Advances in supportive care continue to lead to improvements in hematopoietic stem cell transplant (HSCT) outcomes. The 1-year transplant-related mortality (TRM) rate for children with acute leukemia and unrelated donor HSCT performed before 1995 approached 40%. More recently, rates from 2003 to 2006 fell by more than half to approximately 15%, and the 3-year TRM rate continues to fall, from 27% in 2000–04 to 21% in 2005–09. Furthermore over the course of the past decade, utilization of umbilical cord blood units and haploidentical donors have become standard of care. This has led to significantly more alternative donor HSCTs performed for a wide variety of nonmalignant diseases, including T-cell and phagocyte primary immunodeficiencies, hemoglobinopathies, bone marrow failure syndromes, and metabolic syndromes. However, these children often have relatively intact immune systems at the time of HSCT and thus require increased pre-HSCT immunoablation to prevent graft rejection. This often leads to delays in post-HSCT immune reconstitution, which in turn is associated with significant opportunistic infections. In addition to causing significant morbidity and prolonged hospitalizations, opportunistic infections are directly responsible for 25% to 27% of transplant-related mortality following allogeneic HSCT.
Evidence indicates that certain opportunistic infections may play a role in the triggering of alloreactivity and graft-versus-host disease (GVHD). For example, animal models suggest that administration of probiotics may alter the intestinal microflora and decrease inflammation in mesenteric lymph nodes, thereby abrogating GVHD, and human studies have demonstrated that low intestinal microbial diversity at transplant is associated with poor survival, primarily due to the subsequent development of severe GVHD. A randomized trial of fluconazole versus placebo demonstrated less severe GVHD of the intestinal tract in the fluconazole recipients, possibly as a result of decreased intestinal antigenic stimulation. Some data suggest that both cytomegalovirus (CMV) and human herpesvirus–6 (HHV-6) reactivations can trigger the development of GVHD. Because GVHD is another significant component of transplant-related mortality following allogeneic HSCT, further understanding of the interplay between opportunistic infections and initiation of GVHD may provide another avenue toward making HSCT a safer procedure with improved overall outcomes.
Epidemiology
Although opportunistic infections do occur after autologous HSCT, the much more profound and ongoing T-cell dysfunction that occurs before and after allogeneic HSCT makes opportunistic infections far more likely to occur in this population. Multiple therapy-induced alterations of host defenses contribute to this risk. The three major contributors to the development of an opportunistic infection are (1) breakdown in natural barriers (e.g., indwelling central venous catheters and mucositis), (2) defects in cell-mediated immunity (e.g., lymphopenia from corticosteroids and other anti–T-cell cytotoxic agents), and (3) deficient numbers of phagocytes (e.g., as a result of myeloablative chemotherapy). Knowledge of the timing of the variety of infections that can occur after HSCT allows clinicians to develop rational approaches to antimicrobial prophylaxis, diagnostic monitoring for infections, and earlier treatment of proved infections. Classically three phases of risk for opportunistic infections occur after HSCT, as shown in Fig. 69.1 .
Phase I: Preengraftment (<30 Days)
Infections in phase I of HSCT are similar to those seen with other forms of profoundly myelosuppressive chemotherapy, and include gram-positive and gram-negative bacteremia, candidemia, invasive aspergillosis, and reactivation of herpes simplex virus contributing to oral mucositis. Administration of granulocyte-colony stimulating factor (G-CSF) during this period will shorten the time to recovery of neutrophils by several days and may decrease rates of documented infections. However, less evidence exists that G-CSF improves infection-related or transplant-related mortality, and it may increase the incidence of acute GVHD. Therefore only approximately 60% of HSCT centers use G-CSF routinely.
Phase II: Early Postengraftment (30 to 100 Days)
Some infections in phase II are caused by a combination of persistent defects in the function of the patients’ phagocytes (partly from the administration of corticosteroids to treat acute GVHD) and retention of central venous catheters, which can lead to gram-positive bacteremia and candidemia. Other infections are due to the ongoing relative and functional lymphopenia and involve reactivations of CMV and other double-stranded DNA (dsDNA) viruses, Pneumocystis jiroveci, or certain parasitic infections.
Phase III: Late Postengraftment (>100 Days)
Infections in phase III are generally caused by ongoing immunosuppressive therapy for the treatment of chronic GVHD, which also is associated with functional asplenia. Thus patients can develop infections with encapsulated bacteria, P. jiroveci, and dsDNA viruses. There is also an important second peak of invasive aspergillosis during this time.
Major Types of Opportunistic Infections After Hematopoietic Stem Cell Transplantation
Bacterial
Classic Gram-Positive and Gram-Negative Bacteria
Bacterial infections after HSCT most commonly divide into gram-positive organisms originating from the skin or gastrointestinal tract and gram-negative organisms translocating from the gastrointestinal tract. The period of highest risk for bacterial bloodstream infections, especially with enteric gram-negative rods, is the pre-engraftment period, during which the incidence of bacteremia can range from 21% to 34% and 21% to 58% for patients undergoing autologous and allogeneic HSCT, respectively, although some studies report no difference between the two groups. In HSCT recipients, bloodstream infections before engraftment are a significant independent predictor of mortality. Several studies have demonstrated that either host or donor polymorphisms in genes responsible for immunity may contribute to the risk for bacterial infections.
Given the significant risk for developing bacteremia, it is surprising that there is little evidence that routine antibacterial prophylaxis plays a role in pediatric HSCT recipients. In adult patients undergoing HSCT, general consensus exists regarding the utility of a prophylactic quinolone with antipseudomonal activity based on several small trials included in larger meta-analyses. The rates of fever and bacteremia are significantly reduced in patients receiving levofloxacin, but the impact of prophylaxis on mortality is less clear. Similar results have been reported using ciprofloxacin and vancomycin as a prophylactic regimen for autologous and allogeneic HSCT patients. Few of the trials stringently evaluated rates of quinolone resistance, although one recent retrospective report suggested it has not increased in the era of routine prophylaxis. All of these studies were done in adult patients; therefore caution must be used in applying the specific results to pediatric HSCT recipients. The Children’s Oncology Group (COG) recently completed a large randomized trial in pediatric HSCT recipients, the pending results of which may inform future practice.
Other approaches to antibacterial prophylaxis use nonsystemic treatments to potentially spare medication toxicities and the development of resistant organisms. Chlorhexidine gluconate is an antiseptic bactericidal to gram-positive and gram-negative bacteria, including multidrug resistant organisms. The mechanism of action involves bacterial membrane disruption; its onset is relatively rapid, and the effect is persistent. A 2% chlorhexidine gluconate (CHG)–impregnated cloth product has been shown to be effective at decreasing central-line associated infections and acquisition of multidrug-resistant organisms as a skin cleansing product in the critical care setting in both adults and children. However, the effectiveness of CHG bathing outside of the critical care setting is controversial, with only one study showing a possible benefit and another demonstrating increasing CHG-resistance. An ongoing randomized trial by the COG may provide insight on the effectiveness and safety of CHG bathing on bloodstream infections in children undergoing HSCT. Similarly, because many cases of bacteremia are seen in the setting of central venous catheters, the use of ethanol lock solutions may potentially decrease central venous catheter colonization without the concern of resistance from antibiotic locks. However, results from randomized trials in adults receiving chemotherapy or HSCT have been controversial, with one demonstrating the benefit of ethanol locks versus heparin and another showing no benefit. Studies of prophylactic ethanol locks in pediatric HSCT recipients are currently lacking.
