Volume 13, Issue 1 , Pages 74-81, January 2007
Treatment of Adenovirus Disease in Stem Cell Transplant Recipients with Cidofovir
Article Outline
- Abstract
- Introduction
- Methods
- Case reports (Tables 1 and 2)
- Results
- Discussion
- Acknowledgments
- References
- Copyright
Abstract
Invasive adenovirus (AdV) disease is fatal in >50% of allogeneic hematopoietic stem cell transplant (SCT) recipients. Treatment with cidofovir may improve outcomes based on in vitro susceptibility data and case reports. Six consecutive cases of invasive AdV disease treated with cidofovir were reviewed among 84 allogeneic adult SCT recipients (incidence, 7.1%). Cidofovir was administered intravenously at 5 mg/kg per dose (1-7 doses). All patients received intravenous immune globulin. Blood AdV DNA levels (viral loads, VLs) were monitored with a real-time quantitative polymerase chain reaction assay. Published reports of cidofovir treatment of AdV disease in SCT recipients were critically reviewed. The primary manifestations of AdV disease were hepatitis (n = 3), colitis (n = 2), and nephritis (n = 1). All patients had detectable AdV VLs, with peak values from 5 × 105 to 2 × 108 copies/mL. All patients received CD34+ selected grafts (n = 3) and/or had graft-versus-host disease (n = 4) and had CD4 counts <100 cells/mm3. Only 1 of 5 patients (20%) who received ≥2 doses of cidofovir died with active AdV disease. Four patients exhibited improvement within days of treatment with cidofovir as documented by clinical criteria and declines in AdV VLs (without a change in immunosuppression). In contrast, 1 patient treated late after onset of AdV disease died after 1 dose of cidofovir. In our review of 70 published cases treated with ≥2 doses of cidofovir, 13 (19%) died from AdV disease. In conclusion, early treatment of AdV disease with cidofovir inhibits viral replication in vivo and reduces mortality in allogeneic SCT recipients compared with historical data.
Key words: Adenovirus, Cidofovir, Hematopoietic stem cell transplantation
Introduction
Opportunistic pathogens such as adenovirus (AdV) have emerged in the hematopoietic stem cell transplant (SCT) recipient population as new techniques have reduced the risk of graft-versus-host disease (GVHD) but resulted in more profound and prolonged immunosuppression. SCT recipients are susceptible to invasive infections caused by AdV, including pneumonitis, hepatitis, colitis, and hemorrhagic cystitis [1, 2, 3, 4]. AdV infections occur more frequently in pediatric than in adult SCT recipients [2, 5, 6]. Patients who receive an allogeneic transplant, in particular with a T cell-depleted or CD34+ (stem cell) selected graft, and patients who develop GVHD have a higher incidence of AdV infection [7].
Until recently, ribavirin was the only antiviral agent used against AdV infections, and responses were limited [5, 8, 9]. Cidofovir is a monophosphate nucleotide analogue of cytosine that inhibits viral DNA polymerases and exhibits activity against multiple DNA viruses. Cidofovir has been shown to have in vitro activity against AdV [10]. Since 1999, there have been a number of case reports of cidofovir use in SCT recipients with AdV infection [3, 9, 11, 12, 13, 14].
Based on the in vitro data and case reports with cidofovir, we started to treat our adult allogeneic SCT recipients who developed invasive AdV disease with cidofovir in 2003. In this report, we describe 6 consecutive patients who developed invasive AdV infections and were treated with cidofovir. A real-time quantitative polymerase chain reaction (PCR) in plasma (viral load, VL) was used to measure AdV replication and to monitor the response to cidofovir treatment. In addition, a critical review of the literature on the use of cidofovir for AdV disease in SCT recipients was performed.
Methods
Patients
Six consecutive cases of AdV disease diagnosed in adult SCT recipients at Thomas Jefferson University Hospital from 2003 to 2005 were reviewed retrospectively. This study was approved by the institutional review board.
