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Infections in Hematopoietic Stem Cell Transplant Recipients
Infections in Hematopoietic Stem Cell Transplant Recipients
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Infections in Hematopoietic Stem Cell Transplant Recipients Jorge Luján-Zilbermann and David M. Berman
Hematopoietic stem cell transplantation (HSCT) has broad indications in pediatrics, including treatment of cancer, primary immunodeficiency syndromes, bone marrow failure syndromes, hemoglobinopathies, and an assortment of genetic conditions, including inborn errors of metabolism, and nonmalignant conditions such as osteopetrosis.1–3 Patients undergoing HSCT have increased risks of infections that are somewhat predictable based on the acquired immune deficiencies that occur after HSCT.4–7
HSV RSV Parainfluenza virus Adenovirus
Viral
CMV EBV VZV
ETIOLOGIC AGENTS Patients who have had HSCT have immune deficiencies in the phagocytic, humoral, and cellular arms of the immune system.4 These immune defects lead to pathogen susceptibility and infectious complications in three predictable risk periods (Fig. 96.1).4 After the conditioning regimen, a period of neutropenia occurs for 3 to 4 weeks, during which bacteria and fungi cause most infections. Herpes simplex virus (HSV) and seasonal respiratory viral infections also can occur.4,7,8 The middle period occurs after granulocyte recovery and continues until approximately 100 days after HSCT. Infectious complications during this period are associated with profound impairment of humoral and cellular immunity. Although bacterial and fungal infections still can occur, they are much less frequent than during the neutropenic period. Cytomegalovirus (CMV) is a major infecting agent, but Pneumocystis jirovecii disease also can occur. With the advent of effective prophylaxis against both of these agents, the incidence of associated disease has decreased. Infections due to adenovirus and Epstein–Barr virus (EBV) can occur, especially with the use of mismatched HSCT and T-lymphocyte–depleted HSCT.9–11 The late period is associated with deficits in humoral immune responses, cellular immune responses, and reticuloendothelial function begins 100 days after HSCT. Varicella-zoster virus (VZV) and encapsulated bacteria,
Gram-negative Gram-positive
Bacterial
Encapsulated bacteria Candida and Aspergillus Fungal
Pneumocystis jirovecii Toxoplasma
Protozoal 0
30
60
90
120
150
180
365
Days After Transplantation FIGURE 96.1 Temporal association of infectious agents and hematopoietic stem cell transplantation. Day 0 is the time of stem cell infusion. Boldness of the line denotes increasing frequency of infection with the offending agent. CMV, cytomegalovirus; EBV, Epstein–Barr virus; HSV, herpes simplex virus; RSV; respiratory syncytial virus; VZV, varicella–zoster virus.
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PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION O Infections and Transplantation
BOX 96.1 Predisposing Factors for Infectious Complications in Hematopoietic Stem Cell Transplant Recipients • • • • • • •
Underlying illness Type of transplant Conditioning regimen Infectious disease history Indwelling medical device Occurrence and severity of graft-versus-host disease Immunosuppressive regimen administered to prevent graft-versus-host disease • Epidemiology of infection in hospital or transplantation care unit
particularly Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), are major pathogens during this period.
EPIDEMIOLOGY Among HSCT recipients, most infections are derived from their microbial flora or reactivation of latent infections. Many factors account for the high risk of infectious complications among HSCT recipients (Box 96.1). Immune deficiency associated with the underlying disease is a determinant of the degree of immune suppression. Allogeneic HSCT recipients (i.e., matched unrelated donor or unrelated cord blood transplantation) are at high risk for graft-versus-host disease (GvHD), which enhances the infection rate by delaying the return of normal immune function and by ulceration of the gastrointestinal tract. Moreover, the risk of infection is directly related to the degree of donor-recipient mismatch. To abrogate GvHD, immune-suppressing medications are administered as prophylaxis. These agents increase the risk of infection by depressing the cell-mediated immune response and by disrupting mucosal barriers. The conditioning regimen with or without concomitant irradiation compromises the immune system and can disrupt mucosal barriers. Purging of the bone marrow in autologous transplants to reduce the load of malignant cells and T-lymphocyte depletion used in allogeneic transplants to reduce the incidence of GvHD predispose the host to infection. The serologic status of the donor and the recipient is important because many infections in transplant recipients are caused by reactivation (Table 96.1). This is most notable for the herpesviruses. CMV is a major cause of pneumonitis in allogeneic transplant recipients. Other herpesviruses, especially HSV, VZV, and EBV; Toxoplasma gondii; and adenovirus infections are prone to reactivate after the transplantation. All HSCT recipients have a central venous catheter (CVC) placed before transplantation, providing a potential site for infection. Patients who have other indwelling medical devices (e.g., cerebrospinal fluid shunts) have an increased risk of infection. Patients with a history of invasive aspergillosis who are undergoing HSCT require adequate antifungal prophylaxis and treatment to prevent relapse of the disease.12 Knowledge of the epidemiology of pathogens associated with the local hospital and the transplantation unit allows assessment of the risk of environmental organisms such as Aspergillus and Legionella species. Rates of infection can be reduced substantially by preventive mechanisms that inhibit aerosolization of organisms, such as the use of laminar flow rooms or high-efficiency particulate air (HEPA)–filtered rooms.6
Early Period Several types of infection are more likely to occur during the early period (i.e., before engraftment) of the transplantation process. Herpes Simplex Virus Gingivostomatitis. HSV infection occurs primarily as a result of reactivation in seropositive patients undergoing HSCT. The diagnosis is difficult because lip lesions are rare and mucosal ulcerations are similar to those that occur as a result of the conditioning regimen. Central Venous Catheter–Related Bloodstream Infections. During the neutropenic period, HSCT recipients are at high risk for bacterial infection, comparable with the risk for patients with cancer who develop chemotherapy-induced neutropenia. Central line–associated bloodstream infections (CLABSIs) are common because of the uniform use of indwelling CVCs in HSCT patients for administration of medications, hyperalimentation, blood products, and blood sampling. Measures to prevent CLABSIs should be followed.6,13 Staphylococcus epidermidis and other coagulase-negative staphylococci are the most common causes of bloodstream infections (BSIs) during the three periods after transplantation.14–16 Other gram-positive organisms associated with BSIs in HSCT recipients include viridans streptococci and S. aureus.14–16 Viridans streptococci infections have been associated with chemotherapy-induced mucositis and poor dental hygiene.17,18 Most gram-positive catheter-related infections can be treated successfully without removal of the catheter. Gram-negative bacillary infections occur after mucosal damage with bacterial translocation from the intestinal mucosa into the bloodstream and are the second most frequent cause of BSI. The predominant organisms in this class include Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa, although other gram-negative organisms are common.14,16 Antibiotic resistance among these organisms is common. Catheterrelated infections with some gram-negative bacilli, Candida spp., and Bacillus cereus can be problematic and require catheter removal. Fungal Infections. The major causes of fungal infection include Aspergillus spp., Candida spp., and agents of mucormycosis (e.g., Mucor, Absidia, Rhizopus spp.).19–21 Other fungi recognized as pathogens include Trichosporon spp., Fusarium spp., Curvularia spp., and Alternaría spp.21–23 Infection with these organisms usually occurs after a period of antibiotic therapy and correlates with the degree and duration of neutropenia. Although Candida albicans is the most frequent Candida species causing BSI, C. tropicalis may cause more severe disease. Other Candida species,
TABLE 96.1 Evaluation of Patients Before Hematopoietic Stem Cell Transplantation Study Type
Organism or Test
Serum antibody assay
CMV EBV HSV VZV Hepatitis B (HBsAg, HBsAb, HBcAb) Hepatitis C RPR Human immunodeficiency virus
Other laboratory tests
Serum hepatic enzymes (ALT, AST, bilirubin) Renal function tests (BUN, creatinine) Complete blood cell count with differential leukocyte count Stool for ova and parasites
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CLINICAL SYNDROMES, DIFFERENTIAL DIAGNOSIS, AND CLINICAL APPROACH
Tuberculosis test
Tuberculin skin test (TST); for children >5 years of age, interferon γ release assay (blood) is acceptable
The approach to a patient who has had HSCT takes into account the infections that can occur during each of the risk periods (see Fig. 96.1). This provides the framework for matching possible causative agents with the clinical syndrome. Because some of these clinical syndromes are highlighted in Chapters 97 and 98, the following discussion focuses on the clinical approach to the HSCT recipient.
Radiographic testing
Chest, posteroanterior and lateral Sinus series, if clinically indicated
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; cAb, core antibody; CMV, cytomegalovirus; EBV, Epstein–Barr virus; RPR, rapid plasma reagin; sAb, surface antibody; sAg, surface antigen.
