Infectious Complications in Solid Organ Transplant Recipients

HORIZONS IN ORGAN TRANSPLANTATION

0039-6109/94 $0.00 + .20

INFECTIOUS COMPLICATIONS IN SOLID ORGAN TRANSPLANT RECIPIENTS Veronika Nicholson, MD, and Philip C. Johnson, MD

Over the past decade, solid organ transplantation has become widely accepted as a therapeutic option for chronic diseases of the kidney, liver, heart, and lung. Organ transplantation is a frequent procedure in small and large medical centers. Over the last four decades important advances have been made in surgical techniques, better targeting of immunosuppressive therapy, improved preoperative and postoperative care, and development of prophylactic antimicrobial agents with activity against viral and fungal pathogens. Even with these advances, infection and allograft rejection remain the major causes of morbidity and mortality in these patients. Furthermore, infection and rejection are closely related. The prevention and treatment of infectious disease complications of solid organ transplantation are discussed in this article. The solid organ allografts we consider include kidney, heart, liver, and lung. Heart-lung transplantation is grouped with lung transplantation because the infectious disease complications are similar. We focus on infections resulting from immunosuppression with prednisone, cyclosporine, antilymphocyte globulins, and azathioprine. EPIDEMIOLOGY

More than 80% of transplant recipients have at least one episode of clinical infection postoperatively.73 Besides the specific characteristics of each transplanted solid organ and the immunosuppression regimen, the risk factors that predispose allograft recipients to infection include diabetes mellitus, prior hepatitis Band C, leukopenia, splenectomy, persistent uremia, the use of cadaveric donor organs, and repeated treatment of persistent or recurrent rejection.19 The

From the Center for Infectious Diseases (VN) and the Division of General Medicine (PCJ), The University of Texas Medical School at Houston, Houston, Texas

SURGICAL CLINICS OF NORTH AMERICA VOLUME 74 • NUMBER 5 • OCTOBER 1994

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latter two characteristics are the most important because they require the transplant recipient to be exposed to increased and/or repeated doses of immunosuppressive agents for prolonged periods of time. Immunosuppression is a twoedged sword that protects the transplanted donor organ from the recipient's immune defenses but causes the recipient to be susceptible to infection. Transplant recipients are at risk for common infections seen in immunologically normal hosts, just as they are also at risk for opportunistic infections. These infections arise from the transplanted allograft, technical complications of surgery, reactivation of latent infections, and environmental exposure to new microbes. Infectious diseases vary in a predictable pattern depending on which organ is transplanted, the immunosuppressive regimen, and the postoperative time course. Rubin59 developed a schema that demonstrates the time course of bacterial, fungal, viral, and other infections which occur after transplantation. A modification of this schema for cyc1osporine/prednisone-treated patients is shown in Figure 1. In general, infections occurring within the first month after transplantation result from transplanting an infectious agent present prior to surgery in the donor tissue or occur as postoperative infections similar to those observed in any surgical patient.52,59 The period from 1 month to 6 months after transplant is a time of opportunistic infections resulting from the high initial levels of immunosuppression required to prevent acute rejection. 52,59 The period from 6 months to 1 year represents a return to routine bacterial infections and the development

Viral CMV HSV EBV. VZV. papovavirus. adenOVirus

I

I

Hepatiiis Hepatitis B

II

I

Onset of hepatitis C ~I-------------------------------------------------

B-act-e-ria-,-----,l

r-I

Wound Pneumonia Line·related

I

Community-acquired pneumonia

I

I

UTI: Bacteremia. pyelonephritis

UTI: Relatively benign

PCP. toxoplasmosis

1

I

Fungal. TB. Nocardia Cryptococcus

o Transplant

2

4

3

5

6

Months

Figure 1. Timing of infectious diseases in solid organ transplant recipients treated with cyclosporine and prednisone. (Modified from Rubin RH, Wolfson JS, Cosimi AB, et al: Infections in the renal transplant recipient. Am J Med 70:405-411, 1981; with permission.)

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of slower growing chronic fungal and mycobacterial infections as the recipient receives less immunosuppression.52,59 Another concept to consider in managing infectious diseases in organ transplant recipients is the increased susceptibility of the transplanted organ to infection during the first months after transplant. Renal transplant recipients are at high risk to develop pyelonephritis, liver transplant recipients develop cholangitis, heart transplant recipients develop endocarditis, and lung transplant recipients develop bronchitis and pneumonia. These infections are directly related to altered anatomy and the susceptibility of foreign tissue to infection.

PREOPERATIVE EVALUATION Evaluation of the Recipient

Patients with organ failure are more susceptible to infection than otherwise healthy individuals. Potential transplant recipients should have a complete history and physical evaluation directed at the susceptibility of the patient to infectious diseases. Prior infections that may be dormant in the recipient should be known and evaluated in advance. Examples include a history of exposure to tuberculosis and the status of a purified protein derivative (PPD) skin test, hepatitis B, recurrent herpetic lesions, varicella, and exposures to bacterial and fungal infections. Residence in the endemic area for Histoplasma capsulatum, Coccidioides immitis, and Strongyloides stercoralis should be determined and, if necessary, appropriate testing to determine risk is useful. Human immunodeficiency virus (HIV) infection is considered a contraindication to transplantation. Testing for these and other infectious diseases is outlined in Table 1. Diabetics are at increased risk for infections. This predisposition is exacerbated by the use of corticosteroids in all immunosuppressive regimens. A neurogenic bladder is sometimes seen in diabetics. Past osteomyelitis as a result of diabetic peripheral neuropathy and diabetic foot ulcers can be reactivated following transplantation. Diabetics have a greater risk of Staphylococcus aureus carriage than does the general population. This predisposes them to wound infections with S. aureus. Patients with a history of dental problems and sinus infections should have these problems corrected prior to organ transplantation. We routinely request Zonarc radiographs of the mouth to exclude caries and sinus series in patients with a history of sinus infection. Liver, heart, and lung transplant recipients who are hospitalized for prolonged periods waiting for a suitable donor organ become colonized and infected with nosocomial organisms. They typically have previously been treated with broad-spectrum antimicrobials. In these patients, the routine pretransplant prophylaxis regimen should be altered to cover the resident flora present in the hospital or cultured as colonizers from the patient. In liver transplant recipients, most of the infections that occur in the early post-transplant period are due to gram-negative aerobic organisms and fungi that colonize the gastrointestinal tract. In an effort to decrease these infections, most transplantation centers have instituted the use of selective bowel decontamination (SBD). This involves the use of nonabsorbable oral antimicrobial agent combinations, such as polymyxin E, tobramycin, and fluconazole or norfloxacin and nystatin. Depending on the transplantation center, medication is started either when the patient is placed on the active waiting list or the day of transplantation. SBD is continued for as little as 5 days after transplantation in pedi-

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Table 1. SCREENING OF RECIPIENTS FOR POSSIBLE INFECTION Test

