Disseminated Adenovirus Infections Research Articles

1705. Treatment of Disseminated Adenovirus with Cidofovir in a Patient with HIV and ESRD

BackgroundAdenovirus is a common cause of upper respiratory infections and gastroenteritis. Severe adenovirus infections and disseminated disease are known to occur in immunocompromised hosts. Cidofovir has been associated with clinical improvement in patients with severe or disseminated disease in which immunosuppression cannot be readily reversed or those unresponsive to supportive care. However, a narrow therapeutic index has limited its clinical use particularly in patients with end-stage renal disease (ESRD).MethodsWe present a case of disseminated adenovirus in a well-controlled person living with HIV (PLWHIV) treated successfully with dose-reduced cidofovir in the setting of ESRD on hemodialysis (HD) at the University of California Los Angeles. A literature review was conducted to investigate the treatment of severe adenovirus disease and use of cidofovir in patients with ESRD.ResultsOur patient is a 59 year-old woman who presented with fever, non-productive cough, and diarrhea. She is living with HIV/AIDS with virologic control and CD4 count of 470 treated with dose adjusted lamivudine, tenofovir alafenamide, and dolutegravir in the setting of ESRD on HD, chronic hepatitis B, and group I pulmonary hypertension. Her course was complicated by development of multifocal pneumonia with hypoxemic respiratory failure requiring high-flow nasal cannula. Adenovirus PCR was detected in stool, respiratory, and serum samples. Given high risk intubation, dose-reduced cidofovir 0.5 mg/kg weekly was given twice over three weeks with symptomatic improvement, elimination of serum adenovirus DNA, and without development of adverse medication-related effects.Sixteen primary and review articles were identified discussing adenovirus pathology and treatment. A single pharmacokinetic study outlined a dosing regimen for cidofovir of 0.5 mg/kg weekly which provided comparable serum drug levels in asymptomatic patients with ESRD on HD compared to controls with adequate renal function.ConclusionThis case report illustrates although there is limited data to establish the efficacy and safety of cidofovir for treatment of disseminated adenovirus infections in ESRD patients, dose-reduced cidofovir 0.5 mg/kg weekly while on HD appears to have been effective and well tolerated.Disclosures All Authors: No reported disclosures

Fatal adenovirus meningoencephalitis in end stage renal disease patient

Background: Severe disseminated adenovirus infections that presented with severe pneumonia in respiratory failure, encephalitis or septicemic shock causes high mortality in immunocompromised patients. We reported a case ofadenovirus encephalitis in an end stage renal disease (ESRD) who presented with seizure, subsequently adenovirus DNA was detected from his cerebrospinal fluid with typical findings on electroencephalography (EEG). It highlights the need for consideration of adenovirus as cause of encephalitis. Case Description: A 66 y old gentleman with (ESRD) on regular hemodialysis was initially admitted to another hospital for 1w. He was found unconscious in the bathroom at home and subsequently developed tonic-clonic seizure prior to arrival to hospital. Patient had fever and productive cough for three days prior. On arrival to emergency department, he was intubated in view of low Glasgow coma scale (GCS) (E1V2M3). Neurological examination revealed normal tone. Contrast enhanced Computer Tomography (CT) of brain revealed multifocal old infarct with small right parieto-temporal scalp hematoma. Cerebrospinal fluid (CSF) showed high protein 871 ng/L and normal glucose ratio with elevated white cell count 10 cells/mm3 predominantly lymphocytes. CSF cryptococcal antigen and Indian Ink were negative and other cultures had no growth. He was treated as meningoencephalitis and started on intravenous ceftriaxone 2 g BD and IV acyclovir 250 mg OD Second lumbar puncture repeated on day 9 on transfer to our hospital of illness in view of no clinical improvement showed elevated opening pressure 22 cm H2O. CSF analysis revealed elevated protein 510 ng/L with adenovirus PCR was positive (4.5 log 10 DNA copies/ml). (EEG) revealed periodic lateralized epileptiform discharges. No other bacterial or fungal pathogen was identified s and tuberculous PCR was negative Intravenous cidofovir was initiated. However, his condition continued to deteriorate and succumbed 5 d following first dose of cidofovir (day 17 of hospitalisation). Discussion: This case highlights the need of consideration of adenovirus meningoencephalitis and illustrates the potential fatal disease in dialysis dependent renal disease patient. The initial diagnosis in this case is challenging as the initial clinical presentation is mimicking severe bacterial infection or septicaemia. Conclusion: Adenovirus meningoencephalitis is a rare but fatal manifestation of severe adenovirus infection with mortality rate up to 39%.