Infections in Hematopoietic Stem Cell Transplant Recipients
BOX 96.2 Differential Diagnosis of Hemorrhagic Cystitis in Hematopoietic Stem Cell Transplant Recipients
BOX 96.3 Causes of Pneumonitis in Hematopoietic Stem Cell Transplant Recipients
INFECTIOUS CAUSES
INFECTIOUS CAUSES
Virus
Bacteria
Adenovirus Cytomegalovirus Polyomaviruses, especially BK virus and JC virus Herpes simplex virus
• Enterobacteriaceae • Staphylococcus aureus • Legionella pneumophila
Bacteria
Fungus
• • • •
Urinary tract infection Fungus ball
Viruses
Urinary tract infection, predominantly gram-negative bacilli
NONINFECTIOUS CAUSES Chemotherapy (e.g., cyclophosphamide) Graft-versus-host disease Mechanical trauma from Foley catheter
including C. glabrata, C. parapsilosis, and C. krusei, also have emerged because of resistance to fluconazole, which is used as prophylaxis.20–22 The portal of entry for Aspergillus and agents of mucormycosis is the respiratory tract, as opposed to that for Candida spp., which is the gastrointestinal tract. Aspergillus is associated with sinopulmonary disease and dissemination (Fig. 96.2), but it is rarely recovered from blood cultures. Diagnosis usually depends on tissue histology and culture of material obtained from bronchoscopy, lung aspiration, or open-lung biopsy. The galactomannan assay can be useful in the early diagnosis of invasive aspergillosis in high-risk patients.12,24 Hemorrhagic Cystitis. Hemorrhagic cystitis is associated with a variety of infectious and noninfectious causes (Box 96.2).25 The onset can occur at any time during the transplantation period; chemotherapy-induced cystitis occurs soon after commencing the conditioning regimen. The most common infectious causes are polyomaviruses (BK virus and JC virus) and adenovirus.25–27 Bacterial and fungal pathogens also must be considered. Enteric Infections. Diarrhea after transplantation is caused most commonly by mucositis and GvHD. Enteric infections can occur throughout the transplantation period. Antibiotic-associated diarrhea, including that due to Clostridium difficile, usually occurs during the neutropenic period, when antimicrobial agents are frequently administered. Other infecting
FIGURE 96.2 Invasive aspergillosis in a patient after hematopoietic stem cell transplantation. Computed tomography of the chest shows bilateral pulmonary involvement, including aspergilloma in the right middle lobe (arrow).
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Fungi
• • • • • • • • •
Aspergillus species Mucormycosis Pneumocystis jirovecii Candida species
Parainfluenza types 1–4 Adenovirus Respiratory syncytial virus Human metapneumovirus Cytomegalovirus Influenza Human herpesvirus 6 Coxsackievirus and echoviruses Rhinovirus
NONINFECTIOUS CAUSES Pulmonary damage by radiation exposure Pulmonary damage by chemotherapeutic agents (e.g., bleomycin) Underlying cancer Pulmonary edema Alveolar hemorrhage Idiopathic interstitial pneumonia Pulmonary vascular disease Pneumomediastinum
agents, including enteric adenovirus, rotavirus, coxsackievirus, and noroviruses, should also be considered.11,28 Infections caused by enteric viruses typically are seasonal in occurrence.
Middle Period The middle period (i.e., early engraftment), which spans days 30 through 100 after transplantation, was once was dominated by CMV infection, but the incidence of CMV infection has diminished with the use of ganciclovir as pre-emptive therapy. Bacterial infections are less problematic during this period, except for those associated with indwelling catheters. Fungal infections occur in patients with GvHD. Pneumonitis. Pulmonary infiltrates can have infectious or noninfectious causes (Box 96.3). Although signs and symptoms can occur throughout the transplantation period, viral infections are more common during the early engraftment period. CMV manifests at a median time of 40 to 50 days after the transplantation period (see Fig. 96.1). CMV most commonly occurs because of reactivation of latent virus in seropositive individuals but also can occur in seronegative patients who receive a transplant from a seropositive donor. Risk factors for CMV pneumonia include seropositivity of the donor, type of transplant (i.e., allogeneic more than autologous), human leukocyte antigen (HLA)–mismatched transplant, older age of the patient (>10 years), and development of acute GvHD.29 CMV infection occurs in 30% to 50% of patients undergoing HSCT; pneumonia occurs in 10% to 15% of these patients and has a mortality rate of 85%. CMV infection and disease also occur in autologous HSCT recipients, although at a much lower incidence. The clinical manifestations of CMV disease vary from asymptomatic infection to the constellation of fever, hepatitis, and leukopenia to life-threatening diseases such as interstitial pneumonitis, esophagitis, and encephalitis.30
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PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION O Infections and Transplantation
Other viral causes of respiratory tract infections include adenovirus, respiratory syncytial virus (RSV), human metapneumovirus, parainfluenza virus, influenza virus, human herpesvirus 6 (HHV-6), coxsackievirus, and rhinovirus.31–37 RSV, influenza virus, and parainfluenza virus can cause sinusitis and life-threatening pneumonia.31,32,37 Pneumocystis jirovecii also causes pneumonia after engraftment.38 Clinical manifestations are similar to those in other immunocompromised hosts. The incidence of Pneumocystis pneumonia (PCP) has been curtailed markedly by routine prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) and pentamidine. Adenovirus Infection. Adenovirus infection occurs in approximately 30% of pediatric HSCT recipients and can become latent in lymphoid tissue and kidneys.39 The most common clinical manifestations of infection include diarrhea, febrile illness, hemorrhagic cystitis, and pneumonia but also can include hepatitis and encephalitis.39 Toxoplasmosis. Toxoplasmosis is a rare but almost always fatal infection after HSCT. Toxoplasmosis usually occurs 2 to 6 months after HSCT, and the central nervous system is affected most often. Symptoms include focal neurologic signs, fever, seizures, and altered mental status. Imaging of the brain typically shows multiple lesions in both hemispheres and the basal ganglia.40,41 Encephalopathy. Encephalopathy is a poorly characterized complication of HSCT. It has a very poor prognosis for pediatric patients, with a mortality rate of 65% in one study.42 Several infectious and noninfectious causes have been described (Box 96.4).33,41,42 HHV-6 has been associated with encephalitis and delayed platelet engraftment.35,36,43
Late Period At 100 days after transplantation, the late period begins. It lasts for 6 to 12 months or longer, depending on the complications of transplantation, especially GvHD. Bloodstream Infection. Bacterial infections occur less commonly during the late period, but patients continue to be immunosuppressed and susceptible to bacterial infection and BSI. Chronic GvHD augments this immunosuppression. Encapsulated bacteria, especially S. pneumoniae and Hib, are the most common agents responsible for bacterial infections that are not related to the existence of an indwelling catheter.4
BOX 96.4 Differential Diagnosis of Meningitis, Encephalitis, and Encephalopathy in Hematopoietic Stem Cell Transplantation Recipients INFECTIOUS CAUSES Viruses • Adenovirus • Human herpesvirus 6 and 7 • Polyomaviruses, especially BK virus and JC virus (progressive multifocal leukoencephalopathy) • Herpes simplex virus and varicella-zoster virus • Postviral (acute disseminated encephalomyelitis) Bacteria • Streptococcus pneumoniae Fungi • Aspergillus species Protozoa • Toxoplasma gondii NONINFECTIOUS CAUSES Medications (e.g., cyclosporine, amphotericin B) Nonconvulsive seizures Thrombotic thrombocytopenic purpura Multiorgan system failure Stroke
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Varicella-Zoster Virus Infection. VZV infections occur in 25% to 40% of patients after HSCT.44 Reactivation occurs more frequently in association with chronic GvHD but also has been described in patients after autologous HSCT. A prodrome of a burning sensation or pain over the involved dermatome can occur. Groups of vesicles appear in the distribution of one to three sensory dermatomes. If appropriate therapy with acyclovir is not instituted, dissemination can occur in 36% of infected patients, with a mortality rate of 10%. Hepatitis. Acute or chronic hepatitis can follow HSCT and has infectious and noninfectious causes (Box 96.5). Hepatitis C virus can infect HSCT recipients, and activation occurs at the time of discontinuation of immunosuppressive therapy.45
LABORATORY FINDINGS AND DIAGNOSIS Microbiologic evaluation is the gold standard for the diagnosis of infection. Microbiologic tests include blood cultures for bacteria and fungi. Blood cultures should be obtained from each lumen of the central venous line and a peripheral vein.46 If bacteria or fungi are detected in the blood culture, use of real-time polymerase chain reaction (PCR) can reduce the time to identification of microorganisms and can identify certain antimicrobial resistance genes.47 When clinically indicated, additional testing includes detection of viral infection by serology, culture, PCR, and immunohistochemical stains on pathologic specimens. PCR testing is extremely helpful for the screening and diagnosis of viral infections. PCR is available for all the herpesviruses, adenovirus, and polyomaviruses.11,26,35,48 PCR panels can be used to detect viruses from respiratory specimens, allowing rapid detection of influenza virus, RSV, parainfluenza virus, metapneumovirus, adenovirus, and others.49,50 Other laboratory tests are of limited value. The use of the (1-3)-β-dglucan assay as a screening tool for fungal infection has limited value primarily because several factors can confound the interpretation of the results.23,46,51 The galactomannan assay is best used longitudinally and only for patients at risk for invasive aspergillosis.46 A single negative serum test should never be used to rule out invasive fungal infection.46 Complete blood cell counts can be used to assess engraftment status. An absolute neutrophil count of <500/mm3 is associated with higher incidence of bacterial infections. Serum hepatic enzyme levels and renal function tests can provide evidence of pathology from an infectious agent or insults from chemotherapy or GvHD (see Boxes 96.2 and 96.5).
