InternalMed_Harrison

InternalMed_Harrison. Catheter-related bloodstream infections derive largely from the cutaneous microflora of the insertion site, with pathogens migrating extraluminally to the catheter tip, usually during the first week after insertion. In addition, contamination of the hubs of CVCs or of the ports of “needle-less” systems may lead to intraluminal infection over longer periods, particularly with surgically implanted or cuffed catheters. Intrinsic (during the manufacturing process) or extrinsic (on-site in a health care facility) contamination of infusate, although rare, is the most common cause of epidemic device-related bloodstream infection; extrinsic contamination may cause up to half of endemic bacteremias related to arterial infusions used for hemodynamic monitoring. The most common pathogens isolated from vascular device–associated bacteremias include coagulase-negative staphylococci, S. aureus (with ≥50% of isolates in the United States resistant to methicillin), enterococci, nosocomial


InternalMed_Harrison

InternalMed_Harrison. isolated from vascular device–associated bacteremias include coagulase-negative staphylococci, S. aureus (with ≥50% of isolates in the United States resistant to methicillin), enterococci, nosocomial gram-negative bacilli, and Candida. Many pathogens, especially staphylococci, produce extracellular polysaccharide biofilms that facilitate attachment to catheters and provide sanctuary from antimicrobial agents. “Quorum-sensing” proteins, a target for future interventions, help bacterial cells communicate during biofilm development.


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InternalMed_Harrison. Evidence-based bundles of control measures (Table 168-4) have been strikingly effective, eliminating almost all CVC-associated infections in one ICU study. Additional control measures for infections associated with vascular access include use of a chlorhexidine-impregnated 916 patch at the skin-catheter junction; daily bathing of ICU patients with chlorhexidine; application of semitransparent access-site dressings (for ease of bathing and site inspection and protection of the site from secretions); avoidance of the femoral site for catheterization because of a higher risk of infection (most likely related to the density of the skin flora); rotation of peripheral catheters to a new site at specified intervals (e.g., every 72–96 h), which may be facilitated by use of an IV therapy team; and application of aseptic technique when accessing pressure transducers or other vascular ports. Unresolved issues include the role of gut translocation rather than vascular access sites as a cause of


InternalMed_Harrison

InternalMed_Harrison. application of aseptic technique when accessing pressure transducers or other vascular ports. Unresolved issues include the role of gut translocation rather than vascular access sites as a cause of primary bacteremia in immunocompromised patients and the implications for surveillance definitions; the best frequency for rotation of CVC sites (given that guidewire-assisted catheter changes at the same site do not lessen and can even increase infection risk); the appropriate role of mupirocin ointment, a topical antibiotic with excellent antistaphylococcal activity, in site care; the relative degrees of risk posed by peripherally inserted central catheters (PICC lines); and the risk-benefit of prophylactic use of heparin (to avoid catheter thrombi, which may be associated with increased risk of infection) or of vancomycin or alcohol (as catheter flushes or “locks”— i.e., concentrated anti-infective solutions instilled into the catheter lumen) for high-risk patients. Vascular


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InternalMed_Harrison. risk of infection) or of vancomycin or alcohol (as catheter flushes or “locks”— i.e., concentrated anti-infective solutions instilled into the catheter lumen) for high-risk patients. Vascular device–related infection is suspected on the basis of the appearance of the catheter site or the presence of fever or bacteremia without another source in patients with vascular catheters. The diagnosis is confirmed by the recovery of the same species of microorganism from peripheral-blood cultures (preferably two samples drawn from peripheral veins by separate venipunctures) and from semiquantitative or quantitative cultures of the vascular catheter tip. Less commonly used diagnostic measures include (1) differential (faster) time to positivity (>2 h) for blood drawn through the vascular access device than for a sample from a peripheral vein and (2) differences in quantitative cultures (a threefold or greater “step-up”) for blood samples drawn simultaneously from a peripheral vein and from a


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InternalMed_Harrison. than for a sample from a peripheral vein and (2) differences in quantitative cultures (a threefold or greater “step-up”) for blood samples drawn simultaneously from a peripheral vein and from a CVC, which should show the step-up if infected. When infusion-related sepsis is considered (e.g., because of the abrupt onset of fever or shock temporally related to infusion therapy), a sample of the infusate or blood product should be retained for culture. Therapy for vascular access–related infection is directed at the pathogen recovered from the blood and/or infected site. Important considerations in treatment are the need for an echocardiogram (to evaluate the patient for endocarditis), the duration of therapy, and the need to remove potentially infected catheters. In one report, approximately one-fourth of patients with intravascular catheter– associated S. aureus bacteremia who were studied by transesophageal echocardiography had evidence of endocarditis; this test may be useful in


InternalMed_Harrison

InternalMed_Harrison. one-fourth of patients with intravascular catheter– associated S. aureus bacteremia who were studied by transesophageal echocardiography had evidence of endocarditis; this test may be useful in determining the appropriate duration of treatment. Detailed consensus guidelines for the management of intravascular catheter–related infections have been published and recommend catheter removal in most cases of bacteremia or fungemia due to nontunneled CVCs. When attempting to salvage a potentially infected catheter, some clinicians use the “antibiotic lock” technique, which may facilitate penetration of infected biofilms, in addition to systemic antimicrobial therapy (see www.idsociety.org/Other_Guidelines/). The authors of the consensus treatment guidelines advise that the decision to remove a tunneled catheter or implanted device suspected of being the source of bacteremia or fungemia should be based on the severity of the patient’s illness, the strength of evidence that the device is


InternalMed_Harrison

InternalMed_Harrison. a tunneled catheter or implanted device suspected of being the source of bacteremia or fungemia should be based on the severity of the patient’s illness, the strength of evidence that the device is infected, the presence of local or systemic complications, an assessment of the specific pathogens, and the patient’s response to antimicrobial therapy if the catheter or device is initially retained. For patients with track-site infection, successful therapy without catheter removal is unusual. For patients with suppurative venous thrombophlebitis, excision of affected veins is usually required.


InternalMed_Harrison

InternalMed_Harrison. Written policies for the isolation of infectious patients are a standard component of infection control programs. To replace its prior pathogen-specific guidelines, the CDC published recommendations in 2006 for the control of multidrug-resistant organisms in health care settings; in 2007, the CDC published a revised edition of its basic isolation guidelines to provide updated recommendations for all components of health care, including acute-care hospitals and long-term, ambulatory, and home-care settings (see www.cdc.gov/hicpac/pdf/isolation/ Isolation2007.pdf).


InternalMed_Harrison

InternalMed_Harrison. Standard precautions are designed for the care of all patients in hospitals and aim to reduce the risk of transmission of microorganisms from both recognized and unrecognized sources. These precautions include gloving as well as hand cleansing for potential contact with (1) blood; (2) all other body fluids, secretions, and excretions, whether or not they contain visible blood; (3) nonintact skin; and (4) mucous membranes. Depending on exposure risks, standard precautions also include use of masks, eye protection, and gowns.


InternalMed_Harrison

InternalMed_Harrison. Precautions for the care of patients with potentially contagious clinical syndromes (e.g., acute diarrhea) or with suspected or diagnosed colonization or infection by transmissible pathogens are based on probable routes of transmission: airborne, droplet, or contact, for which personnel don, at a minimum, N95 respirators, surgical face masks, or glove and gown, respectively. Sets of precautions may be combined for diseases that have more than one route of transmission (e.g., contact and airborne isolation for varicella).


InternalMed_Harrison

InternalMed_Harrison. Some prevalent antibiotic-resistant pathogens, particularly those that colonize the gastrointestinal tract (e.g., vancomycin-resistant enterococci [VRE] and even multidrug-resistant gram-negative bacilli such as carbapenemase-producing strains of K. pneumoniae [KPCs]), may be present on intact skin of patients in hospitals (the “fecal patina”). This issue has led some experts to recommend gloving for all contact with patients who are acutely ill and/or in high-risk units, such as ICUs or LTACHs. Wearing gloves does not replace the need for hand hygiene because hands sometimes (in up to 20% of interactions) become contaminated during wearing or removal of gloves.


InternalMed_Harrison

InternalMed_Harrison. Outbreaks are always big news but probably account for <5% of nosocomial infections. The investigation and control of nosocomial epidemics require that infection control personnel (1) develop a case definition, (2) confirm that an outbreak really exists (since apparent epidemics may actually be pseudo-outbreaks due to surveillance or laboratory artifacts), (3) review aseptic practices and disinfectant use, (4) determine the extent of the outbreak, (5) perform an epidemiologic investigation to determine modes of transmission, (6) work closely with microbiology personnel to culture for common sources or personnel carriers as appropriate and to type epidemiologically important isolates, and (7) heighten surveillance to judge the effect of control measures. Control measures generally include reinforcing routine aseptic practices and hand hygiene, ensuring appropriate isolation of cases (and instituting cohort isolation and nursing if needed), and implementing further controls on the basis


InternalMed_Harrison

InternalMed_Harrison. routine aseptic practices and hand hygiene, ensuring appropriate isolation of cases (and instituting cohort isolation and nursing if needed), and implementing further controls on the basis of the investigation’s findings. Examples of some emerging and potential epidemic problems follow.


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InternalMed_Harrison. VIRAL RESPIRATORY INFECTIONS: PANDEMIC INFLUENZA Infections caused by the severe acute respiratory syndrome globally in 2003 (Chap. 223), and in 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) emerged as a more geographically localized problem (Chap. 223). For SARS, basic infection-control measures helped to keep the worldwide case and death counts at ~8000 and ~800, respectively, although the virus was unforgiving of lapses in protocol adherence or laboratory biosafety. The epidemiology of SARS—spread largely in households once patients were ill or in hospitals—contrasts markedly with that of influenza (Chap. 224), which is often contagious a day before symptom onset; can spread rapidly in the community among nonimmune persons; and, even in its seasonal variety, kills as many as 35,000 persons each year in the United States.


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InternalMed_Harrison. Control of seasonal influenza has depended on (1) the use of effective vaccines, with increasingly broad evidence-based recommendations for vaccination of children, the general public, and health care workers; (2) the use of antiviral medications for early treatment and for prophylaxis as part of outbreak control, especially for high-risk patients and in high-risk settings like nursing homes or hospitals; and (3) infection control (surveillance and droplet precautions) for symptomatic patients. Controversial infection-control issues have been the questionable role of airborne spread of influenza and the need to mandate influenza vaccination of health care workers because of the embarrassingly low rates of vaccination in this high-risk group.


