Infectious complications of vascularized composite allograft transplantation

Abstract

Purpose of review

Vascularized composite allograft (VCA) transplants constitute multiple tissues transplanted together as one functional unit. These procedures are increasing in frequency and complexity, yet data about graft survival, quality of life, and infection risk remain limited.

Recent findings

Informative guidance for this patient population is often inferred from the solid organ transplantation literature. Yet, it is important to understand that VCA transplantation additionally carries its own significant and distinctive risk factors for infection.

Summary

In this review, we give an overview of previously described infectious complications of VCA transplantation in the literature, discuss risk factors for future infection in these patients, and discuss how to manage such obstacles.

INTRODUCTION

A vascularized composite allograft (VCA) refers to the transplantation of multiple tissues, typically muscle, blood vessel and nerve bundles, and associated viscera, delivered and transplanted as a single functional unit [1]. This has included most commonly face, hand(s), and uterus transplants, although larynx and abdominal wall transplantation have also been completed, and other en-bloc tissue grafts can be considered. As this is a new and emerging domain, data on these patients is limited and often deduced from solid organ transplantation (SOT) literature, along with case reports and allograft-specific small-number clinical reviews. Yet while there are overlapping similarities, this discipline also has many differences from SOT. A key distinction is that the primary indication and goal for a VCA transplant is typically life-affirming (or in the case of uterus transplants, life-giving), rather than life-extending, as seen with other transplants. Although this novel and diverse specialty is very promising, it does carry a range of unique infectious risks that are increasingly recognized as experience in this field grows. The objective of this review is to address potential impending infectious risk factors in these patients and how to best approach them, including a synopsis of the infectious complications of VCA transplantation reported in the literature.

GENERAL INFORMATION

Similar to SOT, there are many components of VCA care that are applicable across multiple different allografts. Induction immunosuppressive regimens are similar compared with SOT, especially deceased donor renal transplants, and include polyclonal and monoclonal antibodies and corticosteroids [2–7,8■]. This suggests a similar level of infection risk, and allows for the extrapolation of data from the SOT literature. Maintenance immunosuppression again is similar to the SOT data, and frequently consists of triple therapy with a calcineurin inhibitor, mycophenolate mofetil, and corticosteroids [9–11,12■,13].

Like other areas of SOT, infection mitigation begins pretransplant. Prior to transplantation, recipient vaccination history should be obtained and deficits addressed, including measles, mumps, and rubella (if serology indicates lack of immunity and greater than 4 weeks until planned transplant); meningococcal; pneumococcal; hepatitis A and B; tetanus-diphtheria-pertussis; and seasonal influenza. Shingles prevention and vaccination should be discussed, if age-appropriate. Additionally, relevant cancer screening should be pursued, with consideration of human papilloma virus (HPV) vaccination in younger recipients, especially where there is concern for HPV transmission (for example, with a transplant cervix) [14,15].

All donors and recipients should undergo pretransplant screening for transmissible or latent diseases, including (but not limited to) cytomegalovirus (CMV); Epstein-Barr virus (EBV); varicella zoster virus; herpes simplex virus (HSV); HIV; Toxoplasma; hepatitis A, B, and C; and syphilis [16■]. Screening should also be performed for additional pathogens specific to the donor and recipient based on geographic, occupational, and recreational history. Common examples include tuberculosis or endemic fungal infections. Pretransplant microbiologic cultures should be obtained in both donor and recipient, specific to each allograft and outlined in more detail below. Subsequently, appropriate peritransplant antimicrobial prophylaxis should be pursued - including a standardized regimen of antibacterial, antiviral, and antifungal agents, as well as specialized regimens tailored to culture or screening results that arise during transplant workup. Such regimens include antiviral prophylaxis with valganciclovir for CMV, particularly in those who have a serologically mismatched positive donor, or acyclovir for HSV prevention if the recipient is felt to be a low risk for CMV. Additional prophylaxis should also be pursued with trimethoprim-sulfamethoxazole for prevention of both Pneumocystis as well as Toxoplasma.

