Each year more than 500 children undergo heart transplantation around the world, and infection is an important cause of morbidity and some mortality in these patients. The Registry of the International Society for Heart and Lung Transplantation (ISHLT) found that, from 2002 to 2012, infection (not including cytomegalovirus [CMV]) was the cause of death in pediatric heart transplant recipients in 8.5% of patients in the first year after transplant, 5.4% to 5.9% of patients 1 to 10 years posttransplant, and 5.5% of patients more than 10 years after transplantation. Of the 9248 primary pediatric heart transplantations occurring between the years of 1998 and 2010 included in the ISHLT Registry, there were 3061 deaths, of which 9% were secondary to infection.
The Pediatric Heart Transplant Study Group (PHTS) prospectively collected data from 22 pediatric centers in the United States from January 1993 to December 1994 on 332 children younger than 18 years (mean age, 5.5 years) who had undergone heart transplantation. One or more infections (276 total) occurred in 41% of the patients (mean follow-up time, 11.8 months) for an average of 0.84 infections per patient; 22% had one infection, 8% had two infections, and 11% had three or more infections during the study period ( Table 70.1 ). In an updated report from this multicenter group summarizing children who had undergone heart transplantation over the decade starting in 2000, 72% were free from infection at 1 year posttransplant. In a similar multicenter study in adults who had undergone heart transplantation between January 1990 and June 1991, infections developed in 31% of 814 patients, with 22% having one infection and 9% having two or more infections.
| Type | N |
|---|---|
| Bacterial (total) | 164 |
| Coagulase-negative staphylococci | 25 |
| Enterobacter spp. | 21 |
| Pseudomonas aeruginosa | 16 |
| Cytomegalovirus | 51 |
| Varicella zoster | 11 |
| Respiratory syncytial virus | 10 |
| Herpes simplex | 6 |
| Other viruses | 8 |
| Fungal | 19 |
| Candida spp. | 12 |
| Pneumocystis carinii | 7 |
Bacterial infections were the most common type of infection occurring after transplantation in pediatric and adult patients. PHTS reported that 54% of 2038 infections in 1220 patients from January 1993 to December 2004 were bacterial, 32% were viral, 7% were fungal, 0.5% were protozoan, and 7% were unknown. One single-center retrospective review of pediatric patients who underwent heart transplantation and who survived a minimum of 5 years after transplantation reported that infant transplant recipients had an increased risk of serious bacterial infections per 10 years of follow-up (mean, 2.04 ± 0.5) and chronic or recurrent bacterial infections (mean, 4.58 ± 0.67) compared with older recipients (means, 0.37 ± 0.19 and 1.87 ± 0.70, respectively). Risk factors for an infectious cause of death in pediatric heart transplant recipients include pretransplant factors such as use of pretransplant extracorporeal membrane oxygenation (ECMO), presence of pretransplant infection, diagnosis of congenital heart disease, higher pretransplant creatinine, and higher sensitization levels as well as any cardiac reoperation prior to discharge and positive donor CMV serology.
From 2009 to June 2014, ISHLT reported that 68% of children who underwent heart transplantation received induction immunosuppression, most commonly with antithymocyte globulin (47%) or interleukin-2 (IL-2) receptor antagonist (24%). Maintenance immunosuppressive therapy after transplant included a combination of a calcineurin inhibitor (tacrolimus in 84% and cyclosporine in 15%), an antimetabolite (mycophenolate mofetil or mycophenolic acid in 91% or azathioprine), and prednisone (70%). At 5 years posttransplant, 96% of patients were on a calcineurin inhibitor, 75% were on an antimetabolite, 36% were on a steroid, and 19% were on a mammalian target of rapamycin (mTOR) inhibitor (such as sirolimus). Calcineurin inhibitors predominantly block the effect of IL-2 on T cells, an action resulting in a diminished T-cell response to mitogen stimulation. The infections seen in heart transplant patients outside the postoperative period generally are a result of this block in T-cell function. Because the types of infections seen in these patients vary with the time elapsed since transplantation, this chapter is organized in such a manner.
Pretransplantation Evaluation
Several infectious agents may be transmitted to the patient via the transplanted organ or can become “reactivated” after transplantation. Determining the antibody status of the recipient and the donor against selected microorganisms (CMV, Epstein-Barr virus [EBV], Toxoplasma gondii ) helps physicians anticipate, prevent, and diagnose infections that develop after transplantation. A reasonable pretransplant evaluation for children is outlined in Box 70.1 but varies depending on the patient’s history and geographical location. The child’s immunization status is documented, and vaccinations are completed when possible (i.e., hepatitis B vaccine, Haemophilus influenzae type b, or Streptococcus pneumoniae ). The Committee on Infectious Diseases of the American Academy of Pediatrics recommends that candidates for solid organ transplantation should receive all vaccinations as appropriate for age, exposure history, and immune status. The 23-valent pneumococcal polysaccharide vaccine (PPSV23) should be given to patients 2 years of age or older at least 8 weeks after the last 13-valent pneumococcal conjugate vaccine has been administered. If possible, appropriate vaccines should be administered at least 1 month before the patient undergoes transplantation. Evidence of selected active infections is a contraindication for transplantation. Chemoprophylaxis should be considered strongly for children with a positive tuberculin skin test (purified protein derivative). Dental status also is assessed.
