A Clinical guide to pediatric infectious disease

19

Infection in Solid Organ Transplant Recipients

The past decade has brought a great increase in the number of pediatric patients undergoing solid organ transplantation. Although initially cared for by hospital-based specialists, after transplantation they often receive ongoing care from primary care physicians.

Infections in the First Month

Infections in solid organ transplantation are typically grouped according to the time following transplantation. In the first month after transplantation, most infections are related to the actual surgical procedure of transplantation. Patients undergoing transplantation are often colonized with a wide variety of bacterial or fungal pathogens. These pathogens may become invasive after surgery with the resultant placement of catheters and surgical drains. An evaluation for infection in the first weeks after transplantation should focus on the sites of surgical incision and any indwelling catheters. Empiric treatment is difficult because the causative bacteria may be related to the nosocomial pathogens found in a particular hospital setting. Knowledge of these pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, and resistant gram-negative enteric organisms, can help guide empiric therapy.

Latent Infections in Transplantation

After the first month of transplantation, infections in the transplant recipient change from nosocomial pathogens to the activation of latent infections. A latent infection is one in which the patient has had past exposure and, although currently asymptomatic, has not completely cleared the pathogen. This is a common occurrence with many of the herpesviruses, including herpes simplex virus, cytomegalovirus (CMV), and Epstein-Barr virus (EBV). The activation of latent infections

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causing symptomatic or “active” disease is a major cause of morbidity and mortality in the transplant recipient.

It is also important to realize that in the transplant recipient, there are actually two individuals: the donor and the recipient. For a number of latent infections, including EBV, CMV, and toxoplasmosis, the greatest risk for activation occurs when the donor is seropositive (D+) and the recipient is seronegative (R—). This designation of D+/R— is often referred to as a mismatch. When a mismatch occurs, the process of transplantation often resembles an acute (primary) infection in the recipient. Primary infection in the setting of intense immunosuppression has a high likelihood of causing symptomatic disease. Documentation of donor and recipient status is very important in evaluating the possibility of infection in a transplant recipient in the months after transplantation.

Additional terms frequently used in describing solid organ transplantation infection include secondary infection, in which the previously exposed recipient (R+) has a latent infection reactivate during the course of immunosuppression. Superinfection refers to the case in which both donor and recipient are seropositive. Because there is often heterogenicity among various viral strains, the reactivation of the donor strain after transplantation and intense immunosuppression may result in clinical disease. Because of this heterogenicity of viral infections, one cannot assume that a D+/R+ transplantation will have no subsequent problems with that particular latent infection.

Certain latent infections are frequently seen in the transplant recipient. The following is a discussion of these infections and their typical presentation and diagnosis.

Cytomegalovirus

Etiology

CMV, a double-stranded DNA virus, is the most important pathogen affecting transplant recipients. Infection can occur at the time of transplantation, often through a D+/R— mismatch. Seronegative recipients of organs from seropositive donors have a greater than 50% risk for the development of symptomatic CMV disease following their primary infection.

Presentation

The manifestations of CMV disease in the transplanted patient include prolonged fever, often with accompanying leukopenia and hepatitis. Pneumonia, colitis, and long-term graft dysfunction are additional manifestations of active CMV disease in the transplant patient.

Diagnosis

Serology is of little value in the diagnosis of CMV disease in transplant patients because even previously seronegative individuals may not reliably produce an adequate

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antibody response. Several specific techniques are used to diagnose CMV infection. A shell vial assay refers to a technique whereby fibroblast cells are grown in monolayers in a special shell vial container. Clinical specimens are placed within this container and, after 1 to 2 days of incubation, are stained with a monoclonal antibody specific for early CMV antigen. This technique is quicker and more sensitive than conventional viral cultures. In addition, polymerase chain reaction (PCR; nucleic acid amplification) can be used to quantitate CMV in blood or other body fluids. Symptomatic CMV infection is often preceded by viremia. Treatment is sometimes considered in patients who show increasing viral loads by PCR.

Management

The treatment of clinical CMV disease is intravenous ganciclovir at 5 mg/kg given intravenously every 12 hours for a minimum of 2 weeks or until clearance of the viremia is documented. It is important to document the resolution of viremia because the clinical relapse rate in patients with persisting viremia can be greater than 50%. CMV hyperimmune globulin is also available and is often used in the treatment of severe or relapsing disease.

There is increasing appreciation of CMV that is ganciclovir resistant. The overall incidence is about 2%, but certain transplant populations have increased risk. Risk for cytomegaloviral ganciclovir resistance is thought to include mismatch at the time of transplantation, high CMV viral load, kidney-pancreas transplantation, and treatment that results in suboptimal concentrations of ganciclovir. Documentation of ganciclovir resistance in CMV disease involves the identification of a variety of mutations by PCR. This technique is difficult, and in practical terms, ganciclovir resistance is often suspected when patients fail to respond to ganciclovir, as determined by clinical evaluation or by rebound in CMV viral load. Treatment with foscarnet has been used for infection due to ganciclovir-resistant CMV.

