Infections Following Facial Composite Tissue Allotransplantation—Single Center Experience and Review of the Literature
Presented in abstract form at the 2012 American Transplant Congress, Boston, MA, June 2, 2012. Abstract 831.
Corresponding author: Francisco M. Marty
We reviewed medical records of all patients (n = 4) who underwent facial composite tissue allotransplantation (FCTA) at our center between April 2009 and May 2011; data were censored in June 2012. We searched for FCTA publications and reviewed them for infectious complications and prophylaxis strategies.
Three patients received full and one partial FCTA at our institution. Two recipients were cytomegalovirus (CMV) Donor (D)+/Recipient (R)− and two CMV D+/R+. Perioperative prophylaxis included vancomycin, cefazolin and micafungin and was adjusted based on peritransplant cultures. Additional prophylaxis included trimethoprim-sulfamethoxazole and valganciclovir. Two recipients developed surgical site infection and two developed pneumonia early after transplantation. Both CMV D+/R− recipients developed CMV disease after discontinuation of prophylaxis, recovered with valganciclovir treatment and did not experience subsequent rejection. Other posttransplant infections included bacterial parotitis, polymicrobial bacteremia, invasive dermatophyte infection and Clostridium difficile-associated diarrhea.
Nine publications described infectious complications in another 9 FCTA recipients. Early posttransplant infections were similar to those observed in our cohort and included pulmonary, surgical-site and catheter-associated infections. CMV was the most frequently described opportunist.
In conclusion, infections following FCTA were related to anatomical, technical and donor/recipient factors. CMV disease occurred in D+/R− recipients after prophylaxis, but was not associated with rejection.
antibody to hepatitis B core antigen
rabbit antithymocyte globulin
blood stream infection
facial composite tissue allotransplantation
hepatitis B virus
hepatitis C virus
- hIL-2 AB
human interleukin 2 antibody
herpes simplex virus
methicillin-resistant Staphylococcus aureus
Facial composite tissue allotransplantation (FCTA) is a new and complex procedure for reconstruction of severe facial deformities not amenable to conventional plastic surgery [1-11]. FTCA entails transplantation of tissues with various structures and immunogenicity. Technical and anatomical aspects of the procedure can lead to infectious complications. Specifically, the flora colonizing donor oral and respiratory mucosa, peripheral ganglia  and lymph nodes are transferred at transplantation and predispose recipients to donor-derived infections. Furthermore, FTCA protocols typically include intense immunosuppressive therapy initially, thereby increasing the recipient's risk of opportunistic infections.
To date, over 20 FCTAs have been performed worldwide, not all of which have been reported in detail [1-11]. In particular, characterization of the infectious complications of FCTA has been limited [1-11]. Three full facial and one partial FCTA were performed at our center between April 2009 and May 2011 [10, 11]. Although mentioned in part in prior publications [10, 11], herein we report the detailed infectious complications observed after FCTA at our institution with more than 1 year of follow-up, and review available literature on infectious complications followingFCTA.
Medical records of patients who underwent FCTA at Brigham and Women's Hospital were reviewed for demographic and medical data. We recorded all infectious diseases events and antimicrobial use. Data were censored in June 2012.
All FCTA recipients at our institution received induction immunosuppression with mycophenolate mofetil (MMF) 1 g before surgery, methylprednisolone 1.5 g over 3 days and rabbit antithymocyte globulin (ATG) 1.5 mg per kg daily for 4 days [10, 11]. Initial maintenance immunosuppression included MMF 2 g/day, tacrolimus (adjusted to a trough level of 10–15 mcg/mL) and a prednisone taper discontinued 60–100 days posttransplant.
Perioperative antimicrobial prophylaxis at our institution included vancomycin and cefazolin in all cases, and micafungin in three of four patients for at least 4 days after surgery. After FCTA the perioperative antimicrobial regimen was adjusted based on donor and recipient cultures obtained at the time of transplantation. Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole and cytomegalovirus (CMV) prophylaxis with valganciclovir were given for 6 months post-FCTA, or longer if FCTA recipients received treatment for acute rejection. No patients received antifungal prophylaxis after the immediate perioperative period.
