Severe community acquired adenovirus pneumonia in an immunocompetent host successfully treated with IV Cidofovir.
ABSTRACT: Adenovirus is a common cause of acute febrile respiratory infection in children and are generally self-limiting although pneumonia can occur in neonates and adults with compromised immunity. However, severe adenovirus pneumonia in healthy adults has been rarely described. Here, we report a case of severe community-acquired adenovirus pneumonia in a previously healthy patient successfully treated with intravenous Cidofovir.
Project description:Most adenovirus infections are self-limiting in immunocompetent individuals. Here, we report a case of adenovirus pneumonia in a 17-year-old immunocompetent male. He was admitted to our emergency room complaining of a febrile sense, cough, and diarrhea for four days. Crackles in the left lung and a high fever (40.7?°C) were revealed. Initial chest X-ray and computed tomography images showed consolidation in the left lung. We immediately started empirical antibiotic treatment, but his clinical symptoms and pneumonic consolidation in radiography had not improved by hospital day three. Because adenovirus was detected in his sputum using RT-PCR, he was administered Cidofovir. After 24 h of Cidofovir treatment, the symptoms and fever subsided, and the consolidation in his X-ray was significantly reduced by hospital day nine. The early administration of Cidofovir could be beneficial for the treatment of adenovirus infection in immunocompetent patients.
Project description:The benefits of treatment with antiviral therapy for severe adenovirus (AdV) pneumonia are not well established. We described the clinical characteristics and treatment outcomes of early cidofovir treatment of severe AdV pneumonia in non-immunocompromised patients. We retrospectively reviewed the medical records of all patients diagnosed with severe AdV pneumonia between 2012 and 2014. A total of seven non-immunocompromised patients with severe AdV pneumonia were identified, and all isolates typed (n = 6) were human AdV-B55. All patients had progressive respiratory failure with lobar consolidation with or without patchy ground glass opacity. Three patients required vasopressors and mechanical ventilation. All patients had abnormal laboratory findings including: leukopenia, thrombocytopenia, or elevated liver enzymes. After admission, all patients received antiviral therapy with cidofovir, and the median time from admission to cidofovir administration was 48 h and median the time from onset of symptoms to cidofovir administration was 7.1 days. After cidofovir administration, complete symptomatic improvement occurred after a median of 12 days and radiographic resolution occurred after a median of 21 days. Consequently, all patients completely improved without complications. Our data suggest that early administration of cidofovir in the course of treatment for respiratory failure as a result of AdV pneumonia in non-immunocompromised patients could be a treatment strategy worth considering, especially in cases of HAdV-55 infection.
Project description:<h4>Objective</h4>To compare outcomes of early and delayed treatment with cidofovir for human adenovirus (HAdV) pneumonia.<h4>Methods</h4>A retrospective cohort study in Korean military hospitals was conducted between January 2012 and December 2018. Patients with potentially severe HAdV pneumonia with risk factors for respiratory failure were included and divided into early (within 7 days from symptom onset) and delayed (after 7 days from symptom onset) treatment groups. The primary outcome was respiratory failure development within 21 days after symptom onset.<h4>Results</h4>A total of 89 patients with potentially severe HAdV pneumonia were enrolled in the cohort; they included 62 early and 27 delayed treatment patients. All patients were males in their early 20s. Significantly fewer patients in the early treatment group progressed to respiratory failure (8/62, 12.9%), compared to the delayed group (18/27, 66.7%, p < 0.001). Early treatment was associated with a lower 21-day probability of respiratory failure by the Kaplan-Meier method (p < 0.001). On multivariate analysis, monocyte count, hypoxaemia, confusion, whole lung involvement, and early cidofovir treatment within 7 days from symptom onset were included, and monocyte count (HR 0.995, 95%CI 0.991-1.000, p 0.042), confusion (HR 4.964, 95%CI 1.189-20.721, p = 0.028), and early cidofovir treatment (HR 0.319, 95%CI 0.115-0.883, p = 0.028) were significantly associated with respiratory failure.<h4>Conclusions</h4>Early administration of cidofovir was associated with a lower hazard for respiratory failure development. It is suggested that cidofovir be administered within 7 days from symptom onset to prevent respiratory failure in patients with potentially severe HAdV pneumonia.