MANAGEMENT AND PRESUMPTIVE THERAPY Initial management of patients with fever and neutropenia is similar to management of patients with chemotherapy-induced fever and
BOX 96.5 Differential Diagnosis of Hepatitis After Hematopoietic Stem Cell Transplantation INFECTIOUS CAUSES Hepatitis viruses A, B, C, D, and E Herpes simplex virus Cytomegalovirus Adenovirus Echovirus Epstein–Barr virus Varicella-zoster virus Human herpesvirus 6 NONINFECTIOUS CAUSES Veno-occlusive disease Graft-versus-host disease Chemotherapy-induced hepatitis Hepatopathy of total parenteral nutrition Cholestatic liver injury due to septicemia Nonchemotherapeutic drugs, including acetaminophen and antibiotics
Infections in Hematopoietic Stem Cell Transplant Recipients
neutropenia (see Chapter 97). An empiric antibiotic therapy regimen consists of an antipseudomonal β-lactam, cefepime or piperacillintazobactam, or carbapenem.46,51 With rising antimicrobial resistance, every effort should be made to reserve carbapenems for patients with antibiotic allergy or resistant gram-negative infections. Monotherapy has shown to be noninferior to combination therapy.46,51 β-Lactam monotherapy avoids the use of aminoglycoside in patients who have received nephrotoxic drugs. Cefepime and piperacillin-tazobactam provide empiric coverage for Pseudomonas aeruginosa, other gramnegative, and susceptible gram-positive bacteria. Vancomycin may be added for high-risk patients such as those with severe mucositis, those at risk for infection with methicillin-resistant Staphylococcus aureus (MRSA) or other resistant gram-positive bacteria and those with severe sepsis.46 Vancomycin should be discontinued 2 to 3 days after initiation if no gram-positive resistant bacteria are identified.46 Choice of antibiotic regimens should take into account isolates indicating the patient’s colonization status, the hospital environment, and the antimicrobial resistance pattern within the community and hospital. For persistently febrile neutropenic patients without an identified bacterial source at 96 or more hours, empiric antifungal therapy should be initiated.46,51 Lipid or liposomal formulations of amphotericin B, caspofungin, and voriconazole may be used as empiric therapy.46,51 Liposomal amphotericin B may be less nephrotoxic than amphotericin B deoxycholate.51 Azole agents such as posaconazole and voriconazole are effective for the treatment of invasive aspergillosis in immunocompromised hosts.12,52 The echinocandins, caspofungin, and micafungin, alone or in combination therapy with an azole or amphotericin B, are effective for Candida spp. infections and invasive aspergillosis.53–55 Micafungin has been evaluated for salvage therapy for pulmonary aspergillosis, but the dosage has not been established.12 Viral infections are treated after a diagnosis is made if therapy is available. Acyclovir is the treatment of choice for HSV and VZV infections. Orally administered valacyclovir and famciclovir also can be used to treat HSV infections. CMV pneumonitis is treated with ganciclovir and immune globulin intravenous (IGIV) to inhibit proliferation of CMV and possibly to abrogate the immune response contributing to the pneumonitis. Foscarnet can be used in cases of ganciclovir-resistant CMV or acyclovir-resistant HSV infections. Cidofovir is used to treat adenovirus and BK virus, and it is used as a second-line agent for herpesvirus infections.56–59 There are no randomized, controlled trials of pediatric HSCT to demonstrate the efficacy of treatment of adenovirus infection.56 In a nonrandomized, single-dose pilot study, cidofovir was well tolerated by most children, and the pharmacokinetics, other than a longer drug half-life, were similar to published adult data.56 Adoptive immunotherapy, by transferring virus-specific cytotoxic T lymphocytes to patients after allogeneic HSCT, has been used to treat infections caused by EBV and CMV.60 It also is used selectively to reconstitute immune function against these viruses.61 For respiratory viral infections, pre-emptive aerosolized ribavirin for upper respiratory RSV infection appears to be safe and may decrease the RSV nasal viral load.62 Ribavirin has not been proved efficacious for the treatment of parainfluenza virus infection.63 Current evidence does not support the therapeutic use of palivizumab, an RSV-specific monoclonal antibody, because it may not prevent RSV progression to lower respiratory tract disease.64 Limited data are available for the treatment of human metapneumovirus infection.63 The use of neuraminidase inhibitors should be considered for patients with influenza infection, even if initiation of therapy is delayed, because a beneficial effect still may be observed.63
PREVENTION Prevention of infectious complications is a high priority for recipients of HSCT. Prophylaxis against PCP using TMP-SMX is started after engraftment and is given orally three times per week until 6 months after transplantation. The dose is 5 to 10 mg/kg/day divided into 2 doses or 150 mg/m2/day divided into 2 doses for 3 consecutive days per week. For HSCT recipients with neutropenia, fluconazole, posaconazole, or micafungin is recommended during the period of risk of neutropenia for prophylaxis against candidiasis.55,65 However, the use of fluconazole has been complicated by the emergence of resistant pathogens such as
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Candida krusei and other Candida species.20 Antifungal prophylaxis using posaconazole can be recommended for HSCT recipients with GvHD who are at high risk for invasive aspergillosis.12 The risk of primary CMV infection can be decreased for the CMVseronegative HSCT recipient by using leukocyte-filtered blood products for transfusion. Since the introduction of prophylaxis with ganciclovir for CMV infection, the incidence of CMV disease has been reduced substantially.30 Pre-emptive therapy with ganciclovir or foscarnet is used in seropositive HSCT recipients or in patients receiving a transplant from a seropositive donor. The use of ganciclovir as prophylaxis can cause neutropenia, which increases the risk of a bacterial infection, but the risk of CMV pneumonia justifies its use. Pre-emptive ganciclovir therapy administered early in the course of HSCT delays the median time of onset of CMV infection from 1 to 2 months to 4 to 6 months, when immune reconstitution is more advanced.66
Active Immunizations Reimmunization is important because most allogeneic and a large proportion of autologous recipients of HSCT lose their immunity to vaccine-preventable diseases. When reimmunizing transplant recipients, recent administration of immunoglobulin preparations (except monoclonal antibody to RSV) must be considered because of interference with the response to live virus vaccine (i.e., measles, mumps, rubella, and varicella). Immunization can be started 3 months after HSCT. One schema (Table 96.2) is based on the Infectious Diseases Society of America (IDSA) guidelines for vaccination of the immunocompromised host.67 Inactivated influenza vaccine should be administered annually in early autumn to recipients of HSCT beginning 6 months after transplantation. For people who are less than 6 months after HSCT during the influenza season, chemoprophylaxis should be considered. The live attenuated influenza vaccine should not be administered to HSCT recipients.6,67–71 Vaccination of the donor for the benefit of the recipient is not recommended.67 Inactivated vaccines pose no risk to HSCT recipients. Live vaccines should not be administered to HSCT patients with active GvHD or ongoing immunosuppression.67,69
Passive Immunization and Immunoglobulin Use Because of its antimicrobial and immunomodulatory effect, IGIV has been administered to HSCT recipients with no advantage in terms of survival or infection prevention.72 The indications for passive immunization with specific immune globulin preparations (e.g., hepatitis B,
TABLE 96.2 Immunization Schedule for Hematopoietic Stem Cell Transplant Recipients Months After Transplantation
Vaccines
3–6
Pneumococcala
6–12
DTaP,b,c IPVc, Hibc, meningococcal,d hepatitis Ae and Bc, HPVc,f
24
MMR,g varicella
a
Three doses of 13-valent conjugate vaccine should be given between 3 to 6 months post-HSCT followed by a dose of 23-valent pneumococcal vaccine at 12 months after hematopoietic stem cell transplantation (see Chapters 6 and 123). b For patients ≥7 years of age, a dose of Tdap should replace DTaP, and it should be followed by 2 doses of TD or Td vaccine. c Three doses between 6 to 12 months after transplantation. d Two doses of meningococcal conjugate vaccine if indicated by age. e Consider for patients who have chronic liver disease or chronic GvHD or those who live in areas with endemic infection. f For patients between 11 and 26 years of age. g Two-dose series starting 24 months after hematopoietic stem cell transplantation. Do not use live virus vaccines in patients with chronic GvHD or those receiving corticosteroid therapy. DTaP, Diphtheria and tetanus toxoids and acellular pertussis; GvHD, graft-versus-host disease; Hib, Haemophilus influenzae type B; IPV, poliovirus vaccine inactivated; MMR, measles, mumps, rubella; Tdap, diphtheria, tetanus toxoid, acellular pertussis vaccine; HPV, human papillomavirus vaccine.
