pocket and femoral vascular access sites. Given his
repeated negative infectious work-up, the details of his procedural
history, and the two profound reactions to in-vivo suture placement, the
multi-disciplinary team concluded that the patient’s rejection of
implanted devices was brought on by a type IV hypersensitivity reaction
to the antibiotic-impregnated suture.
In the end, the patient was scheduled for a new defibrillator
implantation. Sadly, the day before the planned surgery, he removed his
defibrillator vest to slide beneath an automobile to perform repairs.
There, he suffered sudden cardiac arrest and was found hours later.
DISCUSSION
Triclosan is a compound with broad-spectrum antibacterial and antifungal
properties (bacteriostatic and bactericidal) used to inhibit microbial
growth on the skin and other surfaces. After becoming licensed for use
in 1964, triclosan became a ubiquitous substance to human exposure with
its inclusion in personal care items, household products, clothing, and
toys.1 Along with paucity of proven efficacy and
potential to develop antimicrobial resistance1,2,
epidemiological studies monitoring long-term triclosan exposure
suggested environmental accumulation and potential human health effects
with cumulative doses3-6. The Food and Drug
Administration (FDA) eventually banned widespread use in consumer soaps
and antiseptic products in 2016 and 2017,
respectively.7 However, triclosan’s antimicrobial
properties remain a component in several commercially available surgical
sutures, including FDA approved triclosan-coated polyglactin 910
antibacterial suture (Vicryl Plus; Ethicon, Johnson & Johnson,
Sommerville, NY, USA), triclosan-coated poliglecaprone 25 antibacterial
suture (Monocryl Plus; Ethicon, Johnson & Johnson, Sommerville, NY,
USA), and triclosan-coated polydioxanone antibacterial suture (PDS Plus;
Ethicon, Johnson & Johnson, Sommerville, NY, USA).
Both in vitro and in vivo animal experiments have shown that
triclosan-coated sutures (TCS) attenuate bacterial
colonization8-11 and exhibit inhibitory activity to a
wide spectrum of pathogens related to surgical site infections
(SSIs)8-13 without altering the physical properties of
sutures or interfering in the wound-healing
process.12,14 Following FDA approval in 2002,
incorporation of antibiotic-coated suture material into primary wound
closure became a common technique in the multi-disciplinary approach to
surgical site infection risk reduction. Randomized control trials
published to date have offered mixed outcomes in achieving the primary
endpoint of SSI reduction15-19, with at least a trend
toward reduced short- and longer-term infection. Multiple systematic
meta-analyses have demonstrated improved outcomes in specific
circumstances, favoring TCS use in adult patients, abdominal procedures
and clean or clean-contaminated surgical wounds.20-22No currently published data has demonstrated reduction of SSI in the
cardiac surgery subgroup and, thus far, no trials have evaluated TCS use
in cardiac implantable electronic device placement.
Considering the evidence quality and trial limitations, the Centers for
Disease Control (CDC) and World Health Organization (WHO) have issued
conditional recommendations to consider antimicrobial-coated suture use
in all surgical procedures.23,24 The American College
of Surgeons (ACS) and the Surgical Infection Society (SIS) offer
recommendations limited to abdominal cases.25Implantable cardiac device pocket infection persists as an important
procedure-related complication with the rate of overall CIED infection
reported between 1.6 and 5.8 percent.26,27 As
triclosan-coated suture remains a ubiquitous procedural tool to minimize
surgical site infection, it becomes increasingly important to recognize
the presentation of allergic contact dermatitis masquerading as the very
complication we are working to avoid.