Infection Human immunodeficiency virus (HIV) Cytomegalovirus (CMV)

HIV IFA' CMV IFA'

Epstein-Barr virus (EBV)

EBVVCAt

Herpes simplex virus (HSV) Hepatitis B

HSV

Hepatitis C

Anti-HCV by ELISA:!:

Bacteria

Baseline cultures of blood, sputum, urine as needed

Methicillin-resistant Staphylococcus aureus (MRSA) Tuberculosis

Nares culture

HBsAg

PPD§

Candidiasis

Complement fixation test in people from endemic area Candida precipitins

Toxoplasmosis

Toxoplasma IFA'

Strongyloidiasis

Enterotest

Syphilis

Reaginic test with non reaginic test for confirmation

Coccidioidomycosis

Interpretation Positive test contraindication to transplantation Positive test at higher risk for CMV if donor CMV negative Seronegative recipients at greater risk for Iymphoproliferative disorder if treated with OKT3 At risk for reactivation of HSV Positive test at risk for chronic liver disease and HDV Positive test at risk for chronic hepatitis Treat postoperative infections promptly with appropriate antibiotics At risk for MRSA infection

Should receive isoniazid prophylaxis prior to transplant if possible Positive test at risk for reactivation Obtain baseline value for further reference Obtain baseline value for further reference Treat patient for strongyloidiasis prior to transplant Treat for syphilis prior to transplant

'Indirect fluorescent antibody test tViral capsid antigen :j:Enzyme-linked immunosorbent assay §Purified protein derivative

atric patients and as long as 21 days after transplantation or until biliary drains are removed in adult patients. Infection rates in the SBD-treated groups range from 6% to 11%, compared with 50% to 53% in nontreated patients.65 These studies show a significant decrease in infection rates in treated liver transplant recipients. Recipients who have or are expected to undergo splenectomy should be vaccinated for Streptococcus pneumoniae and perhaps Haemophilus pneumoniae. Routine vaccinations for diphtheria, pertussis (children), tetanus, influenza, and varicella-zoster virus (when available) should be performed prior to transplantation if possible. Transplant recipients who are hepatitis B surface antigen (HBsAg) negative

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prior to transplantation are at a greater risk than the normal population for exposure to hepatitis B virus (HBV) because they will receive multiple blood products. These patients should receive recombinant HBV vaccine prior to transplantation, even though evidence from one study suggests that the response rate of these patients to developing hepatitis B surface antibody (HBsAb) is only 29%.3 Further investigation into the immune defect in these patients needs to be completed in an attempt to increase vaccine responsiveness.

Evaluation of the Donor

Like the recipient, the organ donor must undergo an extensive evaluation for the presence of infections. Recommended tests for determining infections that are transmitted by organ donation are outlined in Table 2.24 Donors who are HIV- or HBsAg-positive should be excluded from organ donation. Exclusion of donors who are at high risk for HIV infection has been suggested owing to the latency of HIV. Currently testing for HIV antibody is positive in 95% of people

Table 2. EVALUATION OF THE TRANSPLANT DONOR Infection

Test

Human immunodeficiency virus (HIV) Cytomegalovirus (CMV)

CMV IFA'

Epstein-Barr virus (EBV)

EBVVCAt

Hepatitis B

HBsAg

Hepatitis C

Anti-HCV by ELlSA:j:

Bacteria Tuberculosis

Bacterial culture of perfusate PPD§ in donor

Fungi

Fungal culture

Syphilis

Schistosomiasis

Reaginic test with confirmatory non reaginic test Thick smear in donors from endemic area Schistosoma antibody

Toxoplasmosis

Toxoplasma antibody

Trypanosomiasis

Trypanosoma antibody

Malaria

HIV IFA'

-Indirect fluorescent antibody test tViral capsid antigen :j:Enzyme-linked immunosorbent assay §Purified protein derivative

Interpretation Positive test contraindication for transplantation Positive test places recipient at increased risk Positive test causes risk for seronegative recipient especially if OKT3 used Recipient at risk for hepatitis B unless HBsAg positive Recipient at possible risk for HCV Possible transmission of infection to recipient Possible transmission of infection to recipient Possible transmission of infection to recipient Treat recipient after transplant

Possible transmission to recipient Possible transmission to recipient Possible transmission to recipient; heart transplants at greatest risk Possible transmission to recipient

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within 3 months after exposure and in 99% of people 6 months after exposure. HBsAg donors, particularly those who are HBeAg-positive, are at risk of transmitting active disease to the recipient?9 Donor organs, perfusate, and solutions in which the organ is transported are sometimes cultured because the donor may have an underlying asymptomatic infection or the organ may have been contaminated during the harvesting procedure. PROPHYLAXIS FOLLOWING TRANSPLANTATION

Table 3 lists other antimicrobial prophylactic regimens to decrease the incidence of post-transplantation infection. BACTERIAL INFECTIONS

Bacterial infections are the most frequent infections in the solid organ transplant population. They are responsible for the majority of infections during the first postoperative month. These infections are associated with technical procedures, indwelling catheters, other nosocomial exposures, pre-existing bacterial infections in the recipient, and bacteria present in the transplant organ. Kidney transplant patients have a higher incidence of urinary tract infections (UTIs), liver transplant patients have a higher incidence of intra-abdominal infections, Table 3. PROPHYLAXIS OF INFECTIOUS DISEASES IN SOLID ORGAN TRANSPLANT RECIPIENTS

Infectious Disease/Agent Cytomegalovirus (CMV)

Prophylaxis

Herpes simplex

Acyclovir, ganciclovir, CMV immunoglobulin Acyclovir

Herpes zoster

Acyclovir

Influenza

Annual vaccination

Streptococcus pneumoniae Enteric bacteria

Pneumococcal vaccine

Candida

Pneumocystis carinii pneumonia

Toxoplasma gondii

Selective bowel decontamination Nystatin swish and swallow, miconazole troches, vaginal creams or suppositories Trimethoprim/ sulfamethoxazole; aerosolized pentamidine Pyrimethamine

Notes See Table 6 Use immediately after transplant, with febrile illnesses, and treatment for rejection Use in patients with previous zoster Vaccinate prior to transplant if possible Vaccinate prior to transplant if possible Use in liver transplant recipients Use immediately after transplant and when patient is receiving antibiotics Use aerosolized pentamidine in intubated patients. Prophylaxis for 4 to 6 months after transplant Prophylaxis for first 6 weeks after transplant in seronegative recipients of a seropositive donor organ

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and heart/lung transplants have a higher incidence of pneumonia. Table 4 lists empiric antimicrobial regimens suitable for treatment of bacterial infections occurring early after transplantation.19 INFECTIONS FROM INDWELLING CATHETERS