Effectiveness of BCV for the treatment of digestive diseases and disseminated adenovirus infections in recipients of pediatric hematopoietic stem cells

s / Journal of Clinical Virology 70 (2015) S1–S126 S15 and Sofosbuvir (NS5B inhibitor). 31 treatment-naive HIV-HCV co-infected patient samples were sequenced to measure the prevalence of naturally occurring resistance polymorphisms. Metagenomic sequencing was carried out without the need for primer-specific PCR, RNA was extracted using magnetic beads (Magjet), reverse transcribed (Maxima) and fragmented and indexed using transposon-based chemistry (Nextera XT). Sequencing libraries were run on an in house MiSeq Illumina next generation sequencing platform. Identification of resistance associated variants was performed using an inhouse bioinformatic pipeline. Results: The analysis covered 27 residues. Mutations detected at a frequency higher than 50% included NS3: (Q80), NS5A (M28, H58), but none in the NS5B region. Mutations detected at less than 50% of the total circulating population: NS3: (V36:22%, Q41:31%, F43:27%, T54:20%,V55:7%, Q80:57% V107:3%, R109:7%, I132:24%, R155:11%, A156:11%, V163:11%, D168:22%, NS5A: M28:27%, Q30:39%, L31:18%, P32:11%, H58:43%, E62:28%, Y93:20%, NS5B: L159:29%, S282:35%,L320:15%, V321:11%. Conclusion: The role of resistance mutations in patients with HCV therapy remains an area of active research. In addition to the presence of NS3 polymorphisms that may be associated with resistance, natural polymorphisms conferring resistance to NS5A inhibitorsmay also be associatedwith treatment failure. Resistance to the NS5B inhibitor (sofosbuvir) has been detected both in vitro and in vivo at the S282 locus (S282T) although this variant has not been reported as a majority variant natural polymorphism. As the mutation is associated with reduced replication fitness, it is highly likely to revert towildtype followingwithdrawal of the inhibitor; it may therefore be undetected in clinical trials if sampling is not carried out during or immediately after cessation of therapy. Further study into the role of minority variant polymorphisms associated with resistance will be important as new DAAs are rolled out. http://dx.doi.org/10.1016/j.jcv.2015.07.041

Valganciclovir inhibits human adenovirus replication and pathology in permissive immunosuppressed female and male Syrian hamsters.

Adenovirus infections of immunocompromised pediatric hematopoietic stem cell transplant patients can develop into serious and often deadly multi-organ disease. There are no drugs approved for adenovirus infections. Cidofovir (an analog of 2-deoxycytidine monophosphate) is used at times but it can be nephrotoxic and its efficacy has not been proven in clinical trials. Brincidofovir, a promising lipid-linked derivative of cidofovir, is in clinical trials. Ganciclovir, an analog of 2-deoxyguanosine, has been employed occasionally but with unknown efficacy in the clinic. In this study, we evaluated valganciclovir against disseminated adenovirus type 5 (Ad5) infection in our permissive immunosuppressed Syrian hamster model. We administered valganciclovir prophylactically, beginning 12 h pre-infection or therapeutically starting at Day 1, 2, 3, or 4 post-infection. Valganciclovir significantly increased survival, reduced viral replication in the liver, and mitigated the pathology associated with Ad5 infection. In cultured cells, valganciclovir inhibited Ad5 DNA replication and blocked the transition from early to late stage of infection. Valganciclovir directly inhibited Ad5 DNA polymerase in vitro, which may explain, at least in part, its mechanism of action. Ganciclovir and valganciclovir are approved to treat infections by certain herpesviruses. Our results support the use of valganciclovir to treat disseminated adenovirus infections in immunosuppressed patients.