InternalMed_Harrison

InternalMed_Harrison. With the occurrence of localized outbreaks of avian (H5N1) influenza in Asia over the past few years, concerns about potential pandemic influenza led to (1) recommendations for universal “respiratory hygiene and cough etiquette” (basically, “cover your cough”), as described and promoted in the CDC’s 2007 Guideline for Isolation Precautions, and for “source containment” (e.g., use of face masks and spatial separation) for outpatients with potentially infectious respiratory illnesses; (2) re-examinations of the value in the 1918–1919 influenza pandemic of nonpharmacologic interventions, such as “social distancing” (e.g., closing of schools and community venues); and (3) debate about the level of respiratory protection required for health care workers (i.e., whether to use the higher-efficiency N95 respirators recommended for airborne isolation rather than the surgical masks used for droplet precautions).


InternalMed_Harrison

InternalMed_Harrison. In the spring of 2009, a novel strain of influenza virus—H1N1 or “swine flu” virus—caused the first influenza pandemic in four decades. Recombinant events that create new strains (e.g., H7N9) continue to challenge global efforts at infection control and vaccine development (Chap. 224). A new, more virulent strain of C. difficile—NAP1/BI/027—emerged in North America, and overall rates of C. difficile–associated diarrhea (Chap. 161) have increased, especially among older patients, in


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InternalMed_Harrison. U.S. hospitals during the past few years. C. difficile control measures include judicious use of all antibiotics, especially fluoroquinolone antibiotics that have been implicated in driving these changes; heightened suspicion for “atypical” presentations (e.g., toxic megacolon or leukemoid reaction without diarrhea); and early diagnosis, treatment, and contact precautions. To improve diagnosis, use of more sensitive polymerase chain reaction–based rather than enzyme immunoassay– based testing of diarrheal stool is now recommended, with resultant artificial doubling of infection rates in some hospitals. Preliminary data suggest a role for probiotics in the prevention of C. difficile– associated diarrhea in patients in whom systemic antibiotic therapy is being initiated. Fecal transplantation has had dramatic results in the treatment of relapsing cases of C. difficile–associated diarrhea (Chap. 161). Successes with fecal transplants and probiotics have called attention to the potential


InternalMed_Harrison

InternalMed_Harrison. has had dramatic results in the treatment of relapsing cases of C. difficile–associated diarrhea (Chap. 161). Successes with fecal transplants and probiotics have called attention to the potential role of manipulation of the intestinal microbiome as a broader infection-control strategy.


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InternalMed_Harrison. Outbreaks of norovirus infection (Chap. 227) in U.S. and European health care facilities appear to continue to increase in frequency or at least in reporting, with the virus often introduced by ill visitors or staff. This pathogen should be suspected when nausea and vomiting are prominent aspects of bacterial culture–negative diarrheal syndromes. Contact precautions may need to be augmented by aggressive environmental cleaning (given the persistence of norovirus on inanimate objects), prevention of secondary cases in cleaning staff through an emphasis on the use of personal protective equipment and hand hygiene, and active exclusion of ill staff and visitors.


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InternalMed_Harrison. Infection control practitioners institute a varicella exposure investigation and control plan whenever health care workers have been exposed to chickenpox (Chap. 217) or have worked while having or during the 24 h before developing chickenpox. The names of exposed workers and patients are obtained; medical histories are reviewed, and (if necessary) serologic tests for immunity are conducted; physicians are notified of susceptible exposed patients; postexposure prophylaxis with a preparation of varicella-zoster immune globulin (VZIG) is considered for immunocompromised or pregnant contacts, with administration as soon as possible (but as long as 10 days after expo-917 sure) (Table 217-1); varicella vaccine is recommended or preemptive use of acyclovir is considered as an alternative strategy in other susceptible persons; and susceptible exposed employees are furloughed during the at-risk period for disease (8–21 days or, if VZIG has been administered, 28 days). Routine varicella


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InternalMed_Harrison. strategy in other susceptible persons; and susceptible exposed employees are furloughed during the at-risk period for disease (8–21 days or, if VZIG has been administered, 28 days). Routine varicella vaccination of children and susceptible employees has made nosocomial spread less common and less problematic.


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InternalMed_Harrison. Important measures for the control of tuberculosis (Chap. 202) include prompt recognition, isolation, and treatment of cases; recognition of atypical presentations (e.g., lower-lobe infiltrates without cavitation); use of negative-pressure, 100% exhaust, private isolation rooms with closed doors and at least 6–12 air changes per hour; use of N95 respirators by caregivers entering isolation rooms; possible use of high-efficiency particulate air filter units and/or ultraviolet lights for disinfecting air when other engineering controls are not feasible or reliable; and follow-up testing of susceptible personnel who have been exposed to infectious patients before isolation. The use of serologic tests, rather than skin tests, in the diagnosis of latent tuberculosis for infection control purposes has become common, mostly for logistic reasons. As tuberculosis once again is on the decline in the United States, we need to remember that the price of freedom—in this instance, from a


InternalMed_Harrison

InternalMed_Harrison. purposes has become common, mostly for logistic reasons. As tuberculosis once again is on the decline in the United States, we need to remember that the price of freedom—in this instance, from a communicable disease—is eternal vigilance.


InternalMed_Harrison

InternalMed_Harrison. The potential for an outbreak of group A streptococcal infection (Chap. 173) should be considered when even one or two nosocomial cases occur. Most outbreaks involve surgical wounds and are due to the presence of an asymptomatic carrier in the operating room. Investigation can be confounded by carriage at extrapharyngeal sites such as the rectum and vagina. Health care workers in whom carriage has been linked to nosocomial transmission of group A streptococci are removed from the patient-care setting and are not permitted to return until carriage has been eliminated by antimicrobial therapy.


InternalMed_Harrison

InternalMed_Harrison. Fungal spores are common in the environment, particularly on dusty surfaces. When dusty areas are disturbed during hospital repairs or renovation, the spores become airborne. Inhalation of spores by immunosuppressed (especially neutropenic) patients creates a risk of pulmonary and/or paranasal sinus infection and disseminated aspergillosis (Chap. 241). Routine surveillance among neutropenic patients for infections with filamentous fungi, such as Aspergillus and Fusarium, helps hospitals to determine whether they are facing environmental risks. As a matter of routine, hospitals should inspect and clean air-handling equipment, review all planned renovations with infection control personnel and subsequently construct appropriate barriers, remove immunosuppressed patients from renovation sites, and consider the use of high-efficiency particulate air intake filters for rooms housing immunosuppressed patients.


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InternalMed_Harrison. A major multistate iatrogenic outbreak of meningitis, localized spinal or paraspinal infection, and arthritis due to Exserohilum rostratum was recognized in 2012 and traced to contamination of an injectable preservative-free steroid product produced by a single compounding pharmacy (Chap. 241).


InternalMed_Harrison

InternalMed_Harrison. Nosocomial Legionella pneumonia (Chap. 184) is most often due to contamination of potable water and predominantly affects immunosuppressed patients, particularly those receiving glucocorticoid medications. The risk varies greatly within and among geographic regions, depending on the extent of hospital water contamination and on specific hospital practices (e.g., inappropriate use of nonsterile water in respiratory therapy equipment). Laboratory-based surveillance for nosocomial Legionella should be performed, and a diagnosis of legionellosis should probably be considered more often than it is. If nosocomial cases are detected, environmental samples (e.g., tap water) 918 should be cultured. If cultures yield Legionella and if typing of clinical and environmental isolates reveals a correlation, eradication measures should be pursued. An alternative approach is to periodically culture tap water in wards housing high-risk patients. If Legionella is found, a concerted effort should be made


InternalMed_Harrison

InternalMed_Harrison. eradication measures should be pursued. An alternative approach is to periodically culture tap water in wards housing high-risk patients. If Legionella is found, a concerted effort should be made to culture samples from all patients with nosocomial pneumonia for Legionella.


InternalMed_Harrison

InternalMed_Harrison. Emerging multidrug-resistant bacteria like KPCs are harbingers of a potential “postantibiotic” era. Control of antibiotic resistance depends on close laboratory surveillance, with early detection of problems; on aggressive reinforcement of routine asepsis; on implementation of barrier precautions for all colonized and/or infected patients; on use of patient-surveillance cultures to more fully ascertain the extent of patient colonization; on antimicrobial stewardship to lessen ecologic pressures; and on timely initiation of an epidemiologic investigation when rates increase. Molecular typing (e.g., pulsed-field gel electrophoresis and, most recently, whole-genome sequencing) can help differentiate an outbreak due to a single strain (which necessitates an emphasis on hand hygiene and an evaluation of potential common-source exposures) from a polyclonal outbreak (which requires an emphasis on antibiotic prudence and device bundles; Table 168-4). Continuing emergence of


InternalMed_Harrison

InternalMed_Harrison. hygiene and an evaluation of potential common-source exposures) from a polyclonal outbreak (which requires an emphasis on antibiotic prudence and device bundles; Table 168-4). Continuing emergence of multidrug-resistant organisms suggests that control efforts have been insufficient and that regional or broader (national and global) strategies and interventions are urgently needed (see www.cdc.gov/drugresistance/threat-report-2013/ and www.gov.uk/ government/publications/uk-5-year-antimicrobial-resistancestrategy-2013-to-2018/).


InternalMed_Harrison

InternalMed_Harrison. Currently, several antibiotic resistance problems are of particular concern. First, over the past decade or so, the emergence of community-associated methicillin-resistant S. aureus (CA-MRSA) has been dramatic in many countries, with as many as 50% of community-acquired “staph infections” in some U.S. cities now caused by strains resistant to β-lactam antibiotics (Chap. 172). The incursion of CA-MRSA into hospitals is well documented and has impacted surveillance and control of nosocomial MRSA infections.


InternalMed_Harrison

InternalMed_Harrison. Second, in the ongoing global reemergence of nosocomial multidrug-resistant gram-negative bacilli, new problems include plasmid-mediated resistance to fluoroquinolones, metallo-β-lactamasemediated resistance to carbapenems, KPCs, and panresistant strains of Acinetobacter. The problematic New Delhi metallo-β-lactamase (NDM) is plasmid-mediated, has been highly successful in inter-genus transmission, and has quickly become a global threat (see wwwnc.cdc .gov/eid/article/17/10/11-0655_article.htm). For several years, KPCs were a very focal problem in the United States (predominantly in Brooklyn, NY), but more recently these strains have become a national threat. Many multidrug-resistant gram-negative bacilli are susceptible only to colistin, a drug that is consequently being “rediscovered,” or to no available agents.


