I. INTRODUCTION
Recognition of infection is challenging in transplant recipients as presentation is often complicated by noninfectious causes of fever, such as drug interactions or graft rejection.
As a result of the growing population of immunosuppressed patients with prolonged survival, an increased incidence and spectrum of opportunistic infections has been observed.
Guidelines for the diagnosis and treatment of infection in transplant recipients have been developed.2
While there is general agreement on the major infections for which routine screening is performed, centers vary in the extent of infectious disease investigation and the actions taken as a result of those investigations.3
II. INFECTIOUS DISEASE EVALUATION OF THE PRETRANSPLANT CANDIDATE
The successful outcome of SOT requires the careful selection of transplant recipients through a process of medical evaluation and screening.
The identification of active and latent infection, along with the optimization of treatment, is an important role of the transplant specialist.
Early identification of risk factors that predispose transplant candidates to infection and prompt referral to an experienced infectious diseases (ID) specialist when indicated can prevent posttransplant infections and improve patient outcomes.
Identify conditions that may indicate a contraindication to transplantation.
Treat active infection in the pretransplant phase, as clinically indicated.
Recognize the risk of posttransplant infection and develop strategies for prophylaxis.
Implement preventative measures, including updating immunizations.
Childhood infections such as measles, mumps, chickenpox, mononucleosis
Underlying illness causing organ failure including, but not limited to, cystic fibrosis (respiratory failure), hepatitis C virus (HCV cirrhosis/liver failure)
Adulthood infections that can include the following:
Hepatitis B virus (HBV) and hepatitis C virus (HCV)
Human immunodeficiency virus (HIV)
Tuberculosis (TB)
Sexually transmitted diseases
Endemic mycoses (histoplasmosis, blastomycosis, coccidioidomycosis)
Recurrent infections (e.g., urinary tract, pneumonia, staphylococcal skin soft tissue infection, line-related infections)
Concurrent/nosocomial infections such as
Urinary tract infection
Pneumonia
Peritonitis
Wound infection
Occult abscess
Catheter/ventricular assist device-related infection
Immunizations
Travel history
Social risk factors such as
Alcohol/drug abuse
Incarceration
High-risk sexual behavior
Lack of contraceptive barrier use
Multiple sex partners
Tattoos
Body piercings
Socioeconomic challenges
Limited health care access
Poverty
Language barriers
Low health literacy
Environmental exposure such as industrial chemicals, cigarette smoke
Nutritional practices such as the following:
Unsafe source of drinking water
Consumption of raw/undercooked meat, unpasteurized dairy products, seafood
Allergies to antimicrobial agents
See Table 5-1 for Pretransplant Diagnostic Tests and Team Evaluations
TABLE 5-1 Infectious Disease Evaluation | ||||||||||
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III. IMMUNIZATIONS
Transplant candidates and recipients are at increased risk of infectious complications due to end-organ failure and immunosuppression.
Every effort should be made to immunize patients in the early phase of disease because the response to many vaccines is diminished in organ failure.
Transplant recipients may have a suboptimal response to vaccinations due to their immunosuppressed status; therefore, it is critical to update immunizations prior to transplantation.
The ideal time to give vaccines following transplantation is unknown; however, most centers restart vaccinations approximately 3 to 6 months posttransplant.
Adult Candidates
Influenza (administered yearly posttransplantation: inactive vaccine only)
Hepatitis B:
Assess before and monitor after transplant
Administer booster if titers fall below 10 IU/L5
Hepatitis A (liver transplant candidates or patients at high risk for exposure)
Tetanus
Pertussis (Tdap) if no tetanus booster in last 10 years
Inactive polio
Pneumococcal
Meningococcal, especially for
Military personnel
Travelers to high-risk areas
Postsplenectomy patients
College freshmen living on campus
Rabies (exposure or potential exposures due to vocations only)
Human papillomavirus (HPV): males and females ages 9 to 26 years
Measles, mumps, rubella (MMR): if seronegative (see Pediatric Candidates section)
Varicella—if seronegative
Note: Live vaccine: must avoid transplantation 4 weeks following administration
Bacille Calmette-Guérin (BCG)—unavoidable exposure to TB
Pediatric Candidates: same as adult candidates with the following exceptions:
Hepatitis A: all pediatric candidates.
N. meningitidis (MCV4): all candidates 11 to 18 years of age and as young as 9 months with special circumstances (see Adult Candidates section).
Varicella: vaccine should be administered after 12 months of age with second dose approximately 3 months later.
Measles, mumps, rubella (MMR) may be administered as early as 6 months of age and repeated after 4 weeks following the first injection.
Wait at least 4 weeks between administration of live vaccines and transplant procedure for all adult and pediatric candidates.
IV. DONOR-TRANSMITTED INFECTIONS
Donor-transmitted infection is frequently associated with significant recipient morbidity and mortality.6
Despite advances in surgical technique, immunosuppression, and infection prevention, unexpected transmission of infections from donor to recipient is an infrequent complication of transplantation.7
Donor chart review
Discussion with available family, friends, and/or acquaintances for knowledge of
Prior infections
Immunizations
Unusual exposures to infection
Psychosocial history
Alcohol/drug abuse
Incarceration
High-risk sexual behavior/multiple sex partners
Tattoos
Body piercing
Socioeconomic status/challenges
Living conditions
Health care access
Medical adherence
Poverty
Language barriers
Performed by organ procurement team and procuring surgeon
Evidence of active infections including abscesses, ulcers, genital/anal trauma, lymphadenopathy
Evidence of recent drug use such as track marks
Evidence of underlying disease (cirrhosis, skin lesions, or other malignancies)
Other abnormalities such as free spillage of intestinal contents or obvious pus or sign of infection involving specific donor organs and/or vessels
Donor testing includes the following:
Complete blood cell count (CBC)
Microbial cultures (e.g., blood, urine)
Serologic assay (e.g., antibodies against HIV, hepatitis B virus [HBV]), and hepatitis C virus [HCV]) and, in certain cases, nucleic acid testing (NAT) (including assays for HIV, HCV, or HBV).7
Ideally, serologic testing should be performed before and after blood product administration.