All patients provided written consent for FCTA. The Human Research Committee at Brigham and Women's Hospital approved this study.
A literature search was performed using Medline (National Library of Medicine, Bethesda, MD, USA) and Embase (Elsevier, Amsterdam, EU). Key words included “face transplant”, “face transplantation” and “FCTA”. Publications were reviewed for immunosuppressive regimens, antimicrobial prophylaxis and infectious complications.
Patient 1. A 59-year-old CMV seronegative and Epstein–Barr virus (EBV) seropositive male who sustained extensive facial deformities from an electrical burn injury in June 2005 underwent partial FCTA in April 2009 . Pretransplant evaluation revealed methicillin-resistant Staphylococcus aureus colonization (MRSA) of the reconstructed nasal passages, latent tuberculosis, chronic hepatitis C virus (HCV) infection (genotype 3a) and resolved hepatitis B virus (HBV) infection (positive HBV core IgG antibody and HBV surface antibody, negative HBV surface antigen and undetectable HBV DNA). Pretransplant the HCV infection responded to treatment with 28 weeks of ribavirin and pegylated interferon alpha. At the time of transplant, HCV and HBV viral loads were undetectable, and the patient had received over 6 months of a planned 9-month course of isoniazid treatment. Planned perioperative antibiotics included vancomycin, cefazolin and micafungin.
The donor was CMV, EBV and Toxoplasma seropositive. Before transplant donor sputum cultures grew extended spectrum beta-lactamase producing Escherichia coli and Proteus mirabilis, and a donor nasal swab grew methicillin-susceptible Staphylococcus aureus. Donor blood cultures collected on the day of organ recovery grew Proteus mirabilis so the recipient was treated with imipenem in lieu of cefazolin at transplantation. The recipient was also treated with azithromycin for an incidental pulmonary infiltrate seen on the admission chest X-ray.
On day 10 posttransplantation, imipenem was switched to cefepime to complete a 4-week course for preemptive treatment of donor bacteremia. Isoniazid was continued posttransplantation. Recurrent HCV viremia was documented on day + 10 and remains untreated to date due to concerns of interferon-triggered rejection. Alanine aminotransferase levels have been less than 1.25 times the upper limit of normal and HCV virus load was 368 000 copies/mL on the latest measurement. The patient remains HBV surface antigen and DNA negative.
On day 17 after transplant the patient developed facial erythema. Facial and sentinel graft skin biopsy showed lymphocytic infiltrates assessed as grade I–II rejection. He received pulse-dose methylprednisolone for treatment on day 17, and pulse-dose methylprednisolone and basiliximab on days 74 and 107 for similar facial skin biopsy findings , but the facial erythema persisted. Based on further review of skin biopsy specimens, the discordance between sentinel flap and facial findings, rosacea was diagnosed on day 115. The facial erythema resolved within 7 days after the addition of topical metronidazole [10, 13].
On day 96, the patient developed progressive left facial erythema and edema, left orbital and nasal bridge pain and a left temporal headache after a prodrome of rhinorrhea, congestion and mouth dryness. Computed tomography (CT) of the head and neck demonstrated left parotid gland enlargement and marked inflammation with swelling of the left-sided muscles of mastication and sternocleidomastoid muscle, consistent with infectious parotitis. Recent nasal cultures had grown methicillin-sensitive Staphylococcus aureus and Pseudomonas aeruginosa. The symptoms resolved on a 14-day course of cefepime for bacterial parotitis. He had two additional episodes of acute left-sided parotitis 2 and 3 years after FTCA. Both responded quickly to empiric treatment with cephalexin. He underwent dilation of a stenotic left parotid duct and ductoplasty 3 years after transplantation.