InternalMed_Harrison

InternalMed_Harrison. Third, there has been renewed recognition of the role of nursing homes, and now LTACHs, in the spread of resistant gram-negative bacilli such as KPCs. In some LTACHs, as many as 30–50% of patients may be colonized with KPCs. Fourth, there has been increasing community-based spread of E. coli strains harboring an enzyme, CTX-M, that renders them broadly resistant to β-lactam antibiotics. Given the community focus of spread, these strains may be seen as a gram-negative version of CA-MRSA. Finally, clinical infections with MRSA strains exhibiting high-level vancomycin resistance due to VRE-derived plasmids have been reported in a few patients—almost all in the United States and most in Michigan—in the setting of prolonged or repeated treatment with vancomycin and/or VRE colonization. Much more common is vancomycin “MIC creep”: an increasing prevalence of MRSA strains that exhibit upper-limit susceptibility to vancomycin.


InternalMed_Harrison

InternalMed_Harrison. Colonized personnel who are implicated in nosocomial transmission of multidrug-resistant pathogens and patients who pose a threat can be decontaminated, depending on the pathogen. In a few ICUs, nonabsorbed antimicrobial agents for gastrointestinal decontamination of patients have been used successfully as a temporary emergency control measure for outbreaks of infection due to gram-negative bacilli. Potentially, manipulation of patients’ intestinal microbiome could be a more durable strategy to control outbreaks of multidrugresistant pathogens that have a gastrointestinal reservoir.


InternalMed_Harrison

InternalMed_Harrison. In several trials over the past 10 years, source control—i.e., removal of patients’ fecal patina—by daily bathing with chlorhexidine has reduced the risk of bacteremia in ICU patients. “Search-and-destroy” methods—i.e., active surveillance cultures to detect and isolate the “resistance iceberg” of patients colonized with MRSA—in nonoutbreak settings are credited with elimination of nosocomial MRSA in the Netherlands and Denmark. In a recent multicenter trial in the United States, universal source control with chlorhexidine and nasal mupirocin was significantly more effective for controlling MRSA than was a search-and-destroy approach and led to control of other pathogens as well, providing a broad (“horizontal”) rather than a narrower (“vertical”) intervention (see www.ahrq.gov/ professionals/systems/hospital/universal_icu_decolonization/). For some pathogens, such as VRE, enforcement of environmental cleaning also reduces cross-transmission risk.


InternalMed_Harrison

InternalMed_Harrison. Because the excessive use of broad-spectrum antibiotics underlies many resistance problems, “antibiotic stewardship” has been promulgated actively. The main tenets are to restrict the use of particular agents to narrowly defined indications in order to limit selective pressure on the nosocomial flora and, when broad-spectrum therapy is begun empirically in critically ill patients, to “de-escalate” treatment as soon as possible on the basis of the results of culture and susceptibility tests. The horrific attack on the World Trade Center in New York


InternalMed_Harrison

InternalMed_Harrison. The horrific attack on the World Trade Center in New York City on September 11, 2001; the subsequent mailings of anthrax spores in the United States; the Boston Marathon bombing in 2013; and ongoing revelations of terrorist plans and activities in many other countries as well as the United States have made bioterrorism a prominent source of concern to hospital infection-control programs. The essentials for hospital preparedness entail education, internal and external communication, and risk assessment. Up-to-date information is available from the CDC (see www.bt.cdc.gov).


InternalMed_Harrison

InternalMed_Harrison. An institution’s employee health service is a critical component of its infection control efforts. New employees should be processed through the service, where a contagious-disease history can be taken; evidence of immunity to a variety of diseases, such as hepatitis B, chickenpox, measles, mumps, and rubella, can be sought; immunizations for hepatitis B, measles, mumps, rubella, varicella, and pertussis (the only vaccine-preventable childhood disease that is on the rise again in the United States) can be given as needed; baseline tuberculosis testing can be performed; and education about personal responsibility for infection control can be initiated. Evaluations of employees should be codified to meet the requirements of accrediting and regulatory agencies.


InternalMed_Harrison

InternalMed_Harrison. The employee health service must have protocols for dealing with workers exposed to contagious diseases (e.g., influenza) and those percutaneously or mucosally exposed to the blood of patients infected with HIV or hepatitis B or C virus. For example, postexposure HIV prophylaxis (PEP) with combination antiretroviral agents is recommended, as indicated; free consultation is available from the CDC-funded PEPLine (888-HIV-4911). Protocols are also needed for dealing with caregivers who have common contagious diseases (such as chickenpox, group A streptococcal infection, influenza or another respiratory infection, or infectious diarrhea) and for those who have less common but high-visibility public health problems (such as chronic hepatitis B or C or HIV infection) for which exposure-control guidelines have been published by the CDC and by the Society for Healthcare Epidemiology of America.


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InternalMed_Harrison. Infections in Transplant Recipients Robert W. Finberg, Joyce Fingeroth This chapter considers aspects of infection unique to patients receiv-ing transplanted tissue. The evaluation of infections in transplant 169 recipients involves consideration of both the donor and the recipient of the transplanted cells or organ. Two central issues are of paramount importance: (1) infectious agents (particularly viruses, but also bacteria, fungi, and parasites) can be introduced into the recipient by the donor; and (2) treatment of the recipient with medicine to prevent rejection can suppress normal immune responses, greatly increasing susceptibility to infection. Thus, what might have been a latent or asymptomatic infection in an immunocompetent donor or in the recipient prior to therapy can become a life-threatening problem when the recipient becomes immunosuppressed. The pretransplantation evaluation of each patient should be guided by an analysis of both (1) what infections the recipient is


InternalMed_Harrison

InternalMed_Harrison. a life-threatening problem when the recipient becomes immunosuppressed. The pretransplantation evaluation of each patient should be guided by an analysis of both (1) what infections the recipient is currently harboring, since organisms that exist in a state of latency or dormancy before the procedure may cause fatal disease when the patient receives immunosuppressive treatment; and (2) what organisms are likely to be transmitted by the donor, particularly those to which the recipient may be naïve.


InternalMed_Harrison

InternalMed_Harrison. PRETRANSPLANTATION EVALUATION The Donor A variety of organisms have been transmitted by organ transplantation. Transmission of infections that may have been latent or not clinically apparent in the donor has resulted in the development of specific donor-screening protocols. Results from routine blood bank studies, including those for antibodies to Treponema pallidum (syphilis), Trypanosoma cruzi, hepatitis B and C viruses, HIV-1 and -2, human T-lymphotropic virus types 1 and 2 (HTLV-1 and -2), and West Nile virus (WNV), should be documented. Serologic studies should be ordered to identify latent infection with viruses such as herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), Kaposi’s sarcoma–associated herpes-virus (KSHV); acute infection with hepatitis A virus; and infection with the common parasite Toxoplasma gondii. Donors should be screened, when relevant, for viruses such as rabies virus and


InternalMed_Harrison

InternalMed_Harrison. herpes-virus (KSHV); acute infection with hepatitis A virus; and infection with the common parasite Toxoplasma gondii. Donors should be screened, when relevant, for viruses such as rabies virus and lymphocytic choriomeningitis virus as well as for parasites such as Strongyloides stercoralis and Schistosoma species. Clinicians caring for prospective organ donors should examine chest radiographs for evidence of granulomatous disease (e.g., caused by mycobacteria or fungi) and should perform skin testing or obtain blood for immune cell–based assays that detect active or latent Mycobacterium tuberculosis infection. An investigation of the donor’s dietary habits (e.g., consumption of raw meat or fish or of unpasteurized dairy products), occupations or avocations (e.g., gardening or spelunking), and travel history (e.g., travel to areas with endemic fungi) also is indicated and may mandate additional testing. Creutzfeldt-Jakob disease has been transmitted through corneal transplants.


InternalMed_Harrison

InternalMed_Harrison. and travel history (e.g., travel to areas with endemic fungi) also is indicated and may mandate additional testing. Creutzfeldt-Jakob disease has been transmitted through corneal transplants. Whether it can be transmitted by transfused blood is not known. Variant Creutzfeldt-Jakob disease can be transmitted with transfused non-leukodepleted blood, posing a theoretical risk to transplant recipients.


InternalMed_Harrison

InternalMed_Harrison. The Recipient It is expected that the recipient will have been even more comprehensively assessed than the donor. Additional studies recommended for the recipient include evaluation for acute respiratory viruses and gastrointestinal pathogens in the immediate pretransplantation period. An important caveat is that, because of immune dysfunction resulting from chemotherapy or underlying chronic disease, serologic testing of the recipient may prove less reliable than usual.


InternalMed_Harrison

InternalMed_Harrison. The Donor Cells/Organ Careful attention to the sterility of the medium used to process the donor organ, combined with meticulous microbiologic evaluation, reduces rates of transmission of bacteria (or, rarely, yeasts) that may be present or grow in the organ culture medium. From 2% to >20% of donor kidneys are estimated to be contaminated with bacteria—in most cases, with the organisms that colonize the skin or grow in the tissue culture medium used to bathe the donor organ 919 while it awaits implantation. The reported rate of bacterial contamination of transplanted stem cells (bone marrow, peripheral blood, cord blood) is as high as 17% but most commonly is ∼1%. The use of enrichment columns and monoclonal antibody depletion procedures results in a higher incidence of contamination. In one series of patients receiving contaminated stem cells, 14% had fever or bacteremia, but none died. Results of cultures performed at the time of cryopreservation and at the time of thawing were


InternalMed_Harrison

InternalMed_Harrison. In one series of patients receiving contaminated stem cells, 14% had fever or bacteremia, but none died. Results of cultures performed at the time of cryopreservation and at the time of thawing were helpful in guiding therapy for the recipient.


