Management of Infections in Stem Cell Transplant Recipients

Nocardiosis

Nocardia species are gram-positive bacteria found in soil, decaying vegetation, or water. Impaired cellular immunity is a predisposing factor. HCT recipients are usually infected when lymphopenic or while receiving corticosteroids, tacrolimus, or other calcineurin inhibitors. The use of daily trimethoprim-sulfamethoxazole (TMP/SMX) for pneumocystis prophylaxis has decreased the incidence of nocardiosis. Inhalation is the primary route of entry; therefore the lungs are the most common site of infection. More than 40% present as disseminated infection because of hematogenous spread, involving the brain (cerebral abscesses), soft tissue, and skin. Computed tomography (CT) of the chest commonly shows lung nodules; other presentations include consolidations with or without ground-glass opacities, cavitary lesions, or pleural effusions. Most Nocardia spp. are susceptible to TMP/SMX and linezolid, but identification of the species and susceptibility testing are of outmost importance for appropriate treatment. Parenteral cephalosporins or carbapenems are used empirically depending on species identification until susceptibility results are available. A minimum of 2 weeks of intravenous treatment is suggested in the case of pulmonary or skin and soft tissue nocardiosis, but a larger period of 6 weeks is needed if infection of the central nervous system (CNS) before transitioning to oral regimens for 6 to 12 months after completion of treatment.

Mycobacterium Tuberculosis

The incidence of Mycobacterium tuberculosis (MTB) infection after HCT is 10 to 40 times higher than the general population in areas of high endemicity. The use of isoniazid (INH) for treatment of latent TB infection (LTBI) after HCT reduces the incidence of active TB almost fourfold (3.58 per 100-person years in untreated vs. 0 per 100-person years in treated). Its use is challenging during the preengraftment period given INH-associated hepatotoxicity than can also develop during conditioning chemotherapy or associated conditions such as liver venoocclusive disease, engraftment syndrome, or acute GVHD. A strategy to avoid this risk is starting INH therapy for LTBI after engraftment to avoid this concomitant complications.

The greatest risk for tuberculosis reactivation after HCT is at a median time of 7 months (interquartile range 3.9–10.8), and one-third of cases present in the first 100 days post-HCT. The most common presentation of TB reactivation is pulmonary (42.6%), up to one-quarter of cases (23.4%) present as disseminated disease and it has an attributable mortality of 8.5%.

Pulmonary imaging is not specific, and tuberculosis may present as pulmonary nodules with hilar or mediastinal lymphadenopathy, consolidation with pleural effusion, interstitial pneumonitis, diffuse alveolar hemorrhage and as adult respiratory distress syndrome.

Treatment follows previously published guidelines with the consideration of rifamycin’s drug interaction with calcineurin inhibitors and triazoles.

Nontuberculous Mycobacteria

Mycobacterium avium complex is the most common organism causing infection, with an overall incidence of 0.4% to 4.9%. Risk factors are associated with delayed immune recovery like chronic GVHD and cytomegalovirus (CMV) infection. Most common presentation is extrapulmonary from blood stream (catheter related), bone, and widely disseminated. Rapidly growing mycobacteria blood stream infections are mainly catheter related ( Mycobacterium mucogenicum, fortuitum, abscessus , etc.) and the use of combination of antimicrobial agents for a median of 4 weeks with catheter removal is associated with lower relapse rate.

Cytomegalovirus

CMV reactivates during the first 3 months post-HCT, more commonly in patients without prophylaxis. Delayed lymphocyte recovery is one of the most important risk factors for CMV reactivation. Therefore haploidentical HCT recipients have the highest risk of reactivation (71%) compared to matched related recipients (48%).

Letermovir, a nonnucleoside agent that inhibits the terminal phase of CMV replication by targeting the terminase complex, has been approved for prophylaxis in high-risk HCT recipients including CMV D-/R+ serostatus until day 100 posttransplant. Low incidence of breakthrough viremia is seen associated with the appearance of resistant CMV variant mutations at the pUL56 and UL89 genes. Letermovir being a moderate CYP3A inhibitor increases levels of immunosuppressants (cyclosporine, tacrolimus, sirolimus) by two- to threefold, and is a CYP2C9 and CYP2C29 inducer that significantly decreases serum voriconazole levels. Maribavir and Brincidofovir have been unable to prevent clinically significant CMV disease in phase 3 trials.

The use of preemptive therapy in low-risk recipients by measuring CMV deoxuribonucleic acid (DNA) viral levels periodically is used as a strategy to treat CMV reactivation or disease.

The peptide-based enzyme linked immunospot CMV assay that targets intermediate-early 1 (IE-1) and phosphoprotein 65 (pp65) antigens, with a sensitivity of 94% to 96% and negative predictive value of 93% to 95%, may be of use to establish duration of CMV monitoring and CMV prophylaxis.