On day 161, a surveillance serum (1→3)-β-D-glucan was positive at 146 pg/mL (reference,<80 pg/mL). A concurrent serum galactomannan assay was negative. Chest CT imaging showed no pulmonary nodules, consolidation or ground glass opacities. He developed tender erythematous nodules on the dorsal surface of both feet. Skin scrapings of the nodules grew Trichophyton rubrum, consistent with Majocchi's granuloma, an invasive dermatophye infection. The nodules resolved with a 3-month course of terbinafine and (1→3)-β-D-glucan became negative.
On day 460, 2 months after discontinuation of valganciclovir prophylaxis, he presented with fever and leukopenia. CMV virus load was 21 400 copies/mL. His CMV IgM was positive and his CMV IgG level was newly elevated at 4.41 EIU/mL (cut-off 0.99 EIU/mL). He received induction dose valganciclovir 900 mg twice daily for 18 days, followed by maintenance therapy with 450 mg twice a day for 16 weeks. Allograft skin biopsies at the time of the acute CMV syndrome showed no rejection or CMV disease.
Other than the two episodes of acute left-sided parotitis described above, no further infectious events were observed through the latest follow-up visit in June 2012, 38 months after transplantation.
Patient 2. A 25-year-old male underwent full FCTA in March 2011 for repair of severe facial deformities from an electrical burn injury in November 2008. The recipient's reconstructed nasal passages were colonized with MRSA prior to transplantation. Both the recipient and the donor were CMV and EBV seropositive. Perioperative antibacterial prophylaxis included cefazolin and vancomycin.
On day 8 after transplant, he developed increasing submental and left neck fullness and leukocytosis with neutrophilic predominance. Cultures from the incision in this area grew P. aeruginosa and Candida albicans. He received treatment with ceftazidime and micafungin. A CT of the head and neck showed fluid collections adjacent to the left submandibular gland, behind the left parotid and anterior to the left sternocleidomastoid muscle. On day 14, he underwent left neck exploration that revealed a hematoma overlying the sternocleidomastoid muscle and a small amount of pus posterior to the parotid gland. He also underwent aspiration of the submandibular collection. Cultures from all of these areas grew C. albicans. The submental fluid reaccumulated by day 26. An aspirate of the reaccumulated fluid tested positive for amylase, suggesting a sialocele, and cultures grew Peptococcus saccarolyticus. After injection of donor salivary gland with botulinum toxin, the submental fluid did not reaccumulate. He completed a 2-week course of ceftazidime, metronidazole and micafungin followed by 3 months of amoxicillin-clavulanate and fluconazole. No further infections developed through the latest follow-up appointment in March 2012, 1 year after transplantation.
Patient 3. A 30-year-old male underwent full FCTA in April 2011 for restoration of facial form and function after an electrical burn injury in 2001. The recipient was CMV seronegative and EBV seropositive. The donor was CMV and EBV seropositive. Two days after transplant, the recipient developed Haemophilus influenzae pneumonia, for which he received a 10-day course of levofloxacin.
The patient received 500 mg IV methylprednisolone daily for three doses for treatment of grade II acute rejection day 20 posttransplant and has not experienced subsequent rejection.
On day 90, he developed polymicrobial bacteremia with Enterobacter cloacae, alphahemolytic Streptococcus and coagulase-negative Staphylococcus in the setting of an indwelling catheter and dental caries. Both the catheter and the decayed tooth were removed. He was treated with 7 days of vancomycin and piperacillin-tazobactam, followed by 7 days of levofloxacin.
Prophylactic trimethoprim-sulfamethoxazole and valganciclovir ended 7 months after transplant. One month later, he presented with epigastric pain and nausea. Endoscopic biopsies revealed CMV gastritis and duodenitis. Serum CMV virus load was 125 000 copies/mL. Cytomegalovirus IgM was positive and CMV IgG was newly elevated at 3.55 EIU/mL. The symptoms resolved on a 3-month course of valganciclovir 900 mg twice a day. Allograft skin biopsies obtained at the time of CMV disease showed no rejection or CMV. He resumed trimethoprim-sulfamethoxazole prophylaxis when CMV disease was diagnosed through 1 year posttransplantation.
At the latest follow-up visit on day 420, he had developed a herpes simplex virus outbreak involving the allograft lips, chin and nose, which was treated with a 7-day course of valacyclovir.