Transplant Conditioning Regimens
Three patients (cases 1, 3, and 4) received CD34+ selected transplants after a myeloablative preparatory regimen consisting of fludarabine, cytarabine, melphalan, and antithymocyte globulin. CD34+ selection was performed using the Isolex 300i Magnetic cell selector (Nexell Therapeutics, Irvine, Calif). Two patients (cases 2 and 5) received non-myeloablative grafts using a preparative regimen of fludarabine, cytarabine, and cyclophosphamide. The sixth patient received a myeloablative regimen consisting of total body irradiation and cyclophosphamide with an unmanipulated peripheral stem cell product.
Donor Lymphocyte Infusions
All patients who received T cell-depleted grafts were treated with donor lymphocyte infusion (DLI) to expedite immune reconstitution, as part of an investigational study (manuscript in preparation). To reduce the risk of GVHD, donor lymphocytes were modified by treatment with L-leucyl-L-leucine methyl ester to deplete perforin-containing cells (primarily CD8+ T cells and natural killer cells) [15, 16].
Viral Cultures
Urine, stool, throat, respiratory, and tissue specimens were cultured with the R-mix shell vial system (Diagnostic Hybrids, Athens, Ohio).
Quantitative AdV PCR
Blood specimens were assayed with a quantitative real time AdV DNA PCR assay (ViraCor, Lee’s Summit, Mo). Urine, cerebrospinal fluid (CSF), and tissue specimens were tested as clinically indicated.
Definition of AdV Disease
AdV disease was defined as a positive AdV culture from a tissue biopsy with compatible clinical signs and symptoms and no other identifiable causes. In 1 case of hemorrhagic cystitis and probable nephritis (patient 6), AdV disease was diagnosed by a positive urine AdV culture, a positive AdV VL, in addition to fever, hematuria, bilateral flank pain, and elevated creatinine. All patients had extensive workups to exclude other pathogens, including routine, fungal, acid fast bacilli, and viral cultures, and PCR tests for cytomegalovirus, Epstein-Barr virus, and BK virus, as clinically indicated.
Treatment
All patients diagnosed with AdV disease were treated with intravenous cidofovir and intravenous immunoglobulin (IVIG). Cidofovir was dosed at 5 mg/kg intravenously every week for the first 2 weeks, followed by every other week, for a minimum of 4 doses in patients who survived (range, 1-7 doses). Patients were prehydrated before each dose, and probenecid was administered according to the manufacturer’s recommendations. IVIG dosing varied, but patients were generally given 1-2 g/kg, followed by 500 mg/kg administered every other week for a minimum of 4 doses.
Case reports (Table 1, Table 2)
Patient 1
A 23-year-old man with chronic myelogenous leukemia in T lymphoblastic crisis received a T cell-depleted, matched related SCT. He was admitted 88 days after transplantation with chills and fevers. A liver biopsy performed for elevated transaminases was nondiagnostic. He received IVIG and a scheduled DLI and was discharged. He was readmitted on day 112 with recurrent fevers, new right upper quadrant pain, and worsening transaminases. The liver biopsy viral culture was now positive for AdV, and the AdV VL was 1.6 × 106 copies/mL. Treatment with cidofovir was initiated, and IVIG was redosed. The patient developed prompt resolution of the fevers (within 48 hours) and rapid improvement of his transaminases and AdV VL (Figure 1, case 1). The patient remained asymptomatic at 6-month follow-up with negative AdV VLs.