TYPE OF VASCULARIZED COMPOSITE ALLOGRAFT TRANSPLANTATION

Face

Face transplantation includes the transference of skin, muscles, cartilage, bone, nerves, and blood vessels to improve exterior craniofacial features including the scalp, nose, ears, jaw, and chin in patients with severe deformities typically because of a congenital or traumatic source [17–20]. Infection is one of the most common complications to arise early after transplant, and requires close monitoring, particularly of surgical sites [21]. Postoperative and surgical site infections with various fungal and bacterial pathogens have been reported, including Candida spp., Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter baumanii [12■,15,22,23]. Prophylactic and treatment antimicrobial regimens must exercise special consideration of the nose, sinus, and upper airways as these are sites of exposure to inhaled environmental pathogens, leading to both colonization and infection with a number of organisms [24]. Sinusitis has been documented after face transplantation and can be made worse by environmental exposures, changing bacterial flora posttransplant, and mechanical obstruction [15,25]. Mucosal bacterial, mycobacterial, and fungal cultures should ideally be obtained prior to transplant, at the time of procurement, to offer the most timely antibiotic guidance for the recipient [16■]. The importance of preoperative cultures and cautious donor screening is highlighted in the case of a potential donor for face transplantation that was ultimately aborted just prior to the planned surgery when respiratory cultures and pathologic findings were concerning for invasive pulmonary aspergillosis [26,27■]. In routine practice, donor bacterial lower respiratory tract cultures (but not necessarily cultures of the sinuses or oropharynx) are collected by the organ procurement organization (OPO) in the United States. Therefore, it is necessary to communicate closely with the OPO both to confirm that all appropriate cultures are initially obtained, as well as ensure prompt and continuous notification of culture results that may take more time to finalize, including fungal and mycobacterial testing. Sometimes it can be difficult to differentiate colonizing and infecting pathogens especially in polymicrobial cultures, as seen in a face transplant recipient with Enterobacter, Enterococcus faecalis, and Staphylococcus epidermidis isolated from sputum cultures, therefore, perioperative antibiotics may need to be adjusted accordingly to cover all culture results [28,29].

Skin infections are increasingly common with VCA but can be more challenging to differentiate from other immunologic and dermatologic issues. This was demonstrated in a face transplant recipient with transmission of rosacea by allograft, as well as a separate patient with both early rejection and Candida stomatitis, manifesting clinically as oral mucosal erythema [15,30–34]. One particular feature unique to VCA transplantation compared with most of SOT (aside from lung and small bowel) is that most allografts have at least one layer of tissue (i.e. a skin graft) continuously exposed to the outside environment. This can be helpful when assessing for rejection, as the area of concern can be easily identified on physical exam and biopsied without the need for a more invasive procedure or imaging, and without threatening the aesthetics of the graft [35]. However, this constant contact with the surroundings can also increase the risk for infectious complications.

All components of the face should be closely monitored for infection. Palpebral conjunctivitis and bacterial blepharitis have been documented, treated with topical antibacterial ointment [12■]. After transplantation, HSV or HPV can affect the lips and oral mucosa, requiring antiviral treatment and/or reduction of immunosuppression. Molluscum contagiosum of the cheeks has also been described, and like in other settings is treated with direct curettage [14,21,34,36]. Salivary glands are typically included in the face allograft, and an additional complication that may be overlooked is an infectious parotitis or other salivary gland infection [10,12■]. This may require both antimicrobial therapy (including bacterial and yeast-targeting drugs) directed at organisms of the oral mucosa, as well as assessment for and clearance of any occluded ducts.

Akin to other more traditional SOTs, it is also important to remain vigilant for infections that may manifest in other physical locations of the body, particularly in the setting of immunosuppression. One such example is a face transplant recipient who developed Majocchi’s granuloma of the feet because of Trichophyton rubrum, treated with months of terbinafine [10]. Additional reported complications in face transplant recipients that involved other organ systems include bacterial pneumonia because of Haemophilus influenzae; diarrheal illnesses because of Clostridium difficile, Aeromonas, and viral causes; and bloodstream infections with Enterobacter cloacae, Pseudomonas spp., and S. epidermidis [10,12■,22,25,29].