Serology:
Cytomegalovirus a
a Urine CMV PCR for children <18 months rather than serology because maternal antibody may still be present.
Epstein-Barr virus
Coccidioidomycosis b
b Depends on geographic regions patient has lived in or traveled to.
Toxoplasma gondii
Strongyloides c
c If from an endemic area or has eosinophilia.
Human immunodeficiency virus
Hepatitis A, B, and C
Herpes simplex virus
Parvovirus d
d May help with interpretation of molecular tests of endomyocardial biopsies.
Rubeola, mumps, rubella, varicella e
e For children >12 months and previously immunized.
Syphilis f
f Depends on age and history.
Cultures:
Nasopharyngeal, stool, or tracheal aspirates g
h Interferon-γ release assay may be helpful in selected cases.
Skin tests:
Tuberculin skin test h
g See text for an explanation.
Consider freezing of an extra aliquot of serum
Review of the child’s immunization status
In addition to having the routine pretransplant evaluation as outlined in Box 70.1 , each patient should be screened carefully for selected infections appropriate to the individual circumstances. If surgery is planned during the respiratory disease season and the patient has respiratory symptoms just before having surgery, screening for influenza virus or respiratory syncytial virus (RSV) by rapid techniques may facilitate prescribing antiviral therapy postoperatively. In areas where community-acquired methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of infection, performing surface cultures to detect MRSA colonization may modify the choice of antibiotics used for surgical prophylaxis. Providing mupirocin intranasally as well as employing chlorhexidine baths preoperatively may decrease the rate of postoperative MRSA infections in patients colonized with MRSA. In areas where coccidioidomycosis is endemic or for the patient with travel to endemic areas, pretransplant serology for C. immitis is recommended, and, if positive, antifungal prophylaxis is provided. Screening for histoplasmosis is not recommended, but itraconazole prophylaxis may be considered for patients with recent history of active histoplasmosis infection. Children from resource-poor countries may harbor Salmonella or intestinal parasites asymptomatically, and these organisms can cause serious infection after the child undergoes transplantation. Preoperative stool cultures for enteropathogens and examination of the stool for parasites may alert the clinician that these pathogens are present and could be the etiology of postoperative infections. Screening for Strongyloides is recommended for recipients in endemic areas or for patients with unexplained eosinophilia prior to transplant, and patients who are positive should be treated with ivermectin prior to transplantation.
If the patient is being mechanically ventilated before undergoing transplantation, review of recent tracheal aspirate cultures may help in the selection of empirical antibiotics for initial treatment of suspected nosocomial sepsis or pneumonia. Pretransplant infections associated with procedures such as implantation of ventricular assist devices may require prolonged antibiotic therapy after transplantation is performed. Intraoperative cultures of involved tissues including the mediastinum as well as various surfaces from the device should be obtained and the results guide therapy. These infections typically are caused by common nosocomial pathogens and are not a contraindication to undergoing heart transplantation. The reader is referred to more detailed discussions of the pretransplant assessment of the donor and recipient.
Surgical Prophylactic Antibiotics
Prophylactic antibiotics typically are administered to patients undergoing heart transplantation surgery. For each institution, selection of prophylactic antibiotics should be based partly on the organisms isolated from postoperative wound infections in that center and the antimicrobial susceptibility of these organisms. Cefazolin is generally considered the drug of choice for perioperative prophylaxis. If MRSA is a nosocomial pathogen of concern or if the transplant recipient is colonized with MRSA, a single dose of vancomycin, in addition to cefazolin, is suggested. Both vancomycin and cefazolin are recommended because data suggest that vancomycin is less effective than cefazolin for preventing surgical site infections caused by MSSA. Routine use of extended-spectrum cephalosporins is discouraged because it may lead to colonization of the patient by fungal organisms or antibiotic-resistant, gram-negative organisms that hyperproduce β-lactamase, such as Enterobacter cloacae. Expert guidelines recommend prophylactic antibiotics should not be administered beyond 48 hours post heart transplantation as part of a strategy to prevent the development of multidrug-resistant gram-negative bacteria and fungal pathogens.
Immediate Postoperative Infections
Common Infections
During the month after the patient undergoes heart transplantation, the types of infections encountered are the same as those complicating major thoracic surgery. Nosocomially acquired bacteria are the most common causative pathogens, and the incidence of multidrug-resistant organisms is increasing. Pneumonia and bacteremia are the most common postoperative infections. The frequency of bacteremia and the distribution of organisms are similar in children and adults after undergoing heart transplantation. In the PHTS study, the risk of development of any infection was 25% 1 month after transplantation. Overall 60 episodes of bacteremia occurred in the 136 patients who became infected, and the bloodstream was the most common site of bacterial infection. Lung abscesses and mediastinitis are seen less frequently. Familiarity with the organisms and the antimicrobial susceptibility of isolates recovered from other children in the ICUs in which these patients receive care helps direct the initial empirical selection of antibiotics.
