Supportive Care for the Transplant Patient

Epidemiology and Risk Factors

Despite the introduction of effective antiviral therapies, CMV reactivation and infection can be a major cause of morbidity and mortality in allogeneic HCT recipients. The risk of CMV reactivation spans both the early and late transplant period, especially in patients with active GVHD requiring prolonged immunosuppression. Although the incidence of early CMV disease with organ involvement has declined to 3% to 6% with the use of empiric antiviral drug therapy directed by routine surveillance with CMV DNA polymerase chain reaction (PCR) or antigenemia testing (pre-emptive strategy), late onset CMV infection and organ disease remain significant clinical concerns.

Seropositivity of the recipient is the most important risk factor for CMV infection in HCT recipients, and reactivation of latent virus is the most important mechanism resulting in CMV disease. CMV infections (<5%) in seronegative recipients are extremely rare and likely result from exogenous exposure (primary CMV infection). The use of a CMV-seronegative donor in a seropositive recipient carries the worst risk for reactivation and is associated with repeated infections and decreased survival. Other risk factors for CMV reactivation include use of an unrelated donor, UCB or haploidentical donor HCT, in vivo T-cell depletion, older recipient age, increasing donor-recipient HLA mismatch, acute and chronic GVHD, and the need for prolonged immunosuppression, especially with high-dose corticosteroids. CMV reactivation can occur in autologous HCT patients as well, especially in those with extensive lymphodepleting prior therapies (e.g., fludarabine) but the risk of CMV end-organ disease is rare. Significant debate and research have gone into the evaluation of the potential role of CMV reactivation in decreasing post-HCT risk of disease relapse. The largest published study to date, including more than 9000 patients, showed no benefit in relapse risk but a higher a risk of NRM with CMV reactivation.

Clinical Presentation and Diagnosis

CMV infection is often identified as asymptomatic reactivation noted by screening antigenemia or DNA PCR testing. The organs that are usually affected by CMV disease include the lungs (pneumonitis) and the gut (enteritis). CMV retinitis, hepatitis and encephalitis are less common and are usually seen in late-onset, recurrent CMV infection. Indirect effects of CMV infection may include increased risks of secondary graft failure and bacterial and fungal superinfection. Preceding CMV viremia is a strong predictor of subsequent clinical disease. CMV pneumonitis develops in 60% of patients with untreated asymptomatic viremia, and conversely effective treatment of CMV viremia reduces the incidence of CMV pneumonitis.

The diagnosis of CMV can be made either by demonstration of characteristic cytopathic effects in tissue or using more sensitive molecular methods that detect viral protein or DNA. Commonly used molecular assays include CMV DNA detection methods, and the pp65 antigenemia assay. Detection of the CMV pp65 antigen in leukocytes has been a commonly used method for CMV surveillance after HCT but is ineffective during early post-HCT leukopenia. Direct detection of CMV DNA either by PCR or DNA hybrid capture assay is the most sensitive method to detect CMV viremia. Furthermore, plasma CMV DNA PCR can be a valuable tool to monitor CMV during periods of neutropenia when CMV antigenemia testing is unreliable. In addition, quantitative real-time PCR assays allow estimation of viral load which can assist in determining the need for therapy, risk of disease progression and in monitoring response to anti-CMV treatment. Viral cultures of urine, saliva, blood or bronchioalveolar lavage (BAL), using either rapid shell-vial or routine culture techniques, have limited clinical utility since they are less sensitive than antigen or DNA detection techniques and take much longer to report. Since asymptomatic viral shedding in the airways is common, CMV DNA detected in BAL should be carefully interpreted. Higher viral loads and pre-test probability of CMV pneumonitis in these patients increase the positive predictive value of these tests.