Project description:A 5-year-old female child, with known systemic juvenile idiopathic arthritis diagnosed at 18 months of age (on low dose Prednisolone?+?Methotrexate?+?Leflunomide?+?Tocilizumab), presented with fever for 1 day, vomiting, drowsiness followed by seizures. On admission to PICU, she was drowsy, tachycardic, tachypneic, with rashes, and hepatosplenomegaly. Lab findings showed thrombocytopenia, leucopenia, low ESR, normal CRP, elevated liver enzymes, high ferritin, LDH, and triglycerides suggestive of macrophage activation syndrome (MAS). Chest X-ray showed left basal pneumonia and DNA PCR of throat swab revealed adenovirus. She was diagnosed as adenovirus-triggered MAS and was initiated on pulse methylprednisolone (6 mg/kg). Because of suboptimal response after 2 doses, manifested by increasing drowsiness, further fall in platelets and rising ferritin, methylprednisolone dosage was increased to 30 mg/kg/day with the addition of oral cyclosporine (4 mg/kg/day). In view of worsening of the chest X-ray and increasing oxygen requirement, Cidofovir infusion (1 mg/kg thrice weekly) was also started simultaneously considering increased activity of the adenoviral infection concurrent to immunosuppression. Within 48 h, the child showed signs of recovery with improved consciousness, lower oxygen requirements, and improving lab parameters. She was discharged after 3 weeks of IV Cidofovir, on oral prednisolone and cyclosporine. To the best of our knowledge, this is the first reported use of Cidofovir in adenovirus-induced MAS.
Project description:BACKGROUND:Severe community-acquired pneumonia (CAP) due to human adenoviruses (HAdVs) in immunocompetent adults has raised concerns. OBJECTIVE:To describe the clinical, laboratorial, and radiological characteristics of adenovirus pneumonia and detect the type and diversity of human adenoviruses that caused acute respiratory distress syndrome (ARDS) in Beijing. STUDY DESIGN:An etiological study of adult community-acquired pneumonia was carried out prospectively at Beijing Chao-Yang Hospital. A total of 18 cases with laboratory-confirmed adenovirus infections in 487 cases with CAP were observed clinically. The viral type and phylogenetic analysis were tested by polymerase chain reaction (PCR). RESULTS:Patients with adenovirus pneumonia typically reported flu-like symptoms. Some of them developed shortness of breath or severe dyspnea on 6 days after disease onset. The patients with ARDS usually present dyspnea, higher level of serum muscle enzymes and bilateral, mutilobal consolidation and patchy/ground-glass opacities. HAdVs type was detected in 17 samples and all of them belonged to species B (HAdV-11, 7, 3 and 14). Among them, HAdV-11 was most frequently (10/17), followed by HAdV-7 (5/17). Phylogenetic analysis of the partial penton nucleotide confirmed a close relationship with stains circulating in the Beijing region. CONCLUSIONS:Our identification of severe respiratory illness due to adenovirus, especially type 11 may highlight the need for rapid diagnosis and improved surveillance, which may assist with targeted development of antiviral agents or type-specific vaccines.
Project description:Adenovirus is an important cause of haemorrhagic cystitis in kidney transplant recipients. The optimal treatment for adenovirus-associated haemorrhagic cystitis (AAHC) is unknown. Intravenous cidofovir may be effective, but nephrotoxicity is a major concern. The use of intravesical cidofovir for viral haemorrhagic cystitis has been reported in haematopoietic stem cell transplant recipients and may be associated with a lower risk of nephrotoxicity, but its use has not been reported in kidney transplant recipients. We report the use of intravesical cidofovir for the treatment of AAHC in a kidney transplant recipients, along with a review of the literature.
Project description:BACKGROUND:Severe community-acquired pneumonia (CAP) caused by human adenovirus (HAdV), especially HAdV type 55 (HAdV-55) in immunocompetent adults has raised increasing concerns. Clinical knowledge of severe CAP and acute respiratory distress syndrome induced by HAdV-55 is still limited, though the pathogen has been fully characterized by whole-genome sequencing. METHODS:We conducted a multicentre retrospective review of all consecutive patients with severe CAP caused by HAdV in immunocompetent adults admitted to the Emergency Department Intensive Care Unit of two hospitals in Northern China between February 2012 and April 2014. Clinical, laboratory, radiological characteristics, treatments and outcomes of these patients were collected and analyzed. RESULTS:A total of 15 consecutive severe CAP patients with laboratory-confirmed adenovirus infections were included. The median age was 30 years and all cases were identified during the winter and spring seasons. HAdV-55 was the most frequently (11/15) detected HAdV type. Persistent high fever, cough and rapid progression of dyspnea were typically reported in these patients. Significantly increased pneumonia severity index (PSI), respiratory rate, and lower PaO2/FiO2, hypersensitive CRP were reported in non-survivors compared to survivors (P = 0.013, 0.022, 0.019 and 0.026, respectively). The rapid development of bilateral consolidations within 10 days after illness onset were the most common radiographic finding, usually accompanied by adjacent ground glass opacities and pleural effusions. Total mortality was 26.7% in this study. Corticosteroids were prescribed to 14 patients in this report, but the utilization rate between survivors and non-survivors was not significant. CONCLUSIONS:HAdV and the HAdV-55 sub-type play an important role among viral pneumonia pathogens in hospitalized immunocompetent adults in Northern China. HAdV should be tested in severe CAP patients with negative bacterial cultures and a lack of response to antibiotic treatment, even if radiologic imaging and clinical presentation initially suggest bacterial pneumonia.
