Current Diagnosis & Treatment in Infectious Diseases

Section III - Special Patient Populations

24. Infections in Transplant Recipients

Robin Patel MD

Essentials of Diagnosis

• Signs and symptoms include fever, chills, pulmonary infiltrates, skin rash, allograft dysfunction in transplant recipients.
• Distinguishing features include the following:

1. Type of transplant [liver, lung, heart, pancreas, kidney, small bowel, peripheral blood stem cell (PBSC), bone marrow].
2. Immunosuppression history (type, dose, duration).
3. Cytomegalovirus (CMV) serology of donor and recipient (pretransplant).
4. History of infectious diseases.
5. Exposures (travel, tuberculosis, animals, occupation, etc).

General Considerations

Solid-organ, PBSC and bone marrow transplantation have become therapeutic options for many human diseases. PBSC, bone marrow, liver, kidney, heart, and lung transplantation have become standard therapy for selected end-stage diseases. Pancreas (including islet cell) and small bowel transplantation are also being evaluated in this regard. PBSC involves using stem cells mobilized by the administration of recombinant human granulocyte macrophage colony-stimulating factor. There are several types of PBSC or bone marrow transplants:

• Allogeneic transplantation involves transplantation from a human leukocyte antigen identical or non-identical relative or an unrelated donor who is fully or partially matched for human leukocyte antigens.
• Syngeneic transplantation involves transplantation from an identical twin who is completely identical for all genetic loci.
• Autologous transplantation involves harvesting PBSC or bone marrow from a patient, treating the same patient with high doses of intensive chemotherapy and subsequently reconstituting the same patient with his/her own PBSC or bone marrow.

Infection remains a major complication of all types of transplantation. The optimal approach to infection in transplant recipients is prevention; failing this, its prompt and aggressive diagnosis and therapy are essential. The sources of infectious agents post-transplantation include endogenous organisms, the transplant allograft itself, and the environment. An important principle to consider when evaluating transplant recipients for infection is that the usual inflammatory response to an infectious organism may be attenuated as a result of immunosuppressive therapy and therefore that the signs and symptoms of infections may be blunted and diagnostic techniques may be compromised. Because of this, aggressive and often invasive investigations of seemingly minor findings may be warranted.

Pretransplantation Infectious Diseases Evaluation

Before transplantation, all potential candidates should be evaluated for active infection that may require therapy or preclude transplantation, risk factors for infection, including latent infections that might be reactivated post-transplantation, and the use of immunosuppressive agents. A complete history should be obtained, focusing on any history of infection and any unusual exposures (Table 24-1). A complete physical examination should also be performed. Table 24-1 outlines infectious disease tests that should be performed pretransplantation.

Further investigations are pursued depending on elicited risks. For example, serologic testing for Coccidioides immitis may be performed on a patient with a history of travel to or residence in the southwestern United States or Mexico. Patients who have traveled to or resided in an area where Strongyloides stercoralis is endemic should be examined for evidence of infection with this parasite. Lung transplant candidates should be evaluated for colonization of the respiratory tract with such agents as Aspergillus spp.

Timing of Post-Transplantation Infection

1. Solid-Organ Transplantation.There are three time frames, influenced by surgical factors, the level of immunosuppression, and environmental exposures, during which infections of specific types most frequently occur after solid-organ transplantation (Box 24-1). These include the first month; the second through the sixth months; and the late post-transplant period (beyond 6 mo).

Table 24-1. Clues to the diagnosis of infections in transplant recipients.

History o   Immunosuppressive therapy: type and duration (current or past) o   Antibiotic allergies o   Past medical history: infectious diseases Oral: dental caries, sinusitis, pharyngitis, herpes Respiratory: pneumonia, tuberculosis Cardiovascular: valvular heart disease, heart murmur (need for endocarditis prophylaxis) Gastrointestinal: diverticulitis, diarrheal disease, hepatitis A, B, and C, intestinal parasitic infection Genitourinary: urinary tract infections, prostatitis, vaginitis, genital herpes, genital warts, syphilis, gonorrhea, pelvic inflammatory disease, chlamydial infection Cutaneous: skin and nail infections, varicella zoster virus infection Osteoarticular: osteomyelitis; prosthetic joint(s) Childhood illnesses: chickenpox, measles, rubella Other: mononucleosis o   Vaccinations Exposure History o   Travel history: prior residence, travel, or both associated with the geographically restricted endemic mycoses, and/or parasitic disease, especially Strongyloides stercoralis, malaria, etc. o   Tuberculosis: exposure, prior tuberculous skin testing, chest x-ray abnormality o   Risk factors for bloodborne pathogen infection [including human immunodeficiency virus (HIV)] o   Animal and pet exposure (including vaccination status of pets) o   Brucella exposure o   Occupational exposure: farming, animal husbandry, gardening o   Drinking water source o   Exposure to young children o   Dietary habits: consumption of raw meat and seafood and unpasteurized milk products Complete Review of Systems Complete Physical Examination Laboratory Testing o   Pretransplantation: Tuberculin skin test Chest and sinus x-ray Urinalysis and urine culture for bacteria Serologic tests: cytomegalovirus, varicella zoster virus, Epstein-Barr virus, herpes simplex virus,* Toxoplasma gondii,** syphilis, hepatitis A virus, hepatitis B virus, hepatitis C virus, HIV, (coccidioides immitis if history of exposure present—see text) o   Post-transplantation: Cultures and stains for bacteria, viruses, fungi, mycobacteria, etc, as indicated Serologic testing as indicated **Heart transplant candidate *Optional

Most infections during the first month post-transplantation are related to surgical complications and are similar to infections occurring in general surgical patients. These include bacterial and candidal wound infections, pneumonia, urinary tract infections, line sepsis, and infections of biliary, chest, and other drainage catheters. In general, any episode of unexplained fever or bacteremia occurring in the early post-transplantation period should be suspected as being caused by technical or anatomical problems related to the allograft. In the first month post-transplantation, renal and pancreas transplant recipients are at risk for perigraft abscesses, infected or uninfected hematomas, lymphoceles, and urinary leaks. Liver transplant recipients are at risk for portal vein thrombosis, hepatic vein occlusion, hepatic artery thrombosis, biliary stricture formation and leaks, infected and uninfected hematomas and hepatic and perihepatic abscesses. Heart transplant recipients are at risk for mediastinitis and infection at the aortic suture line, with resultant mycotic aneurysm, and lung transplant recipients at risk for disruption of the bronchial anastomosis and pneumonia. The only common viral infection seen during the first month post-transplantation is reactivated herpes simplex virus (HSV) infection in individuals seropositive for this virus pretransplantation. The prophylactic use of acyclovir during this period, however, has significantly reduced the incidence of reactivated HSV infection.

The period from the second to sixth month postsolid-organ transplantation is the time during which infections “classically” associated with solid-organ transplantation manifest. Opportunistic pathogens such as CMV, Pneumocystis carinii, Aspergillus spp., Nocardia spp., Toxoplasma gondii, and Listeria monocytogenes manifest during this period. In addition, during the early and middle periods, reactivation disease syndromes are occasionally encountered because of organisms present in the recipient pretransplantation. The introduction of high-dose immunosuppression may result in clinical illness owing to reactivation of Mycobacterium tuberculosis, an occult focus of bacterial infection, viral hepatitis, Histoplasma capsulatum, or C immitis. Chronic or latent infection of the donor that involves the allograft, such as HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), or fungal or mycobacterial infection, may be transmitted to the immunosuppressed recipient and become clinically apparent during the early and middle periods.

From 6 months post-transplant onward, most solid-organ transplant recipients do relatively well, suffering from the same infections seen in the general community. These include influenza virus infection, urinary tract infection, and pneumococcal pneumonia.

The only opportunistic viral infection commonly seen during this period is reactivated varicella zoster virus (VZV) infection manifesting as shingles. Rarely, CMV retinitis occurs.

Two situations, however, predispose patients to other infections in this late post-transplant period. First, patients who have had frequent episodes of acute rejection requiring augmented immunosuppressive therapy or those with chronic rejection who are maintained at a high baseline level of immunosuppression remain at increased risk for the opportunistic agents more classically seen in the second to the sixth months post-transplant (CMV, P carinii, L monocytogenes, T gondii, Aspergillus spp., and Nocardia spp.). Second, patients with chronic infections such as HIV, HBV, and HCV infections, may suffer from morbidity associated with these agents.