Patient 4. A 57-year-old female underwent full FCTA and bilateral hand and forearm composite tissue allotransplantion in May 2011 for repair of injuries sustained in an animal attack in February 2009. Both the recipient and donor were CMV and EBV seropositive. During surgery, purulent material was found in the recipient's left maxillary sinus; cultures grew C. albicans, Actinomyces odontolyticus, Bacteroides intermedius, Propionibacterium acnes, alphahemolytic Streptococci and P. aeruginosa. The perioperative antimicrobial regimen was modified to treat these pathogens based on susceptibilities.
Day 1 after transplant, the patient developed septic shock in the setting of a new pulmonary infiltrate. Sputum and tracheal aspirate cultures grew Serratia marcescens, Proteus mirabilis and P. aeruginosa. On day 5 posttransplantation, the upper extremity grafts were explanted due to irreversible ischemia that resulted from low perfusion during the septic shock episode. She completed a 3-week course of cefepime, ciprofloxacin, metronidazole and micafungin after transplant that targeted both the donor sinus pathogens and the pathogens causing pneumonia.
Four weeks after transplantation, she developed submandibular fullness and lymphadenopathy. A CT of the head and neck showed an incidental zygomatic fluid collection, an aspirate of which grew vancomycin-resistant Enterococcus. She was treated with 2 weeks of linezolid.
On day 68, the patient received pulse-dose steroids to treat facial erythema and grade I–II rejection on skin biopsy. The facial erythema persisted despite steroid therapy. Concomitant pustules raised the concern for rosacea, and the facial erythema gradually resolved with topical metronidazole treatment.
On day 90, the patient developed Clostridium difficile-associated diarrhea, for which she received a 2-week course of oral vancomycin. She relapsed shortly after discontinuation of vancomycin and received a second course of oral vancomycin followed by an 8-week taper. The C. difficile infection has not recurred since then.
On day 270, the patient developed acute gastroenteritis in the setting of a Norovirus outbreak at her rehabilitation center. Her symptoms resolved within 72 h.
She presented to the outpatient clinic with palpebral conjunctival erythema and purulent drainage around both eye prostheses on day 330. Cultures of the drainage grew S. marcescens, P. aeruginosa, S. aureus and coagulase-negative staphylococci. The symptoms resolved after 10 days of bacitracin/neomycin/polymyxin ophthalmic ointment.
Valganciclovir and trimethoprim-sulfamethoxazole prophylaxis were discontinued 4 months after transplant due to persistent leukopenia. She underwent CMV viral load surveillance until 12 month posttransplantation, with no evidence of CMV reactivation or CMV disease. No further infectious complications were observed at her latest follow-up visit in May 2012.
Table 1 summarizes the infections described in these four patients.
Table 1. Immunosupression, prophylactic regimens and infectious complications after facial composite tissue transplantation
|Devauchelle 2006 ,||38||Partial (lower),||Induction: ATG × 10 d||Amoxicillin-clavulanate||—||Labial HSV1||—||Candida|
|Dubernard 2007 ||Female||animal attack||Maintenance: Tacrolimus 10–15 ng/mL, MMF 2 g/d, prednisone taper, ECP||Ganciclovir IV (5 d), then Valganciclovir (5 mo)|| ||POD 185Molluscum contagiosum 7–8 mo after|| ||stomatitis POD 18|
| || || ||AR POD 18 treated with pulse dose steroids||TMP/SMX (4 mo)|| ||transplant|| || |