Table 1. Patient Characteristics and AdV Disease Manifestations
| Cases | ||||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | |
| Age | 23 | 42 | 39 | 43 | 72 | 33 |
| Diagnosis | CML | MM | ALL | AML | AML | AML |
| Type of transplant | MRD | MRD⁎ | Haplo | MRD | MUD⁎ | MRD |
| T cell depletion | + | − | + | + | − | − |
| Immunosuppression | ||||||
 Steroids | − | + | − | + | + | + |
| Cyclosporine | − | + | − | + | + | − |
| MMF | − | + | − | + | + | − |
| Tacrolimus | − | − | − | − | + | + |
| Sirolimus | − | − | − | − | + | − |
| Infliximab | − | + | + | − | + | − |
| ATG | − | + | − | − | − | − |
| GVHD | − | GI | − | Skin | Skin and GI | Liver |
| AdV disease | Hepatitis | Colitis | Hepatitis | Hepatitis | Colitis | Nephritis |
| Colitis | Pneumonia | Hepatitis | Cystitis | |||
| First positive AdV test (days after SCT) | 91 | 59 | 68 | 187 | 64 | 214 |
| Outcome (6 mo) | Alive | Alive | Died (4 d) | Alive | Died (2 wk) | Alive |
⁎Non-myeloablative. |
Table 2. Laboratory Tests, Signs, and Symptoms of Adenovirus Disease and Treatment
| Cases (Days after SCT) | ||||||
|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 6 | |
| AdV culture | ||||||
| Feces | + (90) | + (57) | + (75) | + (195) | ND | ND |
| Urine | − (99) | − (58) | + (81) | − (197) | ND | + (214) |
| Throat | + (91) | ND | ND | ND | − (67) | ND |
| BAL | ND | ND | − (48) | + (195) | ND | ND |
| Tissue | +Liver (98) | +Duodenum (59) | +Sigmoid (78) | +Liver (197) | +Sigmoid (69) | ND |
| AdV VL (copies/mL) | ||||||
| Setpoint | 2.06 × 105 (92) | 1500 (59) | 7400 (68) | 6.9 × 104 (187) | 1.9 × 105 (64) | 8.6 × 104 (214) |
| Peak | 1.6 × 106 (110) | 5.3 × 104 (62) | 2 × 108 (96) | 6.7 × 107 (197) | 7.4 × 107 (70) | 7.9 × 105 (222) |
| Cidofovir start day | 113 | 66 | 93 | 197 | 68 | 218 |
| IVIG start day | 95 | 56 | 77 | 197 | 68 | 218 |
| DLI days | 102 | ND | 51 | 47125 | ND | ND |
| Signs/symptoms | ||||||
| Fever | + | + | + | + | + | + |
| Diarrhea | − | + | + | − | + | − |
| Abdominal pain | + | + | + | − | + | − |
| Cough/dyspnea | + | − | + | + | − | − |
| Dysuria | − | − | − | − | − | + |
| MS changes | − | − | − | + | + | − |
| Abnormal LFTs | + | + | + | + | + | − |
| Lymphocyte counts (cells/mm3) | ||||||
| CD4/CD8 | 5/5 (92) | ND | 10/4 (75) | 12/34 (200) | 21/2 (77) | 63/132 (214) |
Figure 1.
Plots of the adenovirus viral loads (AdV VL) and aspartate aminotransferase (AST) levels in cases 1-6. CDV indicates cidofovir; DLI, donor lymphocyte infusion; IVIG, intravenous immunoglobulin.
Patient 2
A 42-year-old woman with multiple myeloma received an autologous SCT followed by a non-myeloablative matched related SCT. On day 23 after allogeneic transplantation, she was admitted with nausea, vomiting, and diarrhea. Colonoscopy revealed GVHD of the large bowel, which was treated with initial improvement. On day 53, her diarrhea and abdominal pain worsened and her transaminases became mildly elevated. Upper and lower endoscopic biopsies were nondiagnostic, but the viral culture and PCR from the duodenum biopsy were positive for AdV. IVIG and treatment with cidofovir were initiated without a change in immunosuppression. The patient showed prompt clinical improvement and normalization of her transaminases and AdV VL (Figure 1, case 2). The AdV VLs remained negative despite ongoing GVHD and immunosuppressive therapy at 6-month follow-up.
Patient 3
A 39-year-old man with relapsed acute lymphoblastic leukemia received a T cell-depleted, haploidentical SCT. On day 30 he received a boost of stem cells for bone marrow failure. He developed a biopsy-confirmed idiopathic pneumonitis (day 48) and was treated with infliximab, with improvement. On day 51 the patient received a DLI. He developed diarrhea, and a sigmoid biopsy (day 68) was nondiagnostic, but the viral culture was positive for AdV and an AdV VL was 7400 copies/mL. The patient was treated with IVIG, and his diarrhea decreased. On day 84 he developed mildly elevated transaminases and underwent an open cholecystectomy, without improvement. On day 91 he became febrile, his transaminases rapidly worsened, and his AdV VL increased to 2 × 108 copies/mL (Figure 1, case 3). IVIG and cidofovir were initiated, but the patient expired 4 days later from fulminant hepatitis.