Postoperative bacteremia is related predominantly to the indwelling lines required for monitoring and infusion of medication. S. aureus , coagulase-negative staphylococci, Enterococcus spp., and gram-negative enteric organisms such as Enterobacter spp., Pseudomonas aeruginosa, Klebsiella spp., and Escherichia coli are the most common causes of nosocomial bacteremia in the pediatric ICU. Other foci of infection, such as pneumonia, mediastinitis, or urinary tract infection also may result in bacteremia in heart transplant patients. Vancomycin plus an extended-spectrum penicillin, third- or fourth-generation cephalosporin, or an aminoglycoside is a typical empiric antibiotic combination for suspected bacteremia in patients with central lines in place and without focal evidence of infection. Antibiotics are modified based on the organism(s) isolated and the antimicrobial susceptibilities of the isolate. Vancomycin therapy should be discontinued as soon as possible if an organism requiring the administration of vancomycin is not isolated. A bacterial line infection may be eradicated successfully without removing the line, but the line should be removed if blood cultures remain positive or the patient’s clinical condition deteriorates. Optimally central lines are removed for S. aureus central line–related bloodstream infections. Fungemia, generally with Candida albicans or other Candida spp., also may be associated with line-related infections. Central lines complicated by fungemia should be removed immediately. Candida infections following heart transplantation are not frequent enough to warrant routine prophylaxis, but they are associated with mortality rate of up to 48% in pediatric heart transplant recipients.
As in other critically ill children, pneumonia is a particularly common occurrence in heart transplant patients because of the operative site and requirements for intubation and mechanical ventilation. During the first postoperative week, definite bacterial pneumonia developed in three of 22 children (14%) in an early study from the University of Pittsburgh Medical Center (UPMC). In the PHTS study, 56 bacterial lung infections were identified, 24 of which developed in patients maintained on a ventilator at the time of transplantation. The incident rate of early nosocomial pneumonia in adult heart transplant patients has been reported to be 20% to 35%. Nosocomial pneumonia caused by gram-negative bacilli such as Pseudomonas and Enterobacter or S. aureus is especially common in this setting. Gram stain and culture of a tracheal aspirate or bronchoalveolar lavage (BAL) can help guide therapy for pneumonia.
A broad-spectrum combination of antibiotics, such as an extended-spectrum penicillin with a β-lactamase inhibitor (i.e., piperacillin-tazobactam) plus an aminoglycoside, usually is initiated until a pathogen or pathogens are identified. Empirical therapy should be based on the antibiotic susceptibility patterns of the common nosocomial pathogens in the specific ICU in which the patient is receiving care. Vancomycin also should be considered if MRSA is part of the resident flora in the ICU. Computed tomography (CT) of the chest may detect basilar and retrocardiac pneumonia, which may not be visualized readily by conventional chest radiographs. CT or ultrasound generally is helpful in assessing the size or characteristics of pleural effusions that may require drainage.
If interstitial pneumonitis is encountered, a more aggressive approach to determining an etiology is warranted. Bronchoscopy with BAL should be considered strongly. Lavage fluid is processed for pathogens including bacteria, mycobacteria, viruses, fungi, and protozoa by using culture techniques, special stains, and molecular techniques such as quantitative PCR. Mini-BAL are commonly employed in some pediatric centers, but how their results compare to a formal BAL procedure is not clear and has not been well studied in children. Legionella may be an important consideration in some centers. Noninfectious causes of pulmonary infiltrates in these children include pulmonary edema, atelectasis, hemorrhage, and acute respiratory distress syndrome.
Urinary tract infections (UTIs) also are common occurrences in the month after undergoing heart transplantation. Urinary catheterization and the immunosuppressive agents contribute to the risk for developing a UTI. Gram-negative enteric organisms ( E. coli, K. pneumoniae, P. aeruginosa, and Enterobacter spp.), enterococci, and Candida spp. are isolated most commonly. Removal of the catheter as soon as possible minimizes the potential for development of a UTI, which has occurred in approximately 10% of adults. In the PHTS study, the urinary tract was the site of 16 bacterial infections. In addition, UTIs developed in three children (14%) at UPMC during the 2 to 3 weeks after undergoing transplantation.
The broad-spectrum antibiotics used to treat the bacterial complications of transplantation promote Candida infection of the urinary tract. Along with removal of the urinary catheter, short-course intravenous amphotericin B or fluconazole with careful dosing because of drug interactions with tacrolimus and cyclosporine is an option for treating candidal cystitis. In some patients, especially infants, a urine culture positive for Candida is a clue that a disseminated Candida infection is present and that further investigation, including imaging, is necessary to exclude the involvement of other organs, especially the kidneys.