| || || ||AR POD 214 treated with pulse dose steroids|| || || || || |
|Guo 2008 ||30 Male||Partial (upper and lower), animal attack||Induction: hIL-2 AB 50 mg andmethylprednisolone 1 g × 1 doseMaintenance: Tacrolimus, 15–20 ng/mL, MMF, Prednisone||Metronidazole and Allicin later adjusted for nasopharyngeal culture results toCeftizoxime (2 wks) Acyclovir||—||—||—||—|
| || || ||AR months 3, 5, 17 post transplant; treated with pulse dose steroids|| || || || || |
|Siemionow 2009 ,Gordon 2011 ||45 Female||Partial (upper), ballistic trauma||Induction: ATG 1.2 mg/kg/d × 9 d, Methylprednisolone 1 g||Vancomycin and piperacillin-tazobactam,||CMV D+/R−||CMV viremia 11 mo posttransplant||Pseudomonas and Staphylococcus epidermidis||—|
| || || ||Maintenance: Tacrolimus 12–15 ng/mL, MMF, prednisone||then amoxicillin-clavulanateGanciclovir IV (8 wks)|| || ||catheter-related BSIC. difficile and|| |
| || || ||AR POD 47 treated with a single dose of IV corticosteroids|| then Valganciclovir (5 mo) TMP/SMX Voriconazole|| || ||Aeromonas diarrhea 13 mo posttransplant|| |
|Lantieri 2011 ||29 Male||Full, neurofibroma||Induction: ATG 1 mg/kg × 10 d, Tacrolimus (goal trough 10–13 ng/mL), MMF 2 g/d, prednisone taperMaintenance: Tacrolimus 8–10 ng/mL, MMF, prednisone||Vancomycin and Cefotaxime (48 h) Phenoxymethyl-penicillin for donor syphilisValganciclovir (6 mo) TMP/SMX (6 mo)||CMV D+/R−EBV D+/R+Toxo D+/R−||CMV viremia POD 65 treated with 8 wks of foscarnet||Donor syphilis||—|
| || || ||AR POD 28, pulse dose steroids|| || || || || |
| || || ||AR POD 64, pulse dose steroids and ATG|| || || || || |
|Lantieri 2011 ||27 Male||Partial (lower), ballistic trauma||Induction: ATG 1 mg/kg × 10 d, Tacrolimus (goal trough 10–13 ng/mL), MMF 2 g/d, prednisone||Vancomycin, Cefotaxime (48 h)Valganciclovir (6 mo)TMP/SMX (6 mo)||CMV D−/R−EBV D+/R+Toxo D+/R−||—||Pseudomonas pneumonia||—|
| || || ||taper ECP twice weekly × 1 mo, once monthly for 3 mo|| || || ||POD 2|| |
| || || ||Maintenance: Tacrolimus 8–10 ng/mL, MMF, prednisone|| || || || || |
| || || ||AR POD 0|| || || || || |
|Lantieri 2011 ||37 Male||Partial (upper), third-degree burns||Induction: ATG 1 mg/kg × 10 d, Tacrolimus (goal trough 10–13 ng/mL), MMF 2 g/d, prednisone taper ECP twice weekly||Vancomycin, Cefotaxime (48 h)Valganciclovir (6 mo)TMP/SMX (6 mo)||CMV D+/R−EBV D+/R+Toxo D+/R+||—||Multidrug- resistant Pseudomonas infection of face and left hand||—|
| || || ||× 1 mo, once monthly for 3 mo|| || || ||allograft POD 15. Cardiac|| |
| || || ||Maintenance: Tacrolimus 8–10 ng/mL, MMF, prednisone|| || || ||arrest in setting of hemorrhage from radial|| |
| || || ||No rejection episodes|| || || ||bypass rupture, died POD 33|| |
|Lantieri 2011 ||33 Male||Partial (lower), ballistic trauma||Induction: ATG 1 mg/kg × 10 d, Tacrolimus (goal trough 10–13 ng/mL), MMF 2 g/d, prednisone taper ECP twice weekly||Vancomycin, Cefotaxime (48 h)Valganciclovir (6 mo)TMP/SMX (6 mo)||CMV D+/R–EBV D+/R+Toxo D+/R+||Labial HSV1 POD 3–10||—||—|
| || || ||× 1 mo, once monthly for 3 mo|| || || || || |
| || || ||Maintenance: Tacrolimus 8–10 ng/mL, MMF, prednisone|| || || || || |
| || || ||AR POD 5|| || || || || |
|Barret 2011 ||30 Male||Full, ballistic trauma||Induction: ATG 2 mg/kg × 1 dose Prednisone 1 mg/kg × 1 dose||Type of perioperative antibiotic prophylaxis not reported;||CMV D+/R−EBV D+/R+Toxo D−/R−||—||—||—|
| || || ||Maintenance: Tacrolimus 10–15 ng/mL, MMF 2 g/d, Prednisone 1 mg/kg/d||duration until POD 10 Antifungal prophylaxis (unknown agent) until POD 28 for oral|| || || || |