If serologic testing is done after the donor is transfused, the number of blood product units should be recorded.
Public Health Service (PHS) guidelines developed in 1994 provide guidance to minimize the risk of HIV transmission and to monitor recipients following the transplantation of “high-risk” organs.8
The intent of the PHS guideline is to improve organ transplant recipient outcomes by reducing the risk of unexpected HIV, HBV, and HCV transmission, while preserving the availability of high-quality organs using an evidence-based approach to formulate the recommendations.8
Transplant programs must obtain specific informed consent from the intended recipient according to the guidelines specified in the Organ Procurement and Transplant Network (OPTN) Policy 15.3 (Figure 5-1).8,9
Behavior/History Criteria established by the PHS as “high risk” for transmitting HIV or other infectious diseases despite negative preliminary testing:
People who have had sex with a person known or suspected to have HIV, HBV, or HCV infections in the preceding 12 months
FIGURE 5-1 Organ Procurement and Transplantation Network Policy 15.3: informed consent of transmissible disease risk (available at: www.optn.transplant.hrsa.gov/ContentDocuments/OPTN_Policies.pdf).
Male with male (MSM) sex in the preceding 12 months
Women who have had sex with a man with a history of MSM behavior in the preceding 12 months.
People who have had sex in exchange for money or drugs in the preceding 12 months.
People who have had sex with a person who had sex in exchange for money or drugs in the preceding 12 months.
People who have had sex with a person who has injected drugs by IV, IM, or SQ route for nonmedical reasons in the preceding 12 months.
A child who is <18 months of age and born to a mother known to be infected with or at increased risk for HIV, HBV, or HCV infection.
A child who has been breast-fed within the preceding 12 months and the mother is known to be infected with or at increased risk for HIV infection.
People who have injected drugs by IV, IM, or SQ route for nonmedical reasons in the preceding 12 months.
People who have been in lockup, jail, prison, or a juvenile correction facility for more than 72 hours in the preceding 12 months.
People who have been newly diagnosed with or have been treated for syphilis, gonorrhea, Chlamydia, or genital ulcers for the preceding 12 months.
People who have been on hemodialysis in the preceding 13 months should be identified as high risk for HCV infection only.
V. POSTTRANSPLANT INFECTION10
Early, specific diagnosis and rapid, aggressive treatment are essential in obtaining favorable outcomes when infection occurs posttransplantation.
Etiologies of infections are diverse and include common viral and bacterial diseases and uncommon opportunistic infections that are clinically significant only in immunocompromised hosts.
Immunosuppression impairs inflammatory responses normally associated with microbial invasion.
Epidemiologic exposure
Latent pathogens can reactivate in the setting of immunosuppression
Cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV, shingles), HBV, HCV, papillomavirus, and BK polyomavirus frequently reactivate after transplantation.
Geographically restricted systemic mycoses (histoplasmosis, coccidioidomycosis, diseases caused by the parasite Trypanosoma cruzi) may have occurred many years pretransplantation.
Significance of exposure varies based upon specific immune deficit(s).
Bacterial (Staphylococcus spp., Streptococcus spp.) and fungal (Candida spp., Aspergillus spp.) pathogens are more significant in the setting of neutropenia.11
Viral (CMV) and intracellular (TB) infections are more common with T-cell immune deficits.
Strongyloides stercoralis may reactivate many years after exposure.
Community-acquired pathogens
Respiratory viruses such as influenza, respiratory syncytial virus (RSV), and adenovirus
Bacterial pathogens such as Streptococcus pneumoniae, Legionella, and Salmonella
Food-borne illnesses caused by organisms such as Escherichia coli, Cryptosporidium, Salmonella, Toxoplasma gondii (usually related to contact with cat feces), Vibrio vulnificus, and Campylobacter
Nosocomial infections
Prolonged hospitalization and mechanical ventilation increase vulnerability to hospital-acquired infections in the early postoperative period.
Gram-negative bacilli (Pseudomonas aeruginosa, Legionella)
Antimicrobial-resistant gram-positive organisms (vancomycin-resistant enterococci [VRE], methicillin-resistant Staphylococcus aureus [MRSA])
Fungi (Aspergillus spp. and nonalbicans or azole-resistant Candida species)
Clostridium difficile colitis12
See Table 5-2 for major pathogens that cause infectious disease in SOT recipients
Early postoperative period when immunosuppression doses are highest
Increase in immunosuppressant therapy to treat acute rejection
The posttransplant course can be divided into three time periods related to the risk of infection by specific pathogens (see Figure 5-2):
Early posttransplant period (days 0 to 30)
Infection from either donor or recipient
Infectious complications from surgery and/or hospitalization
Intermediate period (months 1 to 6)
Highest risk for developing opportunistic infections
Reflective of local epidemiology, immunosuppression, and antimicrobial prophylaxis
TABLE 5-2 Major Pathogens that Cause Infection in Transplant Recipients
Bacterial
Viral
Fungal
Parasitic
Enteric gram-negative bacteria
Cytomegalovirus
Candida species
Toxoplasma gondii
Pseudomonas aeruginosa
Epstein-Barr virus
Aspergillus species
Cryptosporidium
Legionella species
Herpes simplex virus
Cryptococcus neoformans
Strongyloides stercoralis
Nocardia asteroides
Varicella zoster virus
Pneumocystis carinii
Listeria monocytogenes
Hepatitis B virus
Coccidioides immitis
Salmonella species
Hepatitis C virus
Histoplasma capsulatum
Mycobacterium tuberculosis
Human herpesvirus 6
Blastomyces dermatitidis
Nontuberculous mycobacteria
Papillomavirus
Adenoviruses
Respiratory syncytial virus
Influenza virus
Enterovirus
Papovavirus
From Green M. Introduction: infections in solid organ transplantation. Am J Transplant. 2013;13(suppl 4):3-8; Jani AA. Infections after solid organ transplantation. Medscape. 2014. Available at http://emedicine.medscape.com/article.430550-overview. Accessed August 26, 2015; Fishman J. Infection in the solid organ transplant. In: Marr K, ed. Up to Date. Waltham, MA: Wolters Kluwer; 2015. Available at http://www.uptodate.com/contents/infection-in-the-solid-organ-transplant-recipient#H5. Accessed August 1, 2015.