1. PBSC and Bone Marrow Transplantation.There are three time frames within which the majority of infections develop after PBSC and bone marrow transplantation (Box 24-1). These include the first month after transplant (before engraftment); the second through the third month after transplant (engraftment); and the late post-transplant period, 3 months or later after transplant. During the first month after transplantation, before engraftment, granulocytopenia and damaged mucosal surfaces caused by pretransplant chemotherapy and radiotherapy are the predominant defects in host defenses. At this time, patients are most susceptible to infections caused by gram-negative and gram-positive aerobic bacteria and fungi. Reactivated HSV infections in patients previously seropositive for HSV are also common, similar to the situation in solid-organ transplant patients. And, similar to the situation in solid-organ transplant patients, the prophylactic use of acyclovir during this period has significantly reduced the incidence of reactivated HSV infection.

During the second to third month after PBSC and bone marrow transplant when engraftment has occurred, patients have profound impairment of both cellular and humoral immunity. These abnormalities are more severe and persist longer in patients with acute graft-versus-host disease (which is the major risk factor for infection during the second to third month after transplantation). Autologous and syngeneic transplant recipients who are not usually at risk for graft-versus-host disease experience significantly fewer and less severe infections after engraftment than allogeneic transplant recipients. Interstitial pneumonia related to CMV and pulmonary aspergillosis are the major infectious complications seen in patients with graft-versus-host disease, especially when high doses of immunosuppressive therapy are given for treatment. Gram-positive bacterial infections related to indwelling intravenous catheters, gram-negative bacteremia in patients with graft-versus-host disease of the gastrointestinal tract, pulmonary infection caused by adenovirus, respiratory syncytial virus, or parainfluenza virus, hemorrhagic cystitis caused by BK virus or adenovirus, as well as viral gastroenteritis, may be seen during this time period.

The period from 3 months onward after PBSC and bone marrow transplantation is characterized by gradual recovery over several months of both cellular and humoral immunity. The process of donor-derived immune reconstitution is generally complete by 1–2 years after transplantation. Except for reactivation of VZV infections (shingles) and infections of the respiratory tract caused by Streptococcus pneumoniae and Haemophilus influenzae or common respiratory viruses, PBSC and bone marrow transplant recipients without graft-versus-host disease experience relatively few late infections. Immune recovery, however, is seriously delayed by chronic graft-versus-host disease, which causes persistent and profound defects in both cellular and humoral immune responses. Decreased secretory IgG production, impaired splenic function, inadequate opsonizing antibody, and the bronchopulmonary sicca syndrome characteristic of chronic graft-versus-host disease contribute to respiratory tract infections. Late onset interstitial pneumonia that is caused by CMV or P carinii may occur in patients with ongoing graft-versus-host disease. The destructive effects of chronic graft-versus-host disease on mucocutaneous surfaces also provide a source for infection by staphylococci and other bacteria.

BOX 24-1 Microbiology of Infection in Solid-Organ Transplant Recipients

Solid-Organ Transplant Recipients First post-transplant month · Bacteria · Candida spp. · Herpes simplex virus Months 2-6 post-transplant · Cytomegalovirus · Pneumocystis carinii · Aspergillus spp. · Nocardia spp. · Toxoplasma gondii · Listeria monocytogenes · Mycobacterium tuberculosis · Histoplasma capsulatum · Coccidioides immitis From 6 months onward post-transplant · Respiratory viruses · Urinary tract infection · Streptococcus pneumoniae · Varicella zoster virus (reactivation) · Cytomegalovirus (retinitis) · Nontuberculous mycobacteria Anytime post-transplant · Cryptococcus neoformans · Hepatitis B or C · Human immunodeficiency virus PBSC and Bone Marrow Transplant Recipients First post-transplant month (neutropenia) · Herpes simplex virus · Candida spp. · Aspergillus spp. · Bacteria Second and third post-transplant months (acute graft-versus-host disease) · Cytomegalovirus · Aspergillus spp. · Bacteria · Adenovirus · RSV · Parainfluenza virus · BK virus From 3 months onward post-translant · Varicella zoster virus (reactivation) · S pneumoniae · Haemophilus influenzae · Respiratory viruses

BACTERIAL INFECTIONS

COMMON BACTERIAL INFECTIONS

Clinical findings and treatment of common bacterial infections in transplant recipients are discussed in the relevant syndrome and organism chapters (see chapter cross references below).

• A. Liver Transplant Recipients.Bacterial infections of the liver, biliary tract, peritoneal cavity, bloodstream, and surgical wound are the most commonly seen bacterial infections in liver transplant recipients (see Chapter 21). Most such infections occur within the first month (or two) after transplantation. Many of these infections are related to technical problems with the liver graft such as bile leaks or biliary obstruction. Bacterial liver abscesses are sometimes associated with biliary strictures but more often are related to ischemia of the allograft from thrombosis of the hepatic artery. Computed tomography, ultrasonography, cholangiography, and/or angiography are required to evaluate anatomic abnormalities. The flora of these infections typically involves enterococci, anaerobes, gram-negative enteric rods, and staphylococci. Risk factors for bacterial infections in liver transplant recipients include CMV infection, acute rejection, prolonged hospitalization, increased operative transfusion requirements, prolonged duration of surgery, rejection, reoperation, retransplantation, and elevated bilirubin or creatinine levels. In liver transplant recipients, the presence of a Roux-en-Y choledochojejunostomy increases the risk of sepsis overall, infectious complications related to liver biopsy, and enterococcal and pseudomonas bacteremia by facilitating reflux of enteric organisms into the biliary system and hence into the hepatic allograft.

Prevention

Selective bowel decontamination reduces gram-negative infections in liver transplant recipients.

• B. Lung Transplant Recipients.The most common type of bacterial infection in the lung transplant recipient is pulmonary (see Chapters 9 and 10). This is a result of denervation of the lungs and airways abolishing the cough reflex distal to the tracheal or bronchial anastomosis, impaired mucociliary clearance, and airway inflammation secondary to rejection. The anastomosis is particularly vulnerable to local pathogen colonization as suture material present may initiate a local immune response. Lung transplant recipients are also at risk for mediastinitis because of leaks from the airway anastomosis. Risk factors for bacterial pneumonia after single lung transplantation include underlying primary or secondary pulmonary hypertension in the presence of airway complications of stenosis or dehiscence.

Prevention

The incidence of bacterial pneumonia in lung transplant recipients may be dramatically reduced by the use of antimicrobial agents tailored to the results of cultures and stains for bacteria and fungi from the airways of the donor and recipient at the time of transplantation.

• C. Heart Transplant Recipients.Pulmonary infections are the predominant bacterial infections seen in heart transplant recipients (see Chapter 11). Other types of bacterial infections seen in heart transplant recipients include wound infections (of which midline sternotomy infection can be particularly devastating); bacteremia, which most commonly results from vascular catheter infection; and urinary tract infection (see Chapter 16).
• D. Renal Transplant Recipients.Renal transplant recipients are at risk for urinary tract infections (see Chapter 16). Multiple factors, including renal insufficiency, nutritional inadequacies, decreased amounts of urine flowing across the uroepithelium, opportunities for sepsis from dialysis accesses, underlying diabetes mellitus, and/or polycystic kidney disease, contribute to this increased incidence. Patients who receive a simultaneous pancreas transplant with bladder drainage have the added risk of enzymatic digestion of the protective glycosaminoglycan layer overlying the uroepithelium. In addition, the change in urinary pH caused by urinary, pancreatic, and endocrine secretions and underlying glycosuria favor bacterial urinary tract infection in combined kidney and pancreas transplant recipients. Pathogens causing urinary tract infections in renal transplant recipients include enterococci, staphylococci, and Pseudomonas aeruginosa, in addition to the usual enteric gram-negative bacteria. Wound infections may also be seen.

Prevention

Prophylaxis with trimethoprim-sulfamethoxazole reduces the incidence of bacterial infection of the urinary tract and bacteremia after renal transplantation. However, controversy exists regarding the exact dosing, timing, and duration of trimethoprim-sulfamethoxazole for urinary tract infection prophylaxis in renal transplant recipients.

• E. Pancreas and Small Bowel Transplant Recipients.The most common bacterial infections in pancreas transplant recipients are wound and intra-abdominal infections (see Chapters 12 and 13). Human small bowel transplant recipients are likewise at risk for intra-abdominal and wound infections.
• F. PBSC and Bone Marrow Transplant Recipients.Since the early 1980s, the bacterial causes of infection in patients undergoing PBSC and bone marrow transplantation during the initial 3 mo after transplant have changed from predominantly gram-negative bacillary organisms to mostly gram-positive organisms. The extensive use of indwelling central intravenous catheters, more severe cases of oral mucositis from chemotherapeutic agents, the administration of oral quinolones for prophylaxis, and the empiric treatment of febrile episodes with antibiotics directed primarily against gram-negative bacilli have likely contributed to this rise in gram-positive bacterial infections. Coagulase-negative staphylococci, viridans streptococci, Staphylococcus aureus, and Corynebacterium spp. are the most common gram-positive bacterial pathogens seen in this group of patients.