When patients develop a fever early after transplant during the neutropenic period, empirical antibacterial treatment is usually started. Although a variety of different regimens exist, they are generally tailored to cover Streptococcus spp. and Staphylococcus spp., plus enteric gram-negative organisms, based on local susceptibility patterns. Recent consensus statements have favored monotherapy, with combination therapy reserved for clinically unstable patients, especially as additional reports suggest a role for anti-anaerobic antibiotics in decreasing intestinal diversity and subsequently altering immune reconstitution post-HSCT.
Clostridium difficile
Although hardly unique to the pediatric HSCT population, because of the widespread use of broad-spectrum antibiotics for empirical therapy of febrile neutropenia Clostridium difficile –associated diarrhea is not uncommon. In adults, approximately 10% to 15% of patients may develop this complication within 30 days of HSCT, although pediatric patients may behave differently, with later onset of disease. The disease tends to be relatively mild, but relapses are very common. Prevention of C. difficile may potentially be accomplished through the administration of certain strains of probiotics. A small pilot trial suggests that this practice may be safe in the immediate post-HSCT phase, even during the period when a combination of neutropenia and compromised intestinal integrity could theoretically lead to the development of bacteremia from the ingested strain, as long as the strain of probiotic is carefully considered. Treatment of C. difficile –associated diarrhea in the pediatric HSCT patient is similar to that of the general population, with metronidazole or oral vancomycin, although caution must be used during the conditioning phase of HSCT, when metronidazole can enhance toxicities from radiation or busulfan. Fidaxomicin is an attractive alternative due to lower rates of relapses (15% vs. 25%) and potentially improved sparing of the intestinal microbiota, which in turn may decrease incidence of severe GVHD. The experience with fecal microbiota transplant after HSCT is still very limited, so it is unclear at this time whether that will ultimately prove to be a safe option.
Encapsulated Organisms
Patients with chronic GVHD appear to have defects in their splenic function, and thus encapsulated bacteria, such as Streptococcus pneumoniae, have been noted to cause significant mortality. Prophylaxis with penicillin appears to diminish this risk, although the optimal duration of treatment is not yet defined. In patients with chronic GVHD (cGVHD), serum immunoglobulin G (IgG) levels should be monitored, and, for patients with levels of less than 400 mg/dL, administration of intravenous gammaglobulin should be considered. When to stop penicillin prophylaxis in relation to resolution of cGVHD is unknown because robust methods to measure splenic function, such as pitted red blood cell percentage and nonswitched memory B cells, have not been tested in a post-HSCT population.
Mycobacteria
Although less common than invasive fungal infections, infections with mycobacteria must always be considered in the differential diagnosis of pulmonary nodules after HSCT. In developed countries, classic Mycobacterium tuberculosis infections are very rare in children undergoing HSCT, although it always should be considered in patients whose households have recently immigrated. More commonly encountered are environmental atypical nontuberculous mycobacteria (NTM), which can cause infections in the lungs, skin, lymph nodes, and bloodstream. Because of the relative rarity of NTM infections, a general paucity of literature exists in the HSCT population. NTM infections have been reported to occur in as many as 9.7% of T-cell depleted and 7% of conventional allogeneic HSCTs in adults, although the mortality rate was low. Pediatric HSCT recipients have a somewhat lower rate of NTM infections (3.8%), which occur at a median of 115 days (range, 14 to 269 days) after HSCT, while a more recent report suggests an even lower incidence (0.2%).
The exact risk factors associated with the development of NTM infections after allogeneic HSCT are not well characterized. The protective immunity against NTM infections appears to be primarily driven by interferon-γ (IFN-γ) production by T cells, as evidenced by the high rate of NTM infections in patients with IFN-γ deficiency. Thus T-cell depletion (ex vivo or with T-cell–depleting antibodies) or treatment of GVHD with immunosuppressants that block IFN-γ might be expected to be risk factors for the development of NTM infections. Similarly patients with an underlying T-cell immunodeficiency might be colonized with an NTM organism pre-HSCT that puts them at risk for developing NTM disease after HSCT. The optimal treatment of NTM infections is not clear. A wide variety of traditional antibiotics and antituberculosis agents have some activity against NTM organisms, but reports vary on the number of agents that must be used in combination and the duration of optimal therapy. In patients with human immunodeficiency virus (HIV) infection, the general recommendation is to treat most cases of NTM infections for 12 months after establishment of negative cultures. It is not clear that such a prolonged duration is required for HSCT recipients who, in the absence of chronic GVHD, tend to have improvement in, and even normalization of, their T-cell function over time.
Fungal
Although bacteria represent the most common infection after HSCT, invasive fungal infections account for a significant amount of posttransplant mortality. Several retrospective reports on the development of invasive fungal infections in pediatric HSCT recipients have been published, with a 1-year incidence as high as 12% to 20% and a 58% to 83% mortality. The most commonly identified invasive fungal organisms after HSCT are Candida and Aspergillus spp. Patients who are considered to be at the highest risk for developing an invasive fungal infection after HSCT are those who undergo transplant from either an unrelated donor (including umbilical cord blood) or a partially matched related donor or for treatment of a malignancy, bone marrow failure syndrome, or congenital immunodeficiency, and those receiving high-dose corticosteroids.
Currently the use of antifungal prophylaxis is nearly universal in HSCT patients. Empirical therapy directed against resistant Candida or molds generally commences after approximately 72 hours of prolonged fevers despite administration of broad-spectrum antibacterials. One surprising feature to note from the original prophylactic fluconazole studies is that, even in the placebo arm, more than 80% of HSCT patients did not develop an invasive fungal infection, although these studies did include lower-risk autologous HSCT recipients. This suggests that other explanations must exist for the development of invasive fungal infection after HSCT. Researchers are now finding that either host or donor polymorphisms in genes responsible for immunity appear to play a significant role in invasive fungal infection risk. Most of these proposed genetic risk factors still require validation in a prospective multicenter cohort, but the future possibility of having different prophylactic strategies based on an a priori risk for developing an invasive fungal infection is promising.
Candida
Invasive candidiasis tends to occur during the neutropenic period immediately after HSCT, although later cases can occur in the setting of GVHD and prolonged immunosuppression, especially when central venous catheters are still in place. Typically invasive candidiasis originates from endogenous Candida spp. colonizing patients’ gastrointestinal tracts. Pediatric patients appear to have relatively more invasive infections caused by C. parapsilosis and fewer infections caused by C. glabrata, in contrast to adults. Two placebo-controlled trials from the early 1990s, performed in patients older than 12 years of age undergoing autologous or allogeneic HSCT, demonstrated that prophylactic administration of fluconazole significantly decreased invasive fungal infections. Long-term follow-up of allogeneic HSCT recipients given fluconazole prophylaxis supports a survival benefit (mortality 20% in the fluconazole arm vs. 35% in the placebo arm; P = .004), postulated to be at least partly due to less severe GVHD in the fluconazole recipients from decreased antigenic stimulation, which may be mediated by T H 17 polarization in response to components of the fungal cell wall. The classic duration of fluconazole prophylaxis administration is during the high-risk period until 75 days after HSCT. Because fluconazole does not cover C. krusei and has variable activity against C. glabrata, alternative agents should be considered for patients known to be colonized with these species. Reasonable options include extended-spectrum triazoles, echinocandins, and lipid-formulations of amphotericin B (LFAB), all of which also have some coverage against Aspergillus spp.