| || || ||AR POD 28 treated with pulse dose steroids||candida colonization|| || || || |
| || || ||AR POD 75 treated with pulse dose steroids||Valganciclovir TMP/SMX|| || || || |
| || || ||AR POD 90 treated with ATG and switch from MMF to sirolimus|| || || || || |
|Sicilia-Castro 2011 ,BenMarzouk 2011 ||35 Male||Partial (lower), neurofibroma||Induction: Basiliximab 20 mg × 2 doses||Type of perioperative antibiotic and PCP||CMV D+/R−EBV D?/R+||CMV viremia wk 3 and 7 post-||Acinetobacterbaumanii||—|
| || || ||Maintenance: Tacrolimus, MMF, steroids||prophylaxis not reported|| ||transplant treated with a 17 day course of VGC each||surgical site infection during first 47 d|| |
| || || ||AR POD 28 treated with pulse dose steroids, oral tacrolimus dose adjustment, and topical tacrolimus||Pre-emptive CMV therapy|| || ||tracheobronchitis during first 47 dEnterobacter cloacae bacteremia during first 47 d|| |
|This publication||59 Male||Partial (lower), electrical burn||Induction: MMF 1 g × 1, methylprednisolone 1.5 g/d × 3 d, ATG 1.5mg/kg/d × 4 d||Vancomycin (12 d) Imipenem (12 d, donor Proteusmirabilis bacteremia)||CMV D+/R−EBV D+/R+Toxo D+/R−||Recurrent HCV POD 10CMV syndrome POD 460||Donor bacteremia with Proteus mirabilis||Majocchi's granuloma (Trichophyton rubrum) POD 187|
| || || ||Maintenance: MMF 2 g/d, tacrolimus (goal trough, 10–15 mcg/mL), prednisone taper over 60–100 d||Micafungin (4 d) Azithromycin (10 d, recipient pulmonary infiltrate on admission)|| || ||Parotitis POD 96, recurrent at 2 years and 3 years|| |
| || || ||AR POD 17 treated with pulse dose steroidsAR2 POD 74 treated with pulse dose steroids and basiliximabAR2 POD 107 treated with pulse dose steroids and basiliximab||Cefepime (16 d, for donor Proteus mirabilis bacteremia) Valganciclovir (13 mo) TMP/SMX (13 mo)|| || || || |
|This publication||25 Male||Full, electrical burn||Induction: MMF 1 g × 1, methylprednisolone 1.5 g/d × 3 d, ATG 1.5 mg/kg/d × 4 d||Cefazolin and vancomycin (4 d) Valganciclovir (6 mo) TMP/SMX (6 mo)||CMV D+/R+EBV D+/R+Toxo D−/R−||—||Pseudomonas aeruginosa surgical site infection POD 8||Candida albicans surgical site|
| || || ||Maintenance: MMF 2 g/d, tacrolimus (goal trough, 10–15 mcg/mL), prednisone taper over 60–100 d|| || || ||Sialocele superinfected with Peptococcus saccarolyticus||infection POD 8|
| || || ||No rejection episodes|| || || ||POD 26|| |
|This publication||30 Male||Full, electrical burn||Induction: MMF 1 g × 1, methylprednisolone 1.5 g/d × 3 d, ATG 1.5 mg/kg/d × 4 d||Vancomycin (4 d), cefazolin (2 d). micafungin (5 d), Cefepime (4 d) and||CMV D+/R−EBV D+/R+Toxo D−/R−||CMV gastritis POD 210HSV reactivation chin POD 420||Haemophilus influenzae pneumonia POD 1||—|
| || || ||Maintenance: MMF 2 g/d, tacrolimus (goal trough, 10–15 mcg/mL), prednisone taper over 60–100 d||levofloxacin (10 d) started at initial detection of H. influenzaepneumonia|| || ||Polymicrobial bacteremia (E. cloacae, α-hemolytic streptococcus,|| |
| || || ||AR POD 20 treated with pulse dose steroids||Valganciclovir (7 mo) TMP/SMX (7 mo)|| || ||coagulase-negative staphylococcus) POD 90|| |
|This publication||57 Female||Full, animal attack||Induction: MMF 1 g × 1, methylprednisolone 1.5 g/d × 3 d, ATG 1.5 mg/kg/d × 4 d||Vancomycin (4 d), cefazolin (2 d), micafungin(20 d) Cefepime (21 d),||CMV D+/R+EBV D+/R+Toxo D−/R−||Presumed viral gastroenteritis POD 270||Donor maxillary cultures with A. odontolyticus, B. intermedius,||Donor maxillary sinus culture|