InternalMed_Harrison

InternalMed_Harrison. Transplantation of hematopoietic stem cells (HSCs) from bone marrow or from peripheral or cord blood for cancer, immunodeficiency, or autoimmune disease most often results in a transient state of complete immunologic incompetence. Immediately after myeloablative chemotherapy and transplantation, both innate immune cells (phagocytes, dendritic cells, natural killer cells) and adaptive immune cells (T and B cells) are absent, and the host is extremely susceptible to infection. The reconstitution that follows transplantation has been likened to maturation of the immune system in neonates. The analogy does not entirely predict infections seen in HSC transplant recipients, however, because the stem cells mature in an old host who has several latent infections already. The choice among the current variety of methods for obtaining stem cells is determined by availability and by the need to optimize the chances of a cure for an individual recipient. One strategy is autologous HSC


InternalMed_Harrison

InternalMed_Harrison. the current variety of methods for obtaining stem cells is determined by availability and by the need to optimize the chances of a cure for an individual recipient. One strategy is autologous HSC transplantation, in which the donor and the recipient are the same. After chemotherapy, stem cells are collected and are purged (ex vivo) of residual neoplastic populations. Allogeneic HSC transplantation has the advantage of providing a graft-versus-tumor effect. In this case, the recipient is matched to varying degrees for human leukocyte antigens (HLAs) with a donor who may be related or unrelated. In some individuals, nonmyeloablative therapy (mini-allo transplantation) is used and permits recipient cells to persist for some time after transplantation while preserving the graft-versus-tumor effect and sparing the recipient myeloablative therapy. Cord-blood transplantation is increasingly utilized in adults; two independent cord-blood units are typically required for suitable neutrophil


InternalMed_Harrison

InternalMed_Harrison. effect and sparing the recipient myeloablative therapy. Cord-blood transplantation is increasingly utilized in adults; two independent cord-blood units are typically required for suitable neutrophil engraftment early after transplantation, even though only one of the units is likely to provide long-term engraftment. In each circumstance, a different balance is struck among the toxicity of conditioning therapy, the need for a maximal graft-versus-target effect, short-term and long-term infectious complications, and the risk of graft-versus-host disease (GVHD; acute versus chronic). The various approaches differ in terms of reconstitution speed, cell lineages introduced, and likelihood of GVHD—all factors that can produce distinct effects on the risk of infection after transplantation (Table 169-1). Despite these caveats, most infections occur in a predictable time frame after transplantation (Table 169-2).


InternalMed_Harrison

InternalMed_Harrison. In the first month after HSC transplantation, infectious complications are similar to those in granulocytopenic patients receiving chemotherapy for acute leukemia (Chap. 104). Because of the anticipated 1to 4-week duration of neutropenia and the high rate of bacterial infection in this population, many centers give prophylactic antibiotics to patients upon initiation of myeloablative therapy. Quinolones decrease the incidence of gram-negative bacteremia among these patients. Bacterial infections are common in the first few days after HSC transplantation. The organisms involved are predominantly those found on skin, mucosa, or IV catheters (Staphylococcus aureus, coagulase-negative staphylococci, streptococci) or aerobic bacteria that colonize the bowel (Escherichia coli, Klebsiella, Pseudomonas). Bacillus cereus, although rare, has emerged as a pathogen early after transplantation and can cause meningitis, which is unusual in these patients. Chemotherapy, use of broad-spectrum


InternalMed_Harrison

InternalMed_Harrison. Pseudomonas). Bacillus cereus, although rare, has emerged as a pathogen early after transplantation and can cause meningitis, which is unusual in these patients. Chemotherapy, use of broad-spectrum antibiotics, and delayed reconstitution of humoral immunity place HSC transplant patients at risk for diarrhea and colitis caused by Clostridium difficile overgrowth and toxin production.


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InternalMed_Harrison. 920 TABLE 169-1 RISk of InfECTIon, By TyPE of HEMAToPoIETIC STEM CELL TRAnSPLAnT aDepending on the disparity of the match (major and minor histocompatibility antigens), GVHD may be severe or mild, the requirement for immunosuppression intense or minimal, and the risk of severe late infections coordinate with the degree of immunosuppression. Abbreviation: GVHD, graft-versus-host disease.


InternalMed_Harrison

InternalMed_Harrison. Beyond the first few days of neutropenia, infections with nosocomial pathogens (e.g., vancomycin-resistant enterococci, Stenotrophomonas maltophilia, Acinetobacter species, and extended-spectrum β-lactamase–producing gram-negative bacteria) as well as with filamentous bacteria (e.g., Nocardia species) become more common. Vigilance is indicated, particularly for patients with a history of active or known latent tuberculosis, even when they have been appropriately pretreated. A form of bacterial colitis among cord-blood recipients has occurred 90–300 days after transplantation, responds to antimicrobial agents such as metronidazole, and—as determined by polymerase chain reaction (PCR) of biopsy specimens—may be attributed to the bacterium Bradyrhizobium enterica (related to B. japonicum). Episodes of bacteremia due to encapsulated organisms mark the late posttransplantation period (>6 months after HSC reconstitution); patients who have undergone splenectomy and those with persistent


InternalMed_Harrison

InternalMed_Harrison. Episodes of bacteremia due to encapsulated organisms mark the late posttransplantation period (>6 months after HSC reconstitution); patients who have undergone splenectomy and those with persistent hypogammaglobulinemia are at particular risk.


InternalMed_Harrison

InternalMed_Harrison. Beyond the first week after transplantation, fungal infections become increasingly common, particularly among patients who have received broad-spectrum antibiotics. As in most granulocytopenic patients, Candida infections are most commonly seen in this setting. However, with increased use of prophylactic fluconazole, infections with resistant fungi—in particular, Aspergillus and other non-Aspergillus molds (Rhizopus, Fusarium, Scedosporium, Penicillium)—have become more common, prompting some centers to replace fluconazole with agents such as micafungin, voriconazole, or posaconazole. The role of anti-fungal prophylaxis with these different agents, in contrast to empirical treatment for suspected infection that is based on a positive β-dglucan assay or galactomannan antigen test, remains controversial (Chap. 104). Documented infection should be aggressively treated, ideally with agents of proven activity. In patients with GVHD who require prolonged or indefinite courses of


InternalMed_Harrison

InternalMed_Harrison. remains controversial (Chap. 104). Documented infection should be aggressively treated, ideally with agents of proven activity. In patients with GVHD who require prolonged or indefinite courses of glucocorticoids and other immunosuppressive agents (e.g., cyclosporine, tacrolimus [FK 506, Prograf], mycophenolate mofetil [Cellcept], rapamycin [sirolimus, Rapamune], antithymocyte globulin, or anti-CD52 antibody [alemtuzumab, Campath—an antilymphocyte and antimonocyte monoclonal antibody]), there is a high risk of fungal infection (usually with Candida or Aspergillus) even after engraftment and resolution of neutropenia. These patients are also at high risk for reactivation of latent fungal infection (histoplasmosis, coccidioidomycosis, or blastomycosis) in areas where endemic fungi reside and after involvement


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InternalMed_Harrison. Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6, human herpesvirus type 6; HPV, human papillomavirus; HSV, herpes simplex virus; VZV, varicella-zoster virus. in activities such as gardening or caving. Prolonged use of central venous catheters for parenteral nutrition (lipids) increases the risk of fungemia with Malassezia. Some centers administer prophylactic anti-fungal agents to these patients. Because of the high and prolonged risk of Pneumocystis jirovecii pneumonia (especially among patients being treated for hematologic malignancies), most patients receive maintenance prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) starting 1 month after engraftment and continuing for at least 1 year.


InternalMed_Harrison

InternalMed_Harrison. The regimen just described for the fungal pathogen Pneumocystis may also protect patients seropositive for the parasite T. gondii, which can cause pneumonia, visceral disease (occasionally), and central nervous system (CNS) lesions (more commonly). The advantages of maintaining HSC transplant recipients on daily TMP-SMX for 1 year after transplantation include some protection against Listeria monocytogenes and nocardial disease as well as late infections with Streptococcus pneumoniae and Haemophilus influenzae, which stem from the inability of the immature immune system to respond to polysaccharide antigens.


InternalMed_Harrison

InternalMed_Harrison. With increasing international travel, parasitic diseases typically restricted to particular environmental niches may pose a risk of reactivation in certain patients after HSC transplantation. Thus, in recipients with an appropriate history who were not screened and/ or treated before transplantation or in patients with recent exposures, evaluation for infection with Strongyloides, Leishmania, schistosomes, trypanosomes, or various parasitic causes of diarrheal illness (Giardia, Entamoeba, Cryptosporidium, microsporidia) may be warranted. HSC transplant recipients are susceptible to infection with a variety of viruses, including primary and reactivation syndromes caused by most human herpesviruses (Table 169-3) and acute infections caused by viruses that circulate in the community. Hepatitis (rare) Varicella-zoster virus Zoster (can disseminate) Cytomegalovirus Associated with graft rejection Abbreviation: HSC, hematopoietic stem cell.


InternalMed_Harrison

InternalMed_Harrison. Hepatitis (rare) Varicella-zoster virus Zoster (can disseminate) Cytomegalovirus Associated with graft rejection Abbreviation: HSC, hematopoietic stem cell. Herpes Simplex Virus Within the first 2 weeks after transplanta-921 tion, most patients who are seropositive for HSV-1 excrete the virus from the oropharynx. The ability to isolate HSV declines with time. Administration of prophylactic acyclovir (or valacyclovir) to seropositive HSC transplant recipients has been shown to reduce mucositis and prevent HSV pneumonia (a rare condition reported almost exclusively in allogeneic HSC transplant recipients). Both esophagitis (usually due to HSV-1) and anogenital disease (commonly caused by HSV-2) may be prevented with acyclovir prophylaxis. For further discussion, see Chap. 216.


InternalMed_Harrison

InternalMed_Harrison. Varicella-Zoster Virus Reactivation of VZV manifests as herpes zoster and may occur within the first month but more commonly occurs several months after transplantation. Reactivation rates are ∼40% for allogeneic HSC transplant recipients and 25% for autologous recipients. Localized zoster can spread rapidly in an immunosuppressed patient. Fortunately, disseminated disease can usually be controlled with high doses of acyclovir. Because of frequent dissemination among patients with skin lesions, acyclovir is given prophylactically in some centers to prevent severe disease. Low doses of acyclovir appear to be effective in preventing reactivation of VZV. However, acyclovir can also suppress the development of VZV-specific immunity. Thus, its administration for only 6 months after transplantation does not prevent zoster from occurring when treatment is stopped. Administration of low doses of acyclovir for an entire year after transplantation is effective and may eliminate most cases of


InternalMed_Harrison

InternalMed_Harrison. does not prevent zoster from occurring when treatment is stopped. Administration of low doses of acyclovir for an entire year after transplantation is effective and may eliminate most cases of posttransplantation zoster, even among cord-blood recipients. For further discussion, see Chap. 217.