Prevention

Because of the high morbidity associated with CMV infection in transplant patients, a variety of strategies have been employed to reduce the risk for symptomatic disease. These strategies are particularly important in patients with the highest risk for developing CMV disease (i.e., patients with D+/R— mismatch and CMV-positive patients undergoing intense immunosuppression). Prophylaxis for CMV refers to the use of ganciclovir postoperatively in selected patients. Patients may receive sequential intravenous and then oral ganciclovir for as long as 100 days after transplantation. CMV-positive individuals receiving antilymphocyte antibody for the treatment of rejection often receive preventive ganciclovir therapy for as long as 3 months to limit viral reactivation. Other centers use “preemptive therapy,” which involves the close monitoring of patients with viral load assays or CMV antigenemia assays. Patients who develop viremia, thought to be a predictor of subsequent clinical disease, are then treated with antiviral agents.

Cytomegalovirus

1.   Mononucleosis syndrome with fever, leukopenia, hepatitis

2.   Colitis

3.   Pneumonia

4.   Diagnosis

1.   Viral culture

2.   PCR

3.   Bronchoalveolar lavage (viral culture)

4.   Biopsy (showing intra-cellular viral inclusions)

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Epstein-Barr Virus

Etiology

EBV is the major cause of posttransplantation lymphoproliferative disease (PTLD). PTLD is the term given for a spectrum of EBV-related disorders in the transplant population that range from infectious mononucleosis to monoclonal lymphoma. Primary disease that occurs after transplantation causes the most severe illness. The increase in pediatric transplantations has led to an increased number of transplant recipients who will be getting primary EBV infection after transplantation with resultant increased risk for PTLD.

EBV infection initially targets host B lymphocytes. Cellular immune response is a key element in control of EBV-infected B cells. B-cell proliferation of EBV infection is normally contained by natural killer (NK) cell activity. The inhibition of T-cell immunity by the immunosuppressive regimens given to transplant patients inhibits this protective mechanism and may result in unchecked proliferation of B cells. As B-cell proliferation continues, it is thought to be associated with progressive disease, emerging monoclonality, and progression to lymphoma (Fig. 19.1).

Presentation

There are a variety of clinical manifestations of PTLD, depending on the precise status of the infected B lymphocytes. A severe mononucleosis syndrome with high fever, leukopenia, and hepatitis is often seen. This can be very similar to the clinical picture of symptomatic CMV disease. Enlarging lymphadenopathy may also be a presenting sign. Asymptomatic enlargement of the tonsils may be a sign of PTLD and should always be examined closely in transplant recipients. Intestinal tract involvement, resulting in anorexia, weight loss, and diarrhea, also is a common presentation (Fig. 19.2).

 

FIG 19.1. Epstein-Barr virus infections in solid organ transplant recipients.

 

FIG. 19.2. Infections in solid organ transplantation. Massive cervical adenopathy in a patient with posttransplantation lymphoproliferative disease (PTLD).

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Diagnosis

The gold standard of diagnosis of PTLD is lymph node biopsy. Biopsy will show the normal lymphoid tissue replaced with a proliferation of B cells in varying stages of transformation. Histologic classification for PTLD is based on the appearance of these B cells. The World Health Organization has suggested the classifications of monomorphic, polymorphic, monoclonal, polyclonal, and Hodgkin's-like PTLD. Progression to malignancy is associated with progressive monoclonality from polymorphic or polyclonal lymphoid hyperplasia.

The measurement of EBV viral load by PCR in peripheral blood or tissue is frequently used in the evaluation of PTLD. These results can be difficult to interpret because differing laboratories use different threshold values as well as different units. A viral load of greater than 4,000 copies/mL of blood is thought to be extremely elevated and in the right clinical context suggests PTLD. Serial measurements of EBV viral loads can be used to follow clinical course; achieving a viral load of less than 200 copies has been correlated with restoration of host immune response and successful resolution of PTLD.

Management

The mainstay of therapy in the treatment of PTLD is reduction or elimination of immunosuppression. This restores T-cell immunity, which then controls the unchecked B-cell proliferation. Heart transplant recipients may need to be monitored in the hospital setting, to receive daily echocardiograms and weekly cardiac biopsy. Antiviral therapy with ganciclovir has been used in treatment of PTLD. Latent B cells represent greater than 90% of the PTLD population, and this population is not amenable to antiviral therapy. Antivirals are often employed in the hope that they may provide some clinical benefit by addressing the remaining 10% of the B-cell population. Rituximab, a monoclonal antibody to the B-cell CD20 antigen, has been used in patients who fail to respond to the elimination of immunosuppression and whose lymphoid biopsy shows this antigen. Chemotherapy has also been used when other treatment modalities have failed or initial presentation is that of monoclonal lymphoma.