FIGURE 5-2 Infections in solid organ transplant recipients.CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; MRSA, methicillin-resistant Staphylococcus aureus; PML, progressive multifocal leukoencephalopathy; PTLD, posttransplant lymphoproliferative disorder; SARS, severe acute respiratory syndrome; VRE, vancomycin-resistant Enterococcus; VZV, varicella-zoster virus. (From Fishman JA; the AST Infectious Diseases Community of Practice. Introduction: infection in solid organ transplant recipients. Am J Transplant. 2009;9(suppl 4):S3. Copyright © 2009 American Society of Transplantation and the American Society of Transplant Surgeons. Reproduced with permission of John Wiley & Sons, Inc. Graphic 58770 Version 5.0.)
Late posttransplant period (>6 months)
Stable and reduced levels of immunosuppression for most patients.
Subject to community-acquired pneumonias and late viral infections.
Patients with suboptimal graft function require higher than normal levels of immunosuppression and are at highest risk for opportunistic infections (i.e., pneumocystis pneumonia [PCP], cryptococcosis, nocardiosis) and severe illness.
Significance of timetable
Common patterns of opportunistic infection are observed following solid organ transplantation based on epidemiologic exposures and the “net state of immunosuppression.”
The time line is altered based on the immunosuppressive regimen and prophylactic medications. The dynamic assessment of infectious risk represents assays that will measure an individual’s risk for infection due to specific pathogens or in general.
Develop differential diagnosis for the SOT recipient with clinical manifestations of infection.
Detect presence of excessive environmental risks (individual, community, nosocomial).
TABLE 5-3 Posttransplant Intervals of Infection | ||||||||||||||||||||||||
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Latent or unappreciated active infection in donor at time of transplant (CMV or Epstein-Barr virus [EBV] infection; toxoplasmosis)
Bloodstream infections (Staphylococcus, Pneumococcus, E. coli, Candida); adequate therapy should be confirmed prior to organ acceptance
Net state of immunosuppression: determined by interaction of several factors10
Immunosuppressive therapies
Type/dose of medications, plasmapheresis, IgG
Comorbidities such as
Diabetes
Malnutrition
Graft abnormalities
Concurrent neutropenia or lymphopenia
Invasive devices—vascular access devices, urinary catheters, drains
Concomitant infection with immunomodulating viruses
CMV
EBV
HHV-6
HBV
HCV
TABLE 5-4 Factors to Consider in Diagnosis of Posttransplant Infection | ||||||||||||||||||||||||
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VI. CLINICAL MANIFESTATIONS OF INFECTION
Significant clinical manifestations of infection include the following10:
Usual signs of infection (e.g., fever, chills, generalized malaise) may be replaced by nonspecific symptoms (altered mental status, elevated liver function tests) due to immunosuppression
Fever without localizing findings or fever with headache
Central nervous system (CNS) changes, including changes in level of consciousness
Unexplained skin lesions
The signs of meningeal irritation may be masked by immunosuppression.
Changes in level of consciousness may be subtle.
The most reliable indication of a CNS infection is the simultaneous presence of unexplained fever and headache.
Patients presenting with these manifestations should have an immediate and complete neurologic workup (CT scan or magnetic resonance imaging [MRI] of brain; lumbar puncture [unless otherwise contraindicated]).
VII. CLASSES OF INFECTIONS
The four classes of infection most prevalent after transplant include the following:
Bacterial
Viral
Fungal
Parasitic
Major infection causing pathogens
VIII. PREVENTION AND SAFE LIVING AFTER TRANSPLANTATION
Leading a healthy and normal life is possible after transplantation.
The risk of exposure to infectious agents will always be present. Therefore, transplant recipients should be counseled on the modes of transmission and means to reduce the risk of infection.
Direct contact
Frequent and thorough hand washing is imperative and should take place
Before cooking and eating
Before and after touching wounds, even when using gloves
Before touching mucous membranes
After blowing nose or touching other secretions
After touching or cleaning up after pets or other animals
After gardening, touching soil or plants
After using the rest room or touching any items having contact with human or animal feces (toilets, bedpans, litter boxes)
Percutaneous exposures
Avoid intravenous and intradermal illicit drug use.
Tattoos and body piercings represent break in skin; all nonsterile practices should be avoided.
Pet safety and animal contact
Wash hands carefully after handling pets.
Avoid cleaning bird cages and feeders, litter boxes, and handling animal feces.
Avoid stray animals.
Avoid animal bites, scratches, and contact with animals having diarrhea.
Avoid contact with nonhuman primates (monkeys).
Wait approximately 6 to 12 months after transplantation before acquiring a new pet.
Safe sexual practices
Use latex condoms during periods of increased immunosuppression and/or outside of long-term monogamous relationships.
Avoid exposure to feces during sexual contact.
Inhalation
Avoid close contact with persons with respiratory illnesses.
Avoid crowded areas (elevators, subways, shopping malls) during periods of increased immunosuppression and epidemic illness circulation.
Avoid tobacco and marijuana smoke, which is associated with fungal spores.
TB exposure
Avoid individuals with known active disease.
Avoid persons with increased risk (i.e., those working in prisons, jails, homeless shelters).
Construction sites, excavations, and some home remodeling projects may have high concentration of dust with increased risk of mold exposure (Histoplasma, Aspergillus)
Ingestion
Water safety
Cryptosporidiosis may occur from drinking contaminated drinking water during recreational activities.
Using filters and/or drinking bottled water may reduce risk.
Abrasions acquired during swimming or bathing in contaminated water may pose risk to exposure to organisms such as Vibrio species, Mycobacterium marinum, or Aeromonas.