InternalMed_Harrison

InternalMed_Harrison. Cytomegalovirus The onset of CMV disease (interstitial pneumonia, bone marrow suppression, graft failure, hepatitis/colitis) usually begins 30–90 days after HSC transplantation, when the granulocyte count is adequate but immunologic reconstitution has not occurred. CMV disease rarely develops earlier than 14 days after transplantation and may become evident as late as 4 months after the procedure. It is of greatest concern in the second month after transplantation, particularly in allogeneic HSC transplant recipients. In cases in which the donor marrow is depleted of T cells (to prevent GVHD or eliminate a T cell tumor) and in cord-blood recipients, the disease may manifest earlier. The use of alemtuzumab to prevent GVHD in nonmyeloablative transplantation has been associated with an increase in CMV disease. Patients who receive ganciclovir for prophylaxis, preemptive treatment, or treatment (see below) may develop recurrent CMV infection even later than 4 months after


InternalMed_Harrison

InternalMed_Harrison. with an increase in CMV disease. Patients who receive ganciclovir for prophylaxis, preemptive treatment, or treatment (see below) may develop recurrent CMV infection even later than 4 months after transplantation, as treatment appears to delay the development of the normal immune response to CMV infection. Although CMV disease may present as isolated fever, granulocytopenia, thrombocytopenia, or gastrointestinal disease, the foremost cause of death from CMV infection in the setting of HSC transplantation is pneumonia.


InternalMed_Harrison

InternalMed_Harrison. With the standard use of CMV-negative or filtered blood products, CMV infection should be a major risk in allogeneic transplantation only when the recipient is CMV-seropositive and the donor is CMV-seronegative. This situation is the reverse of that in solid organ transplant recipients. CMV reactivates from latent reservoirs present in the recipient at a time when donor T cells (especially cord-blood T cells) are too immature to control CMV replication. If the T cells from the donor have never encountered CMV and the recipient carries the virus, the patient is at maximal risk of severe disease. Reactivation disease or superinfection with another strain from the donor also can occur in CMV-positive recipients, but clinical manifestations are typically less severe, presumably because of CMV-specific memory in transplanted donor T cells. Most patients infected with CMV who undergo HSC transplantation excrete virus, with or without clinical findings. Serious CMV disease is much more


InternalMed_Harrison

InternalMed_Harrison. CMV-specific memory in transplanted donor T cells. Most patients infected with CMV who undergo HSC transplantation excrete virus, with or without clinical findings. Serious CMV disease is much more common among allogeneic than autologous recipients and is often associated with GVHD. In addition to pneumonia and marrow suppression (and, less often, graft failure), manifestations of CMV disease in HSC transplant recipients include fever with or without arthralgias, myalgias, hepatitis, and esophagitis. CMV ulcerations occur in both the lower and the upper gastrointestinal tract, and it may be difficult to distinguish diarrhea due to GVHD from that due to CMV infection. The finding of CMV in 922 the liver of a patient with GVHD does not necessarily mean that CMV is responsible for hepatic enzyme abnormalities. It is interesting that the ocular and neurologic manifestations of CMV infections, which are common in patients with AIDS, are uncommon in patients who develop disease after


InternalMed_Harrison

InternalMed_Harrison. enzyme abnormalities. It is interesting that the ocular and neurologic manifestations of CMV infections, which are common in patients with AIDS, are uncommon in patients who develop disease after transplantation. Management of CMV disease in HSC transplant recipients includes strategies directed at prophylaxis, preemptive therapy (suppression of silent replication), and treatment of disease. Prophylaxis results in a lower incidence of disease at the cost of treating many patients who otherwise would not require therapy. Because of the high fatality rate associated with CMV pneumonia in these patients and the difficulty of early diagnosis of CMV infection, prophylactic IV ganciclovir (or oral valganciclovir) has been used in some centers and has been shown to prevent CMV disease during the period of maximal vulnerability (from engraftment to day 120 after transplantation). Ganciclovir also prevents HSV reactivation and reduces the risk of VZV reactivation; thus acyclovir prophylaxis


InternalMed_Harrison

InternalMed_Harrison. period of maximal vulnerability (from engraftment to day 120 after transplantation). Ganciclovir also prevents HSV reactivation and reduces the risk of VZV reactivation; thus acyclovir prophylaxis should be discontinued when ganciclovir is administered. The foremost problem with the administration of ganciclovir relates to adverse effects, which include dose-related bone marrow suppression (thrombocytopenia, leukopenia, anemia, and pancytopenia). Because the frequency of CMV pneumonia is lower among autologous HSC transplant recipients (2–7%) than among allogeneic HSC transplant recipients (10–40%), prophylaxis in the former group will not become the rule until a less toxic oral antiviral agent becomes available. Several are under study. Preemptive treatment of CMV—that is, initiation of therapy with drugs only after CMV is detected in blood by a nucleic acid amplification test (NAAT)—is used at most centers. To limit variability between tests, the World Health Organization (WHO) has


InternalMed_Harrison

InternalMed_Harrison. therapy with drugs only after CMV is detected in blood by a nucleic acid amplification test (NAAT)—is used at most centers. To limit variability between tests, the World Health Organization (WHO) has developed an international reference standard for measurement of CMV load by NAAT-based assays. Because of toxic drug side effects (e.g., neutropenia and bone marrow suppression), the preemptive approach has supplanted prophylactic therapy; it has also replaced treatment of all seropositive (recipient and/or donor) HSC transplants with an antiviral agent (typically ganciclovir). A positive test (or increasing viral load) prompts the initiation of preemptive therapy with ganciclovir. Preemptive approaches that target patients who have quantitative NAAT evidence of CMV infection can still lead to unnecessary treatment of many individuals with drugs that have adverse effects on the basis of a laboratory test that is not highly predictive of disease; however, invasive disease, particularly in


InternalMed_Harrison

InternalMed_Harrison. unnecessary treatment of many individuals with drugs that have adverse effects on the basis of a laboratory test that is not highly predictive of disease; however, invasive disease, particularly in the form of pulmonary infection, is difficult to treat and is associated with high mortality rates. When prophylaxis or preemptive therapy is stopped, late manifestations of CMV replication may occur, although by then the HSC transplant patient is often equipped with improved graft function and is better able to combat disease. Cord-blood transplant recipients are especially vulnerable to disease caused by members of the human herpesvirus family, including CMV. Implementation of the WHO standard for CMV load measurement will facilitate large-scale comparative studies and thus the establishment of optimal guidelines for distinct patient subsets. CMV pneumonia in HSC transplant recipients (unlike that in other clinical settings) is often treated with both IV immunoglobulin (IVIg) and


InternalMed_Harrison

InternalMed_Harrison. of optimal guidelines for distinct patient subsets. CMV pneumonia in HSC transplant recipients (unlike that in other clinical settings) is often treated with both IV immunoglobulin (IVIg) and ganciclovir. In patients who cannot tolerate ganciclovir, foscarnet is a useful alternative, although it may produce nephrotoxicity and electrolyte imbalance. When neither ganciclovir nor foscarnet is clinically tolerated, cidofovir can be used; however, its efficacy is less well established, and its side effects include nephrotoxicity. A lipid-conjugate form of cidofovir and an oral antiviral agent, maribavir, are in clinical trials. Case reports have suggested that the immunosuppressive agent leflunomide may be active in this setting, but controlled studies are lacking. Transfusion of CMV-specific T cells from the donor has decreased viral load in a small series of patients; this result suggests that immunotherapy (e.g., banked T cells) may play a role in the management of this disease in the


InternalMed_Harrison

InternalMed_Harrison. T cells from the donor has decreased viral load in a small series of patients; this result suggests that immunotherapy (e.g., banked T cells) may play a role in the management of this disease in the future. For further discussion, see Chap. 219.


InternalMed_Harrison

InternalMed_Harrison. Human Herpesviruses 6 and 7 Human herpesvirus type 6 (HHV-6), the cause of roseola in children, is a ubiquitous herpesvirus that is reactivated (as determined by quantitative plasma PCR) in ∼50% of HSC transplant recipients 2–4 weeks after transplantation. Reactivation is more common among patients requiring glucocorticoids for GVHD and among those receiving second transplants. Reactivation of HHV6, primarily type B, may be associated with delayed monocyte and platelet engraftment. Limbic encephalitis developing after transplantation has been associated with HHV-6 in cerebrospinal fluid (CSF). The causality of the association is not well defined; in several cases, plasma viremia was detected long before the onset of encephalitis. Nevertheless, most patients with encephalitis had very high viral loads in plasma at the time of CNS illness, and viral antigen has been detected in hippocampal astrocytes. HHV-6 DNA is sometimes found in lung samples after transplantation. However, its role


InternalMed_Harrison

InternalMed_Harrison. viral loads in plasma at the time of CNS illness, and viral antigen has been detected in hippocampal astrocytes. HHV-6 DNA is sometimes found in lung samples after transplantation. However, its role in pneumonitis is unclear, as co-pathogens are frequently present. While HHV-6 is susceptible to foscarnet or cidofovir (and possibly to ganciclovir) in vitro, the efficacy of antiviral treatment has not been well studied. Little is known about the related herpesvirus HHV-7 or its role in posttransplantation infection. For further discussion, see Chap. 219.


InternalMed_Harrison

InternalMed_Harrison. Epstein-Barr Virus Primary EBV infection can be fatal to HSC transplant recipients; EBV reactivation can cause EBV–B cell lymphoproliferative disease (EBV-LPD), which may also be fatal to patients taking immunosuppressive drugs. Latent EBV infection of B cells leads to several interesting phenomena in HSC transplant recipients. The marrow ablation that occurs as part of the HSC transplantation procedure may sometimes eliminate latent EBV from the host. Infection can then be reacquired immediately after transplantation by transfer of infected donor B cells. Rarely, transplantation from a seronegative donor may result in a cure. The recipient is then at risk for a second primary infection.


InternalMed_Harrison

InternalMed_Harrison. EBV-LPD can develop in the recipient’s B cells (if any survive marrow ablation) but is more likely to be a consequence of outgrowth of infected donor cells. Both lytic replication and latent replication of EBV are more likely during immunosuppression (e.g., they are associated with GVHD and the use of antibodies to T cells). Although less likely in autologous transplantation, reactivation can occur in T cell–depleted autologous recipients (e.g., patients being given antibodies to T cells for the treatment of a T cell lymphoma with marrow depletion). EBV-LPD, which can become apparent as early as 1–3 months after engraftment, can cause high fevers and cervical adenopathy resembling the symptoms of infectious mononucleosis but more commonly presents as an extranodal mass. The incidence of EBVLPD among allogeneic HSC transplant recipients is 0.6–1%, which contrasts with figures of ∼5% for renal transplant recipients and up to 20% for cardiac transplant patients. In all cases, EBV-LPD is


InternalMed_Harrison

InternalMed_Harrison. among allogeneic HSC transplant recipients is 0.6–1%, which contrasts with figures of ∼5% for renal transplant recipients and up to 20% for cardiac transplant patients. In all cases, EBV-LPD is more likely to occur with high-dose, prolonged immunosuppression, especially that caused by the use of antibodies to T cells, glucocorticoids, and calcineurin inhibitors (e.g., cyclosporine, tacrolimus). Cord-blood recipients constitute another high-risk group because of delayed T cell function. Ganciclovir, administered to preempt CMV disease, may reduce EBV lytic replication and thereby diminish the pool of B cells that can become newly infected and give rise to LPD. Increasing evidence indicates that replacement of calcineurin inhibitors with mTor inhibitors (e.g., rapamycin) exerts an antiproliferative effect on EBV-infected B cells that decreases the likelihood of development of LPD or unrelated proliferative disorders associated with transplant-related immunosuppression.


