Mucositis

The initial step in eligibility screening was the selection of children who fulfilled the WHO definition of diarrhea (≥3 abnormally loose stools in 24 hours [12 (link)]). In subsequent steps we identified cases of MSD, the primary outcome of interest, intending to capture diarrheal illnesses that would not be expected to resolve spontaneously without medical intervention or without sequelae, because these illnesses constitute priorities for development of vaccines and other new or improved preventive and therapeutic strategies. We reasoned that episodes that would qualify as MSD fell into 2 general categories: (1) those accompanied by dehydration to a degree that the child's survival would likely depend on access to life-saving rehydration fluids, and (2) those with evidence of inflammatory destruction of the intestinal mucosa, thereby at increased risk for disabling sequelae (such as persistent diarrhea [14 (link)] and stunting [15 (link)]) or death [16 (link), 17 (link)].
To capture children who had potentially life-threatening diarrheal dehydration, we adapted the WHO definition of dehydration to our case definition of MSD [18 , 19 ], choosing the most objective signs (sunken eyes more than usual and slow or very slow recoil after an abdominal wall “skin pinch”). In addition, we included the determination by a healthcare provider that the severity of dehydration warranted administration of intravenous fluids. Although not part of our case definition, other signs of dehydration proposed by WHO were documented, including restlessness or irritability and drinking eagerly or appearing thirsty (considered to be signs of “some” dehydration), and lethargy, loss of consciousness, inability to drink, or drinking poorly (as signs of “severe” dehydration). During analysis we will explore the impact on the study findings of including these other signs of dehydration in the definition of MSD. We considered adopting as inclusion criteria elements of systems used widely to define severe illness in rotavirus vaccine trials [20 (link)–22 (link)]. However, many of the components, such as total duration and maximum severity of diarrhea, vomiting, and fever, can only be determined in retrospect when the episode is resolving or resolved, at which point the decision to include a child in GEMS would already have been made. Instead, our approach has been to collect this information for exploration during analysis.
To capture children with evidence of diarrheal diseases caused by inflammation and mucosal injury in the case definition, we enrolled children with dysentery. Because there is no marker to predict which cases of dysentery are likely to experience clinically significant intestinal damage, we included all children with diarrhea who passed at least 1 stool containing visible blood according to either the caretaker or the clinician. Finally, we included children with diarrhea who appeared sufficiently ill to prompt the healthcare provider to recommend overnight admission to the hospital.
We restricted enrollment to children with acute MSD (≤7 days’ duration) to maximize the opportunity to identify the inciting pathogen and to collect new episodes that can be used together with DSS and HUAS data to estimate annual incidence rates. We defined an episode of diarrhea as days with diarrhea beginning after at least 7 diarrhea-free days and ending when diarrhea is not present for 7 days [23 (link), 24 (link)]. Although the WHO definition of a new episode of diarrhea requires only 3 diarrhea-free days [12 (link)], we chose a longer interval (as have other investigators [12 (link), 25 (link)]) to increase our margin of certainty that the episode was new, recognizing that this approach could underestimate the incidence of MSD.