Food safety (items to avoid)
Unpasteurized milk, fruit, or vegetable juice (E. coli, Salmonella, Cryptosporidium)
Cheeses made with unpasteurized milk such as brie, feta (Listeria)
Raw or undercooked eggs (Salmonella)
Raw or undercooked meat, poultry, or fish (bacterial and parasitic infections such as tapeworms and Toxoplasma gondii)
Raw or undercooked seafood (Vibrio species, viruses that cause gastroenteritis or hepatitis, Cryptosporidium)
Cross-contamination of raw and cooked foods
IX. VIRAL INFECTIONS
Epidemiology
Community exposure: influenza, adenovirus, parainfluenza, varicella
Allograft transmission: CMV, EBV, viral hepatitis, HSV
Reactivation of distant viruses: herpes simplex virus, BK virus, herpes zoster as shingles
Clinical
Direct effects: fever, neutropenia, and invasive disease (e.g., pneumonia, hepatitis, meningitis)
Indirect effects:
Alteration in the net state of immunosuppression and increased susceptibility to opportunistic infections
Potential allograft injury
Potential oncogenesis
Eight members of the herpes viruses family that can cause disease after SOT:
Herpes simplex virus 1 and 2
Varicella-zoster virus (VZV)
Epstein-Barr virus or HHV-4
Cytomegalovirus or HHV-5
HHV-6, HHV-7: roseola infantum18
Primary infection first 5 years of life and then latent.
In SOT, cases due to reactivation/reinfection and transient with few clinical symptoms. No antiviral therapy needed.
HHV-8
After SOT, endemic in certain regions (i.e., Saudi Arabia; South Africa) causing Kaposi’s sarcoma (KS), Castleman’s disease, and primary effusion lymphoma.
Treatment consists of reduction/withdrawal of immunosuppression, chemotherapy, and possible conversion to mammalian target of rapamycin (mTOR) inhibitors.
Can be transmitted directly but usually characterized by viral latency.
Replication of latent herpes viruses can be triggered by net immunosuppression in the SOT recipient.17
Herpes virus “infection” versus “disease”
The term “infection” refers to the presence of viral replication as indicated by cultures or serological testing (i.e., polymerase chain reaction [PCR] from cerebrospinal fluid, visceral tissue samples, and/or direct fluorescence antibody from vesicular lesions).
The term “disease” indicates that the patient has specific symptoms that are caused by a herpes virus. Viremia and/or tissue invasion are present. Tissue invasion can manifest as esophagitis, hepatitis, tracheobronchitis, and, often, disseminated disease.
Overview
Approximately 80% of adult transplant recipients are HSV seropositive.
Incidence highest in kidney transplant recipients.
Most common strains associated with mucocutaneous ulcerative infections: HSV-1 and HSV-2.
HSV-1 is more common with oral lesions, which may extend beyond the lip into the oral cavity and esophagus.
Herpes labialis is the most common clinical manifestation of HSV-1.
Lesions may bleed, interfere with nutritional intake, and require local analgesia to control pain.
HSV-2 involves the perianal and genital areas.
After a primary HSV infection, the virus remains latent in the sensory nerve ganglia.
Reactivation infection occurs in up to 40% of recipients, typically during the first posttransplant month.
See Table 5-5 for the clinical manifestations, prevention/prophylaxis, diagnosis, and treatment of HSV.
Overview
VZV is a highly infectious alphaherpesvirus that is acquired through skin-to-skin contact or airborne respiratory droplets.
VZV causes chickenpox as a primary infection and then becomes latent in nerve root ganglia until possible reactivation later in life as shingles.
Most SOT recipients have developed VZV antibodies so that reactivation of the virus accounts for 90% of adult recipients.
TABLE 5-5 Major Organisms Causing Posttransplant Infection: Clinical Manifestations, Prevention/Prophylaxis, Diagnostic Tests, and Treatment Options
Organism
May Cause
Clinical Manifestations
Prophylaxis/Preemptive Therapy
Diagnostic Tests
Treatment Options
CMV syndrome Tissue-invasive disease:
CMV syndrome:
CMV-negative, filtered, or leukocyte-poor blood products
Prophylaxis: valganciclovir is first choice
Oral ganciclovir
IV ganciclovir
Valacyclovir used for minimal risk recipients or if cost an issue
Done for 3-12 mo posttransplant
Preemptive:
Weekly quantitative CMV-PCR assays for at least 3 mo posttransplant
If positive, may treat
Duration of prophylaxis: range: 3-12 mo posttransplant
Serologic: helpful pretransplant but not diagnostic for infection
Complement fixing assay
Immunofluorescence ELISA
Latex agglutination systems
Virologic:
IV ganciclovir
Oral ganciclovir
CMV hyperimmune globulin for tissue-invasive disease
Immunoglobulin
For ganciclovir-resistant organisms:
Fever
Fatigue
Gastroenteritis
Myocarditis
Pneumonitis
Retinitis (rare)
Encephalitis (rare)
Pancreatitis (rare)
Malaise
Leukopenia
Thrombocytopenia
Elevated LFTs
Gastroenteritis:
Antigenemia assay
Quantitative PCR
Foscarnet
Ganciclovir + foscarnet
Anorexia, dysphagia
Abdominal cramping
Nausea, vomiting, diarrhea
Ulceration, bleeding
Tissue culture
Biopsy
Antigenemia: CMV pp65 detected in leukocytes CMV DNA detected in plasma, whole blood, isolated peripheral blood leukocytes, or buffy coat specimens RNAemia: CMV RNA detected in plasma, whole blood, isolated peripheral blood leukocytes
Foscarnet+ Cidofovir
Intravenous immune globulin (IVIG)
Pneumonitis:
Fever
Dyspnea
Mononucleosis PTLD: nodal or extranodal disease of CNS, GI tract, lungs, or bone marrow
Mononucleosis:
Preemptive therapy for patients at high risk (e.g., IV ganciclovir during antilymphocyte antibody therapy)
