Detection of adenovirus hepatitis and acute liver failure in allogeneic hematopoietic stem cell transplant patients

Human adenovirus (HAdV) is an important cause of the common cold and epidemic keratoconjunctivitis in immunocompetent individuals. In immunocompromised patients, HAdV can sometimes cause severe infection such as cystitis, gastroenteritis, pneumonia, encephalitis, hepatitis, or disseminated disease, resulting in significant morbidity and also mortality. In particular, severe cases have been reported in patients after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Indeed HAdV has been recognized as a pathogen that requires careful monitoring in allo‐HSCT patients. While HAdV hepatitis leading to severe acute liver failure is rare, such liver failure progresses rapidly and is often fatal. Unfortunately, HAdV hepatitis has few characteristic symptoms and physical findings, which makes it difficult to promptly confirm and start treatment. We report here four cases of HAdV hepatitis after allo‐HSCT and their autopsy findings

Enterovirus-Associated Hand-Foot and Mouth Disease and Neurological Complications in Japan and the Rest of the World

Enteroviruses (EVs) are responsible for extremely large-scale, periodic epidemics in pediatric cohorts, particularly in East and Southeast Asia. Clinical presentation includes a diverse disease spectrum, including hand-foot and mouth disease (HFMD), aseptic meningitis, encephalitis, acute flaccid paralysis, and acute flaccid myelitis. HFMD is predominantly attributable to EV-A types, including the major pathogen EV-A71, and coxsackieviruses, particularly CV-A6, CV-A16, and CV-A10. There have been multiple EV-A71 outbreaks associated with a profound burden of neurological disease and fatal outcomes in Asia since the early 1980s. Efficacious vaccines against EV-A71 have been developed in China but widespread pediatric vaccination programs have not been introduced in other countries. Encephalitis, as a consequence of complications arising from HFMD infection, leads to damage to the thalamus and medulla oblongata. Studies in Vietnam suggest that myoclonus is a significant indicator of central nervous system (CNS) complications in EV-A71-associated HFMD cases. Rapid response in HFMD cases in children is imperative to prevent the progression to a CNS infection; however, prophylactic and therapeutic agents have not been well established internationally, therefore surveillance and functional studies including development of antivirals and multivalent vaccines is critically important to reduce disease burden in pediatric populations

Infectious human adenoviruses are shed in urine even after disappearance of urethral symptoms.

BACKGROUND:Urethritis is a common sexually transmitted disease, and human adenoviruses (HAdVs) have been found to be associated with nonchlamydial nongonococcal urethritis. However, the level and viability of HAdV in the urine of patients with urethritis remain unclear. METHODS:Male patients with urethritis and an asymptomatic group were screened using their First-void urine (FVU) for urethritis-related pathogens to identify those with HAdV DNA. FVU and gargle fluid were collected from all patients including from those in the asymptomatic group. A swab of eye discharge was also collected from patients with eye symptoms. The pharyngeal and/ or ocular fluid was also screened only in cases in which FVU was positive for HAdV DNA. HAdVs were isolated using A549 cell lines and typed by sequencing, and viral shedding during 2 years was quantified using real-time PCR. The prevalence of HAdV was assessed in the urethritis and asymptomatic groups, and viral load, isolated HAdV types, and urethral symptoms were compared between the groups. RESULTS:The positive detection rate of HAdV DNA was significantly higher in the urethritis group than in the asymptomatic group. Of 398 patients with urethritis, HAdV was isolated in all 32 cases (23 cases in which only HAdV DNA was detected with a mean of 2 × 109 copies/mL in urine samples). Of 124 control cases, one had HAdV monoinfection. The most frequently detected HAdV type was 56, followed by types 37 and 64. Regarding the relationship between symptoms and isolated HAdVs, the virus was isolated for up to 12 days after urethritis symptoms disappeared. CONCLUSIONS:HAdVs were significantly detected and isolated from the FVU of patients with urethritis. Furthermore, high levels of infectious HAdVs are excreted in urine for a long period even after urethritis symptoms disappear

Simultaneous development of Kawasaki disease following acute human adenovirus infection in monozygotic twins: A case report

Abstract Background The etiology of Kawasaki disease (KD) remains unknown. However, many studies have suggested that specific genetic factors and/or some infectious agents underlie the onset of KD. Previous studies have suggested that human adenovirus (HAdV) is one of the triggering pathogens of KD. Here, we report monozygotic twin boys who sequentially developed KD in conjunction with acute HAdV type 3 (HAdV-3) infection. Case presentation The patients were four-year-old monozygotic twin boys. The elder brother developed a high fever and was diagnosed with HAdV infection with an immunochromatographic kit for HAdV (IC-kit). He was transferred to our institute after persistent fever for 7 days. On admission, he already fulfilled all the diagnostic criteria for KD. His laboratory data were as follows: WBC, 9700/μl; CRP, 2.42 mg/dl; IFN-γ, 99.8 pg/ml; and TNF-α, 10.9 pg/ml. He received intravenous immunoglobulin (IVIG) and aspirin and responded well, with no coronary artery abnormalities. The younger brother, who was also IC-kit-positive, was hospitalized on the same day as his elder brother after persistent fever for 3 days. His data on admission were as follows: WBC, 12,600/μl; CRP, 5.54 mg/dl; IFN-γ, 105.0 pg/ml; and TNF-α, 33.6 pg/ml. Although he developed all of the typical KD symptoms by day 4, his fever subsided spontaneously on day 6 without IVIG or aspirin. However, he developed a dilation of the coronary artery in the region of the left circumflex artery bifurcation on day 10. His coronary artery dilation had resolved 3 months after onset. HAdV-3 DNA was detected with PCR in stool samples from both patients, and HAdV3 was isolated from the younger brother’s stool sample. Serum neutralizing antibodies to AdV3 were also significantly elevated in both patients, suggesting seroconversion. Conclusions There have been few reports of the simultaneous development of KD in monozygotic twins. Notably, both twins had an acute HAdV-3 infection immediately before they developed KD. These cases strongly suggest that KD was triggered by HAdV-3 infection, and they indicate that specific immune responses to some pathogens (such as HAdV-3), arising from genetic susceptibility, play a critical role in the pathogenesis of KD