Immunologic and infectious risks increase in the setting of multiple concurrent transplants, and antimicrobial prophylaxis may need to be adjusted accordingly. One patient with simultaneous face and bilateral hand transplantation from the same donor developed necrotic soft tissue infection of the allografts with multidrug-resistant P. aeruginosa within the first month after transplantation. The recipient ultimately passed away despite antibiotic therapy combined with surgical debridement and removal of the infected area [21,36,37]. At a separate institution, a combined face and bilateral hand recipient developed pneumonia with positive respiratory cultures for P. aeruginosa, Proteus mirabilis, and Serratia marcescens as well as vascular insufficiency of the bilateral hand allografts resulting in septic shock. Along with antibiotics, this ultimately necessitated removal of the hand allografts within the first week posttransplant [37]. No significant rejection was found in either patient.

Hand

When evaluating a hand transplant recipient, it is important to consider the future potential environments, the hand may be exposed to in a particular recipient, as well as common afflictions of the organ in normal hosts. It is important to obtain a thorough social and occupational history of both the donor and recipient prior to transplantation [38]. For instance, if the donor has significant agricultural exposure or a gardening hobby, especially with exposures around the time of a donor’s terminal illness, it would be prudent to consider pathogens that may be present in the soil or particular flowers, including Nocardia, endemic fungi, Aspergillus, non-tuberculosis Mycobacterium spp., and Sporotrichosis. However, if the donor had prolonged experience in a water-rich environment during life (i.e. a fisherman) or if the cause of death of the donor was because of drowning, pathogens relevant to aquatic exposure should be considered, such as Vibrio spp., Aeromonas spp., and Mycobacterium marinum. If the donor had notable experience with farm animals, particular zoonoses would include Orf virus, Pox virus, brucellosis, and Coxiella. Other infections may not have a clearly defined exposure. For example, tinea skin infections of the hand have been reported, including the nail [39]. HPV infection has also been reported in the setting of bilateral hand transplantation, treated with topical cidofovir [40,41].

One should have a low threshold for skin biopsy (similar to face transplantation) as multiple pathologic etiology can have a similar appearance on clinical exam. One bilateral hand transplant recipient presented with an erythematous maculopapular rash greater than 10 years after transplantation, both at the site of the graft as well as other exposed cutaneous areas. The diagnosis was only made when skin biopsy confirmed infection with scabies [42].

Penis/scrotum

As with all of transplantation, it is important to screen the donor for infections common to the organ in normal hosts as well as obtaining a thorough social history, including a sexual history if a genitourinary organ is being transplanted. With the help of an engaged OPO, such screening for penis transplantation should include sexually transmitted infections including HSV, HPV, Chlamydia trachomatis, Neisseria gonorrhea, Trichomonas, and syphilis. However, nonsexually transmitted infections may also manifest. This includes documented cutaneous fungal infections with Alternaria alternata, treated with topical antifungals [43–45].

Uterus

Uterine transplant carries its own unique concerns, even amongst the VCA population. First, of the described organs listed in this article, the uterus is the only one where both deceased and living donors have been used successfully. There may be a decreased risk of infection with living compared with deceased donors, akin to living renal donors, but more data is required to confirm this [46]. Deceased donors on the other hand, offer surgeons more operative flexibility [47■]. Postsurgical complications must be monitored for closely in the living donor as well as the recipient. Operative wound infections, ureterovaginal fistula development, urinary tract infections, and C. difficile have all been described in live donors after transplant [48■,49]. Urinary tract infections have also been frequently described postoperatively in recipients, though screening is done more frequently in this population and includes those diagnosed by urinalysis alone as opposed to symptom assessment [48■].

Critically, uterine graft survival is not intended to last for the lifetime of the recipient, but instead solely for the purposes of procreation - about 5 years, up to two pregnancies [50]. Thus, recipients will not require lifelong immunosuppressive therapy, significantly decreasing their overall risk for infection.