Mononucleosis:
Mononucleosis:
Lymph node hyperplasia
Splenomegaly
Atypical mononuclear leukocytes
Abnormal LFTs
CBC
EBV antibody
LFTs
Heterophil agglutination antibody test
Acyclovir
PTLD: benign polyclonal polymorphic B-cell hyperplasia:
May consider acyclovir
Ganciclovir
Fever
PTLD:
Decreased
Sore throat
CT scan: Note: absence of adenopathy does not rule out PTLD; disease can be entirely extranodal
Tissue biopsy
immunosuppression (possibly)
PTLD:
PTLD: early malignant polyclonal polymorphic B-cell lymphoma:
Mononucleosis-like syndrome
Weight loss
Fever of unknown origin
Abdominal pain
Anorexia
Jaundice
Bowel perforation
GI bleeding
Renal and hepatic dysfunction
Pneumothorax
Pulmonary infiltrates
CNS findings (seizures, altered LOC)
Allograft involvement
Acyclovir
Ganciclovir
Interferon-α
Gamma globulin
Anti-B-cell antibodies (anti-CD20)
Decreased immunosuppression (possibly)
PTLD: monoclonal polymorphic B-cell lymphoma:
Chemotherapy
Radiation
Resection
Decreased immunosuppression
Herpes simplex virus 117
Herpes simplex virus 217
Herpes labialis
Herpetic esophagitis
Anogenital lesions
Visceral infection is rare
HSV-1:
Acyclovir (low-dose)
Ganciclovir (has low oral bioavailability)
Valacyclovir
Famciclovir
Duration of prophylaxis: typically 30-90 d
Viral culture
Direct immunofluorescence studies
Tzanck smear
PCR
Acyclovir
Ganciclovir
Valacyclovir
Famciclovir
Foscarnet for resistant strains
Crusted ulcerations
HSV-2:
Coalescing ulcerations without clear-cut vesicles
Localized dermatomal zoster
Disseminated infection
Bone marrow suppression
Encephalitis
Interstitial pneumonitis
Localized dermatomal zoster that involves two or three adjoining dermatomes without visceral involvement (viral reactivation)
Primary, disseminated infection: associated with hemorrhagic pneumonia, skin lesions, encephalitis, pancreatitis, hepatitis, and disseminated intravascular coagulation
Two noncontiguous dermatomal involvement
Fever
Malaise
Rash
Bone marrow dysfunction
Seronegative recipients with significant exposure (same room contact with diagnosed case of chickenpox or direct contact with skin lesion of shingles)
Varicella zoster hyperimmune globulin within 72 h of significant exposure
IV acyclovir within 24 h of eruption of skin rash
None at present
Characteristic unilateral vesicular lesions
VZV antibody titer
Tzanck smear
Direct immunofluorescence studies
PCR
Serologic testing PCR assay
Localized infection:
Acyclovir (oral)
Famciclovir (oral)
Valacyclovir (oral)
Disseminated infection:
Acyclovir (IV; high-dose)
HHV-618
VZV immune globulin for VZV-seronegative recipients within 72 h of exposure to VZV
Ganciclovir
Foscarnet
Acute or chronic hepatitis
Cirrhosis
Recurrent HBV infection:
HBV vaccine for nonimmune transplant candidates
Perioperative anti-HBV immune globulin for liver transplant candidates with HBV infection
HBV:
HBV: Immune globulin
+ HbsAg (typically 2-6 mo posttransplant)
Serologic testing
Hepatocellular symptoms that can range from mild hepatitis to fulminant liver failure
HCV: chronic hepatitis
HCV:
Detection of HCV-RNA by reverse transcriptase PCR
Liver biopsy
Tubulointerstitial nephritis
Ureteral stenosis
Obstructive nephropathy
Progressive graft dysfunction
Graft loss
Fever
Persistent hematuria
Elevated serum creatinine level
Plasma and urine assays: detection of virus DNA by PCR
Urine cytology: detection of characteristic “decoy” cells
Immunohistochemistry
Tissue biopsy (gold standard) May be difficult to differentiate virus infection from rejection; definitive diagnosis requires visualization of polyomavirus inclusion bodies in biopsy specimen
Decrease immunosuppression agents under investigation
Cidofovir
Leflunomide
Quinolone antibiotics
IVIG
Supportive care
Multifocal demyelination in brain
Progressive demyelinating
PML progressive multifocal leukoencephalopathy
Progressive neurologic deficits
May involve cerebral cortex, brain stem, or cerebellum
Cortical syndromes:
MRI of head
CT scan
EEG
PCR analysis of spinal blood and spinal fluid
Biopsy of brain with in situ hybridization for JC virus
Cessation of immunosuppression
Corticosteroid therapy
Nucleoside analogs: interfere with DNA synthesis:
Visual deficits (hemianopsia)
Hemiparesis
Frontal lobe dementia
Cytosine arabinoside
Adenosine arabinoside
Iododeoxyuridine
Brain stem lesions:
Zidovudine
Contralateral hemiparesis or hemisensory deficits
Interferons: stimulate natural killer cells
Unilateral lesions:
Nucleoside analogs: interfere with DNA synthesis:
Clumsiness
Limb incoordination
Cytosine arabinoside
Adenosine arabinoside
Midline lesions:
Iododeoxyuridine
Zidovudine
Imbalance, falls
Disequilibrium
Gait disturbance
Cerebellar lesions:
Blurred vision
Dysarthria
Classic triad: dementia, hemiparesis, hemianopsia
Upper respiratory infection
Lower respiratory tract disease
Organ rejection
Bronchiolitis obliterans
Rhinorrhea
Sinus congestion
Otalgia
Nausea; abdominal pain
Cough
Dyspnea
Fever >100.4°F (38°C)
Wheezing, rales, rhonchi
Infiltrates on chest
radiograph
Sinusitis on sinus radiograph
Aggressive infection control measures
Aerosolized ribavirin
IVIG
Antigen detection by immunofluorescence assay
Antigen detection by immunoassay
RNA detection by reverse transcription PCR
Serology:
Demonstration of RSV-IgM antibody (acute infection)
Significant ↑ in RSV-IgG antibody between acute- and convalescent-stage sera
Culture: less sensitive and specific in adult vs. pediatric population
Aerosolized ribavirin
IVIG
RSV pneumonitis:
Aerosolized ribavirin
Palivizumab (RSV monoclonal antibody) plus aerosolized ribavirin