When patients develop invasive candidiasis after HSCT, the most common site of infection is the bloodstream. In addition to initiation of appropriate antifungal agents, the standard practice is to discontinue all central venous catheters in patients with candidemia. Less common, but more perplexing, disseminated Candida infections of the liver, spleen, or lungs can often be blood culture–negative and may require tissue biopsy to establish a diagnosis. Serum β-glucan levels may be useful for identifying cases of possible invasive candidiasis once the assay has been optimized for use in children. Furthermore in patients with disseminated candidiasis, a formal ophthalmologic evaluation is recommended to rule out Candida endophthalmitis, which may require intravitreal injection of antifungal agents to preserve vision. For treatment of invasive candidiasis, especially those cases that develop on fluconazole prophylaxis, the echinocandins are a class of antifungal agents that target β-(1,3)- d -glucan synthase and interrupt biosynthesis of the glucan polymers that make up fungal cell walls. Because mammalian cells do not possess cell walls, echinocandin administration to human patients has generally resulted in limited toxicity. Echinocandins possess fungicidal activity against most Candida spp.; however, C. paraspiliosis may be less sensitive. In some settings, the echinocandins may be superior to fluconazole or amphotericin B for treatment of invasive candidiasis.
Aspergillus
In adult HSCT recipients, Aspergillus spp. time of infection has a bimodal distribution, with a first peak at a median of 16 days and the second at a median of 96 days after allogeneic HSCT. This second peak may be less pronounced in children. Invasive aspergillosis can be one of the most devastating infections to occur after allogeneic HSCT. In a multivariate analysis of risk factors for mortality among a modern cohort of pediatric patients with invasive aspergillosis, the major risk factor for death was the development of invasive aspergillosis after an allogeneic HSCT. Although treatment options for invasive aspergillosis have increased in recent years, significant attention also has been paid to preventing invasive aspergillosis infections. Although fluconazole prophylaxis has been shown to reduce the risk for invasive fungal infection relative to placebo, fluconazole lacks activity against Aspergillus spp. Given this lack of antimold activity, several trials have compared fluconazole to mold-active agents in hopes of decreasing rates of invasive aspergillosis. The first of these trials compared fluconazole to low-dose conventional deoxycholate amphotericin B (D-AMB). However, D-AMB did not show improvement over fluconazole and resulted in a higher adverse event rate. Several trials, including one in children, have evaluated the LFAB (often given only three times per week) for antifungal prophylaxis in HSCT and acute leukemia patients. However, like D-AMB, LFAB has not been shown superior to fluconazole in overall success and typically demonstrates increased side effects.
Extended-spectrum triazoles such as itraconazole, voriconazole, and posaconazole do possess anti- Aspergillus activity ; however, clear limitations exist to each as a potential prophylactic agent. Several trials of itraconazole versus fluconazole have been performed, and a meta-analysis showed significantly less invasive fungal infections, but because of its common gastrointestinal side effects, greater drug interactions, and poor tolerability, itraconazole prophylaxis has generally been abandoned in children. The results of a multicenter, double-blinded trial showed that voriconazole was not superior to fluconazole in the prevention of invasive fungal infection, although the safety profile was similar. Given voriconazole’s broader spectrum of activity, this result was surprising but may have been due to an incomplete understanding of the complex pharmacokinetics of voriconazole. In adults and children over the age of 12 years, voriconazole has nonlinear pharmacokinetics with relatively well-established dosing regimens. Even in adults, however, recent studies have questioned standard dosing regimens and have proposed dosing based on serum drug levels, with an optimal goal serum voriconazole level of 1 to 5.5 µg/L. Part of this variability may be due to allelic polymorphisms of the gene encoding for cytochrome (CYP)2C19, which can result in an increase or decrease in voriconazole metabolism, and basing dosing on CYP2C19 genotype can improve the number of patients in the target range. In children, the situation is further complicated by linear voriconazole kinetics, so that younger children may need significantly higher dosages of voriconazole. Voriconazole also has significant drug interactions with commonly used agents in a pediatric HSCT population. Voriconazole is a substrate of CYP2CP (major), 2C19 (major), and 3A4 (minor) and an inhibitor of 2C9 (moderate), 2C19 (weak), and 3A4 (moderate). Proton pump inhibitors increase voriconazole levels, while voriconazole increases serum levels and toxicity of corticosteroids, imatinib, and many other medications. The approved voriconazole label reports that concomitant use of voriconazole can cause a 1.7- to 3-fold increase in cyclosporine or tacrolimus levels and recommends that the dosing of cyclosporine be decreased by 50% and the dosing of tacrolimus be decreased by 66% of the normal dose. Furthermore the use of voriconazole with sirolimus is officially contraindicated, and when its use has been reported, investigators have recommended dropping the levels of sirolimus by 90% of original dosing at the time of initiation of voriconazole. Finally extended use of voriconazole has been linked to fluoride-induced periostitis and severe phototoxicity, including development of nonmelanoma skin cancers.
Posaconazole is a triazole with broad coverage of most fungi, including mucormycosis (previously called zygomycosis). In a trial of adult patients with neutropenia, posaconazole prophylaxis was superior to fluconazole or itraconazole but was also associated with an increased risk for serious adverse events. In a trial of teenagers and adults receiving treatment for acute or chronic GVHD, posaconazole was superior to fluconazole at preventing breakthrough and death from invasive fungal infection, with similar rates of toxicity. Unfortunately this did not translate to improved overall survival. Posaconazole also shares many of the same enzymatic pathways—and therefore drug interactions—as voriconazole, albeit without the bone and skin toxicities.
Isavuconazole is the newest triazole and, like posaconazole, has broad coverage of invasive fungi. A phase 3 trial for treatment of invasive molds demonstrated noninferiority to voriconazole and lower rates of toxicities, including hepatotoxicity, visual disorders, and skin disorders. It has also been used successfully as prophylaxis in neutropenic adult patients with acute myeloid leukemia (AML) in a phase II trial. It has excellent bioavailability regardless of food intake and is also available intravenously, with early suggestions that therapeutic drug level monitoring may not be required. However, it still has moderate inhibition of CYP3A4, and modifications of GVHD prophylaxis agents will be required. Finally pediatric experience and dosing information is currently extremely limited. Because of the CYP interactions, azole prophylaxis when used is generally started after the conditioning regimen is complete. For patients who enter the HSCT period being treated for a preexisting invasive fungal infection, discontinuation of azoles 72 hours before the start of conditioning chemotherapy is often done to allow the CYP enzymes to return to baseline function, although some data suggest that fluconazole coadministration may actually help with cyclophosphamide metabolism and decrease toxicity.
