Minimizing infection risks after paediatric organ transplants: Advice for practitioners

Abstract

Paediatric patients who have undergone an organ transplant face risks associated with different infectious diseases. Their susceptibility is increased by treatment with immunosuppressive medications. More of these patients are being cared for in community settings. This practice point provides guidance on key aspects in the prevention and treatment common infections.

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The paediatric patient undergoing an organ transplant is at risk of acquiring various infectious diseases from three possible sources: the endogenous reactivation of latent pathogens (eg, herpes viruses); transmission from the donated organ or tissue; or transmission from within the community or health care setting. Clinicians practicing in community settings often provide care for these vulnerable patients before or after transplantation. Guidelines for the prevention and treatment of these infections were recently published(1) and reviews have been written.(2) This practice point summarizes key aspects of managing transplant patients, with a focus on issues likely to be encountered in community settings.

PREPARING THE PATIENT

The pretransplant period should be used to improve a patient’s overall health and well-being as much as possible, with particular emphasis on optimizing vaccination status (Table 1). The likelihood of an adequate immune response improves when vaccines are administered before the onset of immune suppression. As a general rule, the interval between administering an inactivated vaccine and transplantation should be more than two weeks to allow for an adequate immune response.(3–4) The minimum interval between the last dose of a ‘live’ vaccine and onset of immune suppression should be four weeks.(3–4) Live vaccines (eg, measles vaccine) are relatively contraindicated after transplantation. Also, the patient’s household contacts should have received all age-appropriate vaccines for measles, mumps, rubella, varicella, pertussis, Haemophilus influenzae type b, meningococcal, pneumococcal, rotavirus, and the seasonal influenza vaccine. A second focus in the pretransplant period should be on identifying acute, chronic or latent infections in the transplant candidate as well as in prospective living donors. While this practice point concentrates primarily on the transplant candidate or recipient, clinicians will also need to work closely with their transplant centre and be familiar with protocols for living donor screening. Specific conditions may be determined by patient history (including risks associated with tuberculosis exposure, travel, living abroad, household pets, lifestyle and occupation), by the physical examination or by screening tests (Table 2). Pre-existing infections can contraindicate or delay transplantation. Detailed patient information is critical for assessing the risk of post-transplant infection and for guiding post-transplant prophylaxis (Table 3). Counselling on how to avoid high-risk exposures in the immediate pretransplant period (eg, around lifestyle, travel, food and water sources) should be provided to both recipient and donor.

TABLE 1.

Vaccines recommended and contraindicated in transplant recipients

Vaccine	Inactivated (I)/Live attenuated/(LA)	Recommended before transplantation	Recommended after transplantation
Routine for all transplant recipients
Diphtheria	I	Yes	Yes
Pertussis	I	Yes	Yes
Tetanus	I	Yes	Yes
Polio	I	Yes	Yes
Haemophilus influenzae b (regardless of age)	I	Yes	Yes
Streptococcus pneumoniae (PCV 13/23-valent polysaccharide*)	I	Yes	Yes
Neisseria meningitidis (conjugate serogroup C and conjugate quadrivalent†)	I	Yes	Yes
Influenza	I	Yes	Yes
	LA	No‡	No
Hepatitis B	I	Yes	Yes
Hepatitis A	I	Yes	Yes
Measles§	LA	Yes	No
Mumps§	LA	Yes	No
Rubella§	LA	Yes	No
Varicella§	LA	Yes	No
Rotavirus (if age-appropriate)	LA	Yes	No
Human papillomavirus	I	Yes	Yes
Special circumstances
BCG	LA	Yes	No
Rabies	I	Yes	Yes

Adapted from reference 2.

^*All required doses of conjugate vaccine should be given before polysaccharide vaccine. Children younger than 24 months of age are unlikely to respond to polysaccharide vaccine.

^†Conjugate quadrivalent vaccine is currently not licensed in children under 24 months of age.

^‡The live attenuated vaccine is approved for healthy patients. It may be given to pre-transplant patients who are healthy. If used, the vaccine should be administered two or more weeks before transplantation.

^§These vaccines are usually given at 12 months of age but are sometimes given as early as six months of age in children awaiting transplant. These vaccines must be given ≥4 weeks before transplantation. BCG Bacillus Calmette–Guérin; PCV Pneumococcal conjugate vaccine

TABLE 2.