Influenza syndrome
Secondary bacterial complications
Fever
Chills
Rigors
Cough (typically nonproductive)
Sore throat
Fatigue
Headache
Myalgia
Aggressive infection control measures
Annual vaccination of patients and household contacts (unless otherwise contraindicated)
Annual vaccination of health care workers
History and clinical examination
Detection of virus-infected cells (via nasopharyngeal washing or respiratory secretions) with specific fluorescent-labeled antibody probes
Influenza A: early administration of:
Amantadine
Rimantadine
Influenza B:
Oseltamivir
Zanamivir
If started within 36-48 h of symptom onset
Can cause mild upper respiratory disease
May progress to pneumonia
May mimic influenza
No definitive recommendations
Viral isolation
Viral shell assays
Rapid antigen detection
Ribavirin has been used for lower respiratory tract disease
Asymptomatic or mild respiratory illness that may progress to fatal respiratory failure (SARS)
Fever >100.4°F (38°C)
Chills
Headache
Myalgia
Cough
Shortness of breath
Dyspnea
Hypoxia
Lymphopenia
Thrombocytopenia
Mild ↑ in transaminases
No definitive recommendations
Chest radiograph (evidence of pneumonia or adult respiratory distress syndrome)
Detection of viral RNA by real-time reverse transcription-PCR
Detection of acute and convalescent antibodies to SARS by enzyme immunoassay
Supportive care
Empiric antimicrobial agents
Intravenous administration of ribavirin
Corticosteroids
Investigational
Severe, refractory anemia
Pancytopenia
Thrombotic microangiopathy
Fibrosing cholestatic hepatitis
Graft dysfunction
Chronic anemia
↓ platelets
↓ white blood cell count
Fever
Malaise
Pancytopenia
No definitive recommendations
Detection of parvovirus B19 DNA in serum by PCR assay
High-dose IVIG
↓ in immunosuppression
Discontinuing tacrolimus (if possible)
Cutaneous warts
Anogenital warts
Carcinoma of cervix and bladder
Squamous cell carcinoma
Anogenital carcinoma
Warts
Avoidance of excessive sun exposure and ultraviolet light
Sun precautions
Sunscreen with high sun protection factor (≥15)
Tissue biopsy
Topical keratolytic agents
Caustic agents
Topical retinoids
Oral retinoids
Podophyllin, 5-fluorouracil
Bleomycin
Ablation
Carcinoma (skin, cervix, urinary tract):
Cutaneous
Urogenital
Anal
Squamous cell carcinoma that arises in beds of flat warts
Resection
Reduction or withdrawal of immunosuppression
Radiation chemotherapy
Bacteremia
Meningitis
Meningoencephalitis
Myocarditis
Cerebritis without meningitis
Less common manifestations:
Fever (1-5 d)
Headache
Decreased LOC
Focal neurological deficits
Meningismus
Nuchal rigidity
Spinal fluid: neutrophils, lymphocytes; glucose may be normal
Abdominal cramps, diarrhea
Seizures
TMP-SMZ
Dietary precautions regarding milk, cheeses, undercooked meats, and uncooked vegetables
Blood, sputum cultures
CT scan
MRI
CSF cell count, Gram stain, culture, and protein and sugar determination
Note: organism may be confused with diphtheroids in Gram stain smears of pus or sputum
Diagnosis confirmed by isolation of Listeria monocytogenes from culture of blood, CSF, or other sterile source
Treatment of choice: ampicillin + aminoglycoside
Meningeal doses of penicillin or ampicillin
Gentamicin
TMP-SMZ for penicillin-allergic patients
Pneumonia
Arthritis
Endophthalmitis
Endocarditis
Peritonitis
Myocarditis
Hepatitis
Pulmonary and extrapulmonary infection (CNS, skin, and bone)
Subacute onset is typical
Subacute symptoms:
TMP-SMZ
Typical pneumocystis pneumonia prophylaxis with TMP-SMZ offers some protection
Cultures: sputum, BAL fluid
Gram stain
Modified acid-fast stain
Diagnosis confirmed by the presence of Nocardia species in culture
Sulfonamides preferred
Sulfisoxazole
TMP-SMZ
Amikacin
Imipenem
Third-generation cephalosporins
Minocycline
Linezolid
Isolated pulmonary infection: 3-6 mo of therapy
Disseminated disease: 12 mo of therapy
Fever
Cough
Chest pain
Pulmonary nodules, abscesses, cavitating lesions, infiltrates, effusions
Legionella22
Pneumonia
Fever, chills
Focal pulmonary infiltrate
Headache
Confusion
Minimally productive cough
Diarrhea
Chest pain
Malaise
Dyspnea
Routine culture of hospital water supply
Water treatment to control nosocomial infection
Cultures: sputum, BAL fluid
Direct fluorescent antibody stain of respiratory secretions
Urinary antigen detection: can only detect serogroup 1 of Legionella pneumophila species
Fine needle aspiration of lung
Open lung biopsy
Chest radiograph: dense infiltrates (unilateral or bilateral) that may → cavitation
Diagnosis confirmed by: Legionella antigen in urine
Direct fluorescent antibody stain (respiratory secretions or tissue biopsy)
Culture of lower respiratory tract secretions
Quinolones (particularly levofloxacin or ciprofloxacin)
Rifampin (may interact with other drugs via the hepatic cytochrome p450 system)
Macrolides (azithromycin, erythromycin) interact with immunosuppressive medications and should generally be avoided)
TMP-SMZ (but the side effects include bone marrow suppression, hepatitis, rash)
Pulmonary infection
Extrapulmonary infection (intestinal, skeletal, bone, genitourinary, cutaneous, CNS)
Disseminated disease3
Pulmonary:
Nonproductive cough
Mucopurulent secretions
Hemoptysis
Dyspnea
Chest pain
Fever
Excessive sweating
Weight loss
Organ-specific manifestations
Test and treat before transplantation
Isoniazid (controversial)
Tuberculin test: positive in 25%-33% of recipients infected with this disease
Chest radiograph
Bronchoscopy with BAL
Transbronchial biopsy
Pleural needle biopsy
Tuberculin test: often negative