Iatrogenic causes of infection that develops in the early postoperative period are associated with indwelling catheters and intravascular lines. In liver and heart/lung recipients, central venous access is necessary for Swan-Ganz catheter monitoring. The long-term use of these catheters can result in bacteremia. It is important to remove central lines as soon as they are unnecessary. If the patient develops unexplained fever, the central line should be discontinued or moved to another site and cultures obtained. S. aureus and Staphylococcus epidermidis are the organisms commonly associated with these infections. Treatment should be initiated with an anti-staphylococcal penicillin, a cephalosporin, or vancomycin where known resistant Staphylococcus is suspected. Another source for iatrogenic infection is the use of indwelling urinary catheters. This is of particular concern in kidney transplant recipients. The reported incidence of UTIs in renal transplant recipients has been as high as 83%,17, 19, 61 The transplanted kidney is at particular risk for pyelonephritis. Patients on chronic dialysis develop small, contracted bladders, Into this bladder a donor ureter is sewn using a procedure that minimizes ureteral reflux. The ureter is typically only 6 to 8 cm in length, compared with a normal ureter of 25 cm. Vesicoureteral reflux invariably occurs. Once the bladder is colonized with bacteria, it is not long before the kidney is also infected. UTIs are prevented by early catheter removal and prophylactic antibiotics. Trimethoprim/ sulfamethoxazole (TMP /SMX) used for prophylaxis of Pneumocystis carinii pneumonia prevents UTIs in renal transplant recipients. 22 In the early

Table 4. POTENTIAL ANTIMICROBIAL REGIMENS USED FOR EMPIRIC TREATMENT OF BACTERIAL INFECTIONS OCCURRING AFTER SOLID ORGAN TRANSPLANTATION Aerobic gram-positive cocci Vancomycin First-generation cephalosporin Carbapenem Ampici"in (primarily Enterococcus) Penicillin derivative plus j3-lactamase inhibitor Aerobic gram-negative bacilli Second- and third-generation cephalosporin, or carbapenem agent + aminoglycoside or monobactam Aerobic and anaerobic gram-negative bacilli Aminoglycoside + anti-anaerobic agent Carbapenem Selected second- and third-generation cephalosporins + anti-anaerobic agent Monobactam + anti-anaerobic agent Carboxypenici"in or penicillin derivative with j3-lactamase inhibitor + anti-anaerobic agent Aerobic and anaerobic gram-negative bacilli and gram-positive organisms Ampicillin + aminoglycoside + anti-anaerobic agent Vancomycin + aminoglycoside + anti-anaerobic agent Carbapenem

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postoperative period, UTIs should be treated as if pyelonephritis were present. Intravenous antibiotics are required if the patient has pyelonephritis. Some experts have advocated a 6-week course of antibiotics. 6o In a patient who develops a UTI 6 or more months after transplantation, a 10- to 14-day course of antibiotics may be adequate. These latter patients may not require hospitalization.'" 26, 60 WOUND INFECTIONS

A number of factors predispose transplant recipients to wound infection. These include an underlying disease (Le., renal insufficiency, diabetes mellitus), re-exploration through the same incision, hematoma, leakage from anastomotic sites (biliary tract, bladder, ureter), the use of wound drains, contaminated lymphoceles, and allograft contamination. Overall mortality in the past has been as high as 30%.32. 38 Owing to improved surgical techniques and possibly the institution of prophylactic antibiotics, the incidence of wound infection has decreased Significantly in more recent studies. 5, 17, 32 Wound infections may be difficult to diagnose owing to the lack of symptoms. The patient may have only minimal drainage without fever or leukocyte count elevation. If there is any suspicion of wound infection, cultures should be obtained and the underlying tissue should be evaluated with ultrasonography or computed tomography (CT). If a fluid collection is detected, it should be aspirated and samples sent for cultures and Gram's stain. If the clinical status of the patient deteriorates or there is evidence of ongoing infection despite adequate therapy, the surgeon should be aggressive and re-explore the wound and periallograft region. Superficial wounds require surgical debridement and healing by secondary intention. Deep wound infections can be life-threatening and require allograft removal in the kidney transplant patient. Complications that contribute to mortality include septicemia and mycotic aneurysm. This is particularly a concern if prosthetic material is used to repair vascular injuries. Empiric antibiotic regimens for wound infections should include coverage for both gramnegative and positive aerobes and anaerobes. In heart/lung transplant recipients, wound infections frequently are due to organisms found in the pulmonary allograft. These infections may result from direct infection of the median sternotomy site or from dehiscence of the airway anastomosis, causing mediastinitis. The organisms most often causing early sternal wound infections are S. aureus, Candida albicans, and Mycoplasma hominis. In later infections, the most likely organism is Pseudomonas aeruginosa. Treatment of these infections requires debridement of the sternum and mediastinum, irrigation of the wound, and appropriate antibiotics. In liver transplant recipients, wound infections are usually due to gramnegative bacteria, anaerobic organisms, and yeast. 31 Broad-spectrum antibiotics should be instituted immediately, including amphotericin B. ABDOMINAL INFECTIONS

Abdominal infections occur most frequently in liver transplant recipients and account for more than 50% of the bacterial infections.50 These infections include hepatic abscess, cholangitis, and peritonitis. Predisposing factors include hepatic artery thrombosis, the biliary type of anastomosis, and whether or not an anastomotic leak is present. 31 Compared with the choledochocholedochostomy, the choledochojejunostomy Roux-en-Y loop is associated with a higher rate of

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infection secondary to the reflux of enteric pathogens. 31• 36 As previously mentioned, the institution of SBD has decreased the incidence of intra-abdominal infections. Abdominal infections are usually polymicrobial, involving enteric organisms such as E. coli, Enterococcus, Enterobacter, Klebsiella, and yeast. Pseudomonas infection is less common.35 If an abdominal infection develops, a combination of antibiotics with activity against both anaerobic and aerobic enteric organisms and yeast should be instituted. A CT scan of the abdomen should be obtained to look for fluid collections. If fluid is found, drainage is necessary. Gram's stain and cultures of the fluid should be obtained. Some of these patients may require retransplantation, depending on their response to therapy. If peritonitis is suspected, fluid should be obtained and sent for Gram's stain and cultures. Antibiotics should be adjusted according to the susceptibilities of the organisms isolated. Abdominal infections may also be related to perforation in steroid-treated patients with a underlying diverticulitis or peptic ulcer disease. The physical findings of these infections can be masked. When they are suspected, immediate surgical repair, intra-abdominal lavage, and institution of broad-spectrum empiric antibiotics are necessary. Cholangitis is seen more frequently in liver transplant patients because these patients frequently have a T-tube drain in place postoperatively. Drainage material should be obtained for culture any time an infection is suspected. In these patients, it is sometimes difficult to determine if the organism isolated is a pathogen or a colonizer. When the clinical presentation is associated with increasing liver function studies and fever, therapy for cholangitis should be initiated promptly. PULMONARY INFECTIONS