The Effectiveness Of Cidofovir In Disseminated Adenovirus Infections After Pediatric HSCT Is Closely Related To Lymphocyte Reconstitution

Human Adenovirus (HAdV) reactivation is a frequent and potentially fatal complication in pediatric allogeneic stem cell transplantation (HSCT) recipients, especially after in vivo T-cell depletion. Patients with HAdV reactivations are generally treated with the antiviral agent Cidofovir (CDV), a monophosphate nucleotide analogue. Studies reporting effectiveness of CDV therapy are mostly incomplete due to lack of data on the immune status of the patients. Here, we report the relationship between the effectiveness of CDV therapy and lymphocyte reconstitution as well as the acute and chronic nephrotoxicity of CDV in the setting of pediatric .infections after pediatric HSCT.Between 2003 and 2012, 321 children received 363 allogeneic transplantations in our pediatric HSCT center. HAdV reactivations were monitored by weekly plasma HAdV DNA RQ-PCR. Disseminated infections, defined as two consecutive PCR values above 103 (3 log ) copies / mL occurred in 40 patients (12 %). 30 patients were treated with CDV for infections with an HAdV load ≥ 3 log at start of therapy. In 27 patients, sufficient data were available to evaluate the effectiveness of CDV. Cidofovir was administered IV 3x / week at 1 mg / kg. Prehydration and Probenecid were used to reduce the risk of nephrotoxicity. Patient were median 4.5 (0.5 - 18) years of age and 26 of 27 patients received in vivo T-cell depletion. CDV therapy was initiated median 28 (1 - 121) days after HSCT while the median treatment duration was 15 (1 - 99) days. At start of CDV treatment, the HAdV load was median 4.2 log (range 3.1 log - 6.5 log) copies / mL.Response was evaluated after 14 days of CDV therapy. A ≥ 10x (1 log) reduction of HAdV load was measured in 10 of 27 evaluable patients (37%) while 13 patients (48%) showed a stabilization of HAdV load. CDV treatment failed in 4 patients (15 %), as define by a 1 log increase of HAdV load despite uninterrupted CDV therapy. In 23 patients with a reduction or stabilization of the HAdV load, lymphocyte numbers increased strongly in the two weeks after initiation of CDV treatment (median 130 to 608 lymphocytes / µL, p < 0.0001, Wilcoxon signed-rank test). This increase was caused by reconstitution of NK cells (n = 5), T-cells (n = 4) or both (n = 12). In only 2 patients with a stabilization of HAdV load, no concomitant reconstitution of NK or T-cells was observed.Ultimately, 17 patients (63 %) cleared the virus 5 - 89 (median 33) days after the initiation of CDV therapy. The moment of HAdV clearance was strongly correlated to the first day the T-lymphocytes reached 50 cells/ µl (R2 = 0.79, p < 0.0001, linear regression analysis). 7 patients died of progressive HAdV viremia with multi-organ failure (MOF) at 20 - 154 (median 51) days after initiation of CDV therapy. Three patients were not evaluable as they died of another cause (n=2) or were lost to follow up (n=1) without clearance of the virus.For the analysis of CDV nephrotoxicity, 3 patients with HAdV related MOF during CDV therapy were excluded, leaving 24 patients. In 4 patients (17%), CDV therapy had to be discontinued because of acute glomerular failure, which invariably occurred within the first 2 weeks of treatment. Tubular kidney failure, defined by the need for suppletion of phosphate, magnesium or bicarbonate, was observed in 17 of 24 patients (71%). Kidney failure was transient in the majority of patients. After 1 year, 1 of 12 survivors (8 %) had chronic glomerular and tubular kidney failure that could not be explained by nephrotoxic co-medication. In 9 additional HSCT recipients who received > 7 days of CDV therapy for non-disseminated HAdV infections, 1 of 8 surviving patients (13 %) had chronic kidney failure that was unlikely to be caused by other nephrotoxic medication.In conclusion, a reduction of HAdV load in the first 2 weeks of therapy was always accompanied by lymphocyte recovery while Cidofovir could not prevent further dissemination in 4 of 27 patients. In most patients with a stabilization of the viremia, this could be attributed to both CDV as well as T- or NK-cell reconstitution whereas in only 2 patients (7%), the HAdV load stabilized in the absence of lymphocyte recovery. These data suggest that CDV possibly plays a role in the stabilization of HAdV viremia in the time pending T-cell recovery. In view of the considerable toxicity profile, a multicenter randomized clinical trial is warranted to establish efficacy of CDV treatment for disseminated HAdV infections after pediatric HSCT.▪ Disclosures:Off Label Use: The antiviral agent Cidofovir (CDV), a monophosphate nucleotide analogue, is widely used off-label for the treatment of disseminated Human Adenovirus infections after Pediatric Hematopoietic Stem Cell Tansplantation.

