The Human Virome and Febrile Illness in Children

Definition of the human microbiome is an important scientific priority. This study will expand the scope of the investigation to include viruses, which account for a substantial proportion of infectious disease morbidity and mortality, especially in children. The long-term goal of this project is to describe the human virome in children and to investigate its relevance to febrile illnesses in children. The project will also seek to understand the relationship of the immune system to the composition of the virome. Thus, the project's specific aims are 1) To elucidate the spectrum of viruses that can be detected using non-biased, high throughput sequencing on samples of blood, respiratory, and gastrointestinal secretions from healthy children and to use this information as a basis for understanding the role of viruses in acute febrile illnesses without an obvious source, and 2) to investigate the effect of various forms of immunosuppression on the spectrum of viruses detected in children, and to use this information as a basis for understanding the role of viruses in acute febrile illnesses occurring in these children. Our preliminary studies show that diverse viruses can be detected in children having undiagnosed fever. To carry out the specific aims, well children will be enrolled prior to having elective surgery, and febrile otherwise well children will be enrolled from the Emergency Department at St. Louis Children's Hospital. Immunocompromised children will be recruited from hematopoietic stem cell and solid organ transplant clinics, the HIV/AIDS clinic, and the rheumatology/immunology clinic from the same hospital. Children with fever will have samples obtained at the time of the febrile illness and at 1 and 6-month follow-up visits. Selected samples from each study group will be analyzed at the Genome Center at Washington University (GCWU) using next generation 454 high throughput sequencing to detect and sequence all viral sequences present. We anticipate detecting and sequencing a broad range of viruses, including previously unrecognized agents. A variety of techniques will be used to investigate the significance of viruses detected. Virus-specific PCR assays will be used to determine the frequency and extent of viruses detected by sequencing, using the full range of samples collected. Host response to the detected viruses will be investigated using serologic analysis, cytokine profiling, and microarrays to characterize host gene expression. These studies will take advantage of follow-up samples to compare the acute response with the response in the convalescent period. This study will draw upon the expertise and technological assets of one of the world's most powerful sequencing centers to provide the research community with a comprehensive sequence data base of the viruses that are present in children, which can be used to improve our understanding of the causes of febrile illnesses in young children, many of which are currently undiagnosed.]]>
QUESTIONNAIRE FEBRILE CHILDREN'S STUDYHuman Virome ProjectInclusion criteria will be listed separately for each group of subjects: Febrile otherwise-well children: Fever greater than 38°C, age 2-36 months Afebrile well children: Age 2-36 months Febrile immunocompromised children: Fever greater than 38°C, and a) child with solid organ or hematopoietic stem cell transplant, or b) child followed in immunology/rheumatology clinic with congenital immunodeficiency or being treated with an immunosuppressive medication, or c) child with HIV with CD4 percentage less than 15%. Afebrile immunocompromised children: Same subject groups as 3) Transplant recipients: Child with sold organ or hematopoietic stem cell transplantTransplant donor: Individual whose organ is being used for transplantation into a child. This can include living or cadaver donors. Exclusion criteria are listed separately for each group of subjects: Febrile otherwise-well children: Presence of an immunosuppressive underlying disease, a disease requiring immunosuppressive treatment, other serious chronic disease, indwelling intravascular catheter, Inability to obtain consent Afebrile well children: Any acute illness, Inability to obtain consent Febrile immunocompromised children: Inability to obtain consent Afebrile immunocompromised children: Inability to obtain consent Transplant recipients: Inability to obtain consent ]]>
Starting in July, 2007, we began a study of viral causes of fever in children between 2 and 36 months of age who had fevers without an idententifiable focus. Starting in February 2009, we also began to include well children having same day surgery as controls. During this same time frame, Dr. David Wang began to assemble a repository of specimens from children undergoing organ transplantation. These specimens from these studies were incorporated into the present study which began specimen collection in July, 2009.]]>