When there is evidence of a pulmonary infiltrate on chest radiograph or the suspicion of pneumonia, rapid diagnosis and therapy are necessary.29 Cultures and Gram's stains should be obtained from sputum or transtracheal aspirations as a first step. In heart and renal transplant recipients, pulmonary edema can confuse the clinical picture. Pneumonia is most frequently seen in heart/lung and liver transplant patients. Pulmonary infections are the most common causes of death in the solid organ transplant recipient. In lung transplant recipients, the overall prevalence of pulmonary infection is greater than 60%.9, 15, 44 The predisposing factors that contribute to this high prevalence include injury to airway mucosa with dysfunction of mucociliary clearance, airway anastomosis, impairment of the transport of mucus up the trachea by denervation that eliminates the cough reflex, and interruption of lymphatic drainage. 9 Pneumonia may be associated with the organisms that colonize the donor. Cultures are routinely taken from the donor trachea at harvesting, and prophylactic antibiotics are continued if cultures are positive and organisms are susceptible to them. In the late postoperative period, chronic rejection is a contributing factor. Three fourths of all pneumonias in heart/lung patients are caused by gram-negative rods, primarily Enterobacteriaceae and Pseudomonas families. The remainder are due to S. aureus, Haemophilus influenzae, and Streptococcus pneumoniae. 9 In liver transplant patients, contributing factors that make them more susceptible to early pneumonia include an extensive abdominal surgical procedure, prolonged intubation, fluid fluctuations, and diaphragmatic dysfunction. In liver and kidney transplant patients, most pneumonias within the first month after transplantation are caused by nosocomially acquired organisms (aerobic gram-

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negative bacteria) while the patient is intubated or if the patient has aspirated. The remaining pneumonias are due to community-acquired organisms or are related to severe cytomegalovirus (CMV) disease. We have had good success with a rapid diagnostic team approach. Any transplant recipient with fever, chest radiographic evidence of pneumonia, and hypoxia indicated by an increased arterial-alveolor gradient on arterial blood gases should proceed quickly to bronchoscopy.29 We have found that bronchial alveolar lavage and protected bronchial brush specimens are sufficient to diagnose most cases of pneumonia. In those patients who cannot be diagnosed within 24 hours on the basis of pathologic stains and cultures, CMV is the most common cause.29 On occasion we have resorted to open lung biopsy. TMP ISMX and erythromycin are usually started empirically. Ganciclovir is added if CMV is suspected. In patients with pneumonia in the first month after transplant, the antibiotics that are used empirically should cover nosocomial bacteria present in that particular institution. Treatment should also include postural drainage, chest percussion, and beta-agonists. Bronchodilators are particularly useful in the early postoperative period. If Pneumocystis carinii pneumonia (PCP) is not suspected and the stains for PCP are negative, IMP ISMX is discontinued or substituted for other antibacterial agents to cover the organisms obtained from the bacterial culture. Most transplant patients take prophylactic TMP ISMX, which contributes to the decrease in PCP, NocardUi, and Toxoplasma pneumonia. If the Legionella direct fluorescent antibody is negative, erythromycin is discontinued (Fig. 2).

Figure 2. A and B, Bilateral interstitial infiltrates on a chest radiograph of a renal transplant recipient receiving cyclosporine and prednisone. She had undergone treatment for rejection with high-dose corticosteroids 1 month previously and then presented with fever and shortness of breath. On bronchoscopy, a direct fluorescent antibody of the bronchial secretions was positive for Legionella pneumophi/a. Legionella and CMV grew from cultures.

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OTHER BACTERIA Listeria monocytogenes L. monocytogenes is an intracellular pathogen that occurs in persons with deficient cell-mediated immunity. In transplant recipients it is more common in patients treated with regimens containing azathioprine. It usually presents as a meningitis but may cause brain abscess, meningoencephalitis, bacteremia, or pneumonia in transplant patients. Patients may present with headache, focal neurologic deficits, seizures, and vague neurologic symptoms without meningismus. These patients should undergo a thorough evaluation, including lumbar puncture and a CT scan or magnetic resonance imaging (MRI) of the brain. The stool should be cultured because this is an enteric organism. Early treatment with ampicillin and an aminoglycoside is necessary because Listeria infection has a high overall mortality of as much as 26%? The use of TMP /SMX prophylaxis has decreased the frequency of this infection in the 1- to 6-month postoperative period.

Nocardia

Nocardial infections are more frequently a problem in heart/lung transplant patients but can also occur in other transplant populations." 34, 74, 78 They may occur as a primary infection or a recurrent infection.33 Nocardiosis is initially an infection of the lung (Fig. 3), but it can cause a disseminated disease involving skin, the central nervous system (CNS), and the skeletal system. The diagnosis consists of histologiC identification of filamentous gram-positive organisms or weakly acid fast bacilli (AFB)-positive organisms and growth on culture. Therapy is TMP /SMX for at least 6 months. Amoxicillin/ clavulanic acid is an alternative therapy in renal allograft recipients who cannot take IMP /SMX.

Figure 3. A and B, Chest radiographs of a renal transplant recipient 3 years following the transplant, who developed a 1-month history of fever and cough. The chest radiograph shows bilateral interstitial infiltrates and bilar lymphadenopathy. The infiltrates are worse in the right lower lobe. Nocardia grew from culture of bronchial secretions.

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Mycobacterium

Mycobacterial infections are not frequently seen in the transplant population. The incidence in renal transplant recipients is 0.8%, compared with 0.1% in the general population. 1O• 41 Of these infections, about 30% are atypical mycobacteria (M. kansasii, M. chelonei, and M. haemophilum).l0 M. tuberculosis infection is most often due to reactivation disease. There have been reports in the literature of possible allograft transmission in patients who were PPD skin test negative prior to transplantation and nosocomial transmission in a renal transplant unit. 2s • 41. 51 The most common site of infection is the lung, but extrapulmonary and disseminated diseases have also been seen involving the skin, lymph nodes, musculoskeletal system, and urinary tract (Fig. 4). Patients may not exhibit the usual symptoms of cough, pleuritic chest pain, and dyspnea. They may exhibit only fever. Patients with a recent positive PPD or radiographic evidence of pulmonary disease should be given prophylaxis with isoniazid (INH). Those patients with a previous history of disease and those who receive an organ from a donor who is PPD-positive should be closely monitored for possible reactivation of their infection. 37 In patients who are suspected of having M. tuberculosis infection, invasive diagnostic studies are usually necessary to document infection. Treatment with a multiple drug regimen, including INH, pyrazinamide, and ethambutol, should be instituted for at least 2 months, after which, depending on organism susceptibilities, ethambutol may be discontinued. In the past we have found that the addition of rifampin, a tuberculocidal drug, is detrimental owing to its potent interaction with cyclosporine. 77 VIRAL INFECTIONS

Viral infections are associated with increased morbidity and mortality in transplant recipients. Viral infections may occur as a primary infection or reacti-

Figure 4. Retrograde pyelogram of a renal transplant recipient with polycystic kidneys who had sterile pyuria. Mycobacterium tuberculosis was recovered from morning urine samples. The retrograde study of her left polycystic kidney showed beading of the ureter and hydronephrosis, which are characteristic of renal tuberculosis. The transplant graft was unaffected. The patient was treated with isoniazid and pyrazinamide followed by nephrectomy.