Patient 4
A 43-year-old man with acute myelogenous leukemia (AML) received a T cell-depleted, matched related SCT. He received DLI after transplantation and developed skin GVHD (day 160) that responded to treatment. He was admitted on day 190 with Pseudomonas aeruginosa septicemia and mildly elevated transaminases. His immunosuppressive regimen was tapered, but his fevers persisted and liver function tests worsened. A chest computed tomogram displayed patchy areas of airspace disease involving both lungs. Transbronchial lung biopsy was nondiagnostic. Liver biopsy revealed necrotic foci consistent with viral hepatitis, but no viral inclusions were visualized. The bronchoalveolar lavage and liver viral cultures were positive for AdV. He developed mental status changes and had a negative head computed tomogram; his CSF had no cells but was AdV PCR positive. Upon treatment with IVIG and cidofovir, his fevers, mental status, transaminases, and AdV VLs promptly improved (Figure 1, case 4). At 6-month follow-up, he had recurrent leukemia without a relapse of AdV disease.
Patient 5
A 72-year-old man with AML received a non-myeloablative matched unrelated SCT. On day 31, he was started on high-dose steroids for skin GVHD. A colonoscopy performed on day 35 also revealed GVHD, and his immunosuppression was intensified. Sixty days after transplantation, the patient developed bilateral conjunctivitis, transaminase elevations, and worsening diarrhea. Repeat sigmoid colon biopsy revealed GVHD and was also culture-positive for AdV, and his AdV VL was 188 000 copies/mL. The AdV VL and transaminases started to decrease after treatment with cidofovir, and IVIG was initiated (Figure 1, case 5). However, the patient’s diarrhea subsequently worsened, and he became lethargic. Brain magnetic resonance imaging on day 82 showed abnormalities consistent with rhombencephalitis, and he expired the following day.
Patient 6
A 33-year-old man with AML received an unmanipulated matched related SCT. On day 169, he developed hepatic GVHD, which was treated with a good response. On day 205, he developed acute onset of dysuria, hematuria, and bilateral flank pain. A urine PCR test for BK virus was positive once (600 copies/mL) and was negative thereafter. Ultrasound of the kidneys revealed mild bilateral hydronephrosis. The patient was treated with intravenous hydration, and his immunosuppression was tapered without improvement. A bladder biopsy revealed a denuded bladder wall with mild chronic submucosal inflammation. On day 212 he started to have daily fevers to 103°F, and his creatinine level increased to 1.9 mg/dL. Treatment with cidofovir and IVIG was initiated after a positive urine culture for AdV and elevated AdV VLs were noted. His fevers and flank pain promptly resolved (within 48-72 hours), followed by improvement in his creatinine, dysuria, hematuria, and AdV VLs (Figure 1, case 6). The patient remained asymptomatic at 6 months with negative AdV VLs.
Results
Six cases of AdV disease were identified among 84 allogeneic adult SCT recipients performed during 2003 to 2005, representing an incidence of 7.1%. Patient characteristics are summarized in Table 1. All patients received T cell-depleted grafts (n = 3) and/or developed GVHD (n = 4). Patients’ median age was 40.5 years (range, 23-72 years).
Adenovirus Disease
All 6 patients developed fever, and the liver was the most common site of invasive AdV disease (Table 1, Table 2). Hepatitis was the primary diagnosis in 3 patients (cases 1, 3, and 4), and 2 additional patients had abnormal liver function test results (cases 2 and 5). Colitis was the primary diagnosis in 2 patients (cases 2 and 5) and the initial presentation in case 3. One patient (case 6) developed AdV hemorrhagic cystitis and probable nephritis. Two patients had evidence of pneumonitis (cases 1 and 4). In addition, 2 patients had mental status changes with possible encephalitis: case 4 had a positive CSF AdV PCR result (without cells in CSF) and case 5 had rhombencephalitis on brain magnetic resonance imaging (lumbar puncture was not performed). The median onset of AdV infection (first positive test result) was 114 days after transplantation (range, 59-214 days).