Prevention and Treatment

For seronegative recipients, the use of seronegative donors and CMV-safe blood products is the mainstay of prevention of CMV disease (see box on Approach to Prevention and Treatment of CMV Infection ). For high-risk patients (seropositive recipients), two general strategies can be utilized, both of which have been effective in reducing early CMV infection rates to less than 10%. ⁹ In the “pre-emptive therapy” strategy, patients are monitored periodically (usually weekly) by quantitative PCR with prompt treatment of early CMV viremia with ganciclovir, valganciclovir, or foscarnet before it can lead to clinical disease. In “prophylactic therapy” at-risk patients are treated with anti-viral prophylaxis. Earlier studies evaluating the use of prophylactic ganciclovir and foscarnet did reduce rates of CMV infection but did not result in improved survival and was offset by drug related toxicities such as myelosuppression and renal dysfunction. The antiviral, letermovir was studied in a phase III randomized trial versus placebo in CMV-seropositive allogeneic HCT recipients for 12 weeks post-transplant and resulted in reduced CMV infections and improved all-cause mortality at 24 weeks. Letermovir should be considered in these patients. However, they do need additional acyclovir for prophylaxis against herpes simplex and varicella. Both approaches require aggressive surveillance to allow prompt detection of infection. Unlike ganciclovir, which is administered intravenously, its pro-drug valganciclovir, has excellent oral bioavailability and is often used for prophylaxis and pre-emptive therapy of CMV infection among HCT recipients. Surveillance for CMV is continued weekly until at least day 100 post-transplant for high-risk patients and is continued longer in patients with chronic GVHD on high-dose immunosuppression. In patients receiving prophylactic letermovir, continued monitoring after cessation of drug is recommended to detect rebound infections.

CMV disease, especially pneumonia, must be diagnosed and treated promptly as it is associated with high rates of mortality. The combined use of ganciclovir and IVIG has been the most successful treatment for CMV pneumonia, with resolution in 50% to 75% of non-ventilator dependent patients. Prolonged therapy (>2 months) with the combination is indicated because shorter treatment regimens have been associated with a recurrence of CMV pneumonia, and granulocyte colony stimulating factor (GCSF) often necessary to manage ganciclovir- induced myelosuppression. Foscarnet, cidofovir or the combination of intravenous ganciclovir with foscarnet can be considered as second line therapy and early studies have shown promising data with maribavir for resistant or refractory cytomegalovirus disease. The antiviral management of CMV enteritis, hepatitis and retinitis is similar, although the use of IVIG in these settings is more controversial.

Although rare, rising CMV viral loads and worsening end-organ dysfunction despite optimal therapy, should raise the concern of CMV antiviral resistance. Ganciclovir resistance occurs due to mutations to human cytomegalovirus gene UL97 and ganciclovir, foscarnet and cidofovir resistance through UL54 mutations. Adoptive cellular therapies, using approaches to enhance natural killer (NK) or more commonly infusing donor or third-party CMV-specific cytotoxic T-cells (CTLs) have been studied. CMV-specific CTLs have shown efficacy although third party cells may be hampered by low proliferative capacity and persistence.

Candida infections

Candida albicans has been the leading cause of yeast infections in HCT recipients, but the current widespread use of azole (e.g., fluconazole) prophylaxis in the early transplant period has led to the emergence of a variety of non- albicans species, such as Candida tropicalis, Candida krusei , and Candida glabrata , as important pathogens. Yeasts are normal inhabitants of the skin, oral and gastrointestinal mucosa. Breakdown of mucosal surfaces due to radiation and chemotherapy, compounded by neutropenia in the pre-engraftment period, can greatly increase the risk of invasion and systemic infections. The presence of indwelling central venous catheters, parenteral nutrition and alteration of normal surface flora due to antibiotics are additional risk factors for Candida infections.

Clinical manifestations can range from localized mucocutaneous to disseminated deep-tissue infection. A high index of suspicion is needed for the diagnosis of Candida infections, especially in patients with persistent febrile neutropenia since blood cultures are usually not very sensitive for isolation and identification of Candida spp. Oral and esophageal candidiasis frequently occurs in the early post-transplant period and should be treated aggressively as these can serve as portals for subsequent systemic infection. Venous catheter infections can be difficult to eradicate with antifungal agents alone and necessitate removal of the central line. Patients with candidemia are also at risk for endovascular infections such as endocarditis and thrombophlebitis. Hepatosplenic candidiasis is the most common manifestation of disseminated candidiasis although it is increasingly rare with widespread use of effective anti-candida azoles and echinocandins. Specific signs or symptoms related to organ involvement may be absent and the diagnosis frequently must be made by abdominal CT scan imaging.

Prophylaxis with fluconazole is recommended in the pre-engraftment and early post-engraftment period, especially among allogeneic HCT recipients. In patients who are at high-risk for mold infections (e.g., severe GVHD), triazole antifungals such as posaconazole or voriconazole should be considered. Alternatively, caspofungin or micafungin can also be considered. In patients with severe GVHD, posaconazole prophylaxis compared to fluconazole was noted to be superior in preventing invasive aspergillosis and deaths due to fungal infections in a large phase III trial. C. krusei and C. glabrata are intrinsically resistant to fluconazole and other antifungal agents (e.g., posaconazole, micafungin) should be preferred for prophylaxis in those colonized with fluconazole-resistant Candida species. Itraconazole is another active agent, but its use is limited by its tolerability and absorption. Cross-resistance to azoles can occur among Candida species. Anti-fungal agents for treatment of suspected or known invasive candidiasis include voriconazole or posaconazole, echinocandins or an amphotericin formulation, especially when infection occurs in the setting of ongoing fluconazole prophylaxis.