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vation of latent disease. They may present a spectrum of symptoms ranging from asymptomatic shedding of the virus to fulminant disease. This is most likely related to the degree of impairment of cell-mediated immunity of the patient. A number of viruses have been associated with disease in transplant patients (Table 5). Of these, the DNA viruses are responsible for the more severe infections. In transplant patients, CMV is the principal viral infection. Cytomegalovirus

Cytomegalovirus infection is the most common cause of infection in organ transplant patients after the first post-transplantation month. The incidence of infection is approximately 40% to 70%, whereas the incidence of significant disease ranges from 10% to 30%.14, 20, 40 It may develop as a primary infection, superinfection, or reactivation of latent disease, For pediatric patients it is most likely a primary infection, but in adults most episodes of infection are related to reactivation. Superinfection occurs when a CMV seropositive organ is transplanted into a CMV seropositive recipient and reactivation of the donor CMV strain occurs.2 Primary infection has traditionally meant more severe disease, but in renal transplant recipients treated with cyclosporine and prednisone, primary and secondary disease appear to be equally severe.3D Disease can range from asymptomatic viral shedding to severe disseminated disease resulting in death. 40 Pneumonia, gastrointestinal infection, hepatitiS, pancreatitis, and retinitis are manifestations of severe or life-threatening disease.53 In heart/lung transplant patients pneumonia is more prevalent and in liver transplant patients hepatitis is more prevalent. Patients can present with fever, leukopenia, malaise, lethargy, myalgias, gastrointestinal bleeding, esophagitis, hepatitis, and progressive pneumonitis with severe hypoxia progressing to respiratory failure and death. 53 Patients with CMV infection are at increased risk to develop infection with bacteria, PCP, and Candida. These may be difficult to diagnose because of the fever and manifestations of CMV infection. Continued monitoring both clinically and with laboratory evaluation is necessary in order not to overlook these additional pathogens. The diagnOSis of CMV infection traditionally involved the recognition of cytomegalic inclusion bodies in tissue specimens, cytopathic effect on fibroblast tissue cultures, or a greater than fourfold increase in the CMV serum antibody titer after transplantation. Recently, more rapid diagnostic techniques have become available which allow for earlier diagnosis of CMV infection. These include the shell vial culture technique, CMV early antigen staining of cells, IgM determination, and polymerase chain reaction (PCR). Currently, studies are under

Table 5. VIRUSES CAUSING INFECTIONS IN TRANSPLANT RECIPIENT

RNA Viruses

DNA Viruses

Influenza A and B Parainfluenza 1 Respiratory syncytial virus Hepatitis A Enterovirus Measles Rotavirus Hepatitis C

Herpes simplex 1 and 2 Epstein-Barr virus Cytomegalovirus Varicella Adenovirus Hepatitis B Papovaviruses Parvovirus B19

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way comparing PCR with other viral detection techniques. In spite of these newer techniques, traditional cultures should still be obtained. Prophylaxis of CMV involves transplantation of an organ from a CMV seronegative donor to a CMV seronegative recipient whenever possible, the use of CMV seronegative blood products in CMV seronegative individuals, judicious use of antilymphocyte preparations, and specific antiviral prophylaxis therapies. To date, CMV vaccines remain experimenta1.4, 55, 56 Other considerations include the risk to the patient, the type of solid organ transplanted (kidney versus solid organs for which there are no other treatment options), and the immunosuppressive regimen used. Antilymphocyte preparations (OKT3, antilymphocyte globulin [ALG]) are known to activate latent virus. Cyclosporine potentiates CMV infection once it has developed. Rejection and infection with CMV go hand in hand.40 In our experience with renal transplant recipients treated with cyclosporine and prednisone, rejection occurred prior to CMV infection in half (Fig. 5). There are three different concepts in the management of CMV infection-prophylaxis,46 pre-emptive treatment,45,61 and treatment of diagnosed disease. Preemptive therapy is used when ALGs are given either immediately after transplant or for treatment of rejection.45,61 A scheme for preventing and treating CMV infection is illustrated in Table 6. 16,66-68 Different transplant centers have developed their own regimens for their particular patient population.20,23 Treatment for CMV disease with ganciclovir,5 mg/kg twice a day for 14 to 21 days with or without CMV immunoglobulin, has been shown to be effective with minimal toxicity.IB, 20, 39, 62, 63 Toxicity is related to bone marrow suppression (neutropenia) and usually resolves once ganciclovir is discontinued. Foscarnet is an alternate agent. However, it may be associated with nephrotoxicity and magnesium and calcium shifts. Foscarnet is not recommended for use in kidney transplant patients.

DXofCMV 39%

Percent with rejection 15% 6%

15%

8%

9%

1-2 Months before DX

0-1

0-1

Months after DX

Figure 5. Percentage of renal transplant recipients with acute rejection before and after diagnosis of CMV. The timing of CMV infection and rejection in renal transplant recipients treated with cyclosporine and prednisone is shown. (Data from Lewis RM, Johnson PC, Golden D, et al: The adverse impact of cytomegalovirus infection on clinical outcome in cyclosporine-prednisone treated renal allograft recipients. Transplantation 45:353-359, 1988; with permission.)

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Table 6. SCHEME FOR PREVENTING AND TREATING CYTOMEGALOVIRUS INFECTION

Kidney Transplant

Other Solid Organ Transplants

Prophylaxis Primary Secondary

ACV, CIG* None

CIG ACV

CIG + GCV ACVorGCV

CIG + GCV GCV

CIG + GCV GCV

CIG + GCV GCV

Preemptive therapy Primary Secondary

Treatment Primary Secondary

Abbreviations: ACV, acyclovir; CIG, cytomegalovirus immune globulin; GCV, ganciclovir 'CIG has also been shown to be beneficiaL68 CIG has not been effective in liver transplant recipients.