Screening tests for transplant candidates^*

Tests	Comments/action required for abnormal results
HIV-1 and -2 serology and antigen detection	Refer for HIV management if positive; some centres do not transplant
HTLV-1 and -2 serology	Refer for counselling if positive
Hepatitis A serology	Vaccinate if nonimmune and nontransplant risk factors are present; some experts recommend vaccination routinely
Hepatitis B serology	Obtain full panel of hepatitis B serology, including surface antigen and anticore antibody; vaccinate if nonimmune
Hepatitis C serology	Refer for counselling if positive
Hepatitis D serology	Obtain if hepatitis B surface antigen positive and test available
Cytomegalovirus serology	Obtain IgG; urine culture for seropositive infants <18 months of age; influences post-transplant management
Epstein-Barr virus serology	Viral capsid antigen and Epstein-Barr nuclear antigen; influences post-transplant management; PCR may be considered if seropositive and presence of maternal antibodies suspected†
Herpes simplex virus serology	Influences post-transplant management
Varicella-zoster virus serology	Vaccinate seronegative candidates who have not been vaccinated previously at least four weeks before transplantation; if vaccinated individuals are seronegative, discuss with infectious disease specialist
Toxoplasma gondii serology	Obtain in heart or heart-lung candidates; influences post-transplant management
Measles serology if vaccinated	If negative or not vaccinated, vaccinate; allow for at least four weeks between vaccine dose and transplantation
Mumps serology if vaccinated	If negative or not vaccinated, vaccinate; allow for at least four weeks between vaccine dose and transplantation
Rubella serology if vaccinated	If negative or not vaccinated, vaccinate; allow for at four least weeks between vaccine dose and transplantation
Mycobacterium tuberculosis	Obtain history of potential exposure; Mantoux test; IGRA being evaluated; intervention for latent TB may be required
Strongyloides stercoralis	Obtain if patient has lived in an endemic area; positive serology requires intervention with ivermectin treatment
Respiratory tract pathogens	Obtain sputum cultures from patients with cystic fibrosis and other lung transplant candidates; pretransplant antimicrobial susceptibility data for colonizing bacteria (eg, Burkholderia cepacia) will guide peritransplant antimicrobial therapy; Aspergillus colonization is an indication for suppressive therapy.
Radiographic imaging	Obtain as clinically indicated

Adapted from reference 2.

^*Maternal antibody may lead to false positive serological tests among infants <18 months of age, and false positive tests due to passively transfused antibody may be obtained after recent receipt of blood products;

^†A negative polymerase chain reaction (PCR) does not rule out latent infection in the infant. This is not an all-inclusive list. Other screening tests may be indicated for specific pathogens (eg, syphilis, and Kaposi's sarcoma-associated herpesvirus [HHV8] for individuals from endemic areas. Generally, HHV8 seroprevalence rates are as follows: North America, Asia, northern Europe <5%; Mediterranean basin, Caribbean, Middle East 5% to 20%; Africa, Amazon basin >50%.(24) HTLV Human T-lymphotrophic virus; IgG Immunoglobulin G; IGRA Interferon gamma release assays; TB Tuberculosis

TABLE 3.

Regimens and targets for prophylaxis in the post-transplant period

Infections	Target groups prophylaxis regimens/comments	Suggested duration of prophylaxis
Bacterial infection (post-operative wound infection and sepsis)	All recipients Perioperative antimicrobial regimens vary depending on organ, nature of surgery and recipient factors (eg, selected regimens for cystic fibrosis)	Duration will depend on the organ and nature of surgery
Herpes simplex	Seropositive recipients Acyclovir (if not on ganciclovir for some other indication)	Three months
CMV	Stratification of risk based on CMV donor/recipient serostatus Intravenous ganciclovir (with/without intravenous immune globulin in some centres) Emerging data for valganciclovir in low-to-intermediate risk older children	Typically three months; some centres prophylax for shorter (two weeks) or longer (six months) periods
EBV	High-risk patients are D+R– patients* No established regimens; preemptive reduction in immune suppression to respond to rising EBV load in peripheral blood in use by a growing number of centres; ganciclovir with or without immune globulin employed in some centres	Duration variable if antivirals with/without immune globulin are employed
Candida species	High-risk patients only (eg, liver, intestinal transplants) Fluconazole selectively; lipid amphotericin B products selectively; nystatin often used	Up to four weeks depending on risk factors
Aspergillus	Lung/heart lung recipients Voriconazole; itraconazole; amphotericin B if high-risk factors are present (eg, Aspergillus colonization)	Duration variable; up to four to six months, depending on risk
PJP	All recipients TMP-SMX	Typically six to 12 months, or if receiving steroids or if CD4 <200/mm3; for lung and small bowel transplant recipients, as well as patients with history of prior PJP infection or chronic CMV disease, lifelong prophylaxis may be indicated
Toxoplasma gondii	Heart/heart-lung recipients Pyrimethamine/sulfadiazine for D+R-patients TMP-SMX of some value for R+ patients	Six months