Epstein-Barr Virus

1.   Posttransplantation lymphoproliferative disease

2.   Diagnosis

1.   Serology—generally not helpful

2.   PCR

3.   Biopsy of affected lymph nodes

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Toxoplasma gondii

Etiology

Toxoplasma gondii is a common infection. Cats are the primary host; they acquire the infection by eating other animals or undercooked meats. Oocysts are then excreted and can infect another host. Toxoplasmosis is a latent infection that can be transmitted at the time of organ transplantation. Because the myocardium is one of the sites where latent cysts are located, it is more frequent in cardiac transplantation. The greatest risk is in patients who have the D+/R— mismatch.

Presentation

Symptomatic disease usually occurs within the first 6 months after transplantation. Patients may present with organ system involvement, including chorioretinitis, myocarditis, and intracranial lesions.

Diagnosis

Diagnosis is primarily by demonstrating tachyzoites within biopsy specimens; diagnosis can also be suggested by specific toxoplasmosis serology.

Management

Most of the experience in the treatment of toxoplasmosis is derived from the management of patients with acquired immunodeficiency syndrome (AIDS). Pyrimethamine plus sulfadiazine, given in conjunction with folinic acid, is the standard treatment in this population and is often used in infected patients after organ transplantation. Up to 6 weeks of therapy for acute disease is recommended.

Prophylaxis with trimethoprim-sulfamethoxazole (Bactrim) is typically recommended if such a mismatch for toxoplasmosis is documented.

Toxoplasmosis

1.   Latent in myocardial tissue

2.   Disease manifested as myocarditis, retinitis, brain lesion

3.   Diagnosis by biopsy, serology

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BK Virus

Etiology

BK virus is a human polyomavirus increasingly appreciated as a major cause of morbidity in renal transplantation. BK virus is similar to other viral infections in that seroprevalence in the general population approaches 90%. After acquisition in childhood, the virus establishes latency in renal tubular epithelial cells. Polyomavirus viruria can be found in up to one half of renal transplant recipients in the first 3 months after transplantation.

Presentation

After transplantation and the initiation of immunosuppression, the progressive viral infection may cause ureteral stenosis, hemorrhagic cystitis, and polyomavirus allograft nephropathy (PVAN). The reason for progression of BK renal infection in certain transplant recipients remains unclear; it is speculated that certain risk factors, including graft rejection and HLA mismatch, may play a role. Nearly one half of patients who go on to develop PVAN ultimately lose their graft. The initial manifestation of progressive BK renal infection may be progressive elevation in the serum creatinine and a failure to respond to antirejection or antimicrobial therapy.

Diagnosis

Renal epithelial cells infected with BK virus develop large nuclei and ground-glass intranuclear inclusions termed decoy cells. These renal cells are shed in the urine and can often be found by cytologic examination of urine.

The presence of BK viruria can be assessed by urine cytology, enzyme-linked immunosorbent assay (ELISA) antibody detection, or PCR. Interpretation of urine studies may be difficult because such a large number of patients in the immediate posttransplantation period excrete virus in their urine. Persistent urinary shedding of decoy cells associated with BK viremia is often seen in patients who ultimately develop PVAN. Serum PCR is thought to be better at distinguishing those at risk for actual development of nephropathy and is often used as a potential screening test for kidney involvement. Definitive diagnosis of PVAN requires renal biopsy; positive biopsies typically reveal an intense cellular infiltrate associated with viral inclusions.

Management

There is no consensus on the optimal treatment of PVAN. Reduction of immunosuppression is the recommended therapy; the new antiretroviral agent cidofovir has been reported effective in small numbers of patients.

BK Virus

1.   Ninety percent seroprevalence in general population

2.   High incidence of urinary excretion after transplantation

3.   Nephropathy evaluated by serum PCR, renal biopsy

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Strongyloidiasis

Etiology

Strongyloides stercoralis is a common parasite nematode endemic in Southeast Asia, Latin America, and parts of the southeastern United States. In the United States, the highest rates are found in Kentucky and Tennessee. This parasite is remarkable for its ability to persist and replicate in the gastrointestinal tract for many years while producing minimal symptoms.

Presentation

Patients undergoing transplantation, particularly those receiving corticosteroids, are at risk for disseminated disease. Disseminated disease is characterized by overwhelming pulmonary and gastrointestinal involvement, often with concurrent sepsis with gram-negative enteric organisms.