Aspergillus Infections

Most mold infections in HCT recipients are due to Aspergillus fumigatus, Aspergillus flavus , and Aspergillus niger , which gain entry through breakdown of mucosal surfaces or through the nasal passages and respiratory tract. Examples of non-Aspergillus molds causing infections in this setting include Fusarium species, zygomycetes and rarely Scedosporium . Aspergillus infections can occur early after HCT (during the neutropenic phase) or later, especially with prolonged immunosuppression associated with acute or chronic GVHD. Risk factors for Aspergillus infections include allogeneic HCT, prolonged neutropenia, concomitant CMV infection, and severe GVHD and high-dose steroids is a risk factor for invasive aspergillosis-associated mortality. Underlying primary hematologic diagnosis such as chronic granulomatous disease, aplastic anemia and MDS, which are associated with prolonged pre-transplant neutropenia also increase the risk. A prior history of Aspergillus infection has also been observed to be a risk factor for reactivation after HCT. As pointed out earlier, mold-active triazole prophylaxis should be considered in high-risk patients.

Aspergillus infection is intrinsically difficult to diagnose pre-mortem. A high index of suspicion and an aggressive approach are required to establish diagnosis and initiate therapy. Since the nasal passages and tracheo-bronchial tree are the most common portals of entry for Aspergillus spp., these two sites are also the most common sites of infection. Sinusitis is frequently symptomatic and more advanced disease can be associated with erosion and necrosis of surrounding structures. Pulmonary manifestations typically include nodular infiltrates, usually distributed along the lung periphery, with pleuritic pain or cough as an initial symptom. Frank consolidation (with a halo sign on CT scan) or cavitary lesions can be seen in more advanced stages of pulmonary involvement. Aspergillus has angioinvasive properties and can present with hemoptysis or with intravascular dissemination to the skin or brain.

Blood cultures have a very low sensitivity in detecting Aspergillus and diagnosis relies on demonstration of typical fungal morphology on histopathology or on tests to detect fungal components or nucleic acids. Nasal and bronchial washings for Aspergillus may also not be sensitive and sinus or lung biopsy are often required to confirm diagnosis. The galactomannan assay is an enzyme-linked immunosorbent assay to detect the Aspergillus cell wall glycoprotein; it has a high specificity, but low sensitivity for diagnosing invasive aspergillosis and has not been reproducible. Molecular methods for diagnosis, including PCR for Aspergillus DNA, are also undergoing development. Assays to detect fungal cell wall component (1–3)-β- d -glucan are sensitive to detect most invasive fungal infections (except Cryptococcus and zygomycetes) but are not specific to Aspergillus . Often, tissue biopsy is needed to confirm the presence of Aspergillus in suspicious lesions. When biopsy is not possible, empiric therapy is recommended if clinical suspicion for mold infection is high.

The use of high-efficiency air filters has reduced the nosocomial acquisition of Aspergillus , at least during the early neutropenic phase. The optimal pharmacologic strategy for primary prophylaxis against aspergillosis is not well defined. Posaconazole is effective and recommended as prophylaxis in patients with severe GVHD. A large, randomized trial showed no difference in fungal-free survival between voriconazole and fluconazole prophylaxis in HCT recipients at low risk for disease progression or early HCT mortality, although there was a trend towards fewer Aspergillus infections and less empiric antifungal use in the voriconazole arm. In patients with a previous history of invasive aspergillosis, secondary prophylaxis with a mold-specific azole (e.g., oral voriconazole or posaconazole), parenteral echinocandins, or an amphotericin preparation is recommended during the peri-transplant period and possibly for the duration of intensive immunosuppression. Similarly, in high-risk patients with persistent febrile neutropenia not responding to antibiotics, mold-directed therapy should be promptly initiated. Azoles and echinocandins have a more favorable side effect profile compared to amphotericin formulations. Patients with disease progressing on a single anti-mold drug might need combination therapy. The role of adjunctive measures such as cytokine growth factors, immunoglobulin infusion, or granulocyte transfusion remains undefined.