Adapted from reference 2.

^*D+R– denotes donor seropositive and recipient seronegative status; CMV Cytomegalovirus; EBV Epstein-Barr virus; PJP Pneumocystis jirovecii; TMP-SMX Trimethoprim-sulfamethoxazole

POST-TRANSPLANT INFECTIONS TO EXPECT

In the first month

Greater than 95% of infections occurring in this critical period are similar to infections incurred by nonimmunosuppressed patients who have undergone a comparable surgical procedure.(5–6) The remaining are caused either by an infection that was present in the recipient before transplantation that was exacerbated by surgery, anesthesia and immunosuppressive therapy, or by an infection being transmitted by the allograft.

One to six months post-transplant

In this period, the effects of immune suppression become noticeable and may result in two types of opportunistic infections. In the first category are viral pathogens that are associated with latent or persistent infections, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpes virus 6, and hepatitis B and C viruses. Infection by these pathogens can be primary (typically acquired from the donor rather than from the community), a reactivation of latent pathogens, or reinfection with a new strain of the virus. Typical pathogens in the second category are Listeria monocytogenes, Aspergillus fumigatus and Pneumocystis jirovecii. Infection development with these organisms is aided by sustained immunosuppression with or without the immunomodulating effects of viral infections to create a net state of immunosuppression sufficient to increase susceptibility. Some organ transplants (eg, of the small bowel) carry higher risks of opportunistic infection compared with others (eg, the kidney) because immunosuppression is more intense.

More than six months post-transplant

Published data on infectious complications in this period are limited and may be biased toward serious infections that require hospitalization. Patients who are on maintenance immunosuppression and have good allograft function are likely to acquire the same community-acquired infections as healthy children (eg, common respiratory viruses). Some patients with poorer post-transplant outcomes (eg, acute or chronic immunosuppression, poor allograft function or a chronic viral infection) are at high risk for recurrent infections relating to uncorrected mechanical or anatomical problems (eg, implanted foreign material or an obstruction), as well as for opportunistic infections from P jirovecii, L monocytogenes, Cryptococcus neoformans, and Nocardia asteroides, among others.

EVALUATION OF THE FEBRILE TRANSPLANT PATIENT

Fever in the transplant patient may be due to a common childhood infection or to an infection that is unique to the transplant recipient.(2) The timing of infection after transplantation provides guidance regarding the most likely pathogens. Evaluation and empirical therapy will depend on the clinical status of the patient and whether or not a source of infection has been identified.

When the examination is abnormal and the focus of infection is defined

Hospital admission may be indicated, depending on the clinical status of the patient and the site of infection. Diagnostic evaluation should include, at a minimum, a complete blood count and differential, and blood cultures. Additional investigations depend on the clinical focus and timing of presentation after transplantation.

When the examination is normal and no focus of infection is defined

Hospital admission is usually warranted if the patient is clinically unwell. Diagnostic evaluation is based on the differential diagnoses. Patients who feel well may not require admission, depending on the adequacy of available follow-up, their ability to return to the hospital promptly if a condition worsens, the degree of immune suppression and the interval since transplantation. Diagnostic evaluation should include, at a minimum, a complete blood count and differential, and blood and urine cultures. In the first months following a transplant, the site of infection often relates to the surgical procedures performed. Clinicians need to be aware of viral infections that are associated with fever but have no readily apparent focus of infection (eg, CMV and adenovirus). In the absence of an obvious benign source of fever, such patients should be managed in consultation with their transplant centre. When choosing antibiotics for infections (as appropriate), clinicians need to be aware of potential interactions between antibiotics and selected immunosuppressive drugs; Table 4 lists immunosuppressive agents, while Table 5 shows potential drug interactions.