Type dependent patterns of human adenovirus persistence in human T‐lymphocyte cell lines

Disseminated adenovirus infections cause significant mortality in stem cell transplanted patients and are suspected to originate from asymptomatic adenovirus persistence ("latency") in lymphocytes. The infection of three human T-lymphocyte lines (Jurkat, PM1, and CEM) with human adenovirus types of species A (HAdV-A31), B (HAdV-B3, -B11), and C (HAdV-C2, -C5) was investigated for 150 days in order to establish in vitro models for adenovirus persistence. HAdV-C5 persisted with continuous production of infectious virus progeny (about 10(7) TCID50 /ml) in PM1 cells. More than 100 copies of HAdV-C5-DNA per cell were detected by real-time PCR but hexon immunostaining showed that only 7.5% of the cells were infected ("carrier state infection"). Coxsackie and adenovirus receptor (CAR) expression was decreased in comparison to mock infected cultures suggesting selection of a semi-permissive subpopulation of PM-1 cells. By contrast, latency of HAdV-DNA (10(-3) -10(-4) copies/cell) without production of infectious virus progeny was observed in HAdV-C2 infection of PM1 and Jurkat, HAdV-A31 infection of PM1, and HAdV-B3 infection of Jurkat cells. In addition, transcription of E1A, DNA polymerase and hexon mRNA was not detected by RT-PCR suggesting an equivalent of clinical "HAdV latency." Persistence of HAdV-DNA was not observed in abortive infections of PM1 cells with HAdV-B3 and -B11 and in productive, lytical infections of Jurkat cells with HAdV-C5, HAdV-B11, and HAdV-A31. In conclusion, lytic and persistent infections with and without production of infectious virus were observed depending on the type of adenovirus. Genetic determinants for viral persistence may be investigated using these newly established infection models.

Safety and Efficacy of CMX001 as Salvage Therapy for Severe Adenovirus Infections in Immunocompromised Patients

No therapeutic agent has yet been established as the definitive therapy for adenovirus infections. We describe the clinical experience of 13 immunocompromised patients who received CMX001 (hexadecyloxypropyl cidofovir), an orally bioavailable lipid conjugate of cidofovir, for adenovirus disease. We retrospectively analyzed 13 patients with adenovirus disease and viremia treated with CMX001; data were available for ≥ 4 weeks after initiation of CMX001 therapy. Virologic response (VR) was defined as a 99% drop from baseline or undetectable adenovirus DNA in serum. The median age of the group was 6 years (range, 0.92-66 years). One patient had severe combined immunodeficiency, 1 patient was a small bowel transplant recipient, and 11 were allogeneic stem cell transplant recipients. Adenovirus disease was diagnosed at a median of 75 days (range, 15-720 days) after transplantation. All patients received i.v. cidofovir for a median of 21 days (range, 5-90 days) before CMX001 therapy. The median absolute lymphocyte count at CMX001 initiation was 300 cells/μL (range, 7-1500 cells/μL). Eight patients (61.5%) had a ≥ 1 log10 drop in viral load after the first week of therapy. By week 8, 9 patients (69.2%) demonstrated a VR, with a median time to achieve VR of 7 days (range, 3-35 days). The change in absolute lymphocyte count was inversely correlated with the change in log10 viral load only at week 6 (r = -0.74; P = .03). Patients with VR had longer survival than those without VR (median 196 days versus 54.5 days; P = .04). No serious adverse events were attributed to CMX001 during therapy. CMX001 may be a promising therapeutic option for the treatment of severe adenovirus disease in immunocompromised patients.