Finally, in addition to the infectious risks of the graft itself to the recipient, it is important to recognize impending potential harm for future fetuses planned for development from that uterus. This particularly highlights the need to screen for congenital infections in donor and recipient such as CMV, syphilis, and Toxoplasma prior to transplant.

As with the penis transplant, it is also important to screen donors pretransplantation for sexually transmitted infections. In the literature, one uterine transplant was complicated by genital HSV within the first month posttransplant that ultimately led to postinfectious cervical stenosis [51■]. Dissemination of commonly colonizing organisms of the genitourinary tract can also lead to significant complications. Severe Candida infection complicated an early uterine transplant in the United States resulting in loss of the graft [52], whereas a uterine transplant in a Swedish cohort developed E. faecalis abscess formation that was not responsive to antibiotics and surgical source control and ultimately resulted in graft removal [51■,53]. Other reported complications in recipients after uterine transplant include C. difficile infection and acute appendicitis [54].

Systemic Infections

It is important to remember that in the context of transplantation, systemic infections can have multiple clinical manifestations regardless of the organ involved. Many difficult systemic infections have now been reported in the VCA transplant literature, as one would expect from extrapolating from SOT data.

Cytomegalovirus and Epstein–Barr virus

Herpesviruses, particularly CMV and EBV, can be frequent complications of transplantation, particularly in those who have a serologically mismatched positive donor.

CMV is a commonly reported complication in all of transplantation, including VCA, and is managed in predominantly the same manner as SOT [21,22,29,39,41,55–64]. It is most commonly treated with ganciclovir or valganciclovir, but may also require other antiviral agents, such as foscarnet depending on the severity of the infection and drug resistance of the virus. This infection can arise even in the setting of antiviral prophylaxis if inappropriate dosing is used. If a center prefers a preemptive approach to CMV, that decision tool should be protocolized by the institution, in order to avoid inadvertent symptomatic high level viremia.

EBV can lead to a range of presentations, from viremia to malignancy with posttransplant lymphoproliferative disorder (PTLD) [15,23]. Ganciclovir, foscarnet, and cidofovir have all been used for treatment of severe infection, but there are no dedicated antiviral agents for EBV viremia. The primary aim of treatment is immunosuppression reduction. Additional agents, such as rituximab or other chemo-therapeutics may be added for treatment of PTLD.

Hepatitis C and HIV

Although experience is growing rapidly concerning the management of hepatitis C virus (HCV) and/or HIV infections in transplant recipients, experience is limited in VCA. One face transplant recipient is reported in the literature with a history of chronic HCV, that recurred rapidly after surgery despite pretransplant treatment with ribavirin and pegylated interferon alpha [10]. Contemporaneous treatment options would be very different after the advent of direct acting antivirals for HCV, and so cure in a VCA case of HCV would be expected. There are no VCA transplants reported in the literature for patients living with HIV, but again, there is no reason they could not be transplanted safely, with modern antiretrovirals.

CONCLUSION

VCA is a novel and expanding field in transplantation. Although data is limited, we can learn a great deal about the multiple infections that may lend themselves to more intent follow-up and can be anticipated or promptly managed if appropriate pretransplant measures (including donor/recipient cultures, targeted antimicrobial prophylaxis, and vaccination) are taken. Early and thoughtful discussion with the OPO involved in procurement can be a significant positive step. Also, ensuring appropriate pretransplant screening and posttransplant safe living education is vital. The field of VCA transplant will continue to grow as providers and centers care for these patients and continue to publish their experiences from which others can learn.

KEY POINTS.

• A vascularized composite allograft (VCA) refers to the transplantation of multiple tissues as a single functional unit - there is diversity in the types of allograft transplanted (i.e. hands, face, uterus, penis, abdominal wall).

• Most decisions regarding immunosuppression, tolerance, rejection, and infection in VCA can be extrapolated from the solid organ transplant data, given the similarities in immunosuppression levels. These data can guide healthcare providers about impending infection risk.

• Care of VCA transplant recipients requires a unique multidisciplinary approach, including not only infectious diseases providers, transplant pharmacists, and organ procurement organizations but also numerous surgical teams and rehabilitation and occupational specialists not typically seen in other mainstream transplant teams.