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Key Points: Infections in Hematopoietic Stem Cell Transplantation Recipients EPIDEMIOLOGY AND ETIOLOGIC AGENTS
LABORATORY FINDINGS AND DIAGNOSIS
• Immune deficiencies after HSCT in the phagocytic, humoral, and cellular arms of the immune system cause susceptibility to infectious agents in three distinct periods. • Most infections are derived from the patient’s microbial flora or reactivation of a latent infection. ■ Allogeneic HSCT recipients are at higher risk for infection than autologous HSCT recipients.
• Microbiologic testing is the gold standard for diagnosis. • PCR testing is helpful for screening and confirmation of viral infections.
CLINICAL SYNDROMES, DIFFERENTIAL DIAGNOSIS, AND CLINICAL APPROACH • Approach according to the risk period after transplantation ■ Early period (i.e., before engraftment): HSV, CLABSI, and fungal infection ■ Middle period (i.e., early engraftment): CLABSI, adenovirus, CMV, pneumonitis, and toxoplasmosis ■ Late period: CLABSI, VZV, and hepatitis
MANAGEMENT AND PRESUMPTIVE THERAPY • Manage HSCT patients as for febrile neutropenic patients with cancer. • Begin antifungal therapy if fever continues ≥96 hours after commencement of antibiotic therapy. • Begin antiviral treatment when the diagnosis is made. PREVENTION • Antimicrobial prophylaxis is important to prevent certain infections (e.g., PCP, CMV). • Reimmunization is important because most recipients of HSCT lose prior immunity to vaccine-preventable diseases.
CLABSI, Central line–associated bloodstream infection; CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; PCP, Pneumocystis pneumonia; PCR, polymerase chain reaction; VZV, varicella-zoster virus.
tetanus, rabies) in patients after HSCT are similar to those in otherwise healthy people. Passive immunization is recommended for susceptible people with known exposure to varicella (see Chapter 205). All references are available online at www.expertconsult.com.
KEY REFERENCES 3. Coppes MJ, Fry TJ, Mackall CL (eds). Hematopoietic stem cell transplantation. Pediatr Clin North Am 2010;57:1–342. 5. Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic stem cell transplantation. Curr Opin Hematol 2012;19:324–335. 6. Dykewicz CA, Jaffe HW, Kaplan JE, et al. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Morb Mortal Wkly Rep 2000;49(RR-10):1–128.
13. O’Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Pediatrics 2002;110:e51–e75. 46. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:427–431. 51. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol 2012;30:4427–4438. 63. Chemaly RF, Shah DP, Boeckh MJ. Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies. Clin Infect Dis 2014;59:S344–S351. 67. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58:44–100. 69. Ljungman P, Engelhard D, de la Camara R, et al. Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant 2005;35:737–746.
Infections in Hematopoietic Stem Cell Transplant Recipients
REFERENCES 1. Savasan S, Abella EM. Current issues in pediatric stem cell transplantation. Clin Lab Med 2005;25:519–540. 2. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med 2006;354:1813–1826. 3. Coppes MJ, Fry TJ, Mackall CL (eds). Hematopoietic stem cell transplantation. Pediatr Clin North Am 2010;57:1–342. 4. Sable CA, Donowitz GR. Infections in bone marrow transplant recipients. Clin Infect Dis 1994;19:273–284. 5. Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic stem cell transplantation. Curr Opin Hematol 2012;19:324–335. 6. Dykewicz CA, Jaffe HW, Kaplan JE, et al. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Morb Mortal Wkly Rep 2000;49(RR-10):1–128. 7. Benjamin DK Jr, Miller WC, Bayliff S, et al. Infections diagnosed in the first year after pediatric stem cell transplantation. Pediatr Infect Dis J 2002;21:227–234. 8. Maltezou HC, Kafetzis DA, Abisaid D, et al. Viral infections in children undergoing hematopoietic stem cell transplant. Pediatr Infect Dis J 2000;19:307–312. 9. Bordon V, Padalko E, Benoit Y, et al. Incidence, kinetics, and risk factors of EpsteinBarr virus viremia in pediatric patients after allogeneic stem cell transplantation. Pediatr Transplant 2012;16:144–150. 10. Mynarek M, Ganzenmuller T, Mueller-Heine A, et al. Patient, virus, and treatmentrelated risk factors in pediatric adenovirus infection after stem cell transplantation: results of a routine monitoring program. Biol Blood Marrow Transplant 2014;20:250–256. 11. de Mezerville MH, Tellier R, Richardson S, et al. Adenoviral infections in pediatric transplant recipients: a hospital based study. Pediatr Infect Dis J 2006;25:815–818. 12. Walsh TJ, Anaissie EJ, Denning DW. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008;46: 327–360. 13. O’Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Pediatrics 2002;110:e51–e75. 14. Adler A, Yaniv I, Steinberg R, et al. Infectious complications of implantable ports and Hickman catheters in paediatric haematology-oncology patients. J Hosp Infect 2006;62:358–365. 15. Mullen CA, Nair J, Sandesh S, Chan KW. Fever and neutropenia in pediatric hematopoietic stem cell transplant patients. Bone Marrow Transplant 2000;25:59–65. 16. Ortega M, Rovira M, Almela M, et al. Bacterial and fungal bloodstream isolates from 796 hematopoietic stem cell transplant recipients between 1991 and 2000. Ann Hematol 2005;84:40–46. 17. Graber CJ, de Almeida KN, Atkinson JC, et al. Dental health and viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2001;27:537–542. 18. Glenny AM, Gibson F, Auld E, et al. The development of evidence-based guidelines on mouth care for children, teenagers and young adults treated for cancer. Eur J Cancer 2010;46:1399–1412. 19. Marr KA, Seidel K, White TC, Bowden RA. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Infect Dis 2000;181:309–316. 20. Safdar A, van Rhee F, Henslee-Downey JP, et al. Candida glabrata and Candida krusei fungemia after high-risk allogeneic marrow transplantation: no adverse effect of lowdose fluconazole prophylaxis on incidence and outcome. Bone Marrow Transplant 2001;28:873–878. 21. Kontoyiannis DP, Marr KA, Park BJ. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001–2006: overview of the Transplant- Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis 2010;50:1091–1100. 22. Dvorak CC, Steinbach WJ, Brown JM, Agarwal R. Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2005;36:621–629. 23. Segal BH, Almyroudis NG, Battiwalla M, et al. Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts. Clin Infect Dis 2007;44:402–409. 24. Maertens J, Van Eldere J, Verhaegen J, et al. Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients. J Infect Dis 2002;186:1297–1306. 25. Hale GA, Rochester RJ, Heslop HE, et al. Hemorrhagic cystitis after allogeneic bone marrow transplantation in children: clinical characteristics and outcome. Biol Blood Marrow Transplant 2003;9:698–705. 26. Hatakeyama N, Suzuki N, Yamamoto M, et al. Detection of BK virus and adenovirus in the urine from children after allogeneic stem cell transplantation. Pediatr Infect Dis J 2006;25:84–85. 27. Verghese PS, Finn LS, Englund JA, et al. BK nephropathy in pediatric hematopoietic stem cell transplant recipients. Pediatr Transplant 2009;13:913–918. 28. Danziger-Isakov L. Gastrointestinal infections after transplantation. Curr Opin Gastroenterol 2014;30:40–46. 29. Russell MY, Palmer A, Michaels MG. Cytomegalovirus infection in pediatric immunocompromised hosts. Infect Disord Drug Targets 2011;11:437–448. 30. Ariza-Heredia EJ, Nesher L, Chemaly RF. Cytomegalovirus diseases after hematopoietic stem cell transplantation: a mini-review. Cancer Lett 2014;342:1–8. 31. Lujan-Zilbermann J, Benaim E, Tong X, et al. Respiratory virus infections in pediatric hematopoietic stem cell transplantation. Clin Infect Dis 2001;33: 962–968.