An increased risk of both colonization and bacteremia caused by viridans streptococci has been associated with quinolone prophylaxis in PBSC and bone marrow transplant recipients. Septic shock and the adult respiratory distress syndrome are occasionally seen in association with viridans streptococcal bacteremia. Despite the apparent decline in gram-negative bacterial infections, the possibility of infection caused by Escherichia coli and other Enterobacteriaceae, as well as P aeruginosa and other nonfermenting gram-negative bacilli, must still be considered when decisions about empiric antibiotic therapy are being made.

Bacteremia and soft tissue infections are the most common presentations of bacterial infections during the initial months after PBSC and bone marrow transplant (see Chapter 13). Exit site infections of intravenous catheters, infections involving the perirectal area, and oral mucositis are common local types of bacterial infection. Bacterial infections of the respiratory tract may occur at anytime, including 4 or more months after transplantation. At this later time period, encapsulated bacteria (eg, S pneumoniae and H influenzae) are frequent pathogens that may cause pneumonia, bronchitis, sinusitis, and, less commonly, meningitis.

Prevention

Bacterial infections in PBSC and bone marrow transplant patients with graft-versus-host disease after engraftment may be prevented by prophylaxis with trimethoprim-sulfamethoxazole. Oral chemophylaxis with quinolones in granulocytic patients is widely used. Oral quinolones are well tolerated and eliminate most gram-negative bacterial infections. The use of quinolones for prophylaxis is, however, controversial.

LEGIONELLA SPECIES

General Considerations

Legionella infection can occur in any type of transplant recipient, can be nosocomial or community acquired, and can be seen at any time post-transplant. Legionella pneumophila is the most common species involved but Legionella micdadei, Legionella bozemanii, Legionella dumoffii, and other Legionella spp., may be pathogens in transplant recipients. More details are found in Chapter 58.

Clinical Findings

1. Signs and Symptoms.Legionellainfection typically causes pneumonia with symptoms of fever, chills, headache, diarrhea, chest pain, malaise, dyspnea, and cough.
2. Laboratory Findings.Prompt request for diagnostic tests for Legionellaspp. including direct fluorescent antibody testing and culture of sputum or bronchoalveolar lavage specimens as well as urinary antigen testing in any patient with suspected legionellosis is recommended. Serologic testing is of limited usefulness because of the need to obtain acute and convalescent phase titers and because seroconversion is not specific for Legionella infection. Furthermore, the humoral response may be compromised in transplant recipients. Molecular diagnostic assays are under development.
3. Imaging.Pulmonary infiltrates are typically seen on chest X-ray.

Treatment

Treatment is classically with a quinolone or macrolide with or without rifampin (Box 24-2). If legionellal pneumonia is nosocomial, a search should be made for sources of legionella in the environment, especially in the hot water supply and ventilation systems.

NOCARDIA SPECIES

General Considerations

Nocardial infections have been reported to occur in all types of transplant recipients. Nocardial infection is most commonly caused by Nocardia asteroides, but other species of Nocardia may also cause infections in transplant recipients. More details are found in Chapter 63.

Clinical Findings

1. Signs and Symptoms.The most common presentation is pulmonary and includes fever and cough. Central nervous system and cutaneous infections may be present.
2. Laboratory Findings.Gram and modified acid fast stains and cultures of sputum or bronchoalveolar lavage fluid are useful in the diagnosis of pulmonary nocardial infection. All transplant patients with nocardiosis should be evaluated for central nervous system disease.
3. Imaging.Pulmonary infiltrates, pleural effusions, cavitating lesions, or nodules may be visualized on chest x-ray. Nocardial brain abscess, inflamed meninges, and ventriculitis may also be seen.

Treatment

Sulfonamides, either alone or in combination with trimethoprim, are the treatment of choice for nocardiosis (Box 24-2). Alternatives include minocycline, chloramphenicol, erythromycin, amikacin, ampicillin, amoxicillin-clavulanate, ciprofloxacin, imipenem, meropenem, ceftriaxone, cefuroxime, and cefotaxime, but antibiotic susceptibility testing should be performed because resistance may be present. Antimicrobial therapy should be continued for a prolonged period after cure because of the tendency for relapse, although the optimal duration of therapy is unknown.

Prevention

Trimethoprim-sulfamethoxazole used for P carinii prophylaxis may prevent nocardiosis (Box 24-3).

SALMONELLA SPP.

There is an increased incidence of salmonellal infection in renal transplant recipients. The most common presentation is a febrile illness with bacteremia. Salmonella infections are discussed further in Chapter 53.

LISTERIA MONOCYTOGENES

General Considerations

Transplant recipients are at greatest risk for infection caused by L monocytogenes during the first 2–3 mo after transplant, but listerial infection may occur at any time after transplant. Listeriosis occurs in all types of transplant patients and may be transmitted via contaminated food. It is most commonly seen from the months of July through October. More details are found in Chapter 51.

BOX 24-2 Empiric Therapy of Infections in Transplant Recipients

Common bacteria · Multiple regimens (see specific chapters cited in text) Legionella spp. · Quinolone or · Erythromycin (1 g IV or orally 4 times daily) +/- rifampin (600 mg IV or orally once or twice daily) · Another macrolide Nocardia spp. · Sulfonamides [eg sulfadiazine (1.5-2.0 g four times daily) or trimethoprim-sulfamethoxazole (15 mg/kg/d IV or orally, in three divided doses)] Listeria monocytogenes · Ampicillin (200 mg/kg/day IVin six divided doses) plus gentamicin (6 mg/kg/d IV in four divided doses); trimethoprim-sulfamethoxazole is an alternative Cytomegalovirus · Ganciclovir (5 mg/kg IV twice daily) Herpes simplex virus mucocutaneous disease · Acyclovir (200 mg orally 5 times daily or 400 mg orally 3 times daily or 5 mg/kg IV every 8 h); alternatives include famciclovir, valacyclovir, and foscarnet Varicella zoster virus · Localized dermatomal VZV: acyclovir (10 mg/kg IV every 8 h or 800 mg orally 5 times daily for 7-10 d); alternatives include famciclovir (500 mg orally three times daily) or valacyclovir (1000 mg orally 3 times daily) · Primary VZV infection: acyclovir (10 mg/kg IV every 8 h) plus VZ immune globulin. Epstein-Barr virus (see Table 24-2) Fungi · Amphotericin B* (0.3-1.5 mg/kg IV daily) or · Fluconazole (100-800 mg IV or orally daily) +/- flucytosine (100-150 mg/kg/d orally in four divided doses) or · Itraconazole (200-800 mg orally, once or twice daily) Pneumocystis carinii · Trimethoprim-sulfamethoxazole (15-20 mg/kg/d IV or orally in divided doses) or · Pentamidine (4 mg/kg/d IV for 14-21 days.) Strongyloides stercoralis · Thiabendazole (50 mg/kg/d in two divided doses) or ivermectin (200 µg/kg/d) Toxoplasma gondii · Clindamycin (400-600 mg orally or 600-1200 mg IV, 4 times daily) and pyrimethamine (50-100 mg orally daily) or · Sulfadiazine (1-1.5 g orally, 4 times daily) and pyrimethamine (50-100 mg orally daily) *A lipid preparation of amphotericin B may be appropriate (varicol close)

Clinical Findings

1. Signs and Symptoms.Two-thirds of infected transplant patients have infections involving the central nervous system including meningitis, meningoencephalitis, and encephalitis, and one-third have primary bacteremia. Patients with meningitis present with headache, fever, signs of meningeal irritation, depressed level of consciousness, seizures, and/or focal neurological defects. The portal of entry for L monocytogenesis the gastrointestinal tract, and patients may report cramps and diarrhea as the initial manifestations of their infection.
2. Laboratory Findings.In patients with central nervous system infection, cerebrospinal fluid examination often, but not always, reveals a predominance of polymorphonuclear leukocytes, a low concentration of glucose, and a negative Gram stain. Importantly, L. monocytogenesmay be confused with diphtheroids in Gram-stained smears of pus or sputum.