Project description:Background: Adenoviruses contribute to morbidity and mortality among immunocompromised pediatric patients including stem cell and solid organ transplant recipients. Cidofovir (CDV), an antiviral compound approved by the FDA in 1996, is used for treatment of adenoviral (ADV) infections in immunocompromised patients despite concern of potential nephrotoxicity. Methods: We conducted a retrospective 5-year review at Boston Children's Hospital of 16 patients (mean age = 6.5 years) receiving 19 courses of CDV. During therapy all pertinent data elements were reviewed to characterize potential response to therapy and incidence of renal dysfunction. Results: Of the 19 CDV courses prescribed, 16 courses (84%) were in patients who had a positive blood ADV Polymerase chain reaction (PCR) alone or in combination with positive ADV PCR/ Direct Immunofluorescence Assay (DFA) at another site. Respiratory symptoms with or without pneumonia were the most common presentation (10/19, 53%). In the majority of blood positive courses (10/16, 63%), viral clearance was also accompanied by clinical response. This was not the case in four courses where patients expired despite viral clearance, including one in which death was directly attributable to adenovirus. There was reversible renal dysfunction observed during the use of CDV. Conclusions: CDV appeared safe and reasonably tolerated for treatment of ADV in this pediatric population and was associated with viral response and clinical improvement in the majority of patients but reversible renal dysfunction was a side effect. Further studies of the efficacy of CDV for immunocompromised children with ADV infection are warranted.
Project description:Human adenovirus (AdV) can cause fatal disease in immune-suppressed individuals, but treatment options are limited, in part because the antiviral cytidine analog cidofovir (CDV) is nephrotoxic. The investigational agent brincidofovir (BCV) is orally bioavailable, nonnephrotoxic, and generates the same active metabolite, cidofovir diphosphate (CDVpp). However, its mechanism of action against AdV is poorly understood. Therefore, we have examined the effect of CDVpp on DNA synthesis by a purified adenovirus 5 (AdV5) DNA polymerase (Pol). CDVpp was incorporated into nascent DNA strands and promoted a nonobligate form of chain termination (i.e., AdV5 Pol can extend, albeit inefficiently, a DNA chain even after the incorporation of a first CDVpp molecule). Moreover, unlike a conventional mismatched base pair, misincorporated CDVpp was not readily excised by the AdV5 Pol. At elevated concentrations, CDVpp inhibited AdV5 Pol in a manner consistent with both chain termination and direct inhibition of Pol activity. Finally, a recombinant AdV5 was constructed, containing Pol mutations (V303I and T87I) that were selected following an extended passage of wild-type AdV5 in the presence of BCV. This virus had a 2.1-fold elevated 50% effective concentration (EC50) for BCV and a 1.9-fold increased EC50 for CDV; thus, these results confirmed that viral resistance to BCV and CDV can be attributed to mutations in the viral Pol. These findings show that the anti-AdV5 activity of CDV and BCV is mediated through the viral DNA Pol and that their antiviral activity may occur via both (nonobligate) chain termination and (at high concentration) direct inhibition of AdV5 Pol activity.
Project description:Human adenoviruses can cause serious disseminated infections including death in immunosuppressed patients, especially pediatric allogeneic hematopoietic stem cell transplant (allo-HSCT) patients. There are no drugs approved to treat such infections. Cidofovir is used intravenously in many transplant clinics, probably with some effect, but controlled trials have not been completed. Cidofovir is an acyclic nucleoside phosphonate analog of cytidine monophosphate. Following conversion to its diphosphate form within cells, cidofovir is a preferred substrate for the adenovirus DNA polymerase, leading to viral DNA chain termination. Problems with cidofovir include poor cellular uptake and nephrotoxicity. Brincidofovir, a lipid-linked derivative of cidofovir which is active against five families of double-stranded DNA viruses, represents a major advance in anti-adenovirus therapy. It is administered orally, taken up readily by cells followed by release of cidofovir within cells, and is not nephrotoxic. Brincidofovir, under development by Chimerix, Inc., is being evaluated against adenovirus infections in transplant patients including allo-HSCT patients in a phase III clinical trial (AdVise Study). Preliminary results indicate that brincidofovir is safe and very effective at decreasing adenovirus viremia and adenovirus-induced pathogenicity and mortality. Anti-adenovirus adoptive T cell therapy is another very promising approach to treating allo-HSCT patients as demonstrated in clinical studies.