Antibiotic-associated diarrhea caused by Clostridium difficile is another potential complication related to antibiotics administered both pre- and posttransplant. Toxic megacolon due to fulminant C. difficile infection requiring subtotal colectomy has been reported in a 10-year-old within 1 week after undergoing heart transplantation.
Risk factors for early infection in the PHTS study were younger recipient age (particularly less than 6 months), mechanical ventilation at the time of transplantation, positive donor CMV serology with a CMV-negative recipient, and longer donor ischemic time. Although primarily conducted among adult liver transplantation patients, studies have shown measuring procalcitonin may help distinguish infection from other causes of fever following solid organ transplantation. Studies in adult heart transplant patients have shown that elevated procalcitonin levels beyond the first week after transplantation are correlated with infectious complications and that the use of serial procalcitonin measurements may be more reliable than single values.
Sternal Wounds and Mediastinitis
Sternal wound infections and mediastinitis occur in less than 5% to 15% of adult heart transplant recipients compared with less than 5% of adult patients receiving general cardiac surgery. Most of these infections occur during the first postoperative month, usually within the first 2 weeks, and are superficial. The majority of surgical site infections are caused by bacteria. Staphylococci and other gram-positive bacteria generally are responsible for 50% of cases, and the remainder are caused by a variety of gram-negative bacilli. Higher incidences of fungal pathogens have been reported in heart transplant recipients compared with general cardiac surgery patients. Surgical wound infections developed in eight children in the PHTS study, although the site of the infection was not noted. Over a 15-year period, 15 (0.2%) children at Texas Children’s Hospital (TCH), Houston, Texas, developed mediastinitis after undergoing cardiac surgery; two children had undergone heart transplantation. At another children’s hospital, between 1995 and 2003, 3% (5 of 165) of children undergoing heart and lung transplantation developed mediastinitis.
Risk factors for surgical site infections in adult heart transplant recipients include body mass index greater than 30 kg/m 2 , previous heart surgery, previous ventricular assist device implantation, inotropic support, and prolonged cardiopulmonary bypass time. Immunosuppression regimens that include sirolimus have been identified as a risk factor for surgical site infection, wound dehiscence, and mediastinitis. Postoperative bleeding requiring reexploration is also a risk factor for the development of mediastinitis. Fever, incisional pain, and an unstable sternum suggest mediastinitis; however, patients may have no specific evidence of infection, including fever. The white blood cell count may be elevated. A pericardial effusion frequently is detected with the development of mediastinitis, and pericardiocentesis may yield purulent material. CT of the chest may show a fluid collection or abscess within the mediastinum and can detect sternal osteomyelitis. Most cases of mediastinitis are caused by S. aureus, coagulase-negative staphylococci, or gram-negative bacteria. Median sternotomy wound infections after repair of a congenital heart lesion occur in less than 1% of children in large centers. Mediastinitis caused by gram-negative bacilli in association with pneumonia and bacteremia developed in three of the 22 children in the UPMC series; each occurred within 2 weeks postoperatively. Two of the three patients died. Candida spp. caused both cases of mediastinitis in the two children after heart transplantation in the TCH series. Long and colleagues reported that mediastinitis developed in five patients who had undergone heart and lung transplantation and that the organisms identified in these children were E. coli, Torulopsis glabrata, Aspergillus fumigatus, Burkholderia cepacia, and vancomycin-resistant enterococcus.
A superficial median sternotomy wound infection not associated with an unstable sternum can be treated by local drainage of the infected subcutaneous tissue and administration of appropriate antibiotics. Vacuum-assisted closure may be an important aid in addition to antibiotics. A more aggressive approach is required for more serious infections associated with an unstable sternum, mediastinitis, or osteomyelitis of the sternum. Adequate drainage and debridement of the area are crucial, and any involved wires should be removed. Mediastinal drains usually are kept in place for several days. A reoperation after the initial drainage procedure may be necessary. Pending culture results, antibiotic therapy is directed against S. aureus and gram-negative bacilli. A 4- to 6-week course of antibiotics usually is recommended. Antifungal therapy is initiated if a yeast or fungus is noted on Gram or special stains or isolated from cultures. Careful attention given to surgical technique to minimize postoperative bleeding and early withdrawal of chest and mediastinal tubes placed intraoperatively decrease the incidence of these potentially fatal infections.
Other Infections Encountered During the First Postoperative Month
Herpes Simplex
Herpes simplex infections of the oral mucosa and other superficial surfaces are common after heart transplantation. Oral herpes simplex was observed in 21% (11 of 53) of children undergoing transplantation at Stanford University Medical Center. In the pediatric multiinstitutional PHTS study, only six episodes of herpes simplex infection were noted. Visceral involvement is unusual, although it may develop. Herpes simplex infection typically occurs approximately 13 days (range, 0 to 4 months) after transplantation and is secondary to reactivation, not a newly acquired infection. A decrease in lymphocyte transformation in response to viral antigen in vitro may explain the increased rate of infection that occurs in the first 12 weeks posttransplantation. In a large randomized study comparing azathioprine with mycophenolate mofetil in adult heart transplant recipients who also were receiving cyclosporine and steroids, herpes simplex infection occurred more commonly in the group treated with mycophenolate mofetil (23% vs. 16%; P <.05). Institution of antiviral therapy for herpes simplex infection is warranted in these immunocompromised patients. The most common antiviral agent for herpes simplex is acyclovir, which can be administered orally or intravenously. Valacyclovir dosing in children has been established for children older than 2 years, but a commercial suspension is unavailable.