Allergic contact dermatitis (ACD) represents a type IV hypersensitivity
reaction resulting from contact sensitization to an
allergen28-31 and may be localized to the tissue in
contact with the allergen or may present as a systemic
reaction.32 Allergic contact dermatitis from triclosan
exposure is an uncommon but recognized phenomenon. Retrospective
analyses report a positive reaction rate between 0.32%-0.8% in
patients on whom patch testing was performed with triclosan, 2% in
petrolatum.33,34 However, not all positive reactions
were felt to be clinically relevant.34 Isolated case
reports have been published on ACD from triclosan
exposure,35-40 rarely presenting as antimicrobial
suture use.41-44 To our knowledge, such a case of
CIED-related allergic contact dermatitis to triclosan-coated suture has
not previously been published.
In addition to taking a detailed history and reviewing potential
allergens, the standard approach for aiding in ACD diagnosis, is patch
testing to the suspect culprit(s).31 Standard
screening patch tests include the American Contact Dermatitis Society
(ACDS) Core Series (80 allergens) and the North American Contact
Dermatitis Group (NACDG) Series (70 allergens) which contain the most
common sensitizers that cause ACD.32 Like patch
testing guidelines, these screening series are continuously reviewed and
updated. Given the removal of triclosan from consumer goods and low
sensitizing potential, it was withdrawn from core patch allergen testing
series in the most recent update by the ACDS.45Targeted and limited screening series may be performed, though require a
high degree of clinical suspicion with potential to introduce delay in
patient care.
Further complicating accurate and timely diagnosis is the imperfect
science of patch test interpretation. A positive test result is merely a
sign that sensitization to the tested material has occurred at some
point and requires a physician’s assessment of clinical relevance. This
is best established by clinical improvement following a period of
allergen avoidance.46,47 Conversely, patch test
reactions interpreted as morphologically negative or doubtful can
sometimes be clinically relevant and important for the individual
patient48,49 and may need further work-up. Numerous
factors contribute to false-negative patch tests, including inactive
allergen or insufficient allergen concentration, poor allergen
penetration, poor application technique, insufficient delay between
application and interpretation, and concurrent chronic
immunosuppression.31,32
When allergic contact dermatitis to a suture is suspected, placing a
patch test with the suture material on the epidermis has low
sensitivity. The interrupted dermal stitch test is a recognized
technique to aid in the diagnosis of suspected ACD to a suture
material50-52, although further patch testing may be
necessary to identify the specific culprit ingredient in the suture. Our
case follows this pattern. While our patient’s patch test to triclosan
was negative, he had a robust reaction to in vivo placement of
triclosan-coated polyglactin 910 (Vicryl Plus). Most other cases of
suture allergy testing have performed interpretation around day five. It
is noteworthy that our patient’s test did not become positive until
close to day 14. However, it is a well-known feature of type IV
hypersensitivity reactions that they may occur several weeks after
allergen exposure. Moreover, a hypersensitivity response to absorbable
suture relates to the rate of suture hydrolysis, leading to a relative
increase in allergen concentration as the surface area increases
allowing greater exposure to antigen presenting cells in the dermis.
Published Ethicon data reports an absorption rate between 56 to 70 days
for Vicryl Plus suture.53 Our patient followed this
pattern, demonstrating a robust response to suture material 6-8 weeks
after each device system implantation. The test sites of other suture
material, including uncoated polyglactin 910 (Vicryl), remained
non-edematous and non-erythematous. These results also suggest possible
allergic contact dermatitis to the combination of suture material and
triclosan, but not to each ingredient independently. This phenomenon has
been called “compound allergy”54 and serves an
alternative hypothesis for our patient’s response to epidermal and
intradermal testing.
While not performed in our case, pathology may supplement intradermal
testing in the diagnosis of delayed hypersensitivity. Case reports
published on surgical site pseudoinfections describe histologic findings
of either a foreign body reaction including mixed inflammatory cell
infiltrate, multinucleated giant cells and amorphous birefringent
material or an allergic reaction comprised of a mixed population of
lymphohistiocytes, granulocytes and
eosinophils.42,44,55-58 In contrast, an expected
reaction involves minimal multicellular inflammatory infiltrate
associated with suture filaments after 14 and 21
days.56 While these findings are not specific to ACD,
they serve as another clue in the clinical picture.