Echinocandins possess fungistatic activity against Aspergillus spp. In a prophylactic antifungal trial, micafungin demonstrated reduced need for empirical antifungal therapy and an improved safety profile in contrast to fluconazole. However, the number of pediatric subjects enrolled was small ( n = 84), and a reduction in the incidence of proved or probable invasive fungal infection was not demonstrated. The lack of impact on invasive fungal infection may have been because the incidence of breakthrough invasive fungal infections in both groups was very low, likely as a result of the inclusion of low-risk patients (46% autologous HSCT recipients) and very few patients undergoing umbilical cord blood transplant ( n = 30). Caspofungin has been shown to be at least equivalent to itraconazole in the setting of antifungal prophylaxis, with few caspofungin-related adverse events. The COG is conducting a large multicenter prospective trial in the pediatric HSCT population in North America. The major disadvantages to widespread echinocandin use are cost and the lack of an oral formulation.
If prophylaxis fails, the typical locations where invasive aspergillosis develops after an allogeneic HSCT are the lungs and sinuses, with not uncommon seeding of the brain. It should be noted that children do not always display the classic radiographic findings seen in adults with invasive aspergillosis, such as the air crescent or halo signs, and a high index of suspicion must be maintained. Much attention has been focused on developing noninvasive tests for diagnosing invasive aspergillosis. Galactomannan is a polysaccharide cell-wall component released by Aspergillus during growth. The Platelia EIA Aspergillus galactomannan assay was approved by the U.S. Food and Drug Administration in 2003 for use in adult patients and, in 2006, in children. Early large-scale clinical testing included few children, but available data suggest that detection values for adult patients can be extrapolated to children. Serum β- d -glucan (found in all fungi except Cryptococcus spp. and mucormycosis) can be detected using an approved diagnostic serum assay and has been found to have high specificity and high positive predictive values for the detection of invasive fungal infection in adults. However, data on the performance of this assay in children are limited, especially in the post-HSCT setting. Ultimately obtaining cultures through bronchial alveolar washings or biopsy is the best way to be certain of what organism is being treated. Speciation of the Aspergillus is also important if polyene therapy is planned because of the intrinsic resistance of Aspergillus terreus to amphotericin B.
Based on a pivotal trial performed in teenagers and adults, voriconazole has become the standard therapy for patients with invasive aspergillosis, although the recent success of the apparently less toxic and erratic isavuconazole may alter this approach. Because of the high mortality rate of invasive aspergillosis in post-HSCT patients, there has been great enthusiasm for potentially synergistic combination therapies, such as with a triazole and an echinocandin, and a prospective trial suggested that this combination was safe and more effective than a triazole alone in some specific patients with proven infections. If amenable to a surgical approach, strong consideration should be made for resection of cases of invasive aspergillosis, which has been shown to improve mortality if disease is precariously located near a major vessel. During the neutropenic period in patients who develop invasive aspergillosis, transfusions of irradiated random donor granulocytes have been proposed as a method to improve outcomes, although conclusive proof that this laborious procedure is beneficial is lacking, although a recent trial suggested some benefit if the infused cell doses were high. Finally exciting work has demonstrated the importance of adaptive immunity to fighting invasive aspergillosis. Based on this, work has been done on creating Aspergillus -specific T cells for use in adoptive immunotherapy. It has been demonstrated that a cohort of patients who developed invasive aspergillosis after haploidentical HSCT and who received Aspergillus -specific T cells had significantly better resolution of the infection than a similar cohort not given the specific T cells.
Rare Fungi
Less frequently, infections occur with the agents of mucormycosis ( Mucor, Rhizopus, and Absidia spp.), Trichosporon spp., Fusarium spp., and other saprophytic fungi. For these rare fungi, the key is to obtain culture identification, by biopsy if necessary, so that the optimal antifungal agent may be initiated. Posaconazole is a triazole with broad coverage of most fungi, including mucormycoses and thus may be the optimal treatment for many of these organisms despite all of the caveats mentioned earlier regarding this agent. The newer agent isavuconazole also has activity against mucormycosis. Recent work has demonstrated that Mucorales-specific T cells are generated after an infection with these organisms and thus might be useful as a diagnostic marker, but also suggested that generation of similar cells for treatment of Mucorales infections may one day be possible.
Pneumocystis jiroveci
Previously referred to as Pneumocystis carinii, Pneumocystis jiroveci refers to the distinct species that infects humans. The abbreviation PCP (or now PJP) is often used to refer to pneumocystic pneumonia. PJP reactivations or infections are generally thought to be preventable after HSCT with administration of prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX). However, in the setting of alternative prophylaxis agents or TMP-SMX noncompliance, episodes of PJP may rarely occur beginning about 2 months after HSCT and continuing through recovery of T-cell functional immunity and is associated with increased mortality.
TMP acts by interference with the bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid and thus nucleic acid synthesis. Because of concerns about bone marrow toxicity, TMP-SMX is often held for several weeks after HSCT until evidence of neutrophil recovery, although this practice has been challenged. The necessary amount of TMP-SMX required to prevent PJP has not been well studied, and a variety of dosing regimens exist, with administration 2 or 3 days per week being the most common. Generally TMP-SMX is continued for at least 6 months after an allogeneic HSCT, although this should be lengthened for patients receiving ongoing immunosuppressive therapy. In addition to possible bone marrow suppression, many patients have allergic or other reactions to TMP-SMX that induce clinicians to prematurely discontinue its use. However, the optimal second-line prophylactic agent is not well defined, and all options may be potentially less effective than TMP-SMX. Options that have been used include oral dapsone, intravenous or inhaled pentamidine, and oral atovaquone. Dapsone is inexpensive but has a high incidence of adverse events, especially in patients with glucose-6-phosphate deficiency. Intravenous pentamidine given every 4 weeks also has been used, although inadequate protection has been noted in children under 2 years of age and those undergoing HSCT, who may need more frequent dosing. Aerosolized pentamidine is generally well tolerated, other than occasional bronchospasm, but its effectiveness has been questioned. Atovaquone is generally well tolerated, but absorption can be limited in patients not eating diets containing fatty foods. In vitro, the echinocandin class of antifungal agents appear to have some activity against the cyst form of P. jiroveci . To date, no studies have evaluated the use of echinocandins as a solitary prophylaxis agent; however, a few case reports have described its potential utility in combination with TMP-SMX for the treatment of PJP.