Generation of cytotoxic T-cell lines using overlapping pentadecapeptides derived from conserved regions of the adenovirus hexon protein

Many of the 51 serotypes of adenovirus have been associated with clinically relevant infection. Adenovirus can disseminate rapidly in patients with a compromised immune system, such as that which occurs secondary to haematopoietic progenitor-cell transplantation. The higher rate of infection in recipients of T cell-depleted grafts and in those undergoing T cell-targeted treatment during graft versus host disease demonstrates the importance of a T-cell response in preventing disseminated infection. Studies have shown that the memory response to adenovirus is directed primarily to the hexon protein and is dominated by CD4+ T cells, probably due to the ability of the virus to block its presentation on HLA class I antigens. We have developed an approach to expand adenovirus-specific T cells using a pool of overlapping pentadecapeptides derived from selected conserved regions of hexon. We characterized responses to identify the peptides that are recognized, the responding T-cell subsets and their HLA restriction. Of eight lines that were characterized extensively, seven included both CD4+ and CD8+ T cells and each recognized between two and eight unique peptide sequences. By focusing the response on the conserved sequences of hexon, the cell lines are likely to recognize most of the serotypes responsible for clinically relevant disease. The 15 aa peptides used to prime the responses are more likely than whole virus or longer peptides to expand the less frequent CD8+ memory subset. Lines prepared by using our method may be more effective in adoptive immunotherapy protocols designed to prevent or treat disseminated adenovirus infections in high-risk patients.

Disseminated adenovirus infections after allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcome

We analyzed the factors and outcome of patients with disseminated adenovirus infection (dAdV) after allogeneic hematopoeitic stem cell transplantation (HSCT). Thirty patients with dAdV were identified among 620 allogeneic HSCT recipients. Primary diseases were leukemia (n=17), Fanconi anemia (n=12) or others (n=1). Source of stem cells was unrelated in 28 and related in 2 patients. The graft consisted of peripheral blood (n=3), bone marrow (n=12) and unrelated cord-blood (UCB, n=15). Risk factors for dAdV in unrelated HSCT recipients were previous Fanconi disease (p=0.03) and GVHD (p=0.02) in children, and cord blood source of stem cells (p=0.029) and GVHD (0.024) in adults.

Assessment of disseminated adenovirus infections using quantitative plasma PCR in adult allogeneic stem cell transplant recipients receiving reduced intensity or myeloablative conditioning

Disseminated adenovirus (AdV) infections following allogeneic stem cell transplantation (allo-SCT) are increasingly recognised, particularly in children. This study evaluated the clinical relevance of disseminated AdV infections in adult allo-SCT recipients, after different conditioning regimens. In a cohort of 107 adult allo-SCT recipients, receiving either reduced intensity conditioning (RIC, n = 48) or myeloablative conditioning (MAC, n = 59), AdV DNA levels in plasma were determined retrospectively at 1, 3 and 6 months following transplantation. Results of this screening regimen were compared with a cohort of 58 paediatric allo-SCT recipients, in whom AdV DNA load was monitored prospectively, as part of a pre-emptive treatment strategy. In positive cases, the course of AdV DNA load and clinical outcome were assessed. AdV DNA levels > or =1000 copies/mL were detected in five adults (4.7%) and eight children (13.8%). Screening for AdV viraemia at 1, 3 and 6 months would have detected seven of eight paediatric patients. One adult, receiving MAC, died with disseminated AdV disease and in four (three RIC and one MAC) AdV viraemia was transient without clinical symptoms specifically attributable to AdV. Seven paediatric patients with AdV viraemia were pre-emptively treated with ribavirin or cidofovir and in three of them disseminated AdV infection was related to a fatal outcome. Disseminated AdV infections following allo-SCT was a rare event in the adults and cause morbidity in a minority of these patients. In four of five adult patients, spontaneous clearance of AdV viraemia occurred. Results did not differ between the conditioning regimens that were applied in the adult cohort.

Disseminated Adenovirus Infections after Allogeneic Hematopoietic Stem Cell Transplantation: High Rate of Associated Co-Morbidity and Mortality.