AdV Culture Results
Tissue biopsies were performed in all patients (Table 2). Liver biopsies were performed in cases 1 and 4, and viral cultures were positive for AdV. Patients 2, 3, and 5 underwent endoscopic biopsies: viral cultures were positive for AdV in specimens obtained from the duodenum in patient 2 and the sigmoid colon in patients 3 and 5. Liver biopsy was not performed in case 3 (with prior AdV colitis), but his markedly abnormal liver function test results and high AdV VLs were highly suggestive of fulminant AdV hepatitis. Patient 6 had a positive urine culture for AdV and underwent cystoscopic biopsy, but tissue was not sent for viral culture. AdV isolates from all cases (except case 3) were sent for serotyping: AdV type 1 was identified from cases 1 and 2 (Quest Diagnostics, Teterboro, NJ), 4 (State Lab, Lionville, Pa), and 5 (Focus Technologies, Cypress, Calif); the isolate from case 6 was not typable. Notably, none of the biopsy specimens had viral inclusions identified on routine histopathology.
AdV Viral Loads
All 6 patients had positive AdV VLs that were followed prospectively, as illustrated in Figure 1. Blood was tested retrospectively in cases 1, 3 and 4 and found to be positive for AdV in all 3 cases, preceding the onset of clinical symptoms by a mean of 20 days. The AdV VL peaked within a median of 9 days after onset of clinical symptoms and remained positive for a median of 29.5 days. There was a wide range in VLs among the 6 cases, with the peak value ranging from 53 400 copies/mL to 2 × 108 copies/mL.
Lymphocyte Counts
Lymphocyte counts with subset flow cytometric analysis were followed in cases 1, 3, 4, 5, and 6 (Table 2). Three of these patients received T cell-depleted grafts (cases 1, 3, and 4), followed by modified DLI. For patient 1, the absolute CD4 and CD8 T cell counts were <10 cells/mm3 at the time of onset of AdV disease (day 92). He received DLI on day 102, and his CD4 count increased to 333 and 460 cells/mm3 on days 124 and 153, respectively. Patient 3 had profoundly low T cell counts (<10 cells/mm3 each) throughout his hospital course despite treatment with DLI. Although patient 4 also received DLI, he had very low T cell counts (<50 cells/mm3 each) because he developed AdV disease while receiving treatment for GVHD after DLI. The remaining 3 patients received intensive immunosuppressive therapy for GVHD (Table 1) and had CD4 counts (absolute lymphocyte count in case 2) <100 cells/mm3 at the time of diagnosis of AdV disease.
Outcomes
All 6 patients were treated with cidofovir. Four of 5 patients (80%) who received ≥2 doses of cidofovir had prompt responses as documented by clinical criteria and declines in AdV VLs. One patient with fulminant AdV hepatitis at the time treatment with cidofovir was initiated died 4 days later. Although cidofovir is highly nephrotoxic, none of the patients required treatment interruption. The baseline creatinine level was abnormal (up to 1.9 mg/dL) in case 6 and improved upon treatment with cidofovir, consistent with the diagnosis of AdV nephritis. However, most patients developed transient elevations in creatinine as the number of doses increased.
Discussion
Invasive AdV disease in allogeneic SCT recipients has been associated with fatal outcomes, with mortalities averaging 50% (range, 27%-65%) [5, 8, 9, 17]. Although there is no documented effective therapy, uncontrolled studies and case reports have described clinical responses to cidofovir. The present report describes 6 detailed cases of documented AdV disease in adult SCT recipients who were treated with cidofovir and monitored with a quantitative AdV PCR assay. All patients were severely immunocompromised with CD34+ selected grafts (n = 3) and/or GVHD (n = 4) and had CD4 counts <100 cells/mm3. Four of 5 patients (80%) who received ≥2 doses of cidofovir had prompt responses, documented by clinical criteria and declines in AdV VLs, and recovered from AdV disease. One patient who died from fulminant AdV hepatitis 4 days after a single dose of cidofovir was not evaluable.