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32. Bredius RG, Templeton KE, Scheltinga SA, et al. Prospective study of respiratory viral infections in pediatric hemopoietic stem cell transplantation patients. Pediatr Infect Dis J 2004;23:518–522. 33. Boeckh M, Erard V, Zerr D, Englund J. Emerging viral infections after hematopoietic cell transplantation. Pediatr Transplant 2005;9(suppl 7):48–54. 34. Ison MG, Hayden FG, Kaiser L, et al. Rhinovirus infections in hematopoietic stem cell transplant recipients with pneumonia. Clin Infect Dis 2003;36:1139–1143. 35. Zerr DM, Boeckh M, Delaney C, et al. HHV-6 reactivation and associated sequelae after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012;18:1700–1708. 36. de Pagter PJ, Schuurman R, Visscher H, et al. Human herpes virus 6 plasma DNA positivity after hematopoietic stem cell transplantation in children: an important risk factor for clinical outcome. Biol Blood Marrow Transplant 2008;14:831–839. 37. Srinivasan A, Wang C, Yang J, et al. Symptomatic parainfluenza virus infections in children undergoing hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011;17:1520–1527. 38. De Castro N, Neuville S, Sarfati C, et al. Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study. Bone Marrow Transplant 2005;36:879–883. 39. Yusuf U, Hale GA, Carr J, et al. Cidofovir for the treatment of adenoviral infection in pediatric hematopoietic stem cell transplant patients. Transplantation 2006;81:1398–1404. 40. Martino R, Maertens J, Bretagne S, et al. Toxoplasmosis after hematopoietic stem cell transplantation. Clin Infect Dis 2000;31:1188–1195. 41. Weber C, Schaper J, Tibussek D, et al. Diagnostic and therapeutic implications of neurological complications following paediatric haematopoietic stem cell transplantation. Bone Marrow Transplant 2008;41:253–259. 42. Woodard P, Helton K, McDaniel H, et al. Encephalopathy in pediatric patients after allogeneic hematopoietic stem cell transplantation is associated with a poor prognosis. Bone Marrow Transplant 2004;33:1151–1157. 43. Zerr DM, Corey L, Kim HW, et al. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. Clin Infect Dis 2005;40:932–940. 44. Leung TF, Chik KW, Li CK, et al. Incidence, risk factors, and outcome of varicellazoster virus infection in children after haematopoietic stem cell transplantation. Bone Marrow Transplant 2000;25:167–172. 45. Ljungman P, Locasciulli A, de Soria VG, et al. Long-term follow-up of HCV infected hematopoietic SCT patients and effects of antiviral therapy. Bone Marrow Transplant 2012;47:1217–1221. 46. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:427–431. 47. Pence MA, McElvania TeKippe E, Burnham CA. Diagnostic assays for identification of microorganisms and antimicrobial resistance determinants directly from positive blood culture broth. Clin Lab Med 2013;33:651–684. 48. Zumla A, Al-Tawfiq JA, Enne VI, et al. Rapid point of care diagnostic tests for viral and bacterial respiratory tract infections—needs, advances, and future prospects. Lancet Infect Dis 2014;14:1123–1135. 49. Schönberger S, Meisel R, Adams O, et al. Prospective, comprehensive and effective viral monitoring in children undergoing allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2010;16:1428–1435. 50. Mahony JB. Detection of respiratory viruses by molecular methods. Clin Microbiol Rev 2008;21:716–747. 51. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol 2012;30:4427–4438. 52. Denning DW, Ribaud P, Milpied N. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002;34:563–571. 53. Maertens J, Raad I, Petrikkos G, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis 2004;39:1563–1571. 54. Denning DW, Marr KA, Lau WM, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect 2006;53:337–349. 55. Pappas PG, Kauffman CA, Andes D. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48:503–535. 56. Caruso Brown A, Cohen MN, Tong S, et al. Pharmacokinetics and safety of intravenous cidofovir for life-threatening viral infections in pediatric hematopoietic stem cell transplant recipients. Antimicrob Agents Chemother 2015;59: 3718–3725. 57. Lugthart G, Oomen MA, Jol-van der Zijde CM, et al. The effect of cidofovir on adenovirus plasma DNA levels in stem cell transplantation recipients without T cell reconstitution. Biol Blood Marrow Transplant 2015;21:293–299. 58. Koskenvuo M, Dumoulin A, Lautenschlager I, et al. BK polyomavirus-associated hemorrhagic cystitis among pediatric allogeneic bone marrow transplant recipients: treatment response and evidence for nosocomial transmission. J Clin Virol 2013;56:77–81. 59. Kwon HJ, Kang JH, Lee JW, et al. Treatment of BK virus-associated hemorrhagic cystitis in pediatric hematopoietic stem cell transplant recipients with cidofovir: a single-center experience. Transpl Infect Dis 2013;15:569–574. 60. Bollard CM, Kuehnle I, Leen A, et al. Adoptive immunotherapy for posttransplantation viral infections. Biol Blood Marrow Transplant 2004;10:143–155. 61. Pagliara D, Savoldo B. Cytotoxic T lymphocytes for the treatment of viral infections and posttransplant lymphoproliferative disorders in transplant recipients. Curr Opin Infect Dis 2012;25:431–437.
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PART II Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management SECTION O Infections and Transplantation 62. Boeckh M, Englund J, Li Y, et al. Randomized controlled multicenter trial of aerosolized ribavirin for respiratory syncytial virus upper respiratory tract infection in hematopoietic cell transplant recipients. Clin Infect Dis 2007;44:245–249. 63. Chemaly RF, Shah DP, Boeckh MJ. Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies. Clin Infect Dis 2014;59:S344–S351. 64. de Fontbrune FS, Robin M, Porcher R, et al. Palivizumab treatment of respiratory syncytial virus infection after allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2007;45:1019–1024. 65. van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004;39: 1407–1416. 66. Boeckh M, Fries B, Nichols WG. Recent advances in the prevention of CMV infection and disease after hematopoietic stem cell transplantation. Pediatr Transplant 2004;8(suppl 5):19–27. 67. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58:44–100.
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68. American Academy of Pediatrics. Immunization in special clinical circumstances: hematopoietic stem cell and other transplant recipients. In: Kimberlin DW, Brady MT, Jackson MA, Long SS (eds) Red Book: 2015 Report of the Committee on Infectious Diseases. Elk Grove Village, IL, American Academy of Pediatrics, 2015. 69. Ljungman P, Engelhard D, de la Camara R, et al. Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant 2005;35:737–746. 70. Pao M, Papadopoulos EB, Chou J, et al. Response to pneumococcal (PNCRM7) and Haemophilus influenzae conjugate vaccines (HIB) in pediatric and adult recipients of an allogeneic hematopoietic stem cell transplantation (alloHCT). Biol Blood Marrow Transplant 2008;14:1022–1030. 71. Patel SR, Ortin M, Cohen BJ, et al. Revaccination with measles, tetanus, poliovirus, Haemophilus influenzae type B, meningococcus C and pneumococcus vaccines in children after hematopoietic stem cell transplantation. Clin Infect Dis 2007;44:625–644. 72. Raanani P, Gafter-Gvili A, Paul M, et al. Immunoglobulin prophylaxis in hematopoietic stem cell transplantation: systematic review and analysis. J Clin Oncol 2009;27:770–781.
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Infections in Hematopoietic Stem Cell Transplant Recipients Jorge Luján-Zilbermann and David M. Berman
Hematopoietic stem cell transplantation (HSCT) has broad indications in pediatrics, including treatment of cancer, primary immunodeficiency syndromes, bone marrow failure syndromes, hemoglobinopathies, and an assortment of genetic conditions, including inborn errors of metabolism, and nonmalignant conditions such as osteopetrosis.1–3 Patients undergoing HSCT have increased risks of infections that are somewhat predictable based on the acquired immune deficiencies that occur after HSCT.4–7
HSV RSV Parainfluenza virus Adenovirus
Viral
CMV EBV VZV
ETIOLOGIC AGENTS Patients who have had HSCT have immune deficiencies in the phagocytic, humoral, and cellular arms of the immune system.4 These immune defects lead to pathogen susceptibility and infectious complications in three predictable risk periods (Fig. 96.1).4 After the conditioning regimen, a period of neutropenia occurs for 3 to 4 weeks, during which bacteria and fungi cause most infections. Herpes simplex virus (HSV) and seasonal respiratory viral infections also can occur.4,7,8 The middle period occurs after granulocyte recovery and continues until approximately 100 days after HSCT. Infectious complications during this period are associated with profound impairment of humoral and cellular immunity. Although bacterial and fungal infections still can occur, they are much less frequent than during the neutropenic period. Cytomegalovirus (CMV) is a major infecting agent, but Pneumocystis jirovecii disease also can occur. With the advent of effective prophylaxis against both of these agents, the incidence of associated disease has decreased. Infections due to adenovirus and Epstein–Barr virus (EBV) can occur, especially with the use of mismatched HSCT and T-lymphocyte–depleted HSCT.9–11 The late period is associated with deficits in humoral immune responses, cellular immune responses, and reticuloendothelial function begins 100 days after HSCT. Varicella-zoster virus (VZV) and encapsulated bacteria,
Gram-negative Gram-positive
Bacterial
Encapsulated bacteria Candida and Aspergillus Fungal
Pneumocystis jirovecii Toxoplasma
Protozoal 0
30
60
90
120
150
180
365
Days After Transplantation FIGURE 96.1 Temporal association of infectious agents and hematopoietic stem cell transplantation. Day 0 is the time of stem cell infusion. Boldness of the line denotes increasing frequency of infection with the offending agent. CMV, cytomegalovirus; EBV, Epstein–Barr virus; HSV, herpes simplex virus; RSV; respiratory syncytial virus; VZV, varicella–zoster virus.
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BOX 96.1 Predisposing Factors for Infectious Complications in Hematopoietic Stem Cell Transplant Recipients • • • • • • •
Underlying illness Type of transplant Conditioning regimen Infectious disease history Indwelling medical device Occurrence and severity of graft-versus-host disease Immunosuppressive regimen administered to prevent graft-versus-host disease • Epidemiology of infection in hospital or transplantation care unit
particularly Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), are major pathogens during this period.