BOX 24-3 Control of Infections in Transplant Recipients

Prophylactic Measures Pretransplant infectious disease evaluation See Table 24-1 Vaccinations (administered following PBSC and bone marrow transplantations) · Tetanus-diphtheria (12, 14 and 24 months post-transplant) · Influenza (annual, lifelong, before and ≥6 months post-transplant) · Pneumococcus (23-valent, 12 and 24 months post-transplant) · Hepatitis B (12, 14 and 24 months post-transplant) · Haemophilus influenzae type B (12, 14 and 24 months post-transplant) · Polio (inactivated) (12, 14 and 24 months post-transplant) · MMR (live-attenuated, ≥24 months post-transplant and 2nd dose 6-12 months after) Vaccinations (administered prior to solid-organ transplantation) · Varicella zoster virus for non-immune solid organ transplant candidates (see text for cautions) · Tetanus-diphtheria (booster, or primary series as appropriate) · Pneumococcus (23-valent) · Hepatitis A virus (series, if non-immune) · Hepatitis B virus (series, if non-immune) · Influenza (annual, lifelong) Cytomegalovirus prophylaxis · Ganciclovir (1 g orally 3 times daily or 5 mg/kg IV daily to twice daily) · Valacyclovir (2 g orally 4 times daily) · Immune globulin (various regimens) · Acyclovir (800 mg orally 4-5 times daily or 5 mg/kg IV 3 times daily) · Protective matching · CMV seronegative, filtered, or leukocyte-poor blood products Herpes simplex virus stomatitis prophylaxis · Acyclovir (200 mg orally 3 times daily or 400 mg orally 2 times daily) · Valacyclovir (500 mg orally daily) Varicella zoster virus prophylaxis · Immune globulin and/or acyclovir on exposure · Vaccination (see above) Pneumocystis carinii prophylaxis · Trimethoprim-sulfamethoxazole (either 1 single strength or 1 double strength tablet every day or 1 double strength tablet 2 or 3 times daily on 2 days of the week)1 · Pentamidine (300 mg nebulized monthly) · Atovaquone (1500 mg orally daily) · Dapsone (50 mg orally twice daily or 100 mg daily) Toxoplasma gondii prophylaxis · Trimethoprim-sulfamethoxazole (see above for P carini dosages) · Pyrimethamine (25 mg orally daily) Bacterial infection prophylaxis (PBSC and bone marrow transplant recipients) · Quinolone (various regimens) Fungal infection prophylaxis (PBSC and bone marrow and select solid organ transplant recipients) · Fluconazole (400 mg orally or IV daily) Mycobacterium tuberculosis infection prophylaxis · Isoniazid (300 mg orally daily) Isolation Precautions Avoidance of epidemiologic exposures post-transplantation · See text Mycobacterium tuberculosis · Airborne isolation Varicella zoster virus infection · Avoid contact if VZV nonimmune Cytomegalovirus infection · Universal precautions 1May also prevent nocardiosis, toxoplasmosis, and some bacterial infections.

Treatment

Intravenous ampicillin and gentamicin are recommended for treatment (Box 24-2). Trimethoprim-sulfamethoxazole is also effective.

Prevention

Trimethoprim-sulfamethoxazole, used for P carinii prophylaxis, may additionally prevent listeriosis (Box 24-3).

VIRAL INFECTIONS

CYTOMEGALOVIRUS

General Considerations

CMV is extensively discussed in Chapter 33. CMV infection occurs in the majority of solid-organ and allogeneic PBSC and bone marrow transplant recipients, primarily in the first 3 mo post-transplant. CMV infection also occurs in 40–45% of recipients of syngeneic or autologous PBSC and bone marrow transplant recipients, but symptomatic infections are infrequent in these groups. CMV may be transmitted to transplant recipients via infected donor material or transfused cellular products.

Three major patterns of CMV transmission are observed in transplant recipients. Primary infection develops when a CMV seronegative individual receives cells latently infected with the virus from a seropositive donor followed by viral reactivation. Secondary infection or reactivation infection develops when endogenous latent virus is reactivated in a CMV seropositive individual post-transplantation. Superinfection or reinfection occurs when a seropositive recipient receives latently infected cells from a seropositive donor and the virus that reactivates post-transplantation is of donor origin.

After primary infection with CMV, long-term cellular and humoral immunity usually develop, but CMV remains latent or persistent within the host. Viral persistence is controlled in the immunocompetent host by an intact cellular immune system. Immunosuppression administered after transplantation may lead to uncontrolled viral replication and consequently symptomatic CMV infection. A solid-organ transplant recipient without prior immunity to CMV pretransplantation who receives an organ containing latent or persistent virus (primary infection) is at higher risk of uncontrolled viral replication than a patient who has prior immunity to CMV pretransplantation (secondary infection or reinfection). In PBSC and bone marrow transplant recipients the CMV seropositive recipient with a CMV seronegative donor is at higher risk of uncontrolled viral replication than patients in other serologic groups. Likewise, the higher the degree of immunosuppression, the higher the risk of uncontrolled viral replication. In solid-organ transplant recipients, the use of antilymphocyte preparations (eg. OKT3 monoclonal antibodies) and fulminant hepatitis at the time of transplantation (in liver transplant recipients) are risk factors for symptomatic CMV infection. Graft-versus-host disease is a risk factor for CMV infection in PBSC and bone marrow transplant recipients.

In the immunosuppressed transplant recipient, CMV has four major effects:

1. It causes infectious diseases syndromes (see below).
2. It has been implicated in causing increased immunosuppression, which may explain the frequent association of CMV with other opportunistic infections such as fungal and Pneumocystisinfections.
3. It has been associated with allograft rejection in the form of early onset allograft rejection in renal transplant recipients and chronic allograft rejection (allograft atherosclerosis) in cardiac transplant recipients (in some, but not all, studies) as well as possibly the vanishing bile duct syndrome in liver transplant recipients (controversial).
4. It has been implicated in exerting a negative effect on survival after solid-organ transplantation.

CMV infection therefore has a potential impact on both patient and graft outcome.

Clinical Findings

1. Signs and Symptoms.CMV infection exhibits a wide range of clinical manifestations from asymptomatic infection to severe lethal CMV disease. Most cases of CMV disease after transplantation are of mild to moderate severity and are rarely fatal in the current decade. Manifestations of mild to moderate disease include fever and malaise without additional signs or symptoms. Myalgias, arthralgias, and, at times, arthritis may occur.

Organ involvement by CMV correlates with the organ transplanted as follows: Hepatitis occurs most frequently in liver transplant recipients; pancreatitis occurs most frequently in pancreas transplant recipients; and pneumonitis occurs most frequently in lung, heart and lung, and PBSC and bone marrow transplant recipients. Gastroenteritis is also frequently seen in PBSC and bone marrow transplant recipients. In addition, myocarditis, although rare, typically presents in heart transplant recipients. Other sites of involvement of CMV include the gallbladder, pancreas, epididymis, biliary tract, retina, skin, endometrium, and central nervous system. CMV retinitis is distinctive in that it usually presents > 6 mo post–solid-organ transplantation.

1. Laboratory Findings.CMV may be associated with leukopenia or thrombocytopenia. The diagnosis of CMV infection in tissue has traditionally been based on the recognition of cytomegalic inclusion bodies. CMV may also be detected in tissue specimens by immunohistochemistry or DNA hybridization techniques. Tube cell culture and shell vial culture techniques can be used to detect replicating CMV in body fluids and tissue with the former having the disadvantage of taking 7–14 days of incubation for CMV to exhibit cytopathic effect. The rapid shell vial culture technique, however, can detect the presence of CMV after 16 hours of incubation. Importantly, akin to bacterial blood cultures, multiple viral blood cultures may be necessary to detect CMV by the shell vial assay. Detection of CMV antigenemia in blood leukocytes of transplant recipients is at least as sensitive as and more rapid than the shell vial technique and provides an earlier marker of CMV infection.

Molecular techniques can detect CMV DNA in peripheral blood leukocytes, whole blood, serum, plasma, and other clinical specimens and can detect CMV RNA in peripheral blood leukocytes and whole blood.

The serologic diagnosis of CMV infection is suboptimal compared to the above techniques; many patients with positive CMV cultures do not show concomitant evidence of seroconversion. Serologic testing, however, is recommended for the pretransplantation evaluation of the CMV serostatus of transplant donors and recipients.

Treatment

Effective currently available antiviral agents for the treatment of CMV include ganciclovir, foscarnet, cidofovir, and intravenous immune globulin (Box 24-2). In solid-organ transplant recipients, intravenous ganciclovir is the mainstay of therapy. Ganciclovir alone is generally of little benefit for treatment of either CMV pneumonia or gastroenteritis in PBSC and bone marrow transplant recipients, although the combination of intravenous ganciclovir plus intravenous immune globulin appears to have some efficacy. The absorption of ganciclovir after oral administration is low, and its use cannot be recommended for the treatment of CMV infection and disease after transplantation.

Side effects of ganciclovir include leukopenia, thrombocytopenia, anemia, nausea, infusion site reactions, diarrhea, renal toxicity, seizures, mental status changes, fever, rash, and abnormal liver function tests. Hematologic and renal function should be monitored while patients are receiving ganciclovir. Renal toxicity may occur when ganciclovir is used in conjunction with other nephrotoxic agents such as amphotericin B, azathioprine, aminoglycosides, and cyclosporine.