AdV disease was documented in all cases by positive AdV viral cultures from tissue specimens (cases 1-5) and a positive urine AdV culture and AdV VL in case 6. AdV type 1 was identified from 4 typed isolates (cases 1, 2, 4, and 5). In addition, all patients had compatible clinical presentations and were extensively evaluated to exclude other pathogens. Tissue biopsies failed to reveal viral inclusions in any case, although in case 4 the liver biopsy was interpreted as consistent with viral hepatitis. These cases illustrate the poor sensitivity of routine histopathology in detecting AdV disease in comparison with viral culture.
All 6 patients with AdV disease had detectable viremia, with peak AdV VLs ranging from 5 × 104 to 2 × 108 copies/mL. The 4 patients with VLs >106 copies/mL (cases 1, 3, 4, and 5), were most intensely immunosuppressed and developed the most severe AdV disease; 2 of 4 died related to AdV disease. Viremia has previously been associated with disseminated AdV disease [3, 14, 18]. In addition, Claas et al [19] found that VLs >106 copies/mL were associated with an increased risk for fatal disease. These data support the utility of monitoring AdV VLs in patients with AdV disease.
In 4 cases (1, 2, 4, and 6), dramatic clinical responses and reductions in AdV VLs were observed within days after treatment with cidofovir (Figure 1). In particular, T cell-depleted recipients 1 and 4 were extremely immunocompromised (T cell counts <20 cells/mm3) and developed severe hepatitis with AdV VLs >106 copies/mL. Based on our past experience with this population, both patients would likely have had fatal outcomes without therapy. Notably, patient 1 also received a DLI around the time of onset of AdV disease, and his CD4 and CD8 counts increased within 4 weeks to 333 and 1000 cells/mm3, respectively. Although his initial prompt improvement was coincident with cidofovir treatment, his immune recovery likely contributed to the eventual resolution of his AdV infection. Patient 4 developed AdV disease 4 weeks after starting high-dose steroids, cyclosporine, and mycophenolate mofetil for GVHD after DLI. His rapid improvement was likely due to the cidofovir, because his immune recovery after DLI was delayed by the GVHD and immunosuppressive therapy. Immunosuppression was not tapered in case 2 secondary to active GVHD. In patient 6, his symptoms worsened despite tapering his immunosuppression, but he had a rapid clinical response and decrease in AdV VLs coincident with treatment with cidofovir. Therefore, the prompt responses observed in these cases were likely due to cidofovir treatment rather than the administration of DLI or reduction in immunosuppression.
Two patients (cases 3 and 5) died with active AdV disease. Patient 3 did not receive cidofovir until after he developed fulminant hepatitis, and he died a few days later. It is tempting to speculate whether or not earlier treatment when he initially developed colitis may have improved his outcome. Patient 5 had an initial response to cidofovir with reduction in AdV VLs despite active GVHD and older age but then succumbed due to probable AdV encephalitis and ongoing GHVD.
IVIG was also administered to all patients, but no definite conclusions can be made about its effect. Three patients were first treated with IVIG alone (cases 1, 2, and 3), and IVIG may have been associated with a transient response in case 3 only (Figure 1).
Previous reports that described the use of cidofovir in SCT recipients with AdV disease were analyzed and summarized in Table 3. Comparison between studies was complicated by differences in patient populations, definitions of AdV disease, assessment of responses, and insufficient clinical information. Patients were included in the analysis only if they had probable or definite AdV disease and received ≥2 doses of cidofovir [7, 9, 11, 12, 13, 14, 20, 21, 22]. A positive response was defined as survival or lack of active AdV disease at the time of death. In total, 70 published cases of definite or probable AdV disease treated with cidofovir were analyzed. Most cases were in pediatric SCT recipients, consistent with the epidemiology of AdV infections. Most patients were severely immunocompromised because they received matched unrelated or mismatched related grafts and developed GVHD. At least 15 patients received T cell-depleted grafts. Only 13 of 70 (19%) patients were considered to have died from AdV disease, a rate comparable to the 20% mortality described in the present study.