EPIDEMIOLOGY Among HSCT recipients, most infections are derived from their microbial flora or reactivation of latent infections. Many factors account for the high risk of infectious complications among HSCT recipients (Box 96.1). Immune deficiency associated with the underlying disease is a determinant of the degree of immune suppression. Allogeneic HSCT recipients (i.e., matched unrelated donor or unrelated cord blood transplantation) are at high risk for graft-versus-host disease (GvHD), which enhances the infection rate by delaying the return of normal immune function and by ulceration of the gastrointestinal tract. Moreover, the risk of infection is directly related to the degree of donor-recipient mismatch. To abrogate GvHD, immune-suppressing medications are administered as prophylaxis. These agents increase the risk of infection by depressing the cell-mediated immune response and by disrupting mucosal barriers. The conditioning regimen with or without concomitant irradiation compromises the immune system and can disrupt mucosal barriers. Purging of the bone marrow in autologous transplants to reduce the load of malignant cells and T-lymphocyte depletion used in allogeneic transplants to reduce the incidence of GvHD predispose the host to infection. The serologic status of the donor and the recipient is important because many infections in transplant recipients are caused by reactivation (Table 96.1). This is most notable for the herpesviruses. CMV is a major cause of pneumonitis in allogeneic transplant recipients. Other herpesviruses, especially HSV, VZV, and EBV; Toxoplasma gondii; and adenovirus infections are prone to reactivate after the transplantation. All HSCT recipients have a central venous catheter (CVC) placed before transplantation, providing a potential site for infection. Patients who have other indwelling medical devices (e.g., cerebrospinal fluid shunts) have an increased risk of infection. Patients with a history of invasive aspergillosis who are undergoing HSCT require adequate antifungal prophylaxis and treatment to prevent relapse of the disease.12 Knowledge of the epidemiology of pathogens associated with the local hospital and the transplantation unit allows assessment of the risk of environmental organisms such as Aspergillus and Legionella species. Rates of infection can be reduced substantially by preventive mechanisms that inhibit aerosolization of organisms, such as the use of laminar flow rooms or high-efficiency particulate air (HEPA)–filtered rooms.6
Early Period Several types of infection are more likely to occur during the early period (i.e., before engraftment) of the transplantation process. Herpes Simplex Virus Gingivostomatitis. HSV infection occurs primarily as a result of reactivation in seropositive patients undergoing HSCT. The diagnosis is difficult because lip lesions are rare and mucosal ulcerations are similar to those that occur as a result of the conditioning regimen. Central Venous Catheter–Related Bloodstream Infections. During the neutropenic period, HSCT recipients are at high risk for bacterial infection, comparable with the risk for patients with cancer who develop chemotherapy-induced neutropenia. Central line–associated bloodstream infections (CLABSIs) are common because of the uniform use of indwelling CVCs in HSCT patients for administration of medications, hyperalimentation, blood products, and blood sampling. Measures to prevent CLABSIs should be followed.6,13 Staphylococcus epidermidis and other coagulase-negative staphylococci are the most common causes of bloodstream infections (BSIs) during the three periods after transplantation.14–16 Other gram-positive organisms associated with BSIs in HSCT recipients include viridans streptococci and S. aureus.14–16 Viridans streptococci infections have been associated with chemotherapy-induced mucositis and poor dental hygiene.17,18 Most gram-positive catheter-related infections can be treated successfully without removal of the catheter. Gram-negative bacillary infections occur after mucosal damage with bacterial translocation from the intestinal mucosa into the bloodstream and are the second most frequent cause of BSI. The predominant organisms in this class include Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa, although other gram-negative organisms are common.14,16 Antibiotic resistance among these organisms is common. Catheterrelated infections with some gram-negative bacilli, Candida spp., and Bacillus cereus can be problematic and require catheter removal. Fungal Infections. The major causes of fungal infection include Aspergillus spp., Candida spp., and agents of mucormycosis (e.g., Mucor, Absidia, Rhizopus spp.).19–21 Other fungi recognized as pathogens include Trichosporon spp., Fusarium spp., Curvularia spp., and Alternaría spp.21–23 Infection with these organisms usually occurs after a period of antibiotic therapy and correlates with the degree and duration of neutropenia. Although Candida albicans is the most frequent Candida species causing BSI, C. tropicalis may cause more severe disease. Other Candida species,
TABLE 96.1 Evaluation of Patients Before Hematopoietic Stem Cell Transplantation Study Type
Organism or Test
Serum antibody assay
CMV EBV HSV VZV Hepatitis B (HBsAg, HBsAb, HBcAb) Hepatitis C RPR Human immunodeficiency virus
Other laboratory tests
Serum hepatic enzymes (ALT, AST, bilirubin) Renal function tests (BUN, creatinine) Complete blood cell count with differential leukocyte count Stool for ova and parasites
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Tuberculosis test
Tuberculin skin test (TST); for children >5 years of age, interferon γ release assay (blood) is acceptable
The approach to a patient who has had HSCT takes into account the infections that can occur during each of the risk periods (see Fig. 96.1). This provides the framework for matching possible causative agents with the clinical syndrome. Because some of these clinical syndromes are highlighted in Chapters 97 and 98, the following discussion focuses on the clinical approach to the HSCT recipient.
Radiographic testing
Chest, posteroanterior and lateral Sinus series, if clinically indicated
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; cAb, core antibody; CMV, cytomegalovirus; EBV, Epstein–Barr virus; RPR, rapid plasma reagin; sAb, surface antibody; sAg, surface antigen.
Infections in Hematopoietic Stem Cell Transplant Recipients
BOX 96.2 Differential Diagnosis of Hemorrhagic Cystitis in Hematopoietic Stem Cell Transplant Recipients
BOX 96.3 Causes of Pneumonitis in Hematopoietic Stem Cell Transplant Recipients
INFECTIOUS CAUSES
INFECTIOUS CAUSES
Virus
Bacteria
Adenovirus Cytomegalovirus Polyomaviruses, especially BK virus and JC virus Herpes simplex virus
• Enterobacteriaceae • Staphylococcus aureus • Legionella pneumophila
Bacteria
Fungus
• • • •
Urinary tract infection Fungus ball
Viruses
Urinary tract infection, predominantly gram-negative bacilli
NONINFECTIOUS CAUSES Chemotherapy (e.g., cyclophosphamide) Graft-versus-host disease Mechanical trauma from Foley catheter
including C. glabrata, C. parapsilosis, and C. krusei, also have emerged because of resistance to fluconazole, which is used as prophylaxis.20–22 The portal of entry for Aspergillus and agents of mucormycosis is the respiratory tract, as opposed to that for Candida spp., which is the gastrointestinal tract. Aspergillus is associated with sinopulmonary disease and dissemination (Fig. 96.2), but it is rarely recovered from blood cultures. Diagnosis usually depends on tissue histology and culture of material obtained from bronchoscopy, lung aspiration, or open-lung biopsy. The galactomannan assay can be useful in the early diagnosis of invasive aspergillosis in high-risk patients.12,24 Hemorrhagic Cystitis. Hemorrhagic cystitis is associated with a variety of infectious and noninfectious causes (Box 96.2).25 The onset can occur at any time during the transplantation period; chemotherapy-induced cystitis occurs soon after commencing the conditioning regimen. The most common infectious causes are polyomaviruses (BK virus and JC virus) and adenovirus.25–27 Bacterial and fungal pathogens also must be considered. Enteric Infections. Diarrhea after transplantation is caused most commonly by mucositis and GvHD. Enteric infections can occur throughout the transplantation period. Antibiotic-associated diarrhea, including that due to Clostridium difficile, usually occurs during the neutropenic period, when antimicrobial agents are frequently administered. Other infecting
FIGURE 96.2 Invasive aspergillosis in a patient after hematopoietic stem cell transplantation. Computed tomography of the chest shows bilateral pulmonary involvement, including aspergilloma in the right middle lobe (arrow).
96
Fungi
• • • • • • • • •
Aspergillus species Mucormycosis Pneumocystis jirovecii Candida species
Parainfluenza types 1–4 Adenovirus Respiratory syncytial virus Human metapneumovirus Cytomegalovirus Influenza Human herpesvirus 6 Coxsackievirus and echoviruses Rhinovirus
NONINFECTIOUS CAUSES Pulmonary damage by radiation exposure Pulmonary damage by chemotherapeutic agents (e.g., bleomycin) Underlying cancer Pulmonary edema Alveolar hemorrhage Idiopathic interstitial pneumonia Pulmonary vascular disease Pneumomediastinum
agents, including enteric adenovirus, rotavirus, coxsackievirus, and noroviruses, should also be considered.11,28 Infections caused by enteric viruses typically are seasonal in occurrence.