The possibility of viral resistance should be considered in patients with poor clinical response or persistent viral excretion during ganciclovir therapy. Mutations in viral thymidine kinase and/or DNA polymerase genes mediate resistance.

Prevention

1. Selection of Organs from CMV Seronegative Donors for CMV Seronegative Recipients.Knowledge of the CMV serostatus of the donor and recipient pretransplant will predict which patients will develop CMV disease. Although the solid-organ transplant patient at highest risk for development of CMV infection is the seronegative recipient of a seropositive allograft, protective matching of seronegative donors and recipients is not currently advocated (Box 24-3).

1. Use of CMV Seronegative, Filtered, or Leukocyte-Poor Blood Products.The use of CMV seronegative, filtered, or leukocyte poor blood products reduces CMV transmission, and these should be used at least in seronegative recipients.
2. Active Immunization with a Vaccine.In theory, one of the simplest interventions for the prevention of CMV disease after transplantation would be immunization of seronegative recipients with a vaccine given once in anticipation of future viral challenge. A live attenuated CMV vaccine, which uses the Towne strain of virus, is both safe and immunogenic; however, there is no significant decrease in the incidence of CMV disease in renal transplant recipients receiving this vaccine. New interest in developing a vaccine subunit product has emerged over the last few years. A subunit vaccine containing recombinant glycoprotein B, which is being developed by several biotechnology companies, is undergoing clinical trials.
3. Passive Immunization with Immune Globulins.Immune globulin preparations (including unscreened or unselected and hyperimmune globulin preparations) have been studied as agents for CMV prophylaxis. In solid-organ transplant recipients, intravenous immune globulins have been shown to be effective in preventing CMV disease in renal and non-high-risk (CMV-seropositive donor/CMV-seronegative recipient) liver transplant recipients. It appears that, at least in solid-organ transplant recipients, hyperimmune globulin is more effective in this role than standard immune globulin. Notably, immune globulin prophylaxis typically costs several thousand dollars per patient.
4. Prophylaxis with Antiviral Agents.Oral acyclovir has little role in preventing CMV after transplantation with the exception of possible efficacy in renal transplant recipients. Oral valacyclovir has been shown to be effective in preventing CMV infection and disease in renal transplant recipients. Prophylactic intravenous ganciclovir can prevent CMV disease in PBSC and bone marrow transplant recipients but is associated with neutropenia.

On the basis of published randomized trials, a 2-week course of intravenous ganciclovir may be considered for CMV prophylaxis in certain solid-organ transplant recipients; a 4-week course is recommended for CMV seropositive recipients of heart allografts. Intravenous ganciclovir alone is not effective, however, in solid-organ transplant populations at highest risk for CMV disease, including lung transplant recipients and donor CMV seropositive recipients CMV seronegative individuals, unless it is administered for a prolonged period (90 days). The studies to date have used intravenous ganciclovir, which is not ideal because of the ongoing need for intravenous access and the costs engendered. In this regard, oral ganciclovir has been shown as effective in preventing CMV infection and disease in liver and kidney transplant recipients and has been widely adapted for CMV prophylas, replacing intravenous ganciclovir in most instances.

Limitations associated with oral ganciclovir use include the need to take multiple tablets each day, cost, potential emergence of ganciclovir-resistant CMV stains, and the emergence of late onset CMV disease (following discontinuation of prophylacis). New agents, such as valganciclovir as well as other promising compounds that are being developed, may provide improved CMV prophylacis for solid-organ and PBSC and bone marrow transplant recipients.

1. Adoptive Transfer of CMV Specific T-Cell Clones Generated from the Donor.The development of CMV specific cytotoxic T-lymphocyte responses enhances survival from serious CMV infections. Thus, adoptive transfer of CMV specific T-cell clones generated from the PBSC or bone marrow donor is being studied as an approach to restoring immunity to CMV in the PBSC or marrow recipient.
2. Preemptive Therapy.Preemptive therapy of CMV involves the administration of antiviral agents to a subgroup of patients before the appearance of disease. This is dependent on a laboratory marker or patient characteristic that identifies a subgroup of individuals at high risk of disease at a time when antimicrobial intervention would be maximally effective in aborting the disease process. Compared with a prophylactic approach of administering antiviral agents to all patients, only patients at risk of developing symptomatic CMV infection receive specific antiviral therapy. Therefore fewer patients receive an antiviral agent and probably for a shorter period, leading to advantages in terms of cost, emergence of resistant viral strains, and medication side effects.

Candidate laboratory tests for this therapeutic mode include molecular and antigenemia tests. Many transplantation programs are using molecular or antigenemia tests to monitor their transplant recipients after transplantation and intervening with preemptive therapy based on a positive result.

Identifying patient characteristics that place the transplant recipient at risk for CMV infection is another facet of preemptive therapy. Such risk factors include the use of OKT3 monoclonal antibodies in solid-organ transplant recipients and the presence of fulminant hepatitis at the time of transplantation in liver transplant recipients. Many transplantation programs are intervening with preemptive ganciclovir when antilymphocyte therapy is used in solid-organ transplant recipients. A similar approach based on other risk factors requires further study but may also be beneficial.

 

HERPES SIMPLEX VIRUS

General Considerations

Herpes simplex virus most commonly causes reactivation infection but may cause primary infection transmitted by person to person contact or via the transplant donor. Herpes simplex virus antibodies are found in three-quarters of adult transplant recipients. After primary infection, the virus remains latent in sensory nerve ganglia. Herpes simplex virus infection occurs in all types of transplant recipients. More information is found in Chapter 33.

Clinical Findings

1. Signs and Symptoms.Herpes simplex virus reactivation results in oral or genital mucocutaneous lesions usually during the first month after transplant. Herpes simplex virus occasionally causes pneumonitis, tracheobronchitis, esophagitis, hepatitis, or disseminated infection.

Most orolabial infections are mild, although severe ulceration and discomfort, which may be complicated by bacterial superinfection or esophageal involvement, are noted in some patients. Anogenital infection usually presents as large areas of ulceration and may or may not have the typical vesicular appearance of HSV infection in the nonimmunocompromised host.

Herpes simplex virus can cause pneumonia and may be associated with a high mortality rate. This usually occurs as a secondary pneumonia in intubated patients with severe pneumonia caused by other agents. The virus is reactivated in the oropharynx. The mucosa is traumatized by the endotracheal tube, and the virus is presumably spread via the endotracheal tube to the lower respiratory tract. Certain caveats must be noted. Herpes simplex virus isolated from sputum or other respiratory secretions does not definitively imply HSV pneumonitis. Also, even if HSV is believed to be causing pneumonitis, another pathogen should be sought as HSV is often a secondary pathogen.

Herpes simplex virus esophagitis causes dysphagia and mimics candidal esophagitis. Esophagitis may complicate orolabial infection, particularly if the mucosa has been traumatized by endotracheal intubation or nasogastric tubes. Herpes simplex virus is also a cause of diffuse or focal hepatitis in solid-organ transplant recipients, usually during the first 2 months after transplantation. Diffuse or focal hepatitis secondary to herpes simplex virus is characterized by a rapidly progressive course accompanied by hypotension, disseminated intravascular coagulation, metabolic acidosis, gastrointestinal bleeding, and associated bacteremia. Disseminated HSV disease may rarely occur. Uncommonly, disseminated cutaneous infection with HSV may occur at sites of previous skin injury such as burns or eczema (eczema herpeticum).

1. Laboratory Findings.The diagnosis is made by performing a direct immunofluorescence test, Tzanck test, molecular diagnostic assay or culture of tissue and body fluids or both. Typing of isolates may be performed by a variety of techniques. Serologic techniques are helpful in the determination of the pretransplantation serologic status of transplant recipients.

Treatment

Treatment of HSV infection is with acyclovir (Box 24-2). Side effects of acyclovir include local inflammation or phlebitis after intravenous infusion, renal toxicity caused by precipitation and crystallization of the drug in the renal tubules, confusion, delirium, lethargy, tremors, seizures, nausea, light-headedness, diaphoresis, and rash. Mucocutaneous infection in transplant recipients should be treated with oral acyclovir if the infection has a benign course or with intravenous acyclovir in more serious cases. Disseminated or deep HSV infection should always be treated with intravenous acyclovir.

Newer agents, such as famciclovir and valacyclovir, may be used instead of acyclovir. Although more toxic than acyclovir, ganciclovir and foscarnet are also effective against HSV. A concern with respect to chronic acyclovir use is the development of acyclovir resistant mutants of HSV. Acyclovir resistance may arise from mutations in the genes for thymidine kinase or DNA polymerase. Acyclovir resistance has been associated with progressive and severe disease in immunocompromised patients, particularly in those with HIV, and it is possible that resistance will become a problem for transplant recipients in years ahead.