Epstein-Barr Virus

Epstein-Barr virus (EBV) infection has been associated with a wide range of syndromes in solid organ transplant recipients, including an asymptomatic elevation in antibody titers, clinical hepatitis, a mononucleosis syndrome, and a post-transplant lymphoproliferative disorder (LPD). Of these syndromes, LPD is the most severe and can be life-threatening. It occurs more frequently in individuals with primary infection than with reactivation disease. 8, 25, 58 The risk of LPD also appears to be increased in those who receive OKT3.72 Primary infection with EBV usually occurs in the pediatric population. Most adults have been exposed to EBV infection during childhood and have reactivation disease. The diagnosis is made by both serologic (presence of EBV nuclear antigen and IgM antibody against the viral capSid antigen, or fourfold increase in convalescent IgG-antiviral capsid antigen) and histologic (immunoblasts, lymphocytes, and plasma cells with EBV nuclear antigen staining) criteria. The treatment of LPD is controversial. Most investigators recommend decreasing immunosuppressive therapy and treating with antivirals (high-dose acyclovir or ganciclovir) .17, 54 Herpes Simplex

Herpes simplex virus (HSV) reactivation is common following transplantation and usually presents as an orolabial or genital disease. Disseminated disease has been reported but is infrequent. Patients who are HSV seropositive prior to transplant should be given prophylaxis with acyclovir, 200 mg orally three times a day, in the immediate post-transplant period. 6, 70 Some authors have used this approach to prevent CMV infection as welP Empiric early treatment can be used later to control reactivation. Hepatitis B, C, and Delta Viruses

Liver transplantation in patients who have chronic hepatitis as a result of HBV or HCV infection has been controversial because of the high incidence of

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recurrent disease in the allograft. Patients with HBV infection can also develop co-infection with hepatitis delta virus (HDV); if they have had HDV hepatitis, they may have a recurrence. Reactivation of past hepatitis B and C has also occurred as a 'result of immunosuppression in recipients without chronic liver disease but with a past history of hepatitis. In transplant candidates if there are abnormal liver function tests and serologic evidence of HBV DNA or HBeAg, transplantation should not be undertaken owing to active disease. Liver and kidney transplantation has been completed on patients who are HBsAg positive.42 These patients have an increased rate of recurrent infection as well as decreased rate of survival. In an effort to minimize complications in patients with chronic active hepatitis B, studies have been completed in liver transplant recipients to determine if long- (at least 6 months) or short- (2 months) term prophylaxis with anti-HBs hyperimmune globulin (HIG) is beneficial. In these studies, patients who had HDV-related cirrhosis or fulminant HBV disease prior to transplantation and received long-term prophylaxis with HIG had a decreased incidence of HBV reinfection in the allograft and improved survival. 13, 47, 57 Another approach studied to prevent reinfection of the allograft involved prophylaxis with a combination of long-term HIG and recombinant interferon-a therapy. Results from this study showed a decrease in the reinfection rate of both HDV and HBV.4B Despite the results of studies using HIG prophylaxis, it is difficult to determine if transplantation on HBsAg-positive patients is beneficial long term. HIG is expensive, and reinfection has occurred despite prophylaxis. Further studies are needed to determine the length of prophylaxis and alternative agents that may be effective. HCV, like HBV, can be transmitted from the donor to the recipient. HCV is thought to be acquired through blood transfusions. Individuals who are HCV seropositive develop abnormal liver function studies 50% of the time, with a progression to cirrhosis in 20%.16 Donors who test HCV seropositive by ELISA are used at some institutions for transplantation in recipients who are HCV seropositive because the ELISA test is unreliable and the incidence of recurrent infection is low. Studies are needed to understand the transmission of HCV and the natural history of disease in transplant recipients. Other Viral Infections

Other viruses that cause disease in organ transplant recipients include adenovirus, parainfluenza virus, parvovirus B19, respiratory syncytial virus (RSV), influenza A, varicella-zoster,43,69 and influenza B. Except for adenovirus and varicella-zoster, these viruses are thought to be acquired nosocomially or from environmental exposure. RSV primarily causes seasonal bronchiolitis and pneumonitis. The diagnosis is made by viral culture. Individuals who are severely ill have benefitted from treatment with aerosolized ribavirin. If a patient is to be transplanted during the influenza season, immunization for influenza should be given prior to transplantation. Otherwise yearly influenza vaccination is indicated in transplant recipients. Patients who develop symptoms of influenza A can be treated with amantadine or rimantadine. To date, no effective therapy is available for influenza B. Patients who develop adenovirus infection may present with hemorrhagic cystitis, pneumonitis, or self-limiting disseminated disease. Mortality is rare and it is not known if mortality is due to adenovirus or concurrent superinfection. Adenovirus is thought to be due to reactivation. No antiviral therapy is available for treatment.

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PARASITES

Pneumocystis carinii infection appears to occur in the first 6 months following transplantation. It is frequently seen in association with CMV infection. The highest incidence of PCP occurs in heart/lung transplant recipients. 1s Rapid diagnosis should be made by bronchoscopy or, if bronchoscopy fails, lung biopsy. Mortality of untreated disease is high. With the institution of TMP /SMX prophylaxis, PCP is rarely seen and usually occurs in patients who are not compliant with the prophylaxis regimen or who cannot take it owing to an underlying allergy. The treatment of choice for PCP is TMP /SMX. Alternate regimens include aerosolized pentamidine and dapsone. Treatment with intravenous pentamidine may cause nephrotoxicity. Combination therapy of dapsone and trimethoprim may be tried in those allergic to TMP /SMX. Toxoplasma gondii, an organism that may remain dormant in the heart, liver, and kidney tissue, can reactivate in immunosuppressed transplant recipients. Seronegative recipients who receive an organ from a seropositive donor are at greatest risk of acquiring fatal primary infection. These recipients should be given prophylaxis with pyrimethamine, 25 mg/ day, along with folinic acid for 6 weeks following transplantation. so If a transplant r~cipient is infected with Strongyloides stercoralis, they are at risk of autoinfection and a fatal hyperinfection syndrome.64 Persons from endemic areas such as the southern United States should be screened for S. stercoraliso Routine examination of the stool for ova and parasites may not be an adequate test, and a purged stool or evaluation of small intestine contents is commonly needed?3 An Enterotest or string test is used because eosinophilia may not be present. If the patient is infected, treatment should be given prior to transplantation with either thiabendazole or mibendazole. The patient should also be followed after transplantation with monthly or bimonthly stool and small intestinal fluid examination for recurrent infection. FUNGAL INFECTIONS

Fungal infections remain the major cause of morbidity and mortality throughout the post-transplantation period. Their incidence ranges from 5% in kidney transplant patients to 40% in liver transplant patients. 49 Eighty percent of fungal infections occur within the first 2 months after transplantation. Candida and Aspergillus account for more than 80% of these infections. The mortality from these infections is very high and ranges from 30% to 100%. The possible explanations for such a high mortality include difficulty recognizing early infection, the lack of effective therapy (ie, Aspergillus), limited experience and data on effective prophylactic antifungal regimens, side effects, and drug interactions of certain antifungal medications. Amphotericin B adds to the nephrotoxicity of cyclosporine, and all the azoles and triazoles increase cyclosporine levels. In transplant recipients, the most common site of Candida infections is the oral mucosa. Prophylaxis with clotrimoxazole troches or nystatin is effective and should be started immediately after transplant. Candida esophagitis can be treated with fluconazole or amphotericin B. Candidemia is usually associated with prolonged use of intravenous lines and broad-spectrum antibiotics. Pneumonia rarely occurs and may be difficult to diagnose. If multiple sites, normally sterile regions of the body, or a single blood culture are culture positive for Candida, invasive disease must be considered and therapy should be instituted. Treatment with fluconazole or amphotericin B is appropriate.