PJP must be suspected in HSCT patients presenting with hypoxemia (often disproportionally more severe than the degree of hypercapnia), dyspnea, cough, fever, and bilateral infiltrates, especially if noncompliance is suspected or alternative prophylaxis agents have been used. Although it is highly sensitive in patients with HIV infection, measuring the serum lactate dehydrogenase level is less useful in other immunocompromised patients because of low levels of sensitivity and specificity. Serum β- d -glucan levels could potentially be very useful for identifying cases of PJP once the assay has been optimized for use in children. Until then, the definitive diagnosis of PJP still requires identification of the organism on special stains or polymerase chain reaction (PCR) of induced sputum or bronchoalveolar lavage fluid. Once PJP is identified, the treatment of choice is high-dose TMP-SMX (15 to 20 mg TMP/kg per day divided every 6 hours). This high-dose TMP-SMX may be difficult to administer to a patient recovering from HSCT with marginal bone marrow reserves. Therefore some physicians have used folinic acid “rescue,” analogous to what is used after methotrexate administration, with the hypothesis that bacteria are unable to take up the folinic acid from the environment and thus only the host bone marrow cells are helped. Although no data exist in children undergoing HSCT, caution should be used with this approach because it has been associated with increased treatment failures in patients with HIV infection. Although counterintuitive in a patient with poor T-cell function, TMP-SMX has been combined with a short course of corticosteroids, which appears to be beneficial in preventing temporary worsening of hypoxemia resulting from inflammation caused by dying organisms. The recommended dose is prednisone 1 mg/kg per dose twice daily (maximum 40 mg twice daily) (or the equivalent dose of methylprednisolone) tapered in half after 5 days and then again in another 5 days, then discontinued after 21 days. It should be noted that these data derive solely from the HIV literature in adults, and it is unclear whether this approach is safe or beneficial in pediatric HSCT patients.
Viral
Viral infections after pediatric HSCT can be divided into two broad categories: DNA viruses that occur as a result of reactivation of a previous infection (and occasionally as a de novo infection) and community-acquired respiratory as well as enteric viruses. Other than donor and recipient serostatus, the major risk factor for reactivation of a dsDNA viral infection after HSCT is the use of T-cell depletion, either ex vivo or in vivo with serotherapy. Recently a few polymorphisms in host immune response genes also have been shown to possibly contribute to the development of dsDNA viral infections after HSCT.
Herpes Family Viruses
Herpes simplex virus.
Herpes simplex virus–1 (HSV-1) and HSV-2 infections after HSCT usually occur as a result of reactivations from a previously acquired latent virus. Thus, pretransplant serologies are very useful in identifying at-risk patients. Because acquisition of HSV occurs as patients age, many pediatric HSCT recipients will be seronegative. In the era before routine prophylaxis of seropositive patients, reactivation rates were approximately 70% to 80% and significantly contributed to post-HSCT mucositis. Dissemination of HSV to the lungs, liver, or brain is also possible. Routine acyclovir prophylaxis is usually given during the period of mucositis, and, with this, HSV reactivations are relatively rare and screening of serum by PCR is likely of little benefit. However, severely immunocompromised individuals can continue to develop reactivations for many months after HSCT, and thus some centers will continue prophylaxis for up to 6 months, a typical period for development of T-cell reconstitution in the absence of GVHD. This is not needed for patients who receive ganciclovir for CMV prophylaxis because ganciclovir also has activity against HSV. In addition, some strains of HSV have become acyclovir-resistant, and thus patients with mucositis more severe than anticipated should have a lesion swabbed for HSV culture and resistant strains treated with either foscarnet or cidofovir.
Routine acyclovir prophylaxis does not appear to have a role in HSV-seronegative patients, although consideration of varicella zoster virus (VZV) serostatus also must be taken into account. Furthermore patients with B-cell immunodeficiencies may be unable to mount an antibody response before HSV infection and should be considered for prophylaxis, especially if close contacts such as the parents or siblings have a history of HSV infections.
Cytomegalovirus.
Historically one of the most severe complications of allogeneic HSCT was CMV infection. In the modern era, the use of PCR-based detection strategies has significantly reduced the incidence of CMV disease. More than 50% of healthy adults in the United States are CMV seropositive, and the incidence increases with age, with 36% of children 6 to 11 years of age already exposed. With the use of CMV-negative blood products, the rate of de novo infection in CMV-seronegative donor and recipient (D − R − ) pairs after HSCT is as low as 2%. Thus most infections occur as a result of reactivations, likely of host CMV, because infections are much less common in donor-positive, recipient-negative (D + R − ) transplants than in those in which the recipient is positive (D + R + or D − R + ). Other factors can alter the risk for reactivation in a CMV-seropositive HSCT recipient. Data are conflicting on whether CMV-seropositive donors should be chosen for CMV-seropositive recipients in regard to decreasing mortality, although it does appear to result in lower rates of CMV reactivation and disease. After autologous HSCT, CMV reactivations are not uncommon, but CMV disease is rare except in the setting of CD34 selection. T-cell depletion of donor cells in the allogeneic HSCT setting is a major risk factor for reactivation, which may occur even before neutrophil engraftment. GVHD and its treatment with corticosteroids, and poor T-cell reconstitution even in the absence of GVHD, are major risk factors for CMV reactivation. Of interest, even in the absence of serotherapy, the choice of GVHD prophylaxis regimen may alter the risk for CMV reactivation. Sirolimus, an inhibitor of mammalian (or mechanistic) target of rapamycin (mTOR), appears to provide a protective effect against CMV when used in combination with tacrolimus and in place of other agents. It remains to be determined if this effect is due to direct inhibition of CMV viral replication from sirolimus or enhanced reconstitution of anti-CMV immunity. Overall as many as 65% of seropositive allogeneic HSCT recipients will develop CMV reactivation if not given specific prophylaxis.
Several agents have been used for CMV prophylaxis in at-risk patients (D−R− patients are typically excluded). Because acyclovir has some in vitro activity against CMV, high-dose acyclovir (500 mg/m 2 per dose three times daily) has been shown to prevent CMV. Because of its improved absorption, valacyclovir may be superior to high-dose acyclovir for the long-term prevention of CMV reactivation. Ganciclovir is the most commonly used CMV prophylactic agent. As a result of its marrow-suppressive qualities, it is typically started after neutrophil engraftment, although some have suggested a role for a therapeutic window during the pre-HSCT conditioning. In addition, ganciclovir use may partially inhibit recovery of both normal and CMV-specific T-cell function. Other agents, including brincidofovir and letermovir, have had promising results as CMV prophylaxis in phase II studies; however, randomized phase III results are not yet available. In patients at high risk for early CMV reactivation before neutrophil recovery, foscarnet has been used because of its lack of significant marrow suppression, although it does have significant renal toxicity. If prophylaxis is to be used, it is typically continued for 100 days after HSCT, but longer courses may be indicated for patients with significantly impaired immune systems. All of these prophylactic strategies are generally used in combination with screening for reactivation by serum PCR. An argument against CMV prophylaxis, at least in certain patient populations, is that CMV reactivation has been shown to be protective against relapse in patients with AML undergoing myeloablative conditioning, possibly from stimulating a graft-versus-leukemia effect. However, due to the increased risk of TRM associated with the CMV itself, this benefit does not produce any difference in overall survival. Because all of the anti-CMV agents have some degree of toxicity, the alternative strategy to prophylaxis is preemptive treatment based on detection of CMV viremia. A randomized trial comparing prophylaxis versus preemptive management of CMV showed similar outcomes. Patients are screened at least once weekly for CMV DNA and specific antiviral therapy begun once a threshold amount of virus has been detected. Ganciclovir is the most common first-line agent used, although foscarnet can be considered in patients with poor marrow reserve. Even in patients with good marrow function, ganciclovir can cause neutropenia, and its use requires monitoring of neutrophil counts and often support with G-CSF. Typically ganciclovir is given twice daily for a minimum of 2 weeks, or longer for patients whose viremia is still detectable after 2 weeks. Daily maintenance ganciclovir therapy also has been used in patients at high risk for a second reactivation because of poor immune recovery. The duration of maintenance therapy can vary from 4 weeks after the first negative PCR result or up to day 100. Oral valganciclovir has become more widely used for preemptive therapy, either as a first-line agent or to replace intravenous ganciclovir at the time of switching to maintenance therapy. Early in the treatment course, CMV viral loads may rise, but in antiviral-naïve patients this is typically not a sign of resistance. However, continuing increases in viral loads after 2 weeks of therapy or signs of CMV disease should raise suspicion for a resistant strain of CMV. Mutations in the CMV UL97 phosphotransferase gene typically cause resistance only to ganciclovir, so foscarnet and cidofovir remain alternative agents. Mutations in the UL54 viral DNA polymerase will cause resistance to ganciclovir, and cidofovir, and, occasionally, foscarnet. For the patient who appears be to failing or intolerant of all three drugs, leflunomide is a third-line alternative. Leflunomide is an immunomodulatory agent that inhibits pyrimidine synthesis and results in both antiproliferative and antiinflammatory effects. The active metabolite appears to inhibit replication of both CMV and human polyomavirus type I, commonly referred to as BK virus.