Adenovirus (ADV) infection is associated with significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to determine the cumulative incidence, the evolution and the risk factors of disseminated ADV infection defined as a real time ADV PCR positive in blood and 1 or more additional sites. Between January 2000 and April 2006, 38 patients with disseminated ADV were identified. Median age at diagnosis was 15 years (4 – 48). Primary diseases were leukemia (n=16), Fanconi anemia (n=10) or others (n=2). All but one patient received an unrelated HSCT. The graft consisted in peripheral blood (n=3), bone marrow (n=10) and cord blood (n=15). Plasma ADV PCR was positive at a median of 79 days after HSCT (range: 12 – 460). Involved organs were: liver (n=12), respiratory tract (n=15), gut (n=21), cystitis (n=12) and 19 patients had fever. Twenty-one patients had grade II-IV GVHD. The majority of the patients had other concomitant infections: invasive fungal infection (n=15), 1 to 4 other virus (CMV, EBV, RSV, parainfluenzae, BK virus) (n=21) and bacteremia (n=12). Risk factors for disseminated ADV were analyzed among patients who received an unrelated HSCT, and separately in adults and in children. 265 patients received an unrelated HSCT during the same period. Cumulative incidence (with death as a competing event) of disseminated ADV was 9% (95%CI: 4–3) in adults and 18% (95%CI: 10-27) in children. In adults, grade II–IV GVHD [time dependant covariate, Hazard Ratio (HR): 3.47, 95%CI: 1.14–10.6, p = 0.029] and cord blood as source of stem cell [HR: 7.10, 95%CI: 2.41-20.9, p = 0.0038] were associated with disseminated ADV infection. In children, grade II-IV GVHD [HR: 3.94, 95%CI: 1.15–13.5, p = 0.029] and Fanconi as primary disease [HR: 5.28, 95%CI: 1.69-16.6, p = 0.0043] were associated with disseminated ADV infection. Twenty-three patients were treated by cidofovir. Four patients had complete response (CR) [negative ADV PCR], 2 patients had primary CR followed by relapse and 2 patients had stable disease 90 and 67 days after treatment initiation. Fifteen patients were refractory to treatment. Main differences between responders and non-responders were ADV DNA load at onset of treatment (1343 versus 71 674 copies/ml), median time from HSCT to ADV diagnosis (98 versus 53 days), dosage of corticosteroids at time of treatment (0.75mg/kg/d versus 1.5 mg/kg/d), neutrophil (2× 109/L versus 1.5 × 109/L) and lymphocyte count (0.135 × 109/L and 0.070 × 109/L). An increase in the plasma viral load of ≥ 4 log10 in the 30 days after the first cidofovir dose was always followed by a fatal issue (n=9). Four-month infectious-related mortality and 1-year survival after diagnosis was 72% (95% confidence interval: 55–90) and 23% (95%CI:10–51). The only survivors were among the sustained responders in whom 1-year survival was 33% (95%CI: 7–100). In spite of earlier diagnosis and cidofovir treatment, disseminated ADV disease after HSCT leads to a high mortality rate, mainly related to multiple infections for all patients, reflecting a profound underlying immune defect.

Detection of adenovirus DNA in clinical samples by SYBR Green real‐time polymerase chain reaction assay

Adenoviruses are associated with a variety of diseases including upper respiratory tract infections, acute conjunctivitis, cystitis and gastroenteritis. Adenoviruses can also cause fatal disseminated infections in patients undergoing stem cell transplantation. Measurement of adenovirus load in clinical samples from localized adenovirus infections or disseminated adenovirus infections may provide important information for analyzing the pathogenesis of various adenovirus infections. The purpose of the present study was to develop and optimize a highly sensitive real-time polymerase chain reaction (PCR) assay to detect a wide range of adenoviruses and to detect adenovirus DNA in clinical samples from immunocompetent children. Clinical samples of throat swabs and blood were collected from 111 patients suspected of having adenovirus infection. The copy number of adenovirus DNA was measured by real-time PCR assay. SYBR Green real-time PCR assay is able to detect 10-10(6) copies of standard adenovirus DNA per run. Adenovirus DNA was detected in all culture-positive samples serotyped as 1, 2, 3, 4, 5, 6, 8 and 11. Viral loads on throat swabs from immunocompetent children with adenovirus infection ranged from 10(5) to 10(11) copies/mL. Adenovirus DNA was detected in 60% of blood samples and copy number ranged from 10(3) to 10(5) copies/mL. SYBR Green real-time PCR is a useful quantitative tool for analysis of adenovirus DNA. The present results for immunocompetent children with adenovirus infections provided basic data for comparison with data obtained from immunocompromised patients.