Middle Period The middle period (i.e., early engraftment), which spans days 30 through 100 after transplantation, was once was dominated by CMV infection, but the incidence of CMV infection has diminished with the use of ganciclovir as pre-emptive therapy. Bacterial infections are less problematic during this period, except for those associated with indwelling catheters. Fungal infections occur in patients with GvHD. Pneumonitis. Pulmonary infiltrates can have infectious or noninfectious causes (Box 96.3). Although signs and symptoms can occur throughout the transplantation period, viral infections are more common during the early engraftment period. CMV manifests at a median time of 40 to 50 days after the transplantation period (see Fig. 96.1). CMV most commonly occurs because of reactivation of latent virus in seropositive individuals but also can occur in seronegative patients who receive a transplant from a seropositive donor. Risk factors for CMV pneumonia include seropositivity of the donor, type of transplant (i.e., allogeneic more than autologous), human leukocyte antigen (HLA)–mismatched transplant, older age of the patient (>10 years), and development of acute GvHD.29 CMV infection occurs in 30% to 50% of patients undergoing HSCT; pneumonia occurs in 10% to 15% of these patients and has a mortality rate of 85%. CMV infection and disease also occur in autologous HSCT recipients, although at a much lower incidence. The clinical manifestations of CMV disease vary from asymptomatic infection to the constellation of fever, hepatitis, and leukopenia to life-threatening diseases such as interstitial pneumonitis, esophagitis, and encephalitis.30
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Other viral causes of respiratory tract infections include adenovirus, respiratory syncytial virus (RSV), human metapneumovirus, parainfluenza virus, influenza virus, human herpesvirus 6 (HHV-6), coxsackievirus, and rhinovirus.31–37 RSV, influenza virus, and parainfluenza virus can cause sinusitis and life-threatening pneumonia.31,32,37 Pneumocystis jirovecii also causes pneumonia after engraftment.38 Clinical manifestations are similar to those in other immunocompromised hosts. The incidence of Pneumocystis pneumonia (PCP) has been curtailed markedly by routine prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) and pentamidine. Adenovirus Infection. Adenovirus infection occurs in approximately 30% of pediatric HSCT recipients and can become latent in lymphoid tissue and kidneys.39 The most common clinical manifestations of infection include diarrhea, febrile illness, hemorrhagic cystitis, and pneumonia but also can include hepatitis and encephalitis.39 Toxoplasmosis. Toxoplasmosis is a rare but almost always fatal infection after HSCT. Toxoplasmosis usually occurs 2 to 6 months after HSCT, and the central nervous system is affected most often. Symptoms include focal neurologic signs, fever, seizures, and altered mental status. Imaging of the brain typically shows multiple lesions in both hemispheres and the basal ganglia.40,41 Encephalopathy. Encephalopathy is a poorly characterized complication of HSCT. It has a very poor prognosis for pediatric patients, with a mortality rate of 65% in one study.42 Several infectious and noninfectious causes have been described (Box 96.4).33,41,42 HHV-6 has been associated with encephalitis and delayed platelet engraftment.35,36,43
Late Period At 100 days after transplantation, the late period begins. It lasts for 6 to 12 months or longer, depending on the complications of transplantation, especially GvHD. Bloodstream Infection. Bacterial infections occur less commonly during the late period, but patients continue to be immunosuppressed and susceptible to bacterial infection and BSI. Chronic GvHD augments this immunosuppression. Encapsulated bacteria, especially S. pneumoniae and Hib, are the most common agents responsible for bacterial infections that are not related to the existence of an indwelling catheter.4
BOX 96.4 Differential Diagnosis of Meningitis, Encephalitis, and Encephalopathy in Hematopoietic Stem Cell Transplantation Recipients INFECTIOUS CAUSES Viruses • Adenovirus • Human herpesvirus 6 and 7 • Polyomaviruses, especially BK virus and JC virus (progressive multifocal leukoencephalopathy) • Herpes simplex virus and varicella-zoster virus • Postviral (acute disseminated encephalomyelitis) Bacteria • Streptococcus pneumoniae Fungi • Aspergillus species Protozoa • Toxoplasma gondii NONINFECTIOUS CAUSES Medications (e.g., cyclosporine, amphotericin B) Nonconvulsive seizures Thrombotic thrombocytopenic purpura Multiorgan system failure Stroke
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Varicella-Zoster Virus Infection. VZV infections occur in 25% to 40% of patients after HSCT.44 Reactivation occurs more frequently in association with chronic GvHD but also has been described in patients after autologous HSCT. A prodrome of a burning sensation or pain over the involved dermatome can occur. Groups of vesicles appear in the distribution of one to three sensory dermatomes. If appropriate therapy with acyclovir is not instituted, dissemination can occur in 36% of infected patients, with a mortality rate of 10%. Hepatitis. Acute or chronic hepatitis can follow HSCT and has infectious and noninfectious causes (Box 96.5). Hepatitis C virus can infect HSCT recipients, and activation occurs at the time of discontinuation of immunosuppressive therapy.45
LABORATORY FINDINGS AND DIAGNOSIS Microbiologic evaluation is the gold standard for the diagnosis of infection. Microbiologic tests include blood cultures for bacteria and fungi. Blood cultures should be obtained from each lumen of the central venous line and a peripheral vein.46 If bacteria or fungi are detected in the blood culture, use of real-time polymerase chain reaction (PCR) can reduce the time to identification of microorganisms and can identify certain antimicrobial resistance genes.47 When clinically indicated, additional testing includes detection of viral infection by serology, culture, PCR, and immunohistochemical stains on pathologic specimens. PCR testing is extremely helpful for the screening and diagnosis of viral infections. PCR is available for all the herpesviruses, adenovirus, and polyomaviruses.11,26,35,48 PCR panels can be used to detect viruses from respiratory specimens, allowing rapid detection of influenza virus, RSV, parainfluenza virus, metapneumovirus, adenovirus, and others.49,50 Other laboratory tests are of limited value. The use of the (1-3)-β-dglucan assay as a screening tool for fungal infection has limited value primarily because several factors can confound the interpretation of the results.23,46,51 The galactomannan assay is best used longitudinally and only for patients at risk for invasive aspergillosis.46 A single negative serum test should never be used to rule out invasive fungal infection.46 Complete blood cell counts can be used to assess engraftment status. An absolute neutrophil count of <500/mm3 is associated with higher incidence of bacterial infections. Serum hepatic enzyme levels and renal function tests can provide evidence of pathology from an infectious agent or insults from chemotherapy or GvHD (see Boxes 96.2 and 96.5).