The role of CMV-specific antibodies, either in conventional gammaglobulin products or high-titer products, is of debatable efficacy. On the other hand, efforts to produce donor-derived CMV-specific T cells have shown great promise in treating CMV disease. Given the low rates of GVHD associated with these cells, they may be an upcoming preventive strategy. Furthermore the techniques that enable generation of CMV-specific T cells also can be used to generate T cells active against Epstein-Barr virus (EBV) and adenoviruses, as well as potentially HHV-6, BK virus, and others. These multivirus-specific cells represent an exciting avenue of adoptive immunotherapy in severely immunocompromised post-HSCT patients, although they are not yet available outside of single-center research protocols.
Epstein-barr virus.
EBV infection after HSCT usually results from the reactivation of latent EBV in either residual host B cells or passively transferred donor B cells. As with other herpes family viruses, pre-HSCT serologies can help identify at-risk patients; however, because approximately 95% of adults are seropositive, virtually all patients undergoing adult unrelated-donor HSCT are potentially susceptible. Unlike other herpes family viruses, no clearly effective antiviral agent exists against EBV and thus no post-HSCT prophylaxis strategy exists. Fortunately the rate of EBV reactivation in patients receiving T-replete grafts is quite low. Conversely patients who receive ex vivo T-cell–depleted stem cells, anti–T-cell serotherapy, and umbilical cord blood grafts have an elevated risk. EBV reactivation can lead to the development of posttransplant lymphoproliferative disease (PTLD), signs and symptoms of which can include fever, lymphadenopathy, fulminate sepsis, or mass lesions in lymph nodes, spleen, or central nervous system. Several histologic subtypes exist, and all generally occur within the first 3 to 6 months of the posttransplant period. The first step to be undertaken once an EBV infection is suspected is to reduce immunosuppression when possible. If that fails, because EBV proliferates primarily within B cells, administration of rituximab often is successful at eliminating the infection. Copy numbers of EBV in the blood can be easily monitored after HSCT by PCR (although rare cases of PTLD without EBV viremia have been noted), and routine monitoring of high-risk patients is recommended. Less clear, however, is exactly what threshold level should be used for initiation of preemptive therapy because some patients will have transient self-limited EBV viremia after HSCT. Nevertheless evidence suggests that preemptive rituximab for treatment of EBV viremia is more effective than initiation once PTLD is established, and mortality of PTLD in HSCT recipients is low. Some groups have established methods for enriching for EBV-cytotoxic T lymphocytes, which can both prevent and treat EBV PTLD in high-risk patients with little risk for causing GVHD. For centers without access to specific donor T cells, the fact that most donors are EBV seropositive allows the use of unmanipulated donor lymphocyte infusion, which is often effective, albeit with a high risk for inducing GVHD.
Varicella zoster virus.
With the advent of routine vaccination against VZV at 1 year of age, the majority of immunocompetent patients entering HSCT are seropositive for VZV. In the absence of prophylaxis, reactivations occur in approximately 30% of patients after HSCT regardless of whether myeloablative or reduced intensity conditioning is used. A double-blinded trial of acyclovir prophylaxis given for 1 year after HSCT demonstrated a significant reduction in VZV reactivations, although this duration of treatment was inadequate in patients who continued on immunosuppressive therapy for treatment of chronic GVHD. An unresolved question is whether pediatric HSCT recipients who are VZV seropositive before HSCT as a result of prior live-attenuated vaccination, rather than exposure to wild-type VZV, are at a high enough risk for reactivation to warrant long-term prophylaxis. Several case reports suggest that the live-attenuated strain is capable of causing zoster and even disseminated disease in immunocompromised children. Therefore, until new data are available, the recommendation for acyclovir prophylaxis should be applied to all VZV-seropositive patients.
For post-HSCT patients who are exposed to an individual with active wild-type VZV infection (including shingles) and are not receiving prophylactic acyclovir or intravenous immunoglobulin (IVIG), passive immunization with varicella zoster immunoglobulin should be initiated within 96 hours of exposure. There does not appear to be a significant rate of transmission of live-attenuated vaccine strain VZV to immunocompromised individuals, and thus household contacts of HSCT recipients are allowed to receive the vaccine, although optimally it should be given before the HSCT when possible.
According to the 2011 Centers for Disease Control and Prevention (CDC) recommendations, patients who underwent HSCT may be vaccinated with the live-attenuated strains of VZV on a case-by-case basis after a minimum of 24 months post-HSCT. This may place patients at risk for developing a potentially serious infection during the gap period. However, two reports have since demonstrated the safety and seroconversion rates of the live-attenuated VZV vaccine when given to this patient population after first demonstrating adequate T-cell immune reconstitution.
Human herpesvirus–6.
HHV-6 is a ubiquitous pathogen that has infected the majority of people by the age of 2 years and has been reported to reactivate in approximately 50% of HSCT recipients according to PCR-based monitoring. The majority of these episodes of viremia appear to be self-limited and asymptomatic, significantly limiting recommendations regarding preemptive therapy. However, a variety of reports have linked HHV-6 reactivations to post-HSCT fevers, rashes, hepatitis, pneumonia, and delayed engraftment, as well as to increased TRM and poorer overall survival, although not all reports agree that HHV-6 is a major issue: thus universal PCR screening is controverial. HHV-6 also appears to be a rare cause of post-HSCT encephalitis, typically manifested as memory loss, seizures, hyponatremia, cerebrospinal fluid pleocytosis, and magnetic resonance imaging (MRI) abnormalities in the mesial temporal lobe. Patients manifesting these symptoms should have their cerebrospinal fluid examined for HHV-6 by PCR. HHV-6 replication has also been implicated in the initiation of GVHD. When HHV-6–associated disease is diagnosed, ganciclovir is typically the first-line agent, although both foscarnet and cidofovir also have activity against HHV-6. If the HHV-6 viremia does not appear to be resolving with antiviral treatment, the possibility of chromosomally integrated virus must be considered. This can be determined by paired serum and whole blood PCRs demonstrating that the copy numbers in the whole blood sample are significantly higher and the serum copy numbers are generally very low.