Prevention

Low-dose acyclovir prevents HSV stomatitis in transplant recipients (Box 24-3).

VARICELLA ZOSTER VIRUS

General Considerations

Varicella zoster virus causes two distinct clinical diseases after transplant. Ninety percent of adult transplant recipients are VZV seropositive pretransplant; VZV reactivation in this group will cause herpes zoster (shingles). The remaining 10% are VZV seronegative and thus are at risk for primary infection. More information is found in Chapter 33.

Clinical Findings

1. Signs and Symptoms.Localized dermatomal reactivation results in herpes zoster and may involve two or more adjoining dermatomes. There may be a few sites of cutaneous dissemination at distant sites. Additionally, a syndrome of unilateral pain without skin eruption associated with rises in specific antibody to VZV has been described in transplant patients. Primary VZV infection occurs after exposure of a VZV seronegative transplant recipient to VZV. The virus is transmitted by contact with an infected individual (usually via the respiratory route). This can occur at any time after transplantation and, although rare, can cause a life-threatening disseminated infection characterized by hemorrhagic pneumonia, skin lesions, encephalitis, pancreatitis, disseminated intravascular coagulation, and hepatitis. Primary VZV can also cause a chickenpox syndrome or hepatitis alone.

1. Laboratory Findings.Unilateral vesicular lesions in a dermatomal pattern are usually sufficiently characteristic of herpes zoster to enable a clinical diagnosis; however, culture of VZV on susceptible cell lines, demonstration of multinucleated giant cells on Tzanck smear, and/or direct immunofluorescence or identification of VZV using molecular techniques is recommended for confirmation. These techniques can also be used for diagnosis of primary infection.

Treatment

For localized dermatomal zoster, the recommended treatment is intravenous acyclovir (Box 24-2). Oral famciclovir, valacyclovir, or acyclovir may be used as an alternative. For primary VZV infection, treatment consists of intravenous acyclovir in addition to varicella zoster immune globulin.

Prevention

Because of the high mortality rate associated with primary VZV infection in transplant recipients, all candidates should be screened for antibody to VZV pretransplantation (see Box 24-3). Seronegative individuals should be urged to report promptly all exposures to VZV and varicella zoster immune globulin should be administered within 96 hours of exposure. Intravenous acyclovir should be administered within 24 hours of eruption of a skin rash if one occurs. Unfortunately, progression to severe disease and death can still occur. The use of low-dose acyclovir as HSV prophylaxis probably prevents VZV reactivation and possibly primary infection, although this has not been formally studied. Despite concerns regarding the use of live vaccines in transplant recipients, a recent study has demonstrated the safety of the VZV vaccine in pediatric renal transplant recipients. This vaccine should preferably be administered several months prior to solid-organ transplant, should reduce morbidity in seronegative solid-organ transplant recipients, and should provide considerable cost savings.

Table 24-2. Treatment of EBV-related conditions in the solid-organ recipient.1

Conditions Clinical Findings Treatment Outcome Uncomplicated post-transplantation infectious mononucleosis Fever, pharyngitis, cervical adenopathy, {+/-} splenomegaly · Acyclovir Good Benign polyclonal polymorphic Fever, pharyngitis, cervical adenopathy, · Acyclovir, ganciclovir, (+/-) ↓ immunosuppression Good B-cell hyperplasia Early malignant transformation in polyclonal polymorphic B-cell lymphoma Fever, (+/-) pharyngitis, adenotherapy · Acyclovir, ganciclovir, ↓ immunosuppression, IFN-α,2 gamma globulin, anti-B-cell monoclonal antibodies Intermediate Monoclonal polymorphic B-cell Solid tumor masses in allograft, soft tissue, brain, gastrointestinal tract, lung, liver · ↓ Immunosuppression, chemotherapy, radiation therapy, resection Poor 1Adapted, with permission, from Hanto DW: Classification of Epstein-Barr virus-associated post-transplant lymphoproliferative diseases: implications for understanding their pathogenesis and developing rational treatment strategies. Annu Rev Med 1995; 46: 381. 2IFN, interferon.

It is important to keep in mind that although most infections in transplant recipients are not communicable to health care workers, contact with a patient who has VZV infection, be it shingles or chickenpox, is a risk for all seronegative contacts including healthy staff working in transplant centers.

EPSTEIN BARR VIRUS

General Considerations

Epstein Barr virus (EBV) infection in transplant recipients may be associated with post-transplantation lymphoproliferative disease (PTLD), which is a significant cause of morbidity and mortality (Table 24-2). Post-transplantation lymphoproliferative disease occurs in solid-organ transplant recipients as well as in PBSC and bone marrow transplant recipients. The term PTLD acknowledges the fact that these lesions are heterogeneous and may not meet the diagnostic criteria for lymphoma. The spectrum of PTLD ranges from polyclonal to monoclonal. Monoclonal lesions may or may not contain detectable chromosomal abnormalities. PTLD is often multicentric and may involve the central nervous system, eyes, gastrointestinal tract, liver, spleen, lymph nodes, lungs, allograft, oropharynx, and other organs.

The pathogenesis of PTLD involves EBV replication often stimulated by antilymphocyte therapy, followed by cyclosporin-induced inhibition of virus specific cytotoxic T lymphocytes that normally control the expression of EBV infected, transformed B cells.

Risk factors for PTLD include EBV seronegativity pretransplantation, antilymphocyte therapy for rejection or graft-versus-host disease, and CMV seromismatch. Increased levels of circulating EBV-infected lymphocytes and decreased EBV nuclear antigen antibody responses have been associated with the development of PTLD in solid-organ transplant recipients in some, but not all, studies. More information is provided in Chapter 33.

Clinical Findings

Epstein Barr virus infection (without PTLD) may manifest as malaise, fever, headache, and sore throat. Clinical presentations of PTLD are varied and include a mononucleosis-like syndrome with fever, adenopathy, tonsillitis, and sore throat, fever, abdominal pain, anorexia, jaundice, bowel perforation, gastrointestinal bleeding, renal dysfunction, hepatic allograft dysfunction, pneumothorax, pulmonary infiltrates, and weight loss.

Treatment

Treatment of EBV-related PTLD is outlined in Table 24-2. High-level EBV oropharyngeal shedding found in primary infection is inhibited by acyclovir and ganciclovir, suggesting that antiviral therapy may be useful early when levels of viral replication are low. Unfortunately, once PTLD is established, treatment has been disappointing with the exception of drastically reducing the level of immunosuppression, which appears to have a beneficial effect in localized or polyclonal as well as multifocal or monoclonal PTLD. Disease localized to the transplanted organ or lymph nodes can be reversed with reduced immunosuppression and antiviral therapy; extranodal, multifocal, and brain disease typically require chemotherapy, radiation therapy, or both and are associated with a high mortality rate.

OTHER VIRUSES

General Considerations

Other viruses occasionally cause infection in transplant recipients. Adenovirus (Chapter 32), parainfluenza virus (Chapter 30), respiratory syncytial virus (Chapter 31), and influenza virus (Chapter 29) may cause upper respiratory tract infections and pneumonia (see also Chapter 9). Sporadic outbreaks of gastroenteritis caused by coxsackievirus (Chapter 27) or rotavirus occur (Chapter 37). BK virus (Chapter 45) and adenovirus viruria (Chapter 32) have been associated with hemorrhagic cystitis. BK virus has been associated with allograft nephropathy in renal transplant recipients. Both HBV and HCV may cause liver dysfunction after transplantation (Chapter 39). Transplant recipients are also at risk for human papilloma virus-associated malignancies (Chapter 45).

FUNGAL INFECTIONS

PNEUMOCYSTIS CARINII

General Considerations

P carinii pneumonia has been virtually eliminated in transplant recipients by the use of prophylactic trimethoprim-sulfamethoxazole. Clusters of cases of P carinii pneumonia have been reported, and a question of person-to-person transmission has been raised. More details are found in Chapter 79.

Clinical Findings

1. Signs and Symptoms.P cariniipneumonia typically presents with fever, dyspnea, nonproductive cough, and hypoxemia out of proportion to the physical and radiographic findings present. There is an increased incidence of pneumothorax.
2. Laboratory Findings.The diagnosis is made by examining bronchoalveolar lavage fluid or lung biopsy specimens by one of several techniques including calcifluor white, methenamine silver, and Wright Geimsa staining as well as monoclonal antibody or molecular techniques. In the case of lung biopsy specimens, histopathologic examination is also helpful.
3. Imaging.Typical radiographic findings include diffuse interstitial or interstitial and alveolar infiltrates, but atypical findings may be noted.

Treatment

P carinii pneumonia is treated with high doses of trimethoprim-sulfamethoxazole or intravenous pentamidine (Box 24-2). The former regimen is preferable.

