A Pilot Study of Fecal Microbiome and Neutrophil Cellular Adhesion Molecules in Patients With Sickle Cell Disease (SCD)
A Pilot Study of Fecal Microbiome and Neutrophil Cellular Adhesion Molecules in Patients With Sickle Cell Disease (SCD)
Patients with sickle cell disease often develop painful crisis without any obvious reasons.
 Some patients are more likely to develop this complication than others. It is now clear that
 painful crisis only occurs when sickled red blood cells stick to white blood cells that have
 been activated, usually by inflammation or infections. A recent study in mice with sickle
 cell disease showed that the use of long term antibiotics could reduce the number of
 activated white blood cells and reduce death of the mice during sickle cell crisis.

 The investigators believe that sickle cell patients who develop frequent painful crisis may
 have a different pattern of bacteria in their intestine when compared to those whose painful
 crisis occurs infrequently. In this study, the investigators propose to study sickle cell
 subject's blood to determine how many activated white blood cells he/she have. The
 investigators will also examine his/her stool to compare the bacteria in his/her stool to
 those other sickle cell patients. The investigators will then investigate whether or not the
 results from the blood and stool tests correlate with how frequently the patient develops
 painful crisis.

 The investigators will examine the patients' medical records to find out how many times they
 have been admitted to the hospital for sickle cell crisis in the last 12 months. The
 investigators will also obtain information on the following: their age, their sex, whether
 they are taking hydroxyurea or Penicillin, when they last had a transfusion or exchange
 transfusion therapy and painful crisis needing hospital admission, whether they have received
 any antibiotics (other than Penicillin) in the last 4 weeks, and whether they are
 experiencing a painful crisis at the time that they enter the study. The investigators will
 obtain, from their previous laboratory results, their levels of hemoglobin F and markers of
 inflammation. The investigators will check their hemoglobin F level if they have not already
 had this tested.

 The investigators expect to enroll 50 subjects into this study at Rhode Island
 Hospital/Hasbro Children's Hospital.
The clinical course of sickle cell disease (SCD) is very variable. Some patients experience
 vaso-occlusive disease infrequently, but other patients develop the complication recurrently.
 The reason for the difference remains unclear. Although erythrocyte sickling occurs due to
 factors such as dehydration, infections, extreme of temperatures, acidosis, and hypoxia,
 neutrophil adhesion and activation are crucial in eliciting the vaso-occlusive crisis in
 patients with SCD. Activated neutrophils upregulate the expression of various cellular
 adhesion molecules that increase their "stickiness" in vivo. A murine model of SCD
 demonstrated the importance of the intestinal microbiome in influencing the kinetics of
 ageing neutrophils. Depletion of the microbiota with prolonged courses of broad-spectrum
 systemic antibiotics resulted in a reduction of the number of these neutrophils and
 protection against LPS-induced fatal vaso-occlusive crisis in these mice.

 Intestinal barrier is a functional barrier that separates the gut lumen from the inner host.
 It consists of mechanical elements (mucus, epithelial layer), humoral elements (defensins,
 IgA), immunologic elements (lymphocytes, innate immune cells), muscular and neurological
 element. Although the normal intestinal microbiota is the main source of endogenous
 pathogens, it also contributes to the functional integrity of the intestinal barrier through
 its interaction with the other components of the barrier. Failure of any of these components
 will result in a breakdown of the protective intestinal barrier with the consequence of
 recurrent intestinal-derived bacteremia/septicemia. A breakdown of the normal microbiome has
 been implicated in the development of various pathologic states, including Clostridium
 difficile infection, inflammatory bowel disease, intestinal graft-versus-host disease
 following allogeneic hematopoietic progenitor cell transplant, colon cancer, and metabolic
 disorders such as obesity and non-alcoholic steatohepatitis.

 To explain the reason for the development of frequent vaso-occlusive crisis in some patients
 with SCD, the investigators' stepwise hypothesis is that, due to the sickling process and the
 consequent development of intestinal ischemia, patients with SCD, especially those with
 frequent vaso-occlusive crisis, are more likely to have altered microbiota than healthy
 individuals. If the normal microbiota is altered, the intestinal barrier will be compromised,
 rendering the patients more susceptible to recurrent bacteremia of intestinal origin. Since
 most SCD patients with vaso-occlusive crisis present without any obvious infections, it is
 likely that the compromised intestinal barrier facilitates an inoculum of bacteremia not high
 enough to cause overt infections but sufficient to activate neutrophils and elicit
 vaso-occlusive crisis. The first step towards testing this overall hypothesis is to test the
 sub-hypothesis that altered intestinal microbiomes correlate with increased number of
 activated neutrophils and frequent vaso-occlusive crisis in patients with SCD.
Inclusion Criteria:

 1. Both male and female will be accrued to the study, without any pre-specified sex
 ratio.

 2. Subject must have either HbSS or HbS/beta thal.

 3. Subject is >8 years of age; if subject is <18 years, parental consent is needed.

 4. Understands the process of and is willing to provide a written consent.

 Exclusion Criteria:

 1. Is taking immunosuppressive agents, including corticosteroids with prednisone at a
 dose of > 30 mg/day or other forms of corticosteroid at the equivalent dose.

 2. Has taken systemic antimicrobials (except prophylactic Penicillin) in the preceding
 two weeks.

 3. Has had a vaso-occlusive crisis in the preceding two weeks.

 4. Has a history of colon cancer or an inflammatory bowel disease.

 5. Has a history of clostridium difficile infection in the preceding eight weeks.

 6. History of psychiatric disorder which in the investigators opinion may compromise
 compliance with the protocol or which does not allow for appropriate informed consent.

 7. Pregnant or lactating females.

 8. Patients who are court-mandated to reside at a treatment facility (e.g., drug or
 psychiatric treatment) or prison.