Fatal Disseminated Adenovirus Infections in Immunocompromised Patients

Adenovirus has emerged as an important pathogen in immunocompromised patients, in whom disseminated disease occurs frequently and is associated with a high mortality rate. In a retrospective review of 1,847 consecutive autopsies, we identified 84 cases where adenovirus infection was suspected clinically. Adenovirus infection was confirmed at autopsy in 8 (10%) of 84 cases; all were immunocompromised patients. Six (75%) of these cases had disseminated adenovirus infection that contributed to death. Pathologic findings attributed to adenovirus infection included pneumonia with or without intra-alveolar hemorrhage, hepatic necrosis, enterocolitis with or without mucosal hemorrhage, epicardial hemorrhage, and ulcerations of the larynx, trachea, and ileum. This work shows that severe and fatal adenovirus infections are not infrequent, particularly in the immunocompromised population. Both clinicians and pathologists must become aware of the pathogenicity of adenovirus in this patient population, including its potential for causing life-threatening hemorrhage.

Fatal adenovirus type 7b infection in a child with Smith‐Lemli‐Opitz syndrome

Adenovirus type 7 causes worldwide respiratory tract infections, mainly in children. Severe systemic infections can occur, especially in immunocompromised patients and in patients with underlying chronic diseases. This report describes the first case of a fatal disseminated adenovirus type 7 infection in a child with Smith-Lemli-Opitz syndrome, a rare autosomal recessive disorder due to a primary enzymatic defect in cholesterol metabolism. Nasopharyngeal secretions and autopsy specimens including liver, lung, pleural fluid, and rectum were collected for viral culture. Adenovirus serotype 7 strains were obtained from all anatomic sites, except the liver. All these clinical isolates were analyzed using restriction endonuclease digestion of the genome, identifying them as genome type 7b, a virulent type. In this case, the fatal evolution could have been accelerated by the presence of an immunodeficiency although immunodeficiency is not included in the definition of Smith-Lemli-Opitz syndrome. The frequent recurrent banal infections in Smith-Lemli-Opitz syndrome could be prevented by a cholesterol supplementation regimen. Finally, this report emphasizes the need for efficient therapy for disseminated adenovirus infections, especially for virulent genome types. J. Med. Virol. 65:66–69, 2001. © 2001 Wiley-Liss, Inc.

Fatal adenovirus type 7b infection in a child with Smith‐Lemli‐Opitz syndrome

Adenovirus type 7 causes worldwide respiratory tract infections, mainly in children. Severe systemic infections can occur, especially in immunocompromised patients and in patients with underlying chronic diseases. This report describes the first case of a fatal disseminated adenovirus type 7 infection in a child with Smith‐Lemli‐Opitz syndrome, a rare autosomal recessive disorder due to a primary enzymatic defect in cholesterol metabolism. Nasopharyngeal secretions and autopsy specimens including liver, lung, pleural fluid, and rectum were collected for viral culture. Adenovirus serotype 7 strains were obtained from all anatomic sites, except the liver. All these clinical isolates were analyzed using restriction endonuclease digestion of the genome, identifying them as genome type 7b, a virulent type. In this case, the fatal evolution could have been accelerated by the presence of an immunodeficiency although immunodeficiency is not included in the definition of Smith‐Lemli‐Opitz syndrome. The frequent recurrent banal infections in Smith‐Lemli‐Opitz syndrome could be prevented by a cholesterol supplementation regimen. Finally, this report emphasizes the need for efficient therapy for disseminated adenovirus infections, especially for virulent genome types. J. Med. Virol. 65:66–69, 2001. © 2001 Wiley‐Liss, Inc.