Prophylactic acyclovir is recommended by some experts for heart transplant recipients who are seropositive for herpes simplex. Acyclovir can be given intravenously during the perioperative period and then orally for at least a month following transplantation. Other physicians suggest that because labial or oral herpes simplex is treated so easily, a prophylactic approach after transplant is not warranted. Prophylaxis is generally used during treatment for rejection and for prolonged durations if recurrences are frequent. If the patient is receiving ganciclovir for CMV prophylaxis, additional HSV preventive measures are not necessary.
Legionella pneumophila
Legionella pneumophila infection should be included in the differential diagnosis for fever, respiratory symptoms, and pulmonary infiltrates that develop after heart transplantation. Legionella pneumonia can develop during the first postoperative month, but the frequency with which this infection occurs varies among transplant centers. Although legionnaires’ disease is an uncommon occurrence in children, nosocomial infections have been documented in a children’s hospital, and immunosuppression is a risk factor. Appropriate cultures and direct fluorescent antibody stains for Legionella should be performed on sputum, other respiratory secretions (obtained by invasive techniques), pleural fluid, or lung tissue to detect this pathogen in a timely fashion. A Legionella urinary antigen test is available for serogroup 1 antigens and is quite sensitive.
Macrolides should be considered for empiric therapy if Legionella is a serious consideration in children with nosocomial pneumonia. A 2-week course of erythromycin or azithromycin is generally recommended. Macrolides interact with many of the immunosuppressive agents administered to these patients, however. Quinolones also are quite active against Legionella and avoid many of these interactions; in adult transplant patients, levofloxacin is the agent of choice. The use of quinolones should be considered for pediatric organ transplant recipients in whom infection with L. pneumophila is suspected. In hospitals caring for patients with transplants, routine surveillance culture of the hospital water supply should be considered.
Respiratory Syncytial Virus
Ten episodes of RSV infection were noted in the multiinstitutional study by the PHTS Group. RSV can be acquired in the hospital soon after undergoing transplantation or can be acquired in the community before undergoing surgery or after discharge. Too few patients in whom RSV infection developed after they underwent heart transplantation have been described to comment on the clinical features. Two children in the early UPMC study were noted to be infected with RSV, both infections occurring on postoperative day 10. Rapidly progressive patchy infiltrates on chest radiographs developed in one child after undergoing heart-lung transplantation, and the second child had only mild upper respiratory symptoms. Tachypnea, cough, fever, wheezing, and the use of accessory muscles occurred commonly in the 18 pediatric liver transplant recipients from UPMC with RSV infection. Radiographic changes included interstitial and lobar infiltrates, atelectasis, and pleural effusion in 12 patients. Two patients required mechanical ventilation after the onset of symptoms related to RSV infection occurred; three others were intubated before acquiring RSV infection and subsequently had complicated courses. At Boston Children’s Hospital, there were 34 RSV infections in 851 solid organ transplant recipients from 1993 to 2006. Two deaths were reported: a 1-year-old with RSV 2 days after renal transplant and an 18-year-old 776 days after liver transplant who also had disseminated aspergillosis.
Morbidity and mortality rates related to RSV infection are increased in otherwise immunocompetent children with congenital heart disease, especially when associated with pulmonary hypertension. Because RSV can be acquired in the hospital, RSV infection should be considered in a young transplant patient with respiratory symptoms and fever, especially during the RSV season. RSV infection is documented by culture or by rapid detection of RSV infection by a variety of techniques.
The decision to administer ribavirin to these patients is based primarily on the severity of the illness. In a small group of children with underlying bronchopulmonary dysplasia or congenital heart disease, aerosolized ribavirin seemed to be associated with more rapid improvement than that in patients given placebo. Administration of aerosolized ribavirin to a heart transplant recipient with proved or suspected moderate to severe RSV infection is reasonable. As is the case with children requiring mechanical ventilation because of severe RSV lower respiratory tract infection, however, the efficacy of ribavirin in this situation is unknown. The 2015 Red Book states that “ribavirin … may be considered for use in select patients with documented, potentially life-threatening RSV infection.”