Diagnosis

Patients with disseminated strongyloidiasis often have high eosinophil counts and a distinctive serpiginous skin rash thought to represent intradermal larvae. Definitive diagnosis is made by identification of larvae from stool, bronchoalveolar lavage, or duodenal aspirate.

Management

Treatment is with ivermectin, 200 µg/kg per day for 2 days, although the relapse rate is high in patients with hyperinfection.

Strongyloidiasis

1.   Long-term asymptomatic gastrointestinal tract infection

2.   Disseminated with eosinophilia, pneumonia, gram-negative sepsis

3.   Diagnosis by stool studies, bronchoalveolar lavage, duodenal aspirate

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Fever and Pneumonitis in a Transplant Recipient

Pneumonia in a transplant recipient is serious and potentially life-threatening. Patients may initially present with a mild increase in respiratory rate with increased work of breathing. Chest x-ray may initially be unremarkable, although hypoxia is frequently seen. Pulmonary infiltrates may appear as the clinical picture proceeds.

The differential diagnosis of fever and pulmonary infiltrates is extensive and includes the following:

  • Bacteria.Bacterial pneumonia is a particular concern, particularly in patients with concurrent neutropenia. Bacteria such as Klebsiella pneumoniae and Pseudomonas aeruginosa are common in this setting.
  • Pneumocystis jiroveci(formerly Pneumocystis carinii). The reported incidence of P. jiroveci pneumonia after transplantation is 2% to 10%. Infection can occur by either reactivation of latent organisms or the acquisition of a new infection. Pneumocystis species may cause a diffuse pneumonitis, even when the host is not neutropenic. Patients present with increasing work of breathing and hypoxia; often, the hypoxia occurs before development of pulmonary infiltrates. Continual prophylaxis with trimethoprim-sulfamethoxazole (Bactrim) is often used in transplant patients to reduce the risk for infection. Diagnosis is by bronchoalveolar lavage.
  • “Atypical” pneumonias.These include the community-acquired pathogens such as Mycoplasma pneumoniae, Chlamydia pneumoniae,and Legionella pneumophila.
  • Nocardiaspecies. Nocardia species may present as progressive pulmonary infiltrates unresponsive to traditional antimicrobial therapy. The radiographic picture is often one of consolidation resembling mycobacterial infection.
  • Viruses.Viral infection can be a major cause of pneumonia in immunodeficient patients with normal neutrophil counts. Numerous viruses can cause severe pneumonitis and respiratory failure in the transplant recipient; these include respiratory syncytial virus, adenovirus, influenzae virus A and B, parainfluenza virus, CMV, and rhinovirus.
  • Fungi.Fungal infections that cause pneumonia in transplant patients can be similar to those found in other immunosuppressed patients, including aspergillosis and coccidioidomycosis.
  • Mycobacteriumspecies. These pathogens can include Mycobacterium tuberculosis as well as Mycobacterium avium-intracellulare.
  • Noninfectious causes.Not all pulmonary infiltrates are caused by infectious agents. Pulmonary disease in an immunocompromised patient may also be caused by chemotherapy, drug toxicity, and acute respiratory distress syndrome.

The extensive list of possible etiologies of pulmonary infiltrates in a transplant patient makes empiric treatment difficult. Aggressive diagnostic evaluation is required, often by the use of bronchoscopy to obtain bronchoalveolar fluid for specific testing. Testing of bronchoscopy fluid in this setting should include the following:

Bronchoalveolar Lavage Testing

1.   Bacterial culture

2.   Fungal stain and culture

3.   Acid-fast stain and culture

4.   Pneumocystis species stains

5.   Viral culture and specific testing by direct fluorescent antibody to respiratory syncytial virus, adenovirus, influenza, CMV, and herpes simplex virus

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Empiric treatment often includes a third-generation cephalosporin, an aminoglycoside, trimethoprim-sulfamethoxazole (which will cover bothPneumocystis and Nocardia species), and often ganciclovir (to cover the possibility of CMV). As diagnostic studies become available, this empiric treatment can be altered as indicated.

Selected Readings

Isada CM, Yen-Lieberman B, Lurain NS, et al. Clinical characteristics of 13 solid organ transplant recipients with ganciclovir resistant cytomegalovirus infection. Transpl Infect Dis 2002;4(4):189–194.

Fishman JA, Rubin RH. Infection in organ transplant recipients. N Engl J Med 1998;338(24):1741–1751.

Kwak EJ, Vilchez RA, Randhawa P, et al. Pathogenesis and management of polyomavirus infection in transplant recipients. Clin Infect Dis2002;35(9):1081–1087.

Van der Bij W, Speich R. Management of cytomegalovirus infection and disease after solid organ transplantation. Clin Infect Dis2001;33(Suppl 1):S32–S37.