TABLE 4.

Immunosuppressive drugs used in organ transplantation

Drug	Trade name or common name	Mechanism of action/type of drug	Notable side effects
Polyclonal antibodies
Rabbit antithymocyte globulin	Thymoglobulin	Antibodies against thymus-derived epitopes (protein sites recognized by the immune system)	Anaphylaxis, infusion-related effects (eg, fever, chills, tachycardia, hypertension)
Equine antithymocyte globulin	Atgam*
Monoclonal antibodies
Basiliximab	Simulect†	Antibody to IL2 receptor (CD25)	Hypersensitivity
Rituximab	Rituxan‡	Anti-CD20 antibody	Infusion related reactions (eg, fever, chills, hypotension), angioedema, pancytopenia
Corticosteroids
Prednisone	Steroids	Inhibition of activator protein-1 and NF-κB	Hypertension, diabetes, salt/water retention, osteopenia, hyperlipidemia, Cushingoid features, hirsutism, acne, growth retardation
Methylprednisolone	Steroids
Calcineurin inhibitors
Cyclosporin A	Neoral†	Calcineurin inhibitor	Hirsutism, gingival hyperplasia, nephrotoxicity, hypertension
Tacrolimus	Prograf§ Advagraf§	Calcineurin inhibitor	Tremor, dose-dependent neuropathy, nephrotoxicity, hypertension, hyperglycemia
Antiproliferative agents
Mycophenolate mofetil (MMF)	CellCept‡	Inhibition of purine biosynthesis and inhibition of DNA synthesis	Leukopenia, anemia, thrombocytopenia, gastrointestinal symptoms
Enteric coated mycophenolate sodium (EC-MPA)	Myfortic†
Azathioprine	Imuran¶	Purine analog; inhibition of DNA synthesis	Leukopenia, anemia, thrombocytopenia
mTOR inhibitors
Sirolimus	Rapamycin Rapamune*	Arrest in cell cycle and differentiation	Delayed wound healing, aphthous ulcers, hyperlipidemia, bone marrow suppression, pneumonitis
Everolimus	Afinitor†

^*Pfizer, USA;

^†Novartis, USA;

^‡Genentech, USA;

^§Astellas Pharma US Inc, USA;

^¶Triton Pharma Inc, Canada. mTOR A serine/threonine protein kinase that has direct control of protein synthesis

TABLE 5.

Cytochrome p450 interactions between antimicrobials and immunosuppressive drugs used in transplantation (cyclosporine A, sirolimus, tacrolimus and everolimus)^*

Inducers (decrease levels of immunosuppressants)	Inhibitors (increase levels of immunosuppressants)	Degree of interaction
Antibiotics   Rifampin   Rifabutin	Azithromycin Clarithromycin Erythromycin Metronidazole Levofloxacin Ciprofloxacin	Interaction with erythromycin > clarithromycin which is > azithromycin Beta-lactams safe
Antifungals   Caspofungin (with tacrolimus only; not CYP-mediated)	Fluconazole Ketoconazole Itraconazole Voriconazole	Caspofungin AUC (exposure) increased with cyclosporine Micafungin less likely to affect levels than caspofungin Ketoconazole and itraconazole > fluconazole and voriconazole
Antivirals   Nevirapine   Efavirenz	Indinavir Nelfinavir Ritonavir Lopinavir Amprenavir Saquinavir

^*Degree of inhibition/induction of CYP p450 enzymes is drug- and/or route-specific, affecting the degree of interaction with listed immunosuppressants. The above drug interactions do not preclude use of these antimicrobial agents. However, strategies to manage and monitor interactions/drug levels should be discussed with the transplant team before initiation. AUC Area under the curve; CYP Cytochrome p450

POST-TRANSPLANT IMMUNIZATIONS

Timing and schedule

Most transplant centres provide schedules for immunizing recently transplanted paediatric patients (Table 1). Usually, vaccines are not administered in the first six to 12 months following a transplant (7) with the exception of the seasonal inactivated influenza vaccine, which is administered no earlier than one month after transplantation and yearly thereafter. Clinicians should acquaint themselves with appropriate vaccination schedules. Also, vaccinating household contacts is a key strategy in protecting the vulnerable transplant recipient.