CMV reactivation can manifest as asymptomatic viremia or progress to end organ disease most commonly pneumonitis or GI disease. It is associated with poor graft function, graft failure, and exacerbation of GVHD. Diagnostic criteria include clinical presentation, the presence of CMV DNA in blood and other body fluid samples (bronchoalveolar lavage [BAL], cerebrospinal fluid [CSF], etc.), and histologic confirmation with the presence of viral intranuclear or cytoplasmic inclusions. GI CMV disease is diagnosed most frequently during the early postengraftment period in allogeneic HCT (allo-HCT) recipients (70%–80% of all cases) and has to be differentiated from acute GI GVHD. Unfortunately, CMV DNAemia is often absent at the time of diagnosis, underscoring the importance of tissue diagnosis.

CMV pneumonitis is most frequent in the late postengraftment phase. It usually presents with diffuse ground glass opacities on CT chest but multiple small nodules (1–5 mm) and parenchymal consolidations are also reported. The classic presentation of CNS infection is ventriculoencephalitis with microglial nodules and generally occurs late after transplantation with a median of more than 4 months.

Treatment of CMV viremia starts at different thresholds dependent on the transplant center, the test used and the patient risk, with lower IU/mL used as triggers for the ones with the highest risk (seropositive CMV recipients, and cord blood, haploidentical, or T-cell depleted grafts). Valganciclovir, ganciclovir, or foscarnet are given for at least 2 weeks until two consecutive negative CMV DNA plasma levels are obtained in an interval of at least 4 days. Consideration of maintenance therapy for those at higher risk of recurrence is made at that point. For CMV end-organ disease, treatment includes an induction phase of 2 to 3 weeks until clinical improvement and resolution of symptoms followed by a maintenance therapy.

The combination of ganciclovir and foscarnet at full dose has been used as second-line therapy in severe CMV disease. Cidofovir is considered third-line because of its nephrotoxicity. The use of CMV-specific immunoglobulin or standard immunoglobulin for CMV pneumonitis has not shown any significant improvement in outcome.

Increasing CMV DNA load is expected early during treatment. Resistance usually does not emerge in drug-naïve patients until several weeks on treatment. Refractory CMV infection should be considered if the CMV viral load increases by >1 log ₁₀ after 2 weeks of appropriate antiviral therapy. CMV resistance testing and reevaluation of therapy are indicated at that time . Maribavir most recently has been approved for treatment of posttransplant refractory CMV infections with or without CMV resistance.

Herpes Simplex Virus 1 and 2

Herpes simplex virus (HSV) commonly causes mucocutaneous oral and genital lesions. The incidence of reactivation among HSV-seropositive allo-HCT recipients was 80% within the first 4 weeks after transplant without prophylaxis.

Intravenous acyclovir remains the therapy of choice for severe mucocutaneous or visceral HSV disease. It reduces time to resolution of pain, healing of lesions, and viral shedding. Emergence of acyclovir-resistant strains is related to the use of low-dose prophylaxis or poor absorption. The common resistance mechanism is absence or mutation in the viral thymidine kinase preventing the phosphorylation of acyclovir to its active triphosphate form. Testing for acyclovir-resistant HSV should be considered in patients who do not respond after 1 week of high-dose acyclovir therapy. Available drugs for treatment include foscarnet and cidofovir, which do not require viral thymidine kinase for activation. The use of topical 5% imiquimod has been reported in a case series of recurrent HSV-resistant mucocutaneous infections. Pritelivir, a new antiviral that inhibits HSV viral replication at the helicase-primase complex, was found to be more effective in suppressing genital HSV infection, and it is being evaluated for its use on recurrent resistant HSV mucocutaneous infections.

Human Herpes Virus 6

Human herpes virus (HHV)-6 virus, the cause of exanthema subitum, infects almost all children by the age of 2 years. Therefore most of HHV-6 infections in allo-HCT recipients are from reactivation because of immunosuppression.

This is the only HHV known to integrate into the telomere of every chromosome and is present in this manner in about 1% of the U.S. and UK populations. Chromosomal integration (ciHHV-6) should be suspected in patients with persistently high levels of HHV-6 DNA in blood (usually >10 ⁶ copies/mL in whole blood) or CSF despite the absence of clinical symptoms. CiHHV-6 in the donor is recognized when HHV-6 viral load in the recipient increases with engraftment, otherwise if levels are persistently elevated before and after engraftment can be considered from the recipient. Polymerase chain reaction (PCR) testing of hair follicles or nails for HHV-6 DNA can confirm ciHHV-6 status in recipients.

Asymptomatic HHV-6 reactivation presents within 2 to 6 weeks in up to 50% of allo-HCT recipients.

End-organ disease typically affects the brain, presenting with short-term memory loss, confusion, delirium leading to encephalitis and seizures. Less commonly, HHV-6 may cause fever, rash, hepatitis, bone marrow suppression, and graft failure sometimes associated with CMV coinfection.

In the presence CNS symptoms, a positive HHV-6 DNA in CSF in absence of other identified causes is considered diagnostic of HHV-6 encephalitis. HHV-6 plasma levels of ≥10 ⁴ copies/mL demonstrated a 100% sensitivity and 64.6% specificity for diagnosing HHV-6 encephalitis. Low-plasma HHV-6 levels in an asymptomatic patient must be interpreted with caution since a false positive detection can occur from the virus being latent in lymphocytes and mononuclear cells.