Smears for acid-fast bacilli and mycobacterial culture
Organ-specific histology
Isolates require antimicrobial susceptibility testing
Isoniazid (hepatotoxic)
Rifampin (hepatotoxic)
Pyrazinamide
Ethambutol (may → optic neuritis)
Streptomycin (ototoxic; nephrotoxic)
Increases catabolism of steroids and cyclosporine and tacrolimus; monitor levels of cyclosporine and tacrolimus; monitor patient for rejection
Monitor renal and hepatic function
Recipients with active disease: 9-12 mo of therapy with two agents to which pathogen is susceptible
Pulmonary and extrapulmonary infection
Disseminates to:
Depend on site(s) involved
Pulmonary involvement:
No definitive recommendations
Heart, lung, heart-lung recipients: aerosolized amphotericin B
Lung recipients: oral itraconazole for patients with airway colonization
Epidemiologic: minimize contact with fungal spores; shield patient from nosocomial environmental hazards: high-efficiency particulate air filters; high-performance masks
Preemptive: amphotericin B if respiratory tract is colonized
Chest radiography
Amphotericin B
Itraconazole (oral or IV)
Voriconazole: recently shown to have greater efficacy than amphotericin B for invasive disease
Use of voriconazole with sirolimus is contraindicated
Caspofungin: approved for refractory aspergillosis
Absorption may be erratic, especially in patients with low gastric acidity; monitor plasma concentration of drug
Note: may be normal
Nonproductive cough
Pleuritic chest pain
BAL
Transbronchial biopsy
Brain
Liver
Spleen
Kidneys
Heart
Blood vessels
Bones
Joints
GI tract
Pulmonary infiltrates or nodules
Dyspnea
Low-grade fever
Open lung biopsy
CT scan (e.g., lung, sinuses)
Tissue biopsy
CT or MRI for brain abscesses
Sputum cultures
Repeated positive cultures suggest invasive disease
Positive sputum cultures plus cavitary lung disease suggest invasive disease
Invasive/disseminated infection:
Refractory fever
Sinusitis
Epistaxis; nasal pain
Periorbital pain or swelling
Cutaneous embolic lesions
Progressive erythema or induration along tunneled venous catheter
Focal neurologic findings
May → nephrotoxicity in patients on calcineurin inhibitors; monitor renal function (lipid formulations are less likely to be nephrotoxic; may be preferable for chronic treatment)
Associated with higher relapse rates than amphotericin B
Hemoptysis: sign of invasive disease
Mucocutaneous candidiasis
Oropharyngeal thrush
Candidal esophagitis
Vaginitis
Intertrigo
Paronychia
Onychomycosis
Sternal wound infection; mediastinitis
Intra-abdominal abscesses
UTI
Endocarditis
Disseminated infection
Thrush:
Clotrimazole troches
Oral Nystatin
Liver transplant recipients:
Direct fluorescent antibody stain of respiratory secretions
Localized infection:
Amphotericin B and lipid-based preparations
Lipid-based preparations: less nephrotoxic
Clotrimazole
Mycostatin
Fluconazole for esophagitis and refractory candidiasis
Candidemia in unstable or critically ill patients: Amphotericin B followed by fluconazole if organism is sensitive to fluconazole
Candidemia in stable patients: Fluconazole, if organism is sensitive to fluconazole
Candida albicans:
White patches or ulcers in mouth
Vaginitis:
Preoperative oral bowel decontamination with nystatin to ↓ gut colonization
Cultures with Gram stain
White or yellow vaginal discharge
Pruritus
Disseminated candidiasis:
Blood cultures
CT scan
Intertrigo:
Kidney and pancreas-kidney transplant recipients:
Biopsy of skin lesions
Tissue biopsy
Erythematous, popular skin rash
Paronychia:
Preemptive therapy for asymptomatic candiduria
Diagnosis confirmed by isolating Candida species from culture specimens
Redness, swelling, suppuration around nail edge
Pancreas transplant recipients:
Onychomycosis:
Anecdotal reports of fluconazole prophylaxis for high-risk patients:
Thickened, discolored nails
Intravascular catheter infections
Fever, sepsis
Enteric drainage
Fluconazole
Itraconazole
Pretransplant peritoneal dialysis
Candida krusei:
Typically resistant to fluconazole
Pancreas after kidney transplant
Reperfusion pancreatitis
Retransplantation
Requires maximal doses of amphotericin B
Newer agents: for Candida species
Caspofungin
Voriconazole
Monitor renal function and cyclosporine levels; adjust dose accordingly
Effective for most Candida species except Candida krusei and Candida glabrata
When used with cyclosporine, may ↑ risk of hepatotoxicity; monitor liver function
When used with tacrolimus, may → ↓ tacrolimus levels; monitor tacrolimus levels
Predilection for CNS
Meningitis
Brain abscesses
Secondary seeding of skin, CNS, eye, urinary tract, and skeletal system
Pulmonary infection
Pulmonary infection: cough
Primary prophylaxis: not recommended
Lumbar puncture
CT scan
MRI
Blood culture
CSF analysis: cell count; protein and sugar; Gram stain; acid-fast and fungal stains and cultures (fungal, bacterial, and mycobacterial)
Cryptococcal antigen test on blood, CSF, and pleural fluid
CSF in meningitis:
Lymphocytic pleocytosis
↑ protein
↓ sugar
↑ opening pressure
Definitive diagnosis: detection of antigen in serum and CSF
Amphotericin B
Amphotericin B with 5-flucytosine
Fluconazole with 5-flucytosine
Fluconazole
Course of treatment: minimum of 8-10 wk
Requires monitoring of renal function and cyclosporine levels
Requires monitoring of 5-flucytosine levels to minimize hepatic and bone marrow toxicity
Lung nodules
CNS involvement:
Progressive headache
Memory or attention deficits
Emotional disturbance
Disorders of balance
Cranial nerve dysfunction
Fever
Meningismus
Confusion
Dysphagia
Muscle weakness, tremor