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Aspergillus occurs predominantly in the lungs and subsequently disseminates. The most common site of dissemination is the CNS. The species of Aspergillus most often associated with disease include A. niger, A. flavus, and A. jumigatus. Patients with Aspergillus invariably have a defect in cell-mediated immunity and the presence of prolonged leukopenia. The outcome of aspergillosis is usually fatal despite the use of amphotericin B. Recently itraconazole has been used in patients to treat Aspergillus infections, and the results have been promisingy,12 The difficulties associated with the use of itraconazole include its increase in cyclosporine levels and the fact that it is available only in oral form. The dose of itraconazole associated with the least toxicity is 200 mg twice a day. Resection of cavitary disease and aspergillomas should be considered in addition to antifungal agents to prevent relapse and cure the disease. As previously mentioned, liver transplant patients have the highest incidence of fungal infections. They usually present as abdominal infections (abscess, peritonitis) and subsequently disseminate. About 88.5% of these infections are caused by Candida and 14% are caused by Aspergillus. The overall mortality of Candida infections is 50% to 70% and nearly 100% for Aspergillus infections in these patients, Kidney transplant recipients have the lowest rate of fungal infections, with an incidence of 5%. The urinary tract is the most common site of fungal infections, especially with Candida, This can disseminate and lead to candidemia, which requires prompt therapy. In these patients fluconazole is well tolerated and is not nephrotoxic like amphotericin B. Cyclosporine levels need to be monitored because fluconazole can cause an increase in cyclosporine blood levels. A fluconazole dose of 200 mg/ day is effective for most infections. Most of the Candida strains are sensitive to fluconazole except C krusei, which is resistant and requires therapy with amphotericin B. Eighty-five percent of renal transplant recipients with aspergillosis present with pulmonary disease (Fig, 6). Early diagnosis with invasive biopsy procedures and institution of proper therapy are necessary for possible cure. Cryptococcus neoformans is a fungal infection that usually involves the lungs and the CNS. Prolonged fever is the most frequent symptom, occurring in 89% of the patients? There can be concurrent pulmonary and CNS disease; therefore, any patient with documented cryptococcal pulmonary disease should undergo lumbar puncture. Patients with unexplained pulmonary disease should have a cryptococcal antigen determination. Disease may be insidious or present with headache, seizures, and meningitis. Diagnosis is made by detection of the cryptococcal antigen in CSF, blood, or urine? India ink preparations and cultures may also demonstrate the organism. Therapy is with amphotericin B with or without 5-flucytosine. The use of 5-flucytosine in patients with renal insufficiency is difficult and requires careful monitoring of drug levels. The duration of therapy depends on the clinical response. Fluconazole is an effective suppressive agent, but no studies have demonstrated complete cure in transplant recipients. Mucor and Rhizopus are other fungal species that can produce locally invasive rhinocerebral infections, which can be very difficult to treat. These infections do not respond well to antifungal therapy, and reduction or discontinuation of immunosuppressive agents and repeated surgical debridement are necessary for cures. Relapse is frequent and disease is often fatal. Histoplasma capsulatum, Coccidioides immitis, Paracoccidioides immitis, and Blastomyces dermatitidis must be considered in patients from specific endemic areas. Infection initially involves the lungs and then disseminates. Diagnosis is made by histologic identification of the fungi in tissue or culture. A Histoplasma capsulatum radioimmunoassay that measures antigen in serum and urine has proved

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Figure 6. A and B, Chest radiographs of a renal transplant recipient treated with cyclosporine, azathioprine, and prednisone, who developed bilateral pulmonary nodules. One month previously, he was treated for rejection. He had been neutropenic. Fever and a cough developed. A transbronchial biopsy specimen revealed fungal elements consistent with Aspergillus. Within 10 days, the nodules had cavitated. The patient was treated with amphotericin.

useful in diagnosis. sI In coccidioidomycosis, complement fixation serologies are the most useful to diagnose the disease. Blastomycosis serologic tests have not proven to be beneficial owing to the increased frequency of false positives. Therapy of histoplasmosis and blastomycosis is amphotericin B. Recently itraconazole has been shown to be as effective with minimal toxicity. Standard therapy for coccidioidomycosis and paracoccidioidomycosis is amphotericin B. The use of azoles is controversial. Itraconazole appears to be more effective than ketoconazole. 75 SUMMARY

Infections remain a major problem for individuals who undergo solid organ transplantation. The risk of these infections is determined by previous or future environmental exposures as well as the patient's immune status. With the use of prophylactic antibiotics, antifungal agents, and the development of selective immunosuppressive agents, the incidence of infection should decrease. Rapid diagnosis and the institution of appropriate therapy are necessary for cure. Further investigation is required to determine the optimal prophylaxis necessary for disease prevention. ACKNOWLEDGMENT The authors wish to thank Estella Wheatley for excellent manuscript preparation.