Other Double-Stranded DNA Viruses
Adenovirus.
A large number of serotypes of adenovirus have been implicated in causing human disease, and, by the age of 5 years, most individuals have been exposed to at least one serotype, thereby allowing latent virus to enter the system. Thereafter reactivation during a period of intense immunosuppression results in the majority of cases of adenoviral viremia after HSCT. The major risk factor for adenoviral reactivation is the degree of immunosuppression experienced by the patient, especially among recipients of T-cell–depleted grafts or grafts from unrelated donors and those being treated for GVHD. Of interest, for reasons that are not entirely clear, younger age also appears to be a risk factor.
With the advent of PCR-based testing of blood and other body fluids, it has been demonstrated that adenoviral reactivations occur in approximately 27% to 32% of pediatric HSCT recipients. Because of this high incidence, many centers perform routine screening of blood by PCR for early detection of adenoviral reactivations in high-risk patients. When adenovirus viremia progresses to invasive disease, manifestations include pneumonia, hepatitis, enteritis, cystitis, and nephritis. Adenoviral disease after HSCT has been associated with mortality rates as high as 78%. The only currently available agent for treatment of adenoviral viremia or disease is intravenous cidofovir, typically given on a schedule of three times per week. However, intravenous cidofovir has potentially significant toxicities to both the kidneys and bone marrow. This makes its use as a preemptive agent problematic, especially when some patients appear to spontaneously clear the viremia without treatment. An oral liposomal formulation of cidofovir (brincidofovir) may potentially be less toxic than the intravenous formulation and may serve as a preemptive agent if FDA approved. Furthermore, because the major risk factor for the development of adenoviral infection is profound immunosuppression, rapid tapering or withdrawal of immunosuppression, when possible, may potentially play a role in the treatment. For patients who develop adenoviral infection after T-cell–depleted HSCT, researchers are also working on developing adenovirus-specific T cells for adoptive immunotherapy, either alone or in combination with specificity for other viruses.
Human polyomavirus type I.
Human polyomavirus type I, typically referred to as BK virus, is a common asymptomatic infection in adults, 90% of whom are seropositive. Like other dsDNA viruses, it can reactivate during periods of intense immunosuppression, and between 50% and 80% of HSCT recipients will be found to shed BKV in their urine in the first several months after HSCT. Much of the time, this viruria is asymptomatic, but BK virus reactivation can be associated with the development of hemorrhagic cystitis (HC) in approximately 5% to 15% of HSCT recipients, typically 3 to 6 weeks after HSCT. The patients at highest risk for developing BK virus–associated HC appear to be those who received cyclophosphamide-based conditioning regimens and T-cell–depleted grafts. Furthermore BK virus can be found in the blood of some patients after HSCT, and high levels have been associated with the development of BK virus–associated nephropathy, which can be definitively diagnosed only by renal biopsy. Of interest, fluoroquinolone antibiotics inhibit BK viral replication in vitro, and some data suggest that their use as antibacterial prophylaxis after HSCT also may decrease rates of BK virus–associated HC. Decreasing immunosuppression, whenever possible, is the first step toward treating BK virus disease. If the BK virus disease persists, cidofovir is the most commonly used antiviral agent, although leflunomide also appears to have some efficacy and may potentially be better tolerated than cidofovir in patients with significant renal dysfunction. If approved, brincidofovir may be an attractive option for patients with severe BK virus infections. Finally, T cells with BK virus specificity, among others, are also being generated for eventual clinical usage.
Respiratory Viruses
In pediatric HSCT recipients, respiratory viral infections as a whole play a significant role in TRM, especially in patients with low lymphocyte counts and/or high doses of corticosteroids. They have also been reported to be associated with later development of alloreactive lung injury. As such, it has been advocated that patients should undergo, at minimum, testing for respiratory viruses pre-HSCT and delay in HSCT whenever possible and possibly even pre-HSCT detailed pulmonary screening with high-resolution CT scan and bronchoalveolar lavage (BAL).
Influenza.
During seasonal outbreaks (typically October to March in the northern hemisphere), HSCT recipients are at risk for developing influenza infections from close contacts. Although upper respiratory tract symptoms are common, systemic symptoms such as fever or myalgias may be absent. Thus a high index of suspicion must be maintained during the peak season, because 20% to 50% of influenza infections can rapidly progress to lower respiratory tract disease with hypoxemia and a risk for mechanical ventilation and death. Bronchoalveolar lavage (BAL) may be needed in patients with evidence of lower respiratory tract symptoms because highly immunosuppressed patients are at risk for harboring multiple pathogens. Early preemptive treatment with neuraminidase inhibitors (the choice depending on that year’s circulating strain) appears to be relatively efficacious at preventing progress to lower respiratory tract disease. Although the data are limited, combination regimens have been employed for patients with resistant strains or with respiratory failure. Peramivir is an available parenteral agent in the United States, and zanamivir is undergoing investigation or is available through emergency use authorization. The use of moderate dosages of corticosteroids to reduce excessive inflammation is controversial but does not appear to result in worse outcomes. There are limited data on whether other forms of immunosuppression should be lowered.
Prevention strategies for influenza center around strict infection control practices, including hand-washing, isolation, and eliminating potential exposures via universal vaccination of health care workers, patient family members, and caregivers. If a recent (<2 years or still immunocompromised) HSCT recipient has a significant exposure to a confirmed case of influenza, prophylactic administration of a neuraminidase inhibitor is recommended. This strategy also could be considered if a nosocomial outbreak was to occur on a HSCT unit.
Vaccination of HSCT recipients (with the inactivated strain) is highly recommended to occur for several years beginning at 6 months after HSCT, before which time the majority of adult patients are unlikely to mount a serologic response. Higher doses may be required to produce significant immunogenicity. However, pediatric data are limited, and a fixed 6-month rule fails to take into account the significant variation in immunologic recovery times that occurs among patients depending on stem cell source and presence of GVHD. It is not unreasonable to allow earlier vaccination for patients on tapering doses of immunosuppression, even without documented B-cell function, because a T-cell response to influenza vaccine also may provide some protection. Finally efforts are under way to create influenza-specific T cells that can be given in a prophylactic fashion following HSCT.
Respiratory syncytial virus.
During seasonal outbreaks, upper respiratory tract infections from the RNA virus respiratory syncytial virus (RSV) are common in HSCT recipients. Approximately 50% of those infected will progress to involve the lower respiratory tract, especially in those with GVHD or severe lymphopenia. A novel “immunodeficiency” scoring system can potentially be used to determine those patients at highest risk of progressing in the absence of therapy, while lower risk patients might spontaneously resolve. Untreated RSV pneumonia in HSCT recipients has a mortality rate as high as 75% to 80%. Ribavirin, a guanosine analog, is available in aerosolized form for the treatment of RSV. Several potential regimens exist, including a continuous 18-hour infusion and a 2- to 3-hour infusion given three times per day. Because of concerns about potential teratogenicity, it is usually administered in a scavenging tent. Respiratory side effects from inhaled ribavirin are common and include potential bronchoconstriction. Despite its problems and costs, a comprehensive review of inhaled ribavirin treatment in adult HSCT recipients suggests that initiation of ribavirin at the time of diagnosis of RSV upper respiratory tract infection can significantly decrease the risk for progression to lower respiratory tract disease and, in those with lower respiratory tract disease, can decrease the risk for death. Antiviral therapy has the strongest effect in those with high-risk immunodeficiency scores, where RSV-associated mortality can potentially be lowered from 63% to 8%. An oral formulation of ribavirin (used for treating hepatitis C) and an intravenous formulation (not available in the United States) have also been used for treating RSV. Newer data suggest that this formulation may as also be effective at preventing RSV-associated death, albeit with the risk of systemic side effects such as hemolytic anemia, lactic acidosis, and altered mental status.