Urinary incontinence
Focal neurologic signs
Seizures
Subacute presentation:
Low-grade fever
Headache
Altered mental status
Cutaneous involvement:
Ulcers
Papules or pustules
Subcutaneous swelling or tumors
Ecchymoses
Granulomata
Abscesses
Vesicles
Palpable purpura or papules
Necrotizing vasculitis
Cellulitis
Pneumonitis
Presentation typically subacute
Fever
Nonproductive cough
Dyspnea
Hypoxemia
Tachypnea
Diffuse pulmonary infiltrates
TMP-SMZ (low dose for 6 mo)
Dapsone
Aerosolized pentamidine
Atovaquone
In patients with G6PD deficiency, evaluate risk of dose-dependent hemolytic anemia
Transbronchial lung biopsy
Needle biopsy of lung
Bronchoalveolar lavage
Chest radiograph (may be negative)
Confirmatory diagnosis: direct staining of specimens: sputum, BAL lavage or lung tissue
TMP-SMZ (high-dose) for 21 d
Pentamidine
Dapsone-trimethoprim
Clindamycin-primaquine (if not G6PD deficient)
Dose may have to be adjusted for renal dysfunction
Histoplasma capsulatum38
Disseminated infection (most common presentation)
Subacute respiratory illness with either focal or disseminated interstitial or miliary infiltrates
Fever (not always present)
Night sweats
Chills
Cough
Headache
Arthritis, myalgias
CNS manifestations
Hepatosplenomegaly
Cutaneous, intestinal, oral mucosal lesions
No firm recommendations; some centers use itraconazole for seropositive recipients
Methenamine-silver stain
Peripheral blood stains
Cultures: blood, respiratory secretions, tissue
Serology
Antigen detection (urine, serum, CSF, BAL fluid)
Chest radiography (may be normal)
Amphotericin B
Itraconazole for maintenance therapy
Requires monitoring of renal function and cyclosporine levels
Absorption may be erratic, especially in patients with low gastric acidity; monitor plasma concentration of drug
Toxoplasma gondii39
Myocarditis
Pericarditis
Pneumonitis
Encephalitis
Hepatitis
Retinochoroiditis
Mononucleosis-like syndrome of fever, malaise, and lymphadenopathy
Myocardial dysfunction that mimics rejection
Pulmonary: fever, dyspnea, cough, hemoptysis
CNS involvement: multiple focal neurologic deficits, altered mental status; fever with headache
Particularly for seronegative recipient/seropositive donor:
Pyrimethamine (for sulfa allergy)
Pyrimethamine + sulfonamide
Pyrimethamine + folinic acid
Co-trimoxazole
Atovaquone
TMP-SMZ
Avoid changing cat litter boxes
Avoid raw or undercooked meat
Endomyocardial biopsy
Antibody titers
Lung lavage and/or biopsy
CT scan of head
Chest radiograph
Tissue and/or blood culture
Serologic assays
Definitive diagnosis: histological detection of trophozoites + inflammation
Pyrimethamine with folinic acid and sulfadiazine
Sulfa allergy: dapsone used instead of sulfadiazine
Clindamycin and pyrimethamine with folinic acid
Folinic acid given to prevent myelotoxicity
Continue therapy for 2-3 wk after acute infection has resolved
Cryptosporidium40
Gastroenteritis
Gallbladder infection
Profuse, watery diarrhea
Abdominal pain
Nausea and vomiting
Fever
Myalgias
Boil water for 5 min or use distilled or filtered water
Avoid ice cubes in restaurants
Avoid soda fountain drinks
Stool testing
Antibody detection assays
Small or large bowel biopsy
Replace fluid and electrolytes
Maintain nutritional status
Spiramycin effective for some patients; adverse effects reported (increased stool output and volume loss)
Strongyloides stercoralis41
Ulcerating hemorrhagic enterocolitis
Hemorrhagic pneumonia
Disseminated disease:
Pulmonary
CNS (gram-negative meningitis)
GI:
Consider preemptive ivermectin for transplant candidates who have traveled to or lived in endemic areas
Screen at-risk candidates for infection
Treat established infection before transplantation
Stool specimen for rhabditiform larvae (may be negative)
Papanicolaou stain of duodenal aspirates, urine, ascitic fluid, sputum, and stool
Jejunal biopsy
Serologic testing
Chest radiograph (frequently inconclusive)
Definitive diagnosis: presence of larvae in stool
Albendazole
Ivermectin
Thiabendazole
Taper immunosuppressive agents
Systemic antibacterial therapy for bacteremia or meningitis
Periodic retreatments may be necessary
Hyperinfection: 7-10 d of antimicrobial therapy
Abdominal pain and distention
Diarrhea
Nausea and vomiting
Adynamic ileus
Small bowel obstruction
Hemorrhage
Pulmonary:
Tachypnea
Dyspnea
Bronchospasm
Cough
Hemoptysis CNS:
Headache
Fever
Eosinophilic meningitis
Mental status changes
Coma
Focal neurologic deficits
Gram-negative meningitis
Skin manifestations:
Migratory, raised, linear rash that may move at a rate of 10 cm/hr
Crops of urticarial eruptions; immediate hypersensitive reactions to migrating worms, especially on the waist and buttocks)
BAL, bronchoalveolar lavage; CT, computed tomography; CMV, cytomegalovirus; CSF, cerebrospinal fluid; CBC, complete blood count; CNS, central nervous system; EBV, Epstein-Barr virus; ELISA, enzyme-linked immunosorbent assay; EEG, electroencephalogram; G6PD, glucose-6-phosphate dehydrogenase; GI, gastrointestinal; LFT, liver function tests; HBV, hepatitis B virus; HbsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HCV-RNA, hepatitis C virus ribonucleic acid; HHV, human herpesvirus 6; HSV, herpes simplex virus; IV, intravenous; IVIG, intravenous immunoglobulin; LOC, level of consciousness; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PTLD, posttransplant lymphoproliferative disease; SARS, severe acute respiratory syndrome; TMP-SMZ, trimethoprim-sulfamethoxazole; VZV, varicella zoster virus; UTI, urinary tract infection.
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