Diagnostic brain imaging with magnetic resonance imaging (MRI) may identify hyperintense lesions within the bilateral medial temporal lobes, affecting hippocampus and amygdala using T-2 weighted and fluid attenuated inversion recovery (FLAIR) sequences. Other abnormal findings may be identified in the basal ganglia and various regions of the cortex. The brain MRI may be normal during the first week in most patients with HHV-6 encephalitis.

Early empiric treatment with high dose of foscarnet or ganciclovir is recommended before diagnosis confirmation. Foscarnet at a dose of 180 mg/kg/day is highly selective and superior to ganciclovir in early treatment response, achieving an adequate therapeutic concentration ratio of CSF to plasma of 0.27. Therapeutic response with improvement or resolution of symptoms and decreasing levels of HHV-6 DNA in CSF should be evaluated within 2 weeks after initiation of treatment. Monitoring of HHV-6 plasma levels, not whole blood (latent lymphocyte infection, delayed whole blood clearance compared to plasma) can be used in those patients for whom CSF studies is not possible. The use of combination of foscarnet and ganciclovir may be considered in those with rapidly progressing disease and seizures, but strong clinical evidence is not available.

Duration of treatment is recommended for a minimum of 3 weeks, there is no evidence that prolonged treatment in patients lacking improvement or with persistent low levels of HHV-6 in plasma or CSF is of benefit.

No studies evaluated the usefulness of primary prophylaxis or preemptive therapy. No recommendations are present for routine monitoring or use of prophylactic antivirals.

Adenovirus

Primary infection is seen in children and transmission occurs through fomites, aerosolized droplets, fecal-oral spread, infected tissue, and blood. Adenovirus (ADV) remains latent in lymphoid tissues and lung epithelial cells. Reactivation of ADV infection most frequently occurs during the first 100 days and up to 6% of allo-HCT recipients.

The risk is increased in recipients of cord blood HCT, T-cell depleting, or myeloablative conditioning regimens, resulting in delayed CD4 immune reconstitution. Also the presence of severe acute GVHD with the use of high-dose steroids equivalent of prednisolone >1 mg/kg/day. ADV may present with acute gastroenteritis, upper and lower respiratory infection, hemorrhagic cystitis, or hepatitis.

Weekly monitoring of ADV viremia levels followed by preemptive therapy in high-risk patients is the standard of care. A cut-off viremia level of 1000 copies/mL is used to start treatment.

Treatment includes decreasing immunosuppression when possible. Antiviral therapy with cidofovir at 1 mg/kg three times weekly or a once-weekly dose of 5 mg/kg in combination with oral probenecid is recommended. Therapy has been limited by nephrotoxicity. Brincidofovir, a lipid-linked derivative of cidofovir, has increased antiviral potency with similar efficacy against ADV, but its use has been limited by diarrhea as a side effect of this medication. Therapeutic monitoring by measuring ADV levels biweekly is recommended, and treatment continues until levels are below the limit of detection for 2 consecutive weeks.

Epstein-Barr Virus

More than 90% of the adult population has been infected with Epstein-Barr virus (EBV). It stays latent in B-lymphocytes and the reticuloendothelial system.

Patients with compromised T-cell immunity can present with EBV viremia that may progress to EBV-related lymphomas including posttransplant lymphoproliferative disorder (PTLD). The majority of PTLD cases occur within the first 6 months post-HCT but can develop up to 10 years posttransplantation. Cases that present within the first 6 months post-HCT are of donor origin.

EBV-PTLD specific risk factors identified are age >50 years, prior splenectomy, periods of immunosuppression with delayed of B-cell and T-cell reconstitution, donor/recipient serology mismatch (highest in D+/R−), and concurrent CMV reactivation.

Weekly EBV monitoring by serum PCR levels should start within 4 weeks post-HCT in high-risk patients until reconstitution of cellular immunity about 4 months or longer post-HCT. A threshold of 1000 EBV copies/mL is recommended to start treatment with rituximab.

Clinical presentation includes fever, lymphadenopathy, progression of pancytopenia, hepatitis, and hemophagocytic lymphohistiocytosis. Other, less common presentations include pneumonia, colitis, nephritis, and cerebritis. Rising peripheral blood EBV DNA levels prompt initiation of a diagnostic workup, but tissue biopsy is needed to confirm presence of PTLD and differentiate from other entities. Other diagnostic tests include positron emission tomography/CT, bone marrow biopsy, CSF analysis, and MRI of brain and whole spine according to clinical presentation.

Treatment includes reduction of immunosuppression, rituximab, or cellular immunotherapy (EBV–cytotoxic T-lymphocytes [CTLs]). The use of other antivirals like acyclovir or ganciclovir has no role, since EBV-infected cells are not in a lytic viral infection phase. Chemotherapy may be indicated for treatment of specific lymphomas.