Table 3. Literature Review of Cidofovir Use in SCT Recipients with Adenovirus Disease
| No. of Cases | P/A | SCT Type⁎ | T Cell Depletion⁎ | GVHD⁎ | Definite/Probable AdV⁎ | AdV Site⁎ | Response⁎ | |
|---|---|---|---|---|---|---|---|---|
| Ribaud et al [20] | 1 | P | MUD§ | No | 0 | 1/0 | Sigmoid Bx | 1 |
| Legrand et al [11] | 7 | P | MUD | No | 5 | 7/0 | Sigmoid Bx (7), gastric Bx (3) | 6 |
| Blood† (2), urine† (3) | ||||||||
| Bordigoni et al [9] | 3 | P/A | MUD (2), MMRD (1) | NA | 0 | 0/3 | NA | 2 |
| Hoffman et al [12] | 7 | P | AD (6), MRD (1) | No | 4 | 0/7 | Urine (6), blood (2), BAL (1) | 7 |
| Suparno et al [7]‡ | 1 | A | MUD | 1 | 1 | 0/1 | Stool | 1 |
| Ljungman et al [13] | 27 | P/A | MRD (4), MUD (18), MMRD (5) | 3 | 27 | 14/13 | Bx (9), blood (19), BAL (5) | 23 |
| Leruez-Ville et al [14] | 3 | P/A | NA | NA | NA | 1/2 | Blood PCR (3), GI (3) | 2 |
| Respiratory (3), CSF (1) | ||||||||
| Muller et al [21] | 10 | P | MRD (1), MUD (8), MMRD (1) | NA | NA | 0/10 | GI (4), multiple (4) | 9 |
| Kampmann et al [22] | 11 | P | MUD (5), MMUD (3) | 11 | 11 | 0/11 | Blood (11) | 6 |
| MMRD (1), Haplo (2) |
⁎Number of cases. |
†Culture and polymerase chain reaction. |
‡Cidofovir dose not available. |
§Cord blood. |
Based on this report and a review of the literature, the use of cidofovir is associated with decreased mortality from AdV disease in allogeneic SCT recipients. Notably, in case 3 and the study by Kampmann et al [22], in which patients were initially treated with ribavirin, a delay in initiating cidofovir therapy was associated with fatal outcomes. Therefore, early detection of viremia and AdV disease may lead to earlier intervention and improved outcomes. Cidofovir can rapidly inhibit AdV replication in vivo, as reflected by prompt reductions in VLs in this study and the study by Leruez-Ville et al [14]. Moreover, new lipid formulations of cidofovir have increased activity against AdV in vitro and appear promising [23].
The fact that, in some cases, immune reconstitution of the SCT recipient results in resolution of AdV disease without specific antiviral treatment suggests that an AdV-specific immune response is crucial for recovery [24, 25]. In SCT recipients in whom immune reconstitution is delayed, such as the cases described in this study, cidofovir treatment rapidly inhibits AdV replication, as reflected by dramatic decreases in AdV VLs. Therefore, cidofovir therapy may help control infection until immune recovery occurs. Notably, none of the 4 patients who survived AdV disease relapsed within 6 months of follow-up, suggesting that they subsequently mounted a virus-specific immune response.
Ideally, cidofovir should be evaluated as a treatment for AdV disease in a placebo-controlled study. In the meantime, given the potential for fatal outcomes, we recommend the use of cidofovir for treatment of AdV disease in recipients of T cell-depleted or CD34+ selected grafts who have severe lymphopenia and in patients receiving high-dose immunosuppressive therapy for active GVHD. For patients who do not reconstitute immune responses and/or cannot tolerate cidofovir, immunotherapy interventions such as DLI should also be considered. In other allogeneic SCT recipients, AdV disease should be monitored closely with AdV VLs, and immunosuppression should be tapered if feasible. Based on our experience and other published data [3, 14], cidofovir therapy should be considered when AdV VLs increase to >100 000 copies/mL. The role of IVIG in treatment of AdV disease also requires further study.
In addition to early diagnosis and monitoring employing AdV VLs, interventions such as tapering of immunosuppression, treatment with cidofovir, and the use of IVIG and DLI have the potential to improve the outcome of AdV disease in SCT patients.
Acknowledgments
We thank the staff of the Blood and Marrow Transplant Program for providing excellent patient care and support.
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PII: S1083-8791(06)00600-8
doi:10.1016/j.bbmt.2006.08.040
© 2007 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 13, Issue 1 , Pages 74-81, January 2007