The monoclonal antibody palivizumab was found to be safe, well tolerated, and effective in preventing serious RSV infections in young children with hemodynamically significant congenital heart disease in a large multicenter randomized, double-blind, placebo-controlled trial. Palivizumab administration to children 24 months or younger who have undergone heart transplantation is reasonable, especially in children who are on medications for heart failure or pulmonary hypertension. The combination of ribavirin and RSV immunoglobulin has been administered to pediatric bone marrow transplant recipients with RSV lower respiratory tract infection. The outcome in these patients was improved over that of historical controls, but no randomized trials have been conducted. RSV immunoglobulin was not efficacious in treating RSV lower respiratory tract infection in children with congenital heart disease who were younger than 2 years. Although palivizumab reduced the concentration of RSV in the tracheal aspirates of children with respiratory failure caused by RSV, its efficacy in treatment is unknown. Many authorities recommend both ribavirin and an antibody product for the management of severe RSV infections in solid organ transplant patients.
Infections Between the First and Sixth Postoperative Months
Cytomegalovirus
CMV is the most frequently identified viral infection in cardiac transplant patients. Asymptomatic or symptomatic infections are noted most commonly between the first and sixth months after undergoing transplantation but can occur late after transplant. In adult series, the majority of patients have developed CMV infection at some time postoperatively. In the multiinstitutional PHTS study, 51 episodes of CMV infection occurred in 332 patients and accounted for 60% of the viral infections, with a peak occurrence in the second month after transplantation. CMV infection occurred more frequently in older children than in infants. In another study, infants younger than 120 days had CMV infection and disease less commonly than did infants older than 120 days after undergoing heart transplantation. Maternal antibody to CMV may have been protective in the younger infants. In the UPMC series, seven children (32%) had CMV infections, with onset occurring at a mean of 33 days posttransplant (range, 23 to 43 days).
CMV infection in transplant recipients occurs in three or four possible settings. In a seronegative recipient, primary CMV infection is acquired through the transplanted heart, through blood transfusions from seropositive donors, or from community exposure. Seropositive recipients can have reactivation of latent CMV infection or be reinfected with a second strain of CMV from the heart or from blood products derived from seropositive donors. The exact site within the donor heart where CMV may reside in a latent form is unknown, but it may be either cardiac cells or leukocytes that remain within the donor heart. When primary CMV infection is acquired from the donor organ, CMV disease tends to be more severe than if CMV infection is acquired from blood or blood products.
Several risk factors for development of CMV infection after undergoing organ transplantation are recognized. Donor and recipient serologic status and the immunosuppressive regimen are the most significant risk factors for acquiring CMV infection after undergoing heart transplantation. Gorensek and colleagues found that positive recipient CMV serology before transplantation and a larger than average dose of corticosteroids were significant risk factors for acquiring CMV infection. Among the group of patients with CMV infection, positive recipient serology was associated with asymptomatic infection, and excessive steroid dosing was a risk factor for acquiring symptomatic CMV infection. CMV tissue invasion occurred more commonly in patients receiving mycophenolate mofetil compared with azathioprine. Use of lymphocyte-depleting agents such as antilymphocyte antibodies increases the risk of CMV disease.
The clinical manifestations of CMV infection vary. Patients may seroconvert or a latent infection may be reactivated, as determined by positive cultures or molecular tests, but these patients have no symptoms attributable to the CMV infection. Fever, leukopenia, and thrombocytopenia are common postoperative manifestations of systemic CMV infection. Patients may complain of arthralgias, myalgias, and nonspecific abdominal pain. Atypical lymphocytes are noted more commonly in adult than pediatric patients. CMV infection can cause hepatitis, pneumonitis, retinitis, myocarditis, and gastrointestinal disease, including colitis. Invasion of organs, especially the gastrointestinal tract, can occur in the absence of detectable CMV in the blood. Retinitis may be asymptomatic or associated with complaints such as floaters or scotomata. Ophthalmologic screening for CMV retinitis is recommended by some authorities for all patients 3 to 4 months after cardiac transplantation.
Of the tissues invaded by CMV, involvement of the lung leads to the greatest mortality rate—13% in one study. CMV pneumonitis is characterized by fever, hypoxemia, and, usually, diffuse interstitial infiltrates, although lobar consolidation may occur. Pulmonary infections with other viruses or with bacteria or Pneumocystis jirovecii and other pathologic processes (infarction) may coexist with CMV pneumonitis. Gastritis, gastric ulceration, duodenitis, esophagitis, pyloric perforation, and colonic hemorrhage can be documented by endoscopy. In the multiinstitutional PHTS study, the lung or gastrointestinal tract was the site of CMV infection in 13 (lung) and six (gastrointestinal tract) episodes. Death related to CMV in the pediatric study occurred in 6%. In another pediatric heart transplant registry spanning 1998 to 2010, CMV was considered the cause of death in 2.7%, 0.4%, and 0.4% of patients 31 days to 1 year, after 3 to 5 years, and after 10 years post transplantation, respectively. In another analysis using a multiinstitutional registry of pediatric heart transplantation patients, clinical CMV infection was uncommon in the setting of antiviral and/or CMV antibody prophylaxis.