| || || ||Maintenance: MMF 2 g/d, tacrolimus (goal trough, 10–15 mcg/mL), prednisone taper over 60–100 d||ciprofloxacin (20 d), metronidazole (19 d) for maxillary sinus purulence, pneumonia and|| || ||P. acnes, alpha-hemolytic Streptococci and P. aeruginosaPneumonia with||with Candida albicans|
| || || ||AR POD 68 treated with pulse dose steroids||shockValganciclovir (4 mo)TMP/SMX (4 mo)|| || ||S. marcescens, P. mirabilis, and P. aeruginosa POD 1Zygomatic fluid collection (vancomycin-resistant Enterococcus) POD 28|| |
| || || || || || || ||C. difficile-|| |
| || || || || || || ||associated diarrhea POD 90Palpebral conjunctivitis POD 330|| |
Multiple case reports have been published describing the technique and short-term outcome of FCTAs [1-11]. To date, nine publications report information regarding antimicrobial prophylaxis and infectious complications after FCTA in nine recipients [1-4, 6-9, 14]. These cases are also summarized in Table 1.
Reported bacterial complications occurring days to 1 month after transplantation include P. aeruginosa pneumonia , tracheobronchitis , Gram-negative surgical site infections [6, 9], Enterobacter cloacae bacteremia  and catheter-related bloodstream infection . In addition, a single fungal infection (Candida stomatitis) was reported during the first month after FCTA [1, 2].
Viral infections typically occurred after the immediate posttransplant period. Those reported include HSV, molluscum contagiosum and CMV [1, 2, 6, 9]. CMV viremia occurred later in patients receiving prophylaxis and earlier after transplant in one patient receiving preemptive therapy [4, 6, 9]. All cases of CMV viremia after FCTA reported in this literature review occurred among CMV seronegative recipients with a CMV seropositive donor, but none were associated with acute rejection [4, 6, 9].
Other than CMV infection and an episode of C. difficile-associated diarrhea over a year after transplant , we found no late infectious complications after FCTA in this literature review.
We describe in detail the infectious complications in this FTCA cohort in which all patients have been followed for more than 1 year. Most infections were related to technical perioperative factors (Table 1). Those observed in the immediate posttransplantation period included donor bacteremia, surgical site infection and pneumonia.
The case reports reviewed do not consistently describe the perioperative antimicrobial prophylaxis regimen or its duration. When reported, perioperative antimicrobial agents included anti-MRSA agents in most cases [4, 6]. Two centers report adjustment of perioperative antimicrobial prophylaxis depending upon donor and recipient intraoperative culture results, similar to the protocol at our institution [3, 4]. The duration of perioperative prophylaxis reported ranged from 2 to 14 days [3, 6, 7]. Gram-negative pneumonia was observed as an immediate postoperative infectious complication in this and other cohorts . Our impression is that the pneumonias observed in this cohort were secondary to aspiration events during the prolonged transplantation procedures. To minimize this risk, we plan to use a cuffed endotracheal tube with a suction device at our center for future FCTAs, as well as 30° elevation of the head of the operating bed and suctioning of the gastric contents every 3–4 h during the operation. In addition, because colonization of the donor or recipient respiratory tract with resistant Gram-negative pathogens as a result of previous hospitalization is common, we now include an antipseudomonal antimicrobial agent as part of the perioperative antimicrobial regimen.