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References 1. Arduino RC, Johnson PC, Miranda AG: Nocardiosis in renal transplant recipients undergoing immunosuppression with cyclosporine. Clin Infect Dis 16:505-512, 1993 2. Balfour HH, Chance BA, Stapleton JT, et al: A randomized, placebo-controlled trial of oral acyclovir for prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 320:1381-1387,1989 3. Berner J, Kadian M, Post J, et al: Prophylactic recombinant hepatitis B vaccine in patients undergoing orthotopic liver transplantation. Transplant Proc 25:1751-1752, 1993 4. Brayman KL, Dafoe DC, Smythe WR, et al: Prophylaxis of serious cytomegalovirus infection in renal transplant candidates using live human cytomegalovirus vaccine. Arch Surg 123:1502-1508, 1988 5. Brayman KL, Stepanian E, Matas AJ, et al: Analysis of infectious complications occurring after solid organ transplantation. Arch Surg 127:38-48, 1992 6. Carrier M, Pelletier GB, Cartier R, et al: Prevention of herpes simplex virus infection by oral acyclovir after cardiac transplantation. Can J Surg 35:513-516,1992 7. Chugh KS, Sakhuja V, Jain S, et al: Fungal infections in renal allograft recipients. Transplant Proc 24:1940-1942,1992 8. Cockfield SM, Preiksaitis JK, Jewell LD, et al: Post-transplant lymphoproliferative disorder in renal allograft recipients. Transplantation 56:88-96,1993 9. Dauber JH, Paradis IL, Dummer JS: Infectious complications in pulmonary allograft recipients. Clin Chest Med 11:291-308, 1990 10. Delaney V, Sumrani N, Hong JH, et al: Mycobacterial infections in renal allograft recipients. Transplant Proc 25:2288-2289, 1993 11. Denning DW, Stevens DA: Antifungal and surgical treatment of invasive aspergillosis: Review of 2,121 published cases. Rev Infect Dis 12:1147-1201, 1990 12. Denning DW, Tucker RM, Hanson LH, et al: Itraconazole in opportunistic mycoses: Cryptococcosis and aspergillosis. JAm Acad DermatoI23:602-607, 1990 13. Didier S, Muller R, Alexander G, et al: Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med 329:1842-1847,1993 14. Dummer SJ: Cytomegalovirus infection after liver transplantation: Clinical manifestations and strategies for prevention. Rev Infect Dis 12:767-775, 1990 15. Dummer SJ, Montero CG, Griffith BP, et al: Infections in heart-lung transplant recipients. Transplantation 41:725-729, 1986 16. Duncan SR, Paradis IL, Dauber JH, et al: Ganciclovir prophylaxis for cytomegalovirus infections in pulmonary allograft recipients. Am Rev Respir Dis 146:1213-1215, 1992 17. Dunn DL: Problems related to immunosuppression. Crit Care Clin 6:955-977,1990 18. Dunn DL, Mayoral JL, Gillingham KJ, et al: Treatment of invasive CMV disease in solid organ transplant patients with ganciclovir. Transplantation 51:98-106,1991 19. Dunn DL, Najarian JS: Infectious complications in transplant surgery. In Davis JM, Shires JG (eds): Principles and Management of Surgical Infections. Philadelphia, JB Lippincott, 1991, pp 425-464 20. Dunn DL, Najarian JS: New approaches to the diagnosis, prevention, and treatment of cytomegalovirus infection after transplantation. Am J Surg 161:250-255,1991 22. Fox BC, Sollinger HW, Belzer FO, et al: A prospective randomized double blind study of trimethoprim-sulfamethoxazole for prophylaxis of infection in renal transplantation: Clinical efficacy, absorption of trimethoprim-sulfamethoxazole, effects on the microflora and the cost-benefit of prophylaxis. Am J Med 89:225-274,1990 23. Freise CE, Pons J, Lake E, et al: Comparison of three regimens for cytomegalovirus prophylaxis in 147 liver transplant recipients. Transplant Proc 23:1498,1991 24. Gottesdiener KM: Transplanted infections: Donor-to-host transmission with the allograft. Ann Intern Med 110:1001-1016, 1989 25. Green M, Michaels MG: Infectious complications of solid-organ transplantation in children. Adv Pediatr Infect Dis 7:181-204, 1992 26. Griffin PJA, Salman JR: Urinary tract infections after renal transplantation: Do they matter? Br Med J 1:710-711, 1979

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27. Hanto OW, Frizzera G, Gajl-Peczalska KJ, et al: Epstein-Barr virus-induced B-cell lymphoma after renal transplantation: Acyclovir therapy and transition from polyclonal to monoclonal B-cell proliferation. N Engl J Med 306:913-918, 1982 28. Jereb JA, Burwen DR, Dooley SW, et al: Nosocomial outbreak of tuberculosis in renal transplant unit: Application of a new technique for restriction fragment length polymorphism analysis of Mycobacterium tuberculosis isolates. J Infect Dis 168:1219-1224, 1993 29. Johnson PC, Hogg KM, Sarosi GA: The rapid diagnosis of pulmonary infections in solid organ transplant recipients. Semin Respir Infect 5:2-9, 1990 30. Johnson PC, Lewis RM, Golden 0, et al: The adverse impact of cytomegalovirus infection on clinical outcome in cyclosporine-prednisone treated renal allograft recipients. Transplantation 45:353-359,1988 31. Keating MR, Wilhelm MR: Management of infectious complications following liver transplantation. Curr Clin Top Infect Dis 13:226-249, 1993 32. Kekec Y, Tavil S, Tokyay R, et al: Infections after kidney transplantation, Transplant Proc 24:1932-1933,1992 33. King CT, Chapman SW, Butkus DE: Recurrent nocardiosis in a renal transplant recipient. South Med J 86:225-228, 1993 34. Kirk JA, Stinson EB, Remington JS: Nocardia infection in heart transplant patients. Ann Intern Med 82:18-26, 1975 35. Korvich JA, Marsh WJ, Starzl TE, et al: Pseudomonas aeruginosa bacteremia in patients undergoing live!: transplantation: An emerging problem. Surgery 109:662-668, 1991 36. Kusne S, Dummer JS, Singh N, et al: Infections after liver transplant: Analysis of 101 consecutive cases. Medicine 67:132-143,1988 37. Kusne S, Reyes J, et al: Mycobacterium tuberculosis after liver transplantation: Management and guidelines for prevention. Clin TranspI6:81-90, 1992 38. Kyriack GK, Simmons RL, Najarian JS: Wound infections in renal transplant wounds: Pathogenetic and prognostic factors. Ann Surg 182:770-775, 1975 39. Levinson ML, Jacobson PA: Treatment and prophylaxis of CMV disease. Pharmacotherapy 12:300-318, 1992 40. Lewis RM, Johnson PC, Golden 0, et al: The adverse impact of cytomegalovirus infection on clinical outcome in cyclosporine-prednisone treated renal allograft recipients. Transplantation 45:353-359,1988 41. Lichtenstein IH, MacGregor RR: Mycobacterial infections in renal transplant recipients: Report of five cases and review of the literature. Rev Infect Dis 5:216-226,1983 42. Lutwick LI, Sywassink JM, Corry RJ, et al: The transmission of hepatitis B by renal transplantation. Clin NephroI19:317-319, 1983 43. Lynfield R, Gerrin JT, Rubin RH: Varicella in pediatric renal transplant recipients. Pediatrics 90:216-220, 1992 44. Mauer JR, Tullis ED, Grossman RF, et al: Infectious complications following isolated lung transplantation. Chest 101:1056-1059, 1992 45. Merigan TC, Renlund DG, Kaey S, et al: A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. N Engl J Med 326:1182-1191,1992 46. Metselaar HJ, Rothbarth PH, Brouwer RML, et al: Prevention of cytomegalovirusrelated death by passive immunization. Transplantation 48:264-266,1989 47. Mion F, Boillot 0, Gille 0, et al: Liver transplantation for posthepatitic B-delta cirrhosis: Prevention of recurrence with high-dose anti-HBs immunoglobulins. Transplant Proc 25:2638-2639,1993 48. Neuhaus P, Steffen R, Blumhardt G, et al: Experience with immunoprophylaxis and interferon therapy after liver transplantation in HBsAg positive patients. Transplant Proc 23:1522-1524, 1991 49. Paya CF: Fungal infections in solid-organ transplantation. Clin Infect Dis 16:677-688, 1993 50. Paya CV, Hermans PE, Washington JA II, et al: Incidence, distribution, and outcome of episodes of infection in 100 orthotopic liver transplantations. Mayo Clin Proc 64:555564, 1989 51. Peters TG, Reiter CG, Bowell RL: Transmission of tuberculosis by kidney transplantation. Transplantation 38:514-515, 1984 52. Peterson PK, Balfour HH, Fryd OS, et al: Fever in renal transplant recipients: Causes,

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Address reprint requests to Philip C. Johnson, MD Division of General Medicine The University of Texas Medical School at Houston 6431 Fannin, MSB 1.122 Houston, TX 77030