Serology is not recommended for establishing the diagnosis of CMV infection after transplantation. Viral load testing by quantitative nucleic acid amplification testing (QNAT), which is the preferred test, or CMV antigenemia is recommended for the diagnosis and monitoring for CMV infection and disease. Whether the CMV infection is causing a symptomatic or invasive illness is more difficult to establish. Histopathologic evidence of CMV infection, such as typical viral inclusions or detection of antigen in tissue by special stains, is required to confirm organ involvement by CMV, although this criterion often is not considered for clinical management and treatment.
In addition to the CMV infection syndromes, CMV infection itself seems to affect the transplant recipient adversely in other ways. Symptomatic or asymptomatic CMV infection is associated with a higher rate of acute rejection and graft loss, a greater risk of development of fungal infection, more frequent and earlier cardiac allograft vasculopathy, and a significantly lower survival rate than occur in patients who do not have CMV infection. In the PHTS study, CMV-positive donor serology in conjunction with CMV-negative recipient serology was a risk factor for the acquisition of earlier infection with any organism.
CMV infection of the wide variety of cells that it invades leads to the activation of protein synthesis and the production of multiple immunologically active molecules, including cytokines, especially tumor necrosis factor-α, which adds to the immune deficits induced by the immunosuppressive agents. Allograft injury or rejection may be associated with CMV infection of the transplanted organ itself.
Successful treatment or suppression of visceral CMV disease by ganciclovir, a nucleoside analogue active in vitro against CMV, requires a timely diagnosis. Ganciclovir has been shown to alter CMV disease favorably in heart transplant patients, along with reduction in immunosuppressive therapy when possible. The recommended length of therapy is determined by weekly monitoring of CMV viral loads and continuing therapy until 1 or 2 consecutive negative samples. The minimum course of therapy is 2 weeks. The dose of ganciclovir is 5 mg/kg every 12 hours with careful monitoring of hematologic parameters and renal function if renal function initially is normal. Modification of the dose is necessary if renal function is impaired. The most common adverse reactions to ganciclovir are neutropenia, thrombocytopenia, impaired renal function, seizures, and other central nervous system (CNS) abnormalities. Many experts will use oral valganciclovir instead of intravenous ganciclovir in nonsevere CMV disease. Some transplant centers will use secondary prophylaxis with once daily oral valganciclovir for 1 to 3 months after completion of therapy for CMV infection.
The role of CMV hyperimmunoglobulin in treating CMV infection in these patients requires further study. After bone marrow transplantation, the addition of CMV immunoglobulin to ganciclovir may be superior to ganciclovir alone in treating CMV pneumonia.
In one pediatric study, symptomatic CMV disease developed in five children after they had undergone heart transplantation; each had blood cultures and PCR positive for CMV. Four were treated with ganciclovir for 14 days; one received ganciclovir for 30 days. All received CMV-IgG (150 mg/kg) weekly for 3 weeks. Symptomatic CMV disease was treated successfully in each case. CMV-IgG may be beneficial in treating life-threatening CMV disease such as pneumonitis and enteritis. For CMV disease in thoracic organ transplant recipients with hypogammaglobulinemia, intravenous immunoglobulin or CMV-IgG is recommended as adjunctive therapy as well.
If possible, prevention of CMV infection in heart transplant recipients is optimal. Only seronegative blood should be used for transfusions when the recipient and the donor are seronegative. Careful control of immunosuppressive therapy, especially with corticosteroids, may help avoid the acquisition of some infections. Prophylactic administration of intravenous ganciclovir followed by oral valganciclovir for 3 to 6 months appears to be the strategy of choice for preventing CMV infection in adults at risk following heart transplantation. The updated CMV consensus statement recommends 3 to 6 months for adult patients who are CMV seronegative and receive a heart from a CMV seropositive donor; 3 months is recommended if the recipient is CMV seropositive regardless of the donor’s status. The longer duration is determined in part by the degree of immunosuppression required. The duration of prophylaxis in children is not as well established and varies among centers. In the situation of a seronegative recipient of a heart from a seropositive donor, the addition of prophylactic administration of CMV immunoglobulin to ganciclovir may be useful. If the prophylactic approach is used, routine monitoring for CMV viral load is not recommended but should be evaluated if patients have symptoms that could be caused by CMV infection.
In one large randomized double-blind, placebo-controlled trial of CMV-seropositive transplant recipients, ganciclovir significantly reduced the incidence of CMV illness during the first 120 days after heart transplantation (9% vs. 46% in controls; P < .001). No differences were noted between the study groups for seronegative recipients.