Superinfected sialocele and parotitis were observed 1 week to 3 months after transplantation, respectively. These complications are specific to anatomical and technical aspects of FCTA. Sialocele can occur post-FCTA due to remaining donor salivary gland tissue  and can be successfully treated with botulinum toxin injection. This complication may be preventable by careful dissection of donor salivary gland tissue prior to transplantation . Sialocele is a potential focus of infection in patients after FCTA and should be considered as a potential cause of submental fluid collection in this population.
Infectious complications observed more than 6 months after transplant in this cohort were similar to those reported in solid-organ transplant recipients and included viral gastroenteritis, bacterial conjunctivitis and HSV reactivation. The literature review revealed relatively few late infectious complications among FTCA recipients at other centers. However, aside from a single review , most FCTA publications have not specifically assessed infectious complications nor have included detailed infectious diseases follow-up beyond the first few months after transplant.
The only classic opportunistic infection observed in our FCTA cohort was CMV. The two CMV seronegative recipients in this cohort who received allografts from CMV seropositive donors developed CMV disease 1–2 months after discontinuation of prophylaxis. Neither CMV episode was associated with acute rejection and both responded clinically to valganciclovir without recurrence. In our literature review we found three episodes of CMV viremia among nine FCTA recipients. Similar to our cohort, these episodes occurred in CMV donor seropositive/recipient seronegative patients and none were associated with acute rejection or allograft dysfunction. All reported cases resolved with valganciclovir, foscarnet or investigational CMX001 (a lipid conjugate of cidofovir ) treatment [4, 6, 9, 14]. Compared to other centers [1, 2, 4, 6], we used a shorter duration of induction therapy with a lower cumulative ATG dose and a steroid-free maintenance regimen, which might explain the benign course of CMV infection in our cohort. Potential strategies to decrease the risk of CMV disease in CMV donor seronegative/recipient seropositive FCTA recipients include extension of the prophylactic valganciclovir course, frequent monitoring for CMV viremia after prophylaxis ends, or in the future, CMV vaccination [16, 17]. The experience reported here and in the literature is supportive of pursuing FTCA in CMV seronegative patients independent of the CMV status of prospective donors.
With the exception of Majocchi's granuloma and Candida surgical site infection, we observed no other invasive fungal infections in this cohort. Three patients received perioperative antifungal prophylaxis with micafungin and the micafungin course was extended beyond 48 h after surgery if Candida spp. grew from intraoperative cultures. Notably, the Candida surgical site infection developed in the only patient who did not receive perioperative antifungal prophylaxis. This surgical site infection was successfully treated with 3 months of fluconazole, but may have been prevented by inclusion of micafungin in the perioperative prophylactic regimen, which is now standard practice at our center.
In conclusion, the majority of infectious complications reported among patients who have undergone FCTA have been related to early surgical site complications and other perioperative issues. These infections have been managed successfully by different transplant teams. Beyond CMV, no other classic opportunistic infections have been described. We found that an interdisciplinary team approach to the care of these patients involving plastic surgery, otolaryngology, transplant surgery, infectious diseases, dermatology and radiology minimized the risk and impact of infectious complications in our FCTA cohort and should be encouraged for optimal outcomes in this emerging discipline.
This work was supported in part by a research contract (W911QY-09-C-0216) between the Department of Defense and Brigham and Women's Hospital under the Biomedical Translational Initiative.
The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. S.P.H. has received research grant support from Merck. F.M.M. has received research grant support and consulting honoraria from Astellas Pharma and Chimerix. All other authors have no disclosures.
Duration indicated if provided in publication
Later determined to be rosacea