MANAGEMENT AND PRESUMPTIVE THERAPY Initial management of patients with fever and neutropenia is similar to management of patients with chemotherapy-induced fever and
BOX 96.5 Differential Diagnosis of Hepatitis After Hematopoietic Stem Cell Transplantation INFECTIOUS CAUSES Hepatitis viruses A, B, C, D, and E Herpes simplex virus Cytomegalovirus Adenovirus Echovirus Epstein–Barr virus Varicella-zoster virus Human herpesvirus 6 NONINFECTIOUS CAUSES Veno-occlusive disease Graft-versus-host disease Chemotherapy-induced hepatitis Hepatopathy of total parenteral nutrition Cholestatic liver injury due to septicemia Nonchemotherapeutic drugs, including acetaminophen and antibiotics
Infections in Hematopoietic Stem Cell Transplant Recipients
neutropenia (see Chapter 97). An empiric antibiotic therapy regimen consists of an antipseudomonal β-lactam, cefepime or piperacillintazobactam, or carbapenem.46,51 With rising antimicrobial resistance, every effort should be made to reserve carbapenems for patients with antibiotic allergy or resistant gram-negative infections. Monotherapy has shown to be noninferior to combination therapy.46,51 β-Lactam monotherapy avoids the use of aminoglycoside in patients who have received nephrotoxic drugs. Cefepime and piperacillin-tazobactam provide empiric coverage for Pseudomonas aeruginosa, other gramnegative, and susceptible gram-positive bacteria. Vancomycin may be added for high-risk patients such as those with severe mucositis, those at risk for infection with methicillin-resistant Staphylococcus aureus (MRSA) or other resistant gram-positive bacteria and those with severe sepsis.46 Vancomycin should be discontinued 2 to 3 days after initiation if no gram-positive resistant bacteria are identified.46 Choice of antibiotic regimens should take into account isolates indicating the patient’s colonization status, the hospital environment, and the antimicrobial resistance pattern within the community and hospital. For persistently febrile neutropenic patients without an identified bacterial source at 96 or more hours, empiric antifungal therapy should be initiated.46,51 Lipid or liposomal formulations of amphotericin B, caspofungin, and voriconazole may be used as empiric therapy.46,51 Liposomal amphotericin B may be less nephrotoxic than amphotericin B deoxycholate.51 Azole agents such as posaconazole and voriconazole are effective for the treatment of invasive aspergillosis in immunocompromised hosts.12,52 The echinocandins, caspofungin, and micafungin, alone or in combination therapy with an azole or amphotericin B, are effective for Candida spp. infections and invasive aspergillosis.53–55 Micafungin has been evaluated for salvage therapy for pulmonary aspergillosis, but the dosage has not been established.12 Viral infections are treated after a diagnosis is made if therapy is available. Acyclovir is the treatment of choice for HSV and VZV infections. Orally administered valacyclovir and famciclovir also can be used to treat HSV infections. CMV pneumonitis is treated with ganciclovir and immune globulin intravenous (IGIV) to inhibit proliferation of CMV and possibly to abrogate the immune response contributing to the pneumonitis. Foscarnet can be used in cases of ganciclovir-resistant CMV or acyclovir-resistant HSV infections. Cidofovir is used to treat adenovirus and BK virus, and it is used as a second-line agent for herpesvirus infections.56–59 There are no randomized, controlled trials of pediatric HSCT to demonstrate the efficacy of treatment of adenovirus infection.56 In a nonrandomized, single-dose pilot study, cidofovir was well tolerated by most children, and the pharmacokinetics, other than a longer drug half-life, were similar to published adult data.56 Adoptive immunotherapy, by transferring virus-specific cytotoxic T lymphocytes to patients after allogeneic HSCT, has been used to treat infections caused by EBV and CMV.60 It also is used selectively to reconstitute immune function against these viruses.61 For respiratory viral infections, pre-emptive aerosolized ribavirin for upper respiratory RSV infection appears to be safe and may decrease the RSV nasal viral load.62 Ribavirin has not been proved efficacious for the treatment of parainfluenza virus infection.63 Current evidence does not support the therapeutic use of palivizumab, an RSV-specific monoclonal antibody, because it may not prevent RSV progression to lower respiratory tract disease.64 Limited data are available for the treatment of human metapneumovirus infection.63 The use of neuraminidase inhibitors should be considered for patients with influenza infection, even if initiation of therapy is delayed, because a beneficial effect still may be observed.63
PREVENTION Prevention of infectious complications is a high priority for recipients of HSCT. Prophylaxis against PCP using TMP-SMX is started after engraftment and is given orally three times per week until 6 months after transplantation. The dose is 5 to 10 mg/kg/day divided into 2 doses or 150 mg/m2/day divided into 2 doses for 3 consecutive days per week. For HSCT recipients with neutropenia, fluconazole, posaconazole, or micafungin is recommended during the period of risk of neutropenia for prophylaxis against candidiasis.55,65 However, the use of fluconazole has been complicated by the emergence of resistant pathogens such as
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Candida krusei and other Candida species.20 Antifungal prophylaxis using posaconazole can be recommended for HSCT recipients with GvHD who are at high risk for invasive aspergillosis.12 The risk of primary CMV infection can be decreased for the CMVseronegative HSCT recipient by using leukocyte-filtered blood products for transfusion. Since the introduction of prophylaxis with ganciclovir for CMV infection, the incidence of CMV disease has been reduced substantially.30 Pre-emptive therapy with ganciclovir or foscarnet is used in seropositive HSCT recipients or in patients receiving a transplant from a seropositive donor. The use of ganciclovir as prophylaxis can cause neutropenia, which increases the risk of a bacterial infection, but the risk of CMV pneumonia justifies its use. Pre-emptive ganciclovir therapy administered early in the course of HSCT delays the median time of onset of CMV infection from 1 to 2 months to 4 to 6 months, when immune reconstitution is more advanced.66
Active Immunizations Reimmunization is important because most allogeneic and a large proportion of autologous recipients of HSCT lose their immunity to vaccine-preventable diseases. When reimmunizing transplant recipients, recent administration of immunoglobulin preparations (except monoclonal antibody to RSV) must be considered because of interference with the response to live virus vaccine (i.e., measles, mumps, rubella, and varicella). Immunization can be started 3 months after HSCT. One schema (Table 96.2) is based on the Infectious Diseases Society of America (IDSA) guidelines for vaccination of the immunocompromised host.67 Inactivated influenza vaccine should be administered annually in early autumn to recipients of HSCT beginning 6 months after transplantation. For people who are less than 6 months after HSCT during the influenza season, chemoprophylaxis should be considered. The live attenuated influenza vaccine should not be administered to HSCT recipients.6,67–71 Vaccination of the donor for the benefit of the recipient is not recommended.67 Inactivated vaccines pose no risk to HSCT recipients. Live vaccines should not be administered to HSCT patients with active GvHD or ongoing immunosuppression.67,69
Passive Immunization and Immunoglobulin Use Because of its antimicrobial and immunomodulatory effect, IGIV has been administered to HSCT recipients with no advantage in terms of survival or infection prevention.72 The indications for passive immunization with specific immune globulin preparations (e.g., hepatitis B,
TABLE 96.2 Immunization Schedule for Hematopoietic Stem Cell Transplant Recipients Months After Transplantation
Vaccines
3–6
Pneumococcala
6–12
DTaP,b,c IPVc, Hibc, meningococcal,d hepatitis Ae and Bc, HPVc,f
24
MMR,g varicella
a
Three doses of 13-valent conjugate vaccine should be given between 3 to 6 months post-HSCT followed by a dose of 23-valent pneumococcal vaccine at 12 months after hematopoietic stem cell transplantation (see Chapters 6 and 123). b For patients ≥7 years of age, a dose of Tdap should replace DTaP, and it should be followed by 2 doses of TD or Td vaccine. c Three doses between 6 to 12 months after transplantation. d Two doses of meningococcal conjugate vaccine if indicated by age. e Consider for patients who have chronic liver disease or chronic GvHD or those who live in areas with endemic infection. f For patients between 11 and 26 years of age. g Two-dose series starting 24 months after hematopoietic stem cell transplantation. Do not use live virus vaccines in patients with chronic GvHD or those receiving corticosteroid therapy. DTaP, Diphtheria and tetanus toxoids and acellular pertussis; GvHD, graft-versus-host disease; Hib, Haemophilus influenzae type B; IPV, poliovirus vaccine inactivated; MMR, measles, mumps, rubella; Tdap, diphtheria, tetanus toxoid, acellular pertussis vaccine; HPV, human papillomavirus vaccine.
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Key Points: Infections in Hematopoietic Stem Cell Transplantation Recipients EPIDEMIOLOGY AND ETIOLOGIC AGENTS
LABORATORY FINDINGS AND DIAGNOSIS
• Immune deficiencies after HSCT in the phagocytic, humoral, and cellular arms of the immune system cause susceptibility to infectious agents in three distinct periods. • Most infections are derived from the patient’s microbial flora or reactivation of a latent infection. ■ Allogeneic HSCT recipients are at higher risk for infection than autologous HSCT recipients.
• Microbiologic testing is the gold standard for diagnosis. • PCR testing is helpful for screening and confirmation of viral infections.
CLINICAL SYNDROMES, DIFFERENTIAL DIAGNOSIS, AND CLINICAL APPROACH • Approach according to the risk period after transplantation ■ Early period (i.e., before engraftment): HSV, CLABSI, and fungal infection ■ Middle period (i.e., early engraftment): CLABSI, adenovirus, CMV, pneumonitis, and toxoplasmosis ■ Late period: CLABSI, VZV, and hepatitis
MANAGEMENT AND PRESUMPTIVE THERAPY • Manage HSCT patients as for febrile neutropenic patients with cancer. • Begin antifungal therapy if fever continues ≥96 hours after commencement of antibiotic therapy. • Begin antiviral treatment when the diagnosis is made. PREVENTION • Antimicrobial prophylaxis is important to prevent certain infections (e.g., PCP, CMV). • Reimmunization is important because most recipients of HSCT lose prior immunity to vaccine-preventable diseases.
CLABSI, Central line–associated bloodstream infection; CMV, cytomegalovirus; HSCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; PCP, Pneumocystis pneumonia; PCR, polymerase chain reaction; VZV, varicella-zoster virus.
tetanus, rabies) in patients after HSCT are similar to those in otherwise healthy people. Passive immunization is recommended for susceptible people with known exposure to varicella (see Chapter 205). All references are available online at www.expertconsult.com.
KEY REFERENCES 3. Coppes MJ, Fry TJ, Mackall CL (eds). Hematopoietic stem cell transplantation. Pediatr Clin North Am 2010;57:1–342. 5. Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic stem cell transplantation. Curr Opin Hematol 2012;19:324–335. 6. Dykewicz CA, Jaffe HW, Kaplan JE, et al. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Morb Mortal Wkly Rep 2000;49(RR-10):1–128.
13. O’Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections. Pediatrics 2002;110:e51–e75. 46. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:427–431. 51. Lehrnbecher T, Phillips R, Alexander S, et al. Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol 2012;30:4427–4438. 63. Chemaly RF, Shah DP, Boeckh MJ. Management of respiratory viral infections in hematopoietic cell transplant recipients and patients with hematologic malignancies. Clin Infect Dis 2014;59:S344–S351. 67. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58:44–100. 69. Ljungman P, Engelhard D, de la Camara R, et al. Vaccination of stem cell transplant recipients: recommendations of the Infectious Diseases Working Party of the EBMT. Bone Marrow Transplant 2005;35:737–746.
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