Possible nosocomial transmission of virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation

Adenovirus (ADV)- or BK virus (BKV)-associated hemorrhagic cystitis (HC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Several risk factors have been previously reported; however, it is unclear whether virus-associated HC can be transmitted. To clarify this point, we performed a retrospective cohort study on 207 consecutive patients who underwent allo-HSCT at Kyoto University Hospital between 2012 and 2018. We evaluated the incidence and risk factors of virus-associated HC and performed a phylogenetic analysis of the ADV partial sequence. The median age at transplantation was 50 (range, 17-68) years. Fifty-eight patients (28%) developed HC. ADVs were detected in 18 cases, BKVs were detected in 51, both were detected in 12, and only John Cunningham virus (JCV) was detected in 1 case. No factor was significantly associated with HC. However, both ADV- and BKV-HC occurred intensively between April 2016 and September 2017, which suggested possible nosocomial transmission of ADV and BKV. Genome sequencing of the hexon, E3, and penton regions of detected ADVs identified 7 cases of ADV type 11, 2 cases of type 35, and 3 cases of a type 79-related strain. A sequence analysis revealed that these strains in each type were almost identical, except for one case of a type 79-related strain. In conclusion, ADV-HCs with possible nosocomial transmission were described based on genotyping of the virus and partial sequencing of the viral genome. Although viral HC after allo-HSCT is thought to mainly be due to reactivation of a latent virus, nosocomial transmission of ADV or BKV should also be considered

Human adenoviral type 54 keratoconjunctivitis accompanied by stellate keratitis and keratic precipitates: two cases

Abstract Background Of the 10 patients with adenoviral type 54 keratoconjunctivitis examined at Nojima Hospital, 2 developed stellate keratitis and mutton-fat keratic precipitates (KPs) following acute symptoms. Case presentation We encountered 10 cases of epidemic keratoconjunctivitis from August to October 2017. All patients were adults with a mean age of 60.9 ± 10.0 years. The species D human adenovirus (HAdV)-54 was detected in the conjunctival scrapings of these patients. Fluorometholone instillation was administered during the first week for acute symptomatic relief. Case 1: A 64-year-old female was prescribed with fluorometholone instillation, which was discontinued after 1 week when her symptoms alleviated. One week after discontinuation of the instillation, she presented with blurred vision in her left eye with KPs and multiple stellate keratitis. The anterior chamber had no apparent cells. Her symptoms disappeared after 1 week of betamethasone instillation. Case 2: A 66-year-old female was prescribed with 0.1% fluorometholone instillation, which was discontinued within10 days. Three months after the appearance of initial symptoms, multiple subepithelial corneal infiltrates (MSI) appeared in her eyes. Stellate keratitis and dark-brown pigmentation were observed in the centres of MSI, with several cells in the anterior chamber. Betamethasone was prescribed, and MSI and stellate keratitis improved within 1 week. However, KPs were observed in the left eye. The instillation was continued for 3 more weeks until symptoms improved. Conclusions MSI is an immune reaction that occurs after the disappearance of acute symptoms. Here, corneal findings and KPs were observed after improvement in eye redness and discontinuation of steroids. These symptoms were presumed to be secondary inflammation due to immune response to the adenoviral antigen. The clinical features of HAdV-54 keratoconjunctivitis on the ocular surface are initially moderate, but become active in the subacute to chronic phases. This may develop atypical findings, including stellate keratitis with KPs. Although early steroid administration can relieve acute symptoms, it may facilitate chronic corneal immunological reaction

Prescription Surveillance and Polymerase Chain Reaction Testing to Identify Pathogens during Outbreaks of Infection

Syndromic surveillance, including prescription surveillance, offers a rapid method for the early detection of agents of bioterrorism and emerging infectious diseases. However, it has the disadvantage of not considering definitive diagnoses. Here, we attempted to definitively diagnose pathogens using polymerase chain reaction (PCR) immediately after the prescription surveillance system detected an outbreak. Specimens were collected from 50 patients with respiratory infections. PCR was used to identify the pathogens, which included 14 types of common respiratory viruses and Mycoplasma pneumoniae. Infectious agents including M. pneumoniae, respiratory syncytial virus (RSV), rhinovirus, enterovirus, and parainfluenza virus were detected in 54% of patients. For the rapid RSV diagnosis kit, sensitivity was 80% and specificity was 85%. For the rapid adenovirus diagnosis kit, no positive results were obtained; therefore, sensitivity could not be calculated and specificity was 100%. Many patients were found to be treated for upper respiratory tract infections without the diagnosis of a specific pathogen. In Japan, an outbreak of M. pneumoniae infection began in 2011, and our results suggested that this outbreak may have included false-positive cases. By combining syndromic surveillance and PCR, we were able to rapidly and accurately identify causative pathogens during a recent respiratory infection outbreak