Palivizumab, an RSV-specific monoclonal antibody, is effective at preventing RSV infections in very young high-risk children. Another potential immunomodulator is IVIG, which often contains anti-RSV antibodies and may decrease RSV-mediated cytokine-induced pulmonary inflammation. A review of the available studies of immunomodulation plus inhaled ribavirin suggests that the combination may be superior at preventing progression to lower respiratory tract disease and RSV-related death than inhaled ribavirin alone. However, because of the small numbers, the report was unable to separate out those who specifically received palivizumab. Once lower respiratory tract disease is established, palivizumab has not been shown to improve outcomes. As a result of the lack of any controlled trial, the use of the expensive palivizumab has been questioned. Even more controversial is the prophylactic use of palivizumab. Fortunately the incidence of RSV infection in the first 100 days after HSCT is still relatively low at 5.8%. However, based on decision tree analysis in children undergoing HSCT, it has been estimated that the use of prophylactic palivizumab may increase the absolute survival rate from 83% to 92%, suggesting that 12 children would need to be treated to prevent one RSV-related death. Clinical confirmation of this concept is lacking.
Even with “optimal” therapy of inhaled ribavirin plus an immunomodulator, the RSV-attributable mortality in HSCT recipients with lower respiratory tract disease is approximately 25%. Therefore improved treatments are desperately needed, and work is under way on higher affinity monoclonal antibodies, high-titer RSV immune globulin, and antisense compounds.
Other Respiratory Viruses
Other respiratory viruses, including parainfluenza virus, human metapneumovirus, rhinovirus, and enterovirus D68, have been implicated in causing lower respiratory tract disease in HSCT recipients. Risk factors for progression from upper respiratory tract infection to viral pneumonia include acquiring the infection early after HSCT, a low absolute lymphocyte count, and corticosteroid usage. There is no FDA-approved antiviral agent with proved efficacy against these three viruses. However, identifying one of these viruses from the nasopharynx or bronchial washings can be useful in limiting empirical usage of potentially toxic agents to treat other infections, although these viruses often show up as co-pathogens. Some uncontrolled reports have suggested that inhaled ribavirin may be useful against parainfluenza ; however, others have questioned its utility. Recently a small case series has demonstrated possible efficacy of DAS181, an inhaled sialidase fusion protein, in HSCT recipients with severe parainfluenza infection. Ribavirin has in vitro activity against human metapneumovirus, and a recent report suggests that ribavirin may play a role in helping resolve lower respiratory tract disease, although controlled comparisons are lacking. Clearly, the best strategy for dealing with respiratory viral infections after HSCT is to avoid them through careful respiratory isolation.
Enteric Viruses
In addition to adenovirus, other enteric viruses such as rotavirus and norovirus, which typically cause self-limited disease in healthy individuals, can be major pathogens in HSCT recipients due to longer duration of symptoms and occasionally even death. Since profuse watery diarrhea may also be a symptom of gastrointestinal GVHD, careful exclusion of these viruses is critical in order to avoid potential over-treatment of that complication. Furthermore it has been suggested that these viruses may also be able to trigger the development of gastrointestinal GVHD. There is no specific antiviral agent for treating either virus, although enteral administration of immunoglobulin has been reported efficacious in a small case series. The antiprotozoal agent nitazoxanide has also been used with some activity against both viruses.
Protozoa
Toxoplasma gondii
The majority of HSCT programs have dietary counseling in place that eliminates most undercooked meat; thus toxoplasmosis after HSCT is generally caused by reactivation of previously acquired cysts. Therefore serologic screening of HSCT candidates can identify most patients at potential risk (excepting those with deficient antibody production), although reports of transmission from white blood cells do exist. In seropositive patients, PJP prophylaxis with TMP-SMX also provides excellent coverage against toxoplasmosis. Patients who cannot tolerate TMP-SMX need careful attention to the possibility of toxoplasmosis because most alternative PJP prophylaxis agents do not appear to provide sufficient protection. A small study suggests that atovaquone may provide some protection; alternatively clindamycin or pyrimethamine combinations can be used as either prophylaxis or preemptive treatment based on routine PCR screening for reactivation.
When toxoplasmosis occurs in a post-HSCT patient the general time frame is 2 to 6 months after HSCT. Because the brain is the most commonly affected organ, fever plus focal neurologic signs, headaches, seizures, or altered mental status are the typical symptoms that should prompt evaluation for toxoplasmosis. Brain MRI may not always show the characteristic ring-enhancing lesions; therefore cerebrospinal fluid confirmation should be obtained.
Strongyloides stercoralis
Strongyloides stercoralis is endemic to the tropics and subtropics, including the southeastern United States. Transmission is usually via penetration of the larvae into exposed skin, from which it migrates into the intestines and possibly the lungs. HSCT candidates with intact immune systems may be asymptomatic or have only eosinophilia, and stool testing should be considered for anyone entering HSCT with elevated eosinophil counts, especially if they have traveled to or emigrated from an endemic area. If positive, treatment with ivermectin is generally effective when disease burden is low. Infected individuals may begin to show evidence of disseminated disease within 1 to 3 months after HSCT. This “hyperinfection syndrome” can manifest as respiratory failure with diffuse pulmonary infiltrates, often with blood-tinged sputum, and/or colonic wall penetration, which leads to superinfection with gram-negative enteric organisms. Despite optimal treatment, mortality rates of hyperinfection syndrome are high.
Cryptosporidium parvum and C. hominis
Cryptosporidium spp. are enteric protozoa acquired from contaminated water supplies or livestock and infect intestinal epithelial cells. They cause seasonal transient nonbloody diarrhea and occasional systemic symptoms in healthy hosts and are frequently mistaken for a viral gastroenteritis. In immunocompromised HSCT recipients, however, cryptosporidiosis can cause a chronic severe diarrhea plus rare biliary tract disease. Multicenter incidence studies have never been performed, but, based on one single-center prospective study, it may be as high as 4% of all HSCT recipients and 10% of those with diarrhea. Patients with B-cell deficiencies and CD40 ligand deficiency appear to be at especially high risk. In HSCT recipients, the symptoms of a Cryptosporidium infection can easily be confused with that of intestinal GVHD, and testing for Cryptosporidium oocysts should be considered before initiation of additional immunosuppressants. Therapy for Cryptosporidium is with paromomycin, azithromycin, or nitazoxanide. HSCT recipients may need combination therapy, and decreases in systemic immunosuppression should be performed when possible.
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