InternalMed_Harrison

InternalMed_Harrison. PCR can be used to monitor EBV production after HSC transplantation. High or increasing viral loads predict an enhanced likelihood of EBV-LPD development and should prompt rapid reduction of immunosuppression and a search for nodal or extranodal disease. If reduction of immunosuppression does not have the desired effect, administration of a monoclonal antibody to CD20 (e.g., rituximab) for the treatment of B cell lymphomas that express this surface protein has elicited dramatic responses and currently constitutes first-line therapy for CD20-positive EBV-LPD. However, long-term suppression of new antibody responses accompanies therapy, and recurrences are not infrequent. Additional B cell–directed antibodies, including anti-CD22, are under study. The role of antiviral drugs is uncertain because no available agents have been documented to have activity against the different forms of latent EBV infection. Diminishing lytic replication and virion production in these patients would


InternalMed_Harrison

InternalMed_Harrison. because no available agents have been documented to have activity against the different forms of latent EBV infection. Diminishing lytic replication and virion production in these patients would theoretically produce a statistical decrease in the frequency of latent disease by decreasing the number of virions available to cause additional infection. In case reports and animal studies, ganciclovir and/or high-dose zidovudine, together with other agents, has been used to eradicate EBV-LPD and CNS lymphomas, another EBV-associated complication of transplantation. Both interferon and retinoic acid have been employed in the treatment of EBV-LPD, as has IVIg, but no large-scale prospective studies have assessed the efficacy of any of these agents. Several additional drugs are undergoing preclinical evaluation. Standard chemotherapeutic regimens are used if disease persists after reduction of immunosuppressive agents and administration of antibodies. EBV-specific T cells generated from the


InternalMed_Harrison

InternalMed_Harrison. evaluation. Standard chemotherapeutic regimens are used if disease persists after reduction of immunosuppressive agents and administration of antibodies. EBV-specific T cells generated from the donor have been used experimentally to prevent and treat EBV-LPD in allogeneic recipients, and efforts are under way to increase the activity and specificity of ex vivo–generated T cells. For further discussion, see Chap. 218.


InternalMed_Harrison

InternalMed_Harrison. Human Herpesvirus 8 (KSHV) The EBV-related gammaherpesvirus KSHV, which is causally associated with Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease, has rarely resulted in disease in HSC transplant recipients, although some cases of virus-associated marrow aplasia have been reported in the peritransplantation period. The relatively low seroprevalence of KSHV in the population and the limited duration of profound T cell suppression after HSC transplantation provide a plausible explanation for the currently low incidence of KSHV disease compared with that in recipients of solid organ transplants and patients with HIV infection. For further discussion, see Chap. 219.


InternalMed_Harrison

InternalMed_Harrison. Other (Non-Herpes) Viruses The diagnosis of pneumonia in HSC transplant recipients poses special problems. Because patients have undergone treatment with multiple chemotherapeutic agents and sometimes irradiation, their differential diagnosis should include—in addition to bacterial and fungal pneumonia—CMV pneumonitis, pneumonia of other viral etiologies, parasitic pneumonia, diffuse alveolar hemorrhage, and chemicalor radiation-associated pneumonitis. Since fungi and viruses (e.g., influenza A and B viruses, respiratory syncytial virus [RSV], parainfluenza virus [types 1–4], adenovirus, enterovirus, bocavirus, human metapneumovirus, coronavirus, and rhinovirus [increasingly detected by multiplex PCR]) also can cause pneumonia in this setting, it is important to obtain a specific diagnosis. Diagnostic modalities include Gram’s stain, microbiologic culture, antigen testing, and—increasingly—multipathogen PCR and mass spectrometry assays. M. tuberculosis has been an uncommon cause of


InternalMed_Harrison

InternalMed_Harrison. Diagnostic modalities include Gram’s stain, microbiologic culture, antigen testing, and—increasingly—multipathogen PCR and mass spectrometry assays. M. tuberculosis has been an uncommon cause of pneumonia among HSC transplant recipients in Western countries (accounting for <0.1–0.2% of cases) but is common in Hong Kong (5.5%) and in countries where the prevalence of tuberculosis is high. The recipient’s exposure history is clearly critical in an assessment of posttransplantation infections.


InternalMed_Harrison

InternalMed_Harrison. Both RSV and parainfluenza viruses, particularly type 3, can cause severe or even fatal pneumonia in HSC transplant recipients. Infections with both of these agents sometimes occur as disastrous nosocomial epidemics. Therapy with palivizumab or ribavirin for RSV infection remains controversial. New agents, some host-directed, are under study. Influenza also occurs in HSC transplant recipients and generally mirrors the presence of infection in the community. Progression to pneumonia is more common when infection occurs early after transplantation and when the recipient is lymphopenic. The neuraminidase inhibitors oseltamivir (oral) and zanamivir (aerosolized) are active against both influenza A virus and influenza B virus and are a reasonable treatment option. Parenteral forms of neuraminidase inhibitors such as peramivir (intravenous) and several new oral agents remain in trial status. An important preventive measure is immunization of household members, hospital staff members, and


InternalMed_Harrison

InternalMed_Harrison. inhibitors such as peramivir (intravenous) and several new oral agents remain in trial status. An important preventive measure is immunization of household members, hospital staff members, and other frequent contacts. Adenoviruses can be isolated from HSC transplant recipients at rates varying from 5% to ≥18%. Like CMV infection, adenovirus infection usually occurs in the first to third month after transplantation and is often asymptomatic, although pneumonia, hemorrhagic cystitis/nephritis, severe gastroenteritis with hemorrhage, and fatal disseminated infection have been reported and may be strain-specific. 923 A role for cidofovir therapy has been suggested, but the efficacy of this agent in adenovirus infection remains to be determined. Banked virus-specific T cell therapy is under study for adenovirus infection (as well as for CMV and EBV infections).


InternalMed_Harrison

InternalMed_Harrison. Although diverse respiratory viruses can sometimes cause severe pneumonia and respiratory failure in HSC transplant recipients, mild or even asymptomatic infection may be more common. For example, rhinoviruses and coronaviruses are frequent co-pathogens in HSC transplant recipients; however, whether they independently contribute to significant pulmonary infection is not known. At present, the overall contribution of these viral respiratory pathogens to the burden of lower respiratory tract disease in HSC transplant recipients requires further study. Infections with parvovirus B19 (presenting as anemia or occasionally as pancytopenia) and disseminated enteroviruses (sometimes fatal) can occur. Parvovirus B19 infection can be treated with IVIg (Chap. 221).


InternalMed_Harrison

InternalMed_Harrison. Rotaviruses are a cause of gastroenteritis in HSC transplant recipients, more frequently in children. Norovirus is a common cause of vomiting and diarrhea, and symptoms can be prolonged in HSC recipients. The polyomavirus BK virus is found at high titers in the urine of patients who are profoundly immunosuppressed. BK viruria may be associated with hemorrhagic cystitis in these patients. In contrast to its incidence among patients with impaired T cell function due to AIDS (4–5%), progressive multifocal leukoencephalopathy caused by the related JC virus is relatively rare among HSC transplant recipients (Chap. 164). When transmitted by mosquitoes or by blood transfusion, WNV can cause encephalitis and death after HSC transplantation.


InternalMed_Harrison

InternalMed_Harrison. Rates of morbidity and mortality among recipients of solid organ transplants (SOTs) are reduced by the use of effective antibiotics. The organisms that cause acute infections in recipients of SOTs are different from those that infect HSC transplant recipients because SOT recipients do not go through a period of neutropenia. As the transplantation procedure involves major surgery, however, SOT recipients are subject to infections at anastomotic sites and to wound infections. Compared with HSC transplant recipients, SOT patients are immunosuppressed for longer periods (often permanently). Thus they are susceptible to many of the same organisms as patients with chronically impaired T cell immunity (Chap. 104, especially Table 104-1). Moreover, the persistent HLA mismatch between recipient immune cells (e.g., effector T cells) and the donor organ (allograft) places the organ at permanently increased risk of infection.


InternalMed_Harrison

InternalMed_Harrison. During the early period (<1 month after transplantation; Table 169-4), infections are most commonly caused by extracellular bacteria (staphylococci, streptococci, enterococci, and E. coli and other gram-negative organisms, including nosocomial organisms with broad antibiotic resistance), which often originate in surgical wound or anastomotic sites. The type of transplant largely determines the spectrum of infection. In subsequent weeks, the consequences of the administration of agents that suppress cell-mediated immunity become apparent, and acquisition—or, more commonly, reactivation—of viruses, mycobacteria, endemic fungi, and parasites (from the recipient or from the transplanted organ) can occur. CMV infection is often a problem, particularly in the first 6 months after transplantation, and may present as severe systemic disease or as infection of the transplanted organ. HHV-6 reactivation (assessed by plasma PCR) occurs within the first 2–4 weeks after transplantation and may be


InternalMed_Harrison

InternalMed_Harrison. and may present as severe systemic disease or as infection of the transplanted organ. HHV-6 reactivation (assessed by plasma PCR) occurs within the first 2–4 weeks after transplantation and may be associated with fever, leukopenia, and very rare cases of encephalitis. Data suggest that replication of HHV-6 and HHV-7 may exacerbate CMV-induced disease. CMV is associated not only with generalized immunosuppression but also with organ-specific, rejection-related syndromes: glomerulopathy in kidney transplant recipients, bronchiolitis obliterans in lung transplant recipients, vasculopathy in heart transplant recipients, and the vanishing bile duct syndrome in liver transplant recipients. A complex interplay between increased CMV 924 TABLE 169-4 CoMMon InfECTIonS AfTER SoLID oRgAn TRAnSPLAnTATIon, By SITE of InfECTIon


InternalMed_Harrison

InternalMed_Harrison. Central nervous system Listeria infection (meningitis); T. gondii Listerial meningitis; cryptococcal meningitis; infection; CMV infection nocardial abscess; JC virus–associated PML Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; PML, progressive multifocal leukoencephalopathy.


