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 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 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.
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).
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.
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.
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.
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.
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.
• Nocardia species. 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.
• Mycobacterium species. 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:
Empiric treatment often includes a third-generation cephalosporin, an
aminoglycoside, trimethoprim-sulfamethoxazole (which will cover both
Pneumocystis 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 Dis 2002;35(9):1081–1087.
Van der Bij W, Speich R. Management of cytomegalovirus infection and disease
after solid organ transplantation.
Clin Infect Dis 2001;33(Suppl 1):S32–S37.
Pictures
Book Source Details
- Book Title: Pediatric Infectious Disease
- Author(s): Donald Janner MD
- Year of Publication: 2004
- Copyright Details: Pediatric Infectious Disease, Copyright © 2004 Lippincott Williams & Wilkins.
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Copyright Details: Pediatric Infectious Disease, Copyright © 2008 Williams & Wilkins.
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