Prevention

Trimethoprim-sulfamethoxazole provides excellent prophylaxis for P carinii pneumonia and should be given to all transplant recipients following transplantation (Box 24-3). Prolonged prophylaxis is indicated for heart-lung and lung transplant recipients and for patients with ongoing risk factors for P carinii pneumonia such as multiple episodes of rejection, ongoing graft-versus-host disease, treatment with antilymphocyte therapy, or persistent allograft dysfunction. Importantly, prophylaxis should be reinstituted if it has been discontinued, in patients receiving augmented immunosuppression. Alternatives to trimethoprim-sulfamethoxazole for prophylaxis include intravenous or aerosolized pentamidine, dapsone, and atovaquone. For single lung allograft recipients who cannot tolerate trimethoprim-sulfamethoxazole, there is some controversy about the use of aerosolized pentamidine that may be inadequately delivered to the remaining diseased and therefore poorly ventilated lung.

CANDIDA SPECIES

General Considerations

Among the Candida species, C albicans is most frequently implicated in causing infections in transplant recipients, however, C krusei, C glabrata, C zeylanoides, and C tropicalis have also been reported as pathogens and may infect any type of transplant recipient. More details are found in Chapter 73.

Clinical Findings

1. Signs and Symptoms.Most fungal infections caused by Candidaspp. occur in the first 2 months after transplantation. Localized infection of the oral cavity, gastrointestinal tract, or skin may occur. Serious candidal infections after transplant can present in myriad ways including intra-abdominal abscesses (most commonly in patients having undergone abdominal surgery such as liver and pancreas transplantation), hepatosplenic candidiasis (in PBSC and bone marrow transplant recipients), pulmonary infection, urinary tract infections (including cystitis, pyelonephritis, ureteral obstruction, and parenchymal fungal balls), esophagitis, arthritis, endocarditis, aortitis, brain abscess, and mediastinitis. Catheter-related sepsis from infection by Candidaspp. (and rarely other fungi) is a common presentation of fungal infection in transplant  recipients and, as in other populations, is associated with prolonged hospitalization, especially in intensive care units, with central venous catheters in place.
2. Laboratory Findings.The diagnosis of candidal infections in transplant recipients is made by obtaining fungal stains and cultures of appropriate specimens. Fine needle aspiration cytology may be useful in the diagnosis of the hepatosplenic candidiasis syndrome in PBSC and bone marrow transplant recipients as well as fungal pyelonephritis in renal transplant recipients.

Treatment

Agents used for the treatment of serious candidal infections in transplant recipients include amphotericin B, fluconazole, ketoconazole, itraconazole and caspofungin (Box 24-2). The choice of the agent depends on the clinical presentation and typical fungal susceptibility pattern of the organism. Importantly, azole antifungal drugs may increase blood levels of cyclosporin.

Prevention

The use of a selective bowel decontamination regimen may reduce the incidence of candidal infections in liver transplant recipients. Fluconazole has been shown to prevent both deep and superficial candidal infections, excluding those caused by C krusei, in liver and PBSC and bone marrow transplant recipients (Box 24-3).

CRYPTOCOCCUS NEOFORMANS

General Considerations

Infections caused by C neoformans can occur at any time after transplantation in any type of transplant recipient. More details are found in Chapter 74.

Clinical Findings

1. Signs and Symptoms.Cryptococcal infection may present with a subacute or occasionally more acute meningitis, pneumonia, pleural infection, cutaneous lesions, fever alone, and rarely other unusual forms of infection such as retinitis, arthritis, pyelonephritis, or fever of unknown origin (see Chapter 18). Cutaneous involvement has been described. In men, foci of cryptococcal infection within the prostate gland may be a source of hematogenous dissemination.
2. Laboratory Findings.The cryptococcal antigen test, performed on serum and cerebrospinal fluid (and occasionally pleural fluid), provides a sensitive and rapid means of diagnosis. In neoformansmeningitis, cerebrospinal fluid may show a lymphocytic pleocytosis, hypoglycorrhachia, and an elevated protein level. Culture and fungal stains (including calcifluor white, India ink, and methenamine silver stains) are helpful in the diagnosis. The cryptococcal antigen test may also be used to monitor response to therapy. Importantly, cryptococcuria, when demonstrated, is almost always indicative of systemic infection; C neoformans is rarely a contaminant or nonpathogenic colonizer of the urinary tract. A cerebrospinal fluid examination should be performed in any transplant recipient with unexplained fever as well as in any such patient with C neoformans isolated from any site.

MYCELIAL FUNGI

General Considerations

The Aspergillus spp. most frequently implicated in causing disease in transplant recipients include A fumigatus, A flavus, A niger, and A terreus. In addition, an expanding list of unusual organisms including Pseudalleschia boydii, Scopulariopsis brumptii, Trichosporon beigelii, Fusarium spp., zygomycetes, and others, have been reported as causes of serious fungal infections in transplant recipients. Most fungal infections caused by Aspergillus spp. occur in the first 3 months after solid-organ transplantation and are associated with a high mortality rate. In PBSC and bone marrow transplant recipients, the onset of aspergillal infections is bimodal, peaking 16 and 96 days after transplant. The portal of entry of Aspergillus spp. is usually the respiratory tract (lungs and sinuses). Rarely, dissemination from a primary skin lesion or contiguous spread from a previously sustained skin lesion to bone may occur. Aspergillus spp. may also invade the gastrointestinal tract or rarely gain entry through an intravenous catheter. More details are found in Chapters 75 and 77.

Zygomycetes, including Rhizopus spp., Mucor spp., Absidia spp., and Cunninghamella bertholletiae have been reported as pathogens in transplant recipients. Underlying metabolic disturbances resulting in an acidotic state such as that associated with diabetic ketoacidosis or that found in pancreatic transplant recipients with a bicarbonate leak and deferoxamine therapy are risk factors for zygomycosis. Zygomycetes are associated with rhinocerebral, pulmonary, gastrointestinal, cutaneous, and disseminated infections.

Endemic dimorphic fungal infections with geographically restricted endemic mycoses (H capsulatum, C immitis, B dermatitidis, and Paracoccidioides brasiliensis) can occur at any time after transplantation. In many cases, and especially with histoplasmosis, disseminated infection is seen. For more details, see Chapter 70.

Clinical Findings

1. Signs and Symptoms.In patients with aspergillosis, pulmonary symptoms including nonproductive cough, pleuritic chest pain, dyspnea, and low-grade fever predominate. From the lungs, Aspergillusspp. may disseminate to almost any organ including the brain, liver, spleen, kidneys, heart, pericardium, blood vessels, thyroid, gastrointestinal tract, bones, and joints. Clinical manifestations of central nervous system aspergillosis include alteration of mental status, diffuse central nervous system depression, seizures, evolving cerebrovascular accidents, and headache. Aspergillus spp. may cause peritonitis in renal transplant recipients on continuous ambulatory peritoneal dialysis and may cause intra-abdominal abscesses in liver transplant recipients.
2. Laboratory Findings.One should consider all pulmonary infections in transplant recipients to be possibly caused by mycelial fungi. Positive cultures for Aspergillusspp. in transplant recipients should never be ignored even though the isolation of Aspergillus spp. from respiratory and wound specimens does not always imply disease because this fungus may be a colonizer or a laboratory contaminant. Repeated isolation of Aspergillus spp. from sputum is suggestive of invasive disease, and the combination of positive sputum cultures and cavitary lung disease is highly suggestive of invasive disease. Conversely, sputum cultures are not always positive for Aspergillus spp. in patients with invasive aspergillosis. Bronchoalveolar lavage may be more helpful in this regard. The diagnosis of extrapulmonary infection is more difficult. Any suspicious lesion (eg, skeletal or cutaneous) should be biopsied.
3. Imaging.Chest radiographic findings in cases of pulmonary aspergillosis include nodular opacities, interstitial infiltrates, cavitary lung disease, or a pulmonary embolus type pattern; the chest x-ray may also be normal. For more details see Chapter 70.

Treatment

Treatment of deep fungal infections in transplant recipients does not differ significantly from that in other types of immunocompromised hosts (Box 24-2). Immunosuppression should be reduced as tolerated. Surgical extirpation or debridement should be performed for diagnostic and therapeutic purposes, if appropriate. Intravenous amphotericin B has been the mainstay of treatment for deep fungal infections in transplant recipients. The combination of cyclosporin and amphotericin B has been associated with renal failure. Some organisms (eg P boydii) are resistant to amphotericin B, emphasizing the need for identification of all fungal isolates in transplant recipients. Lipid formulations of amphotericin B have fewer side effects, especially including nephrotoxicity, than the standard preparation, but are more costly. Because of the high frequency of toxicity seen with amphotericin B, the use of azole antifungal agents for treating select fungal infections in transplant recipients is attractive. This is discussed further in chapters dealing with specific fungal organisms.