Whether the addition of CMV-IgG to antiviral therapy for prophylaxis of high-risk seronegative recipients of hearts from seropositive donors results in added benefits is still under investigation. Avery found that the combination was not particularly effective; symptomatic CMV syndrome developed in 50% of patients. Gajarski and associates provided CMV-IgG (150 mg/kg intravenously at weeks 0, 2, 4, 6, and 8 and 100 mg/kg intravenously at weeks 12 and 16) plus ganciclovir (5 mg/kg every 12 hours intravenously for weeks 1 and 2 and 6 mg/kg per day intravenously at weeks 3 and 4) to 19 children who were recipients of heart transplants from CMV-seropositive donors. CMV disease occurred in three of the 10 children who were CMV-seronegative and in one of the 10 recipients who were seropositive. Adverse effects of these agents were not reported. In the study from Stanford University Medical Center, high-risk recipients received CMV-IgG immediately after undergoing transplantation (150 mg/kg administered within 72 hours after transplantation, followed by 100 mg/kg at weeks 2, 4, 6, and 8 and 50 mg/kg at weeks 12 and 16). In addition, ganciclovir was administered intravenously immediately after transplantation at a dose of 5 mg/kg every 12 hours for 14 days, followed by 6 mg/kg per day for the next 2 weeks. These patients were compared with a historical control group at the same institution that received ganciclovir in the 2 to 3 years before CMV-IgG was used. The 27 recipients treated prophylactically with ganciclovir and CMV-IgG had a higher disease-free incidence of CMV, a lower incidence of rejection, and a higher survival rate than those of the historical cohort treated with ganciclovir alone. Data from the Scientific Registry of Transplant Recipients indicated that, for children undergoing heart transplantation, CMV immune globulin with or without ganciclovir and ganciclovir with or without CMV immune globulin were associated with significant reduction in graft loss and deaths versus no prophylaxis. Immunologic monitoring of CMV may be helpful in assessing the risk of patients developing CMV viremia and disease posttransplantation, although the value of this monitoring is unknown in children.
CMV resistant to ganciclovir may emerge as a result of ganciclovir prophylaxis or treatment. Foscarnet or cidofovir is an alternative agent in this situation. The reader is urged to review the “Updated International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation” document for expert guidance on this subject.
Epstein-Barr Virus
In pediatric heart transplant recipients, EBV may cause a spectrum of diseases, including a mononucleosis-like syndrome, hepatitis, myocarditis, and hematologic abnormalities such as leukopenia, thrombocytopenia, hemophagocytic syndrome, and polyclonal or monoclonal lymphoproliferation, usually of B cells. EBV endomyocardial infection, as determined by detection of EBV viral genome in asymptomatic heart transplant recipients, has also been associated with premature graft loss as a result of premature development of advanced transplant coronary vasculopathy.
In young children, the transplanted organ is thought to be the most frequent source of EBV. Posttransplantation lymphoproliferative disorders (PTLDs) refer to B-cell expansion that may be localized, nodal, extranodal, or widely disseminated. The largest series of children who have undergone heart transplantation is from UPMC; in this series, PTLD developed in 7.7% (six of 78) of pediatric heart transplant recipients. A major risk factor for the subsequent development of PTLD was being seronegative for EBV before undergoing transplantation. PTLD developed in one-third of seronegative recipients of thoracic organs who acquired primary EBV infection (10 of 30). PTLD developed in none of the children who were seropositive before transplantation. Almost all these cases occurred within 1 year of transplantation.
In another series, 19 children were EBV-seropositive and 31 were EBV-seronegative before undergoing heart transplantation. PTLD developed in one of 19 patients who were seropositive before undergoing transplantation and in 12 of 19 who became seropositive after transplantation. It did not develop in any of the 12 recipients who remained EBV-seronegative. In contrast to the UPMC experience, the mean time to confirmation of PTLD was 29 months (range, 3 to 72 months).
Webber and associates reviewed the experience with PTLD after heart transplantation among 1184 primary organ recipients in 19 centers from 1993 to 2002. Fifty-six patients (5%) developed PTLD a mean of 23.8 months posttransplantation. In a study from Germany, 12 of 147 (8.2%) developed PTLD a mean of 3.2 ± 2.2 years posttransplantation. Among 173 heart transplant recipients at the University of Toronto Hospital, 23 (13.3%) developed PTLD within a median of 4 years posttransplantation. Higher maximum EBV viral load and longer duration of induction therapy were associated with increased risk of PTLD. In a study among a multicenter group, PTLD developed in about 5% of 2374 children. Pretransplant seropositivity for EBV and the receipt of induction treatment except OKT3 were associated with a reduced risk of developing PTLD. Chinnock et al. reported that, between 1993 and 2009, among 3170 pediatric heart transplant recipients at 35 institutions, 147 patients developed PTLD, with children age 1 to 10 years having the highest risk compared with children younger than 1 year or age 10 to 18 years. Similarly, data from the United Network for Organ Sharing (UNOS) database from 1987 to 2013 showed that 360 out of 6818 pediatric heart transplant recipients (5169 of whom had follow-up data on posttransplant malignancy) were diagnosed with PTLD and that PTLD was associated with reduced long-term survival after heart transplant.
Symptoms of PTLD may include fever, malaise, sore throat, and lymphadenopathy. Some children may have splenomegaly, CNS symptoms such as lethargy or seizures, or gastrointestinal complaints. Concurrent opportunistic infections are common. Nodules in the lung may be noted on chest radiographs ( Fig. 70.1A ).
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