InternalMed_Harrison

InternalMed_Harrison. replication and enhanced graft rejection is well established: elevated organ, have been noted. High organ-specific content of B lymphoid immunosuppression leads to increased CMV replication, which is tissues (e.g., bronchus-associated lymphoid tissue in the lung), anaassociated with graft rejection. For this reason, considerable atten-tomic factors (e.g., lack of access of host T cells to the transplanted tion has been focused on the diagnosis, prophylaxis, and treatment organ because of disturbed lymphatics), and differences in major of CMV infection in SOT recipients. Early transmission of WNV to histocompatibility loci between the host T cells and the organ (e.g., transplant recipients from a donated organ or transfused blood has lack of cell migration or lack of effective T cell/macrophage/dendritic been reported; however, the risk of WNV acquisition has been reduced cell cooperation) may result in defective elimination of EBV-infected by implementation of screening procedures. In


InternalMed_Harrison

InternalMed_Harrison. been reported; however, the risk of WNV acquisition has been reduced cell cooperation) may result in defective elimination of EBV-infected by implementation of screening procedures. In rare instances, rabies B cells. SOT recipients are also highly susceptible to the development virus and lymphocytic choriomeningitis virus also have been acutely of Kaposi’s sarcoma and, less frequently, to the B cell–proliferative transmitted in this setting; although accompanied by distinct clinical disorders associated with KSHV, such as primary effusion lymphoma syndromes, both viral infections have resulted in fatal encephalitis. As and multicentric Castleman’s disease. Kaposi’s sarcoma is 550–1000 screening for unusual viruses is not routine, only vigilant assessment of times more common among SOT recipients than in the general poputhe prospective donor is likely to prevent the use of an infected organ. lation, can develop very rapidly after transplantation, and can also


InternalMed_Harrison

InternalMed_Harrison. Beyond 6 months after transplantation, infections characteristic of occur in the allograft. However, because the seroprevalence of KSHV patients with defects in cell-mediated immunity—e.g., infections with is very low in Western countries, Kaposi’s sarcoma is not common. Listeria, Nocardia, Rhodococcus, mycobacteria, various fungi, and other Recipients (or donors) from Iceland, the Middle East, Mediterranean intracellular pathogens—may be a problem. International patients and countries, and Africa are at highest risk of disease. Data suggest that global travelers may experience reactivation of dormant infections a switch of immunosuppressive agents—from calcineurin inhibitors with trypanosomes, Leishmania, Plasmodium, Strongyloides, and other (cyclosporine, tacrolimus) to mTor pathway–active agents (sirolimus, parasites. Reactivation of latent M. tuberculosis infection, while rare in everolimus)—after adequate wound healing may significantly reduce Western nations, is far more common


InternalMed_Harrison

InternalMed_Harrison. agents (sirolimus, parasites. Reactivation of latent M. tuberculosis infection, while rare in everolimus)—after adequate wound healing may significantly reduce Western nations, is far more common among persons from developing the likelihood of development of Kaposi’s sarcoma and perhaps of countries. The recipient is typically the source, although reactivation EBV-LPD and certain other posttransplantation malignancies. and spread from the donor organ can occur. While pulmonary disease remains most common, atypical sites can be involved and mortality KIDNEY TRANSPLANTATION rates can be high (up to 30%). Vigilance, prophylaxis/preemptive ther-See Table 169-4. apy (when indicated), and rapid diagnosis and treatment of infections can be lifesaving in SOT recipients, who, unlike most HSC transplant Early Infections Bacteria often cause infections that develop in the recipients, continue to be immunosuppressed. period immediately after kidney transplantation. There is a role for


InternalMed_Harrison

InternalMed_Harrison. SOT recipients are susceptible to EBV-LPD from as early as 2 perioperative antibiotic prophylaxis, and many centers give cephalospomonths to many years after transplantation. The prevalence of this rins to decrease the risk of postoperative complications. Urinary tract complication is increased by potent and prolonged use of T cell–sup-infections developing soon after transplantation are usually related to pressive drugs. Decreasing the degree of immunosuppression may in anatomic alterations resulting from surgery. Such early infections may some cases reverse the condition. Among SOT patients, those with require prolonged treatment (e.g., 6 weeks of antibiotic administration heart and lung transplants—who receive the most intensive immuno-for pyelonephritis). Urinary tract infections that occur >6 months after suppressive regimens—are most likely to develop EBV-LPD, particu-transplantation may be treated for shorter periods because they do not larly in the lungs. Although the disease


InternalMed_Harrison

InternalMed_Harrison. occur >6 months after suppressive regimens—are most likely to develop EBV-LPD, particu-transplantation may be treated for shorter periods because they do not larly in the lungs. Although the disease usually originates in recipient seem to be associated with the high rate of pyelonephritis or relapse B cells, several cases of donor origin, particularly in the transplanted seen with infections that occur during the first 3 months.


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InternalMed_Harrison. History of exposure to active or latent Mycobacterium tuberculosis Isoniazid in patients with recent sero-Chest imaging; TST and/or cell-based tuberculosis aFor information on latent infection with hepatitis B or C virus, see Chap. 362. bSerologic examination, tuberculin skin test, and interferon assays may be less reliable after transplantation. Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6, human herpesvirus type 6; HSC, hematopoietic stem cell; HSV, herpes simplex virus; KSHV, Kaposi’s sarcoma– associated herpesvirus; PCR, polymerase chain reaction; TST, tuberculin skin test; VZV, varicella-zoster virus. Prophylaxis with TMP-SMX for the first 4–6 months after transplantation decreases the incidence of early and middle-period infections (see below, Table 169-4, and Table 169-5).


InternalMed_Harrison

InternalMed_Harrison. Prophylaxis with TMP-SMX for the first 4–6 months after transplantation decreases the incidence of early and middle-period infections (see below, Table 169-4, and Table 169-5). Middle-Period Infections Because of continuing immunosuppression, kidney transplant recipients are predisposed to lung infections characteristic of those in patients with T cell deficiency (i.e., infections with intracellular bacteria, mycobacteria, nocardiae, fungi, viruses, and parasites). A high mortality rate associated with Legionella pneumophila infection (Chap. 184) led to the closing of renal transplant units in hospitals with endemic legionellosis. About 50% of all renal transplant recipients presenting with fever 1–4 months after transplantation have evidence of CMV disease; CMV itself accounts for the fever in more than two-thirds of cases and thus is the predominant pathogen during this period. CMV infection (Chap.


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InternalMed_Harrison. 219) may also present as arthralgias, myalgias, or organ-specific symptoms. During this period, this infection may represent primary disease (in the case of a seronegative recipient of a kidney from a seropositive donor) or may represent reactivation disease or superinfection. Patients may have atypical lymphocytosis. Unlike immunocompetent patients, however, they rarely have lymphadenopathy or splenomegaly. Therefore, clinical suspicion and laboratory confirmation are necessary for diagnosis. The clinical syndrome may be accompanied by bone marrow suppression (particularly leukopenia). CMV also causes glomerulopathy and is associated with an increased incidence of other opportunistic infections. Because of the frequency and severity of disease, a considerable effort has been made to prevent and treat CMV infection in renal transplant recipients. An immune globulin preparation enriched with antibodies to CMV was used by many centers in the past in an effort to protect the group at


InternalMed_Harrison

InternalMed_Harrison. and treat CMV infection in renal transplant recipients. An immune globulin preparation enriched with antibodies to CMV was used by many centers in the past in an effort to protect the group at highest risk for severe infection (seronegative recipients of seropositive kidneys). However, with the development of effective oral antiviral agents, CMV immune globulin is no longer used. Ganciclovir (or valganciclovir) is beneficial for prophylaxis (when indicated) and for the treatment of serious CMV disease. The availability of valganciclovir has allowed most centers to move to oral prophylaxis for transplant recipients. Infection with the other herpesviruses may become evident within 6 months after transplantation or later. Early after transplantation, HSV may cause either oral or anogenital lesions that are usually responsive to acyclovir. Large ulcerating lesions in the anogenital area may lead to bladder and rectal dysfunction and may predispose the patient to bacterial infection. VZV


InternalMed_Harrison

InternalMed_Harrison. lesions that are usually responsive to acyclovir. Large ulcerating lesions in the anogenital area may lead to bladder and rectal dysfunction and may predispose the patient to bacterial infection. VZV may cause fatal disseminated infection in nonimmune kidney transplant recipients, but in immune patients reactivation zoster usually does not disseminate outside the dermatome; thus disseminated VZV infection is a less fearsome complication in kidney transplantation than in HSC transplantation. HHV-6 reactivation may take place and (although usually asymptomatic) may be associated with fever, rash, marrow suppression, or rare instances of renal impairment, hepatitis, colitis, or encephalitis.


InternalMed_Harrison

InternalMed_Harrison. EBV disease is more serious; it may present as an extranodal proliferation of B cells that invade the CNS, nasopharynx, liver, small bowel, heart, and other organs, including the transplanted kidney. The disease is diagnosed by the finding of a mass of proliferating EBV-positive B cells. The incidence of EBV-LPD is elevated among patients who acquire EBV infection from the donor and among patients given high doses of cyclosporine, tacrolimus, glucocorticoids, and anti–T cell antibodies. Disease may regress once immunocompetence is restored. KSHV infection can be transmitted with the donor kidney and result in development of Kaposi’s sarcoma, although it more often represents reactivation of latent infection of the recipient. Kaposi’s sarcoma often appears within 1 year after transplantation, although the time of onset ranges widely (1 month to ∼20 years). Avoidance of immunosuppressive agents that inhibit calcineurin has been associated with less Kaposi’s sarcoma, less EBV disease,


InternalMed_Harrison

InternalMed_Harrison. although the time of onset ranges widely (1 month to ∼20 years). Avoidance of immunosuppressive agents that inhibit calcineurin has been associated with less Kaposi’s sarcoma, less EBV disease, and even less CMV replication. The use of rapamycin (sirolimus) has independently led to regression of Kaposi’s sarcoma.