Prevention

Laminar air flow isolation in PBSC and bone marrow transplant units prevents aspergillal infections. Intravenous amphotericin B should be given to PBSC and bone marrow transplant recipients with a well-documented history of invasive aspergillosis pretransplant.

MYCOBACTERIAL INFECTIONS

MYCOBACTERIUM TUBERCULOSIS

General Considerations

All types of transplant recipients are at increased risk for both primary and reactivation M tuberculosis infection and disseminated disease is more commonly seen in transplant recipients than in nonimmunocompromised populations. For more information, see Chapter 61.

Clinical Findings

1. Signs and Symptoms.Presentations of M tuberculosisinfection after transplantation include typical cavitary pulmonary disease as well as non-cavitary pulmonary, intestinal, skeletal, cutaneous, disseminated, and central nervous system disease. M tuberculosis infection in transplant recipients is usually accompanied by pyrexia. M tuberculosis is highly contagious, and all patients with pulmonary tuberculosis should be promptly isolated.
2. Laboratory Findings and Imaging.The diagnosis of tuberculosis differs little in the transplant population compared to other populations.

 

Treatment

See Chapter 61.

Prevention

A detailed history of tuberculosis exposure should be obtained on all transplant candidates and a tuberculin test should be performed on all solid-organ transplant candidates and on PBSC and bone marrow transplant candidates with a history of tuberculosis exposure. Isoniazid prophylaxis is recommended for patients with positive tuberculin tests or other risk factors for tuberculosis. If possible isoniazid prophylaxis should be administered for nine months pretransplantation. If this is not feasible, isoniazid can be given following transplantation. In addition, tuberculin test positive transplant recipients who have not previously received treatment or prophylaxis might benefit from isoniazid prophylaxis when they receive antilymphocyte preparations.

NONTUBERCULOUS MYCOBACTERIA

General Considerations

Nontuberculous mycobacteria reported as pathogens in transplant recipients include M kansasii, M avium-intracellulare, M fortuitum, M xenopi, M haemophilum, M marinum, M chelonai, M abscessus, M gastri, M scrofulaceum, M szulgai, and M thermoresistibile, among others. These infections are rare, generally occur late in the post-transplant period and are most commonly chronic, manifesting as cutaneous lesions of the extremities, tenosynovitis, and/or joint infection. Less frequently, allograft, pulmonary, or intestinal involvement may occur. For more details, see Chapter 62.

PARASITIC INFECTIONS

Parasitic infections in transplant recipients are generally not associated with distinctive presentations with the exception of Trypanosoma cruzi, Toxoplasma gondii, and S stercoralis.

TRYPANOSOMA CRUZI

General Considerations

In patients with T cruzi-associated cardiomyopathy undergoing heart transplantation, a new acute phase of Chagas' disease may develop. This is characterized by fever, cutaneous lesions (with or without parasites), and myocarditis (with or without parasites) and is responsive to specific drug therapy. Parasites have been demonstrated in the transplanted hearts of such patients, (see also Chapter 85).

TOXOPLASMA GONDII

General Considerations

Toxoplasmosis after transplantation is usually the result of reactivation of latent donor-derived disease in T gondii seronegative heart transplant recipients. This typically occurs in the seropositive donor heart because of a predilection of the parasite to invade muscle tissues. Rarely, T gondii infection may be seen in other types of transplant recipients. Most cases occur within 2 months post-transplantation although cases have been reported between 1 day and 7 years after transplantation. For more details, see Chapter 81.

Clinical Findings

1. Signs and Symptoms.Clinical presentations include meningoencephalitis, brain abscess, pneumonia, myocarditis, pericarditis, hepatitis, and choreoretinitis.
2. Laboratory Findings.The diagnosis is made with certainty only by histopathologic demonstration of trophozoites with surrounding inflammation in tissue. Biopsy specimens may be stained with Wright-Geimsa or periodic acid-Schiff stains or with specific antibodies. Pulmonary organisms may be detected in bronchoalveolar lavage samples; the diagnosis of cardiac disease typically requires multiple cardiac biopsy specimens. Serologic testing is not very useful; however, a positive IgM titer or a fourfold rise in IgG titer supports the diagnosis of toxoplasmosis. Elevations of antibody levels in cerebrospinal fluid or vitreous fluid relative to those in peripheral blood are also indicative of infection in these sites. Antigen detection and molecular techniques are being developed and may be useful.

Treatment

Toxoplasmosis is treated with pyrimethamine with folinic acid and either sulfadiazine or clindamycin (Box 24-2).

Prevention

Toxoplasmosis is generally prevented by the same doses of trimethoprim-sulfamethoxazole used for P carinii prophylaxis (Box 24-3). An alternative is pyrimethamine.

STRONGYLOIDES STERCORALIS

General Considerations

S stercoralis is the one helminth that deserves special mention as concerns transplant recipients (see also Chapter 86).

 

Clinical Findings

1. Signs and Symptoms.There have been reports of hyperinfection syndromes with S stercoralisafter transplantation. This may result in gastrointestinal and pulmonary symptoms including tachypnea, dyspnea, cough, and hemoptysis. Enterocolitis and widespread dissemination of larvae to extraintestinal organs (eg heart, lung, central nervous system, and skin) may occur and larvae may entrain gram-negative bacilli resulting in gram-negative bacteremia and occasionally meningitis.
2. Laboratory Findings.The diagnosis may be made by examining stool specimens for rhabditiform larvae; several stool specimens should be examined since the yield of a single stool examination is only ~27%. Other means of diagnosis include duodenal aspirate, urine, ascitic fluid, wound and sputum examination, jejunal biopsy, culture, and serologic testing. Eosinaphilia may be present.
3. Imaging.Alveolar or interstitial infiltrates may be seen on chest x-ray.

Treatment

Thiabendazole or ivermectin is used to treat strongyloidiasis (Box 24-2).

Prevention

As noted in the discussion on the pretransplantation evaluation, patients who have traveled to or resided in an area of endemic infection should be examined for evidence of infection with this parasite pretransplantation.

Differential Diagnosis in Transplant Recipients

The main differential diagnosis of infections in transplant recipients is rejection. Drug toxicity must also be considered.

Prevention of Infections in Transplant Recipients

1. Vaccinations.Vaccinations as outlined in Box 24-3 should be administered prior to solid-organ transplantation. Live vaccines should generally be avoided. However, for the nonimmune solid-organ transplant candidate with a high likelihood of exposure to measles, consideration may be given to the administration of the measles vaccine prior to transplant (studies are required to document the safety of this approach). Similarly, the MMR vaccine is recommended (Box 24-3) following PBSC and bone marrow transplantation. A recent study has demonstrated the safety of the varicella vaccine in pediatric renal transplant recipients and consideration may be given to immunization of solid-organ transplant candidates with no history of chickenpox. Immunization with live vaccines (eg measles vaccine, varicella vaccine), if performed, should be done as early as possible prior to solid-organ transplantation. All solid-organ transplant recipients should receive influenza vaccinations yearly and pneumococcal vaccine should be administered every 5–6 years, although the immune response to these vaccines may be impaired in transplant recipients.

For PBSC and bone marrow transplant recipients, vaccinations are administered following transplantation (Box 24-3).

1. Avoidance of Epidemiologic Exposures Post-transplantation.After transplantation, patients should be again counseled regarding measures aimed at reducing infections. Patients who are not immune to VZV should be counseled to avoid exposure to persons with chickenpox or shingles. If such an exposure does occur, a physician should be contacted immediately. All fresh fruits and vegetables should be washed. All meat and seafood should be cooked thoroughly. The source of the patient's drinking water should be reviewed. Patients with cats should avoid changing litter boxes if possible. (If changing the litter box is unavoidable, gloves should be worn and the litter box should be changed daily.) Gloves should be worn to clean fish aquaria. A mask should be worn when cleaning bird cages (if this activity is unavoidable). Patients should avoid contact with people who have colds, influenza, tuberculosis, and other contagious infections. Towels should not be shared with others unless they are washed between uses. Any plans for travel outside the United States, Canada, or western Europe should be discussed with the patient's physician before departure. All persons living in the same quarters as the patient should receive a yearly influenza vaccine, and inactivated (rather than oral) polio vaccine should be administered to those requiring polio vaccination.
2. Donor-Related Transmission of Infectious Agents.All potential organ and PBSC and bone marrow donors should be evaluated for any latent or active infection. Serologic studies of the donors should include tests for HIV-1, HIV-2, HBV, HCV, syphilis, CMV, and in many cases, T gondiiand EBV.

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