Contraindicated vaccines

Vaccines that are contraindicated for immunosuppressed transplant patients are shown in Table 3. Some groups recommend giving measles, mumps and rubella vaccines in select low-risk patients with minimal immunosuppression.(3,8–9) Limited data exist for administering the varicella vaccine after transplantation. (10–11) However, most experts consider organ transplant to be a contraindication for the varicella vaccine and, in the event of exposure, susceptible individuals are candidates for varicella-zoster immune globulin. This issue underscores the importance of pre-transplant vaccination. Vaccinating paediatric transplant candidates has been shown to sustain humoral immunity for at least two years, well beyond the period of peak immunosuppression.(12)

Selected indicated vaccines

Pneumococcal vaccines:

Transplant patients are considered to be at high-risk of invasive pneumococcal disease, with heart transplant recipients being particularly vulnerable.(13–14) Consequently, pneumococcal vaccine is one of the most important vaccines given to transplant recipients. Current recommendations are for sequential use of the 13-valent pneumococcal conjugate vaccine (with the number of doses depending on the age of the child) followed in eight weeks by the 23-valent vaccine.(15–16) Some organ transplant patients with functional or anatomical asplenia are candidates for long-term penicillin prophylaxis to prevent invasive pneumococcal disease.

Meningococcal vaccines:

These vaccines may be safely administered using routine childhood schedules. The meningococcal conjugate quadrivalent vaccine (MCV), rather than the polysaccharide quadrivalent vaccine, should be used. Most experts agree there is no role for the polysaccharide vaccine at present. The meningococcal conjugate quadrivalent vaccine is not approved for children younger than 24 months of age.

Human papilloma virus vaccine:

The human papilloma virus (HPV) vaccine can be safely administered after an organ transplant. While data are lacking to support the efficacy of HPV vaccine in recipients whose immune responses may be weaker than those of healthy individuals, the vaccine is strongly recommended for both female and male transplant patients given their particular risk of developing severe genital warts and potentially aggressive HPV-related malignancies.

Hepatitis B and A vaccines:

Hepatitis B vaccine should be given according to the routine immunization schedule, but with double the usual dose. Hepatitis A vaccine is usually recommended for individuals with risk factors for hepatic disease other than transplantation (eg, chronic liver disease or epidemiological factors). However, some experts recommend hepatitis A vaccine even if other risk factors are absent because potentially hepatotoxic drugs may be used to treat immunosuppression.

Inactivated polio, Haemophilus influenzae type b and diphtheria, tetanus and acellular pertussis vaccines:

These vaccines are all recommended, preferably before transplantation, in accordance with the routine schedule for children. If not previously received, Haemophilus influenzae type b vaccine should be given, regardless of age.

Influenza vaccine:

Transplant recipients and all household and other close contacts should receive inactivated influenza vaccine yearly during the fall.

COMMUNITY-ACQUIRED RESPIRATORY VIRUSES

Paediatric organ transplant recipients are at risk for community-acquired respiratory viral infections, including respiratory syncytial virus, influenza viruses, human metapneumovirus, parainfluenza viruses and others.(17) Guidelines for preventing and managing these infections were published recently,(18–19) and influenza management guidelines are published annually in Canada.(20)

POST-TRANSPLANT TARGETS FOR ANTIMICROBIAL PROPHYLAXIS

Transplant patients may require antimicrobial prophylaxis against Candida species, Aspergillus species, herpes group viruses (eg, herpes simplex, CMV, EBV), hepatitis B, P jirovecii, Toxoplasma gondii, Strongyloides, latent tuberculosis infection and other pathogens (Table 2). Of these infective agents, CMV and EBV consume the greatest resources in most paediatric transplant centres. Guidelines on the prevention and treatment of these conditions have been recently updated.(1,21–22)

INFECTION RISKS OF DAILY LIVING AFTER A TRANSPLANT

Besides providing information on the risks of immunosuppressive drugs (Table 4) (23) and their interactions with common antimicrobials (Table 5), clinicians need to counsel young transplant patients about infection risks associated with food and drinking water, pets and other animals, swimming and other water sports, fungal spores (eg, from gardening, farm buildings, construction sites, excavations, caves, marijuana and tobacco), mosquito bites, travel and sexual behaviour, as appropriate.(19)