InternalMed_Harrison

InternalMed_Harrison. The papovaviruses BK virus and JC virus (polyomavirus hominis types 1 and 2) have been cultured from the urine of kidney transplant recipients (as they have from that of HSC transplant recipients) in the setting of profound immunosuppression. High levels of BK virus replication detected by PCR in urine and blood are predictive of pathology, especially in the setting of renal transplantation. JC virus may rarely cause similar disease in kidney transplantation. Urinary excretion of BK virus and BK viremia are associated with the development of ureteral strictures, polyomavirus-associated nephropathy (1–10% of renal transplant recipients), and (less commonly) generalized vasculopathy. Timely detection and early reduction of immunosuppression are critical and can reduce rates of graft loss related to polyomavirusassociated nephropathy from 90% to 10–30%. Therapeutic responses to IVIg, quinolones, leflunomide, and cidofovir have been reported, but the efficacy of these agents has not been


InternalMed_Harrison

InternalMed_Harrison. to polyomavirusassociated nephropathy from 90% to 10–30%. Therapeutic responses to IVIg, quinolones, leflunomide, and cidofovir have been reported, but the efficacy of these agents has not been substantiated through adequate clinical study. Most centers approach the problem by reducing immunosuppression in an effort to enhance host immunity and decrease viral titers. JC virus is associated with rare cases of progressive multifocal leukoencephalopathy. Adenoviruses may persist and cause hemorrhagic nephritis/cystitis with continued immunosuppression in these patients, but disseminated disease like that seen in HSC transplant recipients is much less common.


InternalMed_Harrison

InternalMed_Harrison. Kidney transplant recipients are also subject to infections with other intracellular organisms. These patients may develop pulmonary infections with Mycobacterium, Aspergillus, and Mucor species as well as infections with other pathogens in which the T cell/macrophage axis plays an important role. L. monocytogenes is a common cause of bacteremia ≥1 month after renal transplantation and should be seriously considered in renal transplant recipients presenting with fever and headache. Kidney transplant recipients may develop Salmonella bacteremia, which can lead to endovascular infections and require prolonged therapy. Pulmonary infections with Pneumocystis are common unless the patient is maintained on TMP-SMX prophylaxis.


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InternalMed_Harrison. 926 Acute interstitial nephritis caused by TMP-SMX is rare. However, because transient increases in creatinine (artifactual) and hyperkalemia (manageable) can occur, early discontinuation of prophylaxis, especially after kidney transplantation, is recommended by some groups. Although additional monitoring is indicated, the benefits of TMP-SMX in kidney transplant recipients may outweigh the risks; otherwise, second-line prophylactic agents should be used. Nocardia infection (Chap. 199) may present in the skin, bones, and lungs or in the CNS, where it usually takes the form of single or multiple brain abscesses. Nocardiosis generally occurs ≥1 month after transplantation and may follow immunosuppressive treatment for an episode of rejection. Pulmonary manifestations most commonly consist of localized disease with or without cavities, but the disease may be disseminated. The diagnosis is made by culture of the organism from sputum or from the involved nodule. As it is for P. jirovecii


InternalMed_Harrison

InternalMed_Harrison. of localized disease with or without cavities, but the disease may be disseminated. The diagnosis is made by culture of the organism from sputum or from the involved nodule. As it is for P. jirovecii infection, prophylaxis with TMP-SMX is often efficacious in the prevention of nocardiosis. Toxoplasmosis can occur in seropositive patients but is less common than in other transplantation settings, usually developing in the first few months after kidney transplantation. Again, TMP-SMX is helpful in prevention. In endemic areas, histoplasmosis, coccidioidomycosis, and blastomycosis may cause pulmonary infiltrates or disseminated disease.


InternalMed_Harrison

InternalMed_Harrison. Late Infections Late infections (>6 months after kidney transplantation) may involve the CNS and include CMV retinitis as well as other CNS manifestations of CMV disease. Patients (particularly those whose immunosuppression has been increased) are at risk for subacute meningitis due to Cryptococcus neoformans. Cryptococcal disease may present in an insidious manner (sometimes as a skin infection before the development of clear CNS findings). Listeria meningitis may have an acute presentation and requires prompt therapy to avoid a fatal outcome. TMP-SMX prophylaxis may reduce the frequency of Listeria infections.


InternalMed_Harrison

InternalMed_Harrison. Patients who continue to take glucocorticoids are predisposed to ongoing infection. “Transplant elbow,” a recurrent bacterial infection in and around the elbow that is thought to result from a combination of poor tensile strength of the skin of steroid-treated patients and steroid-induced proximal myopathy, requires patients to push themselves up with their elbows to get out of chairs. Bouts of cellulitis (usually caused by S. aureus) recur until patients are provided with elbow protection.


InternalMed_Harrison

InternalMed_Harrison. Kidney transplant recipients are susceptible to invasive fungal infections, including those due to Aspergillus and Rhizopus, which may present as superficial lesions before dissemination. Mycobacterial infection (particularly that with Mycobacterium marinum) can be diagnosed by skin examination. Infection with Prototheca wickerhamii (an achlorophyllic alga) has been diagnosed by skin biopsy. Warts caused by human papillomaviruses (HPVs) are a late consequence of persistent immunosuppression; imiquimod or other forms of local therapy are usually satisfactory. Merkel cell carcinoma, a rare and aggressive neuroendocrine skin tumor whose frequency is increased fivefold in elderly SOT (especially kidney) recipients, is causally linked to a novel polyomavirus, Merkel cell polyomavirus.


InternalMed_Harrison

InternalMed_Harrison. Notably, although BK virus replication and virus-associated disease can be detected far earlier, polyomavirus-associated nephropathy is clinically diagnosed in a median of ∼300 days and thus qualifies as a late-onset disease. With the establishment of better screening procedures (e.g., urine cytology, urine nucleic acid load, plasma PCR), disease onset is being detected earlier (see “Middle-Period Infections,” above) and preemptive strategies (decrease or modification of immunosuppression) are being instituted more promptly, as the efficacy of antiviral therapy is not well established.


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InternalMed_Harrison. HEART TRANSPLANTATION Early Infections Sternal wound infection and mediastinitis are early complications of heart transplantation. An indolent course is common, with fever or a mildly elevated white blood cell count preceding the development of site tenderness or drainage. Clinical suspicion based on evidence of sternal instability and failure to heal may lead to the diagnosis. Common microbial residents of the skin (e.g., S. aureus, including methicillin-resistant strains, and Staphylococcus epidermidis) as well as gram-negative organisms (e.g., Pseudomonas aeruginosa) and fungi (e.g., Candida) are often involved. In rare cases, mediastinitis in heart transplant recipients can also be due to Mycoplasma hominis (Chap. 212); since this organism requires an anaerobic environment for growth and may be difficult to see on conventional medium, the laboratory should be alerted that its involvement is suspected. M. hominis mediastinitis has been cured with a combination of surgical


InternalMed_Harrison

InternalMed_Harrison. growth and may be difficult to see on conventional medium, the laboratory should be alerted that its involvement is suspected. M. hominis mediastinitis has been cured with a combination of surgical debridement (sometimes requiring muscle-flap placement) and the administration of clindamycin and tetracycline. Organisms associated with mediastinitis may sometimes be cultured from pericardial fluid.


InternalMed_Harrison

InternalMed_Harrison. Middle-Period Infections T. gondii (Chap. 253) residing in the heart of a seropositive donor may be transmitted to a seronegative recipient. Thus serologic screening for T. gondii infection is important before and in the months after cardiac transplantation. Rarely, active disease can be introduced at the time of transplantation. The overall incidence of toxoplasmosis is so high in the setting of heart transplantation that some prophylaxis is always warranted. Although alternatives are available, the most frequently used agent is TMP-SMX, which prevents infection with Pneumocystis as well as with Nocardia and several other bacterial pathogens. CMV also has been transmitted by heart transplantation. Toxoplasma, Nocardia, and Aspergillus can cause CNS infections. L. monocytogenes meningitis should be considered in heart transplant recipients with fever and headache.


InternalMed_Harrison

InternalMed_Harrison. CMV infection is associated with poor outcomes after heart transplantation. The virus is usually detected 1–2 months after transplantation, causes early signs and laboratory abnormalities (usually fever and atypical lymphocytosis or leukopenia and thrombocytopenia) at 2–3 months, and can produce severe disease (e.g., pneumonia) at 3–4 months. An interesting observation is that seropositive recipients usually develop viremia faster than patients whose primary CMV infection is a consequence of transplantation. Between 40% and 70% of patients develop symptomatic CMV disease in the form of (1) CMV pneumonia, the form most likely to be fatal; (2) CMV esophagitis and gastritis, sometimes accompanied by abdominal pain with or without ulcerations and bleeding; and (3) the CMV syndrome, consisting of CMV in the bloodstream along with fever, leukopenia, thrombocytopenia, and hepatic enzyme abnormalities. Ganciclovir is efficacious in the treatment of CMV infection; prophylaxis with ganciclovir


InternalMed_Harrison

InternalMed_Harrison. of CMV in the bloodstream along with fever, leukopenia, thrombocytopenia, and hepatic enzyme abnormalities. Ganciclovir is efficacious in the treatment of CMV infection; prophylaxis with ganciclovir or possibly with other antiviral agents, as described for renal transplantation, may reduce the overall incidence of CMV-related disease.


InternalMed_Harrison

InternalMed_Harrison. Late Infections EBV infection usually presents as a lymphoma-like proliferation of B cells late after heart transplantation, particularly in patients maintained on intense immunosuppressive therapy. A subset of heart and heart-lung transplant recipients may develop early fulminant EBV-LPD (within 2 months). Treatment includes the reduction of immunosuppression (if possible), the use of glucocorticoid and calcineurin inhibitor–sparing regimens, and the consideration of therapy with anti–B cell antibodies (rituximab and possibly others). Immunomodulatory and antiviral agents continue to be studied. Ganciclovir prophylaxis for CMV disease may indirectly reduce the risk of EBV-LPD through reduced spread of replicating EBV to naïve B cells. Aggressive chemotherapy is a last resort, as discussed earlier for HSC transplant recipients. KSHV-associated disease, including Kaposi’s sarcoma and primary effusion lymphoma, has been reported in heart transplant recipients. GVHD prophylaxis with


InternalMed_Harrison

InternalMed_Harrison. earlier for HSC transplant recipients. KSHV-associated disease, including Kaposi’s sarcoma and primary effusion lymphoma, has been reported in heart transplant recipients. GVHD prophylaxis with sirolimus may decrease the risk of both rejection and outgrowth of KSHV-infected cells. Antitumor therapy is discussed in Chap. 103e. Prophylaxis for Pneumocystis infection is required for these patients (see “Lung Transplantation, Late Infections,” below).