In 2000, measles was declared no longer endemic in the United States; however, in 2019, there have been more than 1275 cases of measles in the United States to date.1 Given its rarity in recent decades, many US providers do not have experience managing this vaccine-preventable disease. Few definitive treatments for measles exist; however, the American Academy of Pediatrics recommends using vitamin A in “severe cases, such as hospitalized patients” and the World Health Organization (WHO) recommends it for “all acute cases.”2,3 Recommended dosing for vitamin A is a 2-day dose of 50,000, 100,000 or 200,000 units/d for patients <6, 6–11 or ≥12 months, respectively.3 Because of the pharmacodynamics of vitamin A, it is most effective when given orally/enterally.
We previously examined complications and resource utilization for patients hospitalized for measles at US children’s hospitals and found a low rate of vitamin A use.4 The objective of this current study was to explore specific details surrounding vitamin A use in hospitalized US children.
MATERIALS AND METHODS
We conducted a retrospective cohort study of patients 0–18 years of age admitted between January 1, 2004, and March 31, 2019, to a children’s hospital contributing data to Pediatric Health Information Systems (PHIS) with a discharge diagnosis code for measles. PHIS hospitals are 52 of the largest and most advanced US children’s hospitals, and constitute the most demanding standards of pediatric service. Complex chronic conditions (CCC) flags were generated by PHIS.5 Patients who received one or more doses of vitamin A were compared with patients who received no dose. We used STATA version 14.0 (College Station, TX) for descriptive statistics, and this study was deemed exempt from review by our organization’s Institutional Review Board.
We identified 142 unique patients with measles-related hospitalizations, 47 (33%) of whom received vitamin A (Table 1). Patients with CCCs were less likely to receive vitamin A (4% vs. 23%; P < 0.01) than patients without CCCs. After excluding patients with CCCs, due to inability to distinguish between resource used due to measles infection versus the CCCs, we found no significant differences in median length of stay (3 days, interquartile range 2–4 for both groups; P = 0.78) or median-adjusted estimated cost ($6908 [3806–9840] vs. $5812 [3907–8825]; P = 0.45) between patients who received vitamin A and those who did not. Only 2 patients (0.1%) had a laboratory test done for vitamin A levels.
Among patients receiving vitamin A, the majority received either 10,000 (62%) or 50,000 (13%) unit doses. Oral delivery was most common, with 98% of vitamin A recipients having at least 1 oral dose and only 6% having at least 1 intramuscular dose. When given, vitamin A was most commonly initiated on the first (47%) or second (40%) day of admission for 2 (68%) or 1 (28%) doses. No patients met current dosing recommendations3 for their age.
A low percentage of patients hospitalized for measles at US children’s hospitals were managed with vitamin A, significantly less if they had CCCs. For patients who did receive vitamin A, all of the doses were lower than currently recommended by the WHO.3
Several randomized control trials have shown vitamin A to significantly reduce morbidity and mortality in children with acute measles infection.6–8 Furthermore, vitamin A is inexpensive and has been found to have a relatively low rate of adverse effects, including transient nausea or vomiting.9 While vitamin A may be a low-risk intervention for potentially high-risk disease, this study highlights a gap between existing recommendations for use and actual practice in US children’s hospital. The use of an administrative database precludes ability to analyze provider judgment but we suspect reasons for under-use might include low provider knowledge of vitamin A recommendations.
In reviewing existing recommendations, providers may have difficulty interpreting somewhat inconsistent language. The American Academy of Pediatrics Red Book Report of the Committee on Infectious Disease (2018), for example, states “The WHO currently recommends vitamin A for all children with acute measles, regardless of their country of residence….. even in countries where measles is not usually severe, vitamin A should be given to all children with severe measles (e.g., requiring hospitalization).”2 This statement might be interpreted by 1 provider as all patients with measles need vitamin A, by another as only hospitalized patients need it, and by a third provider as only patients with severe measles. As severity is a subjective term, a provider may not elect to use vitamin A in a child hospitalized for a short duration of intravenous fluids or supportive care as they might think that “severe” only applies to critically ill children.
Furthermore, the impact on patient outcomes, such as mortality, in countries where malnutrition is less common is not as well established. While a previous study found low serum retinol levels in 114 patients admitted for suspected measles in a US hospital,10 there are no recent studies in US hospitals assessing the effect of vitamin A use in measles. This makes it challenging for US providers to know whether their patient has the same risk to benefit ratio of vitamin A use as a patient in low-income economy countries. There are limited liquid options for high-dose vitamin A, which may present administration challenges in young patients. Provider perception that vitamin A use could worsen some of the symptoms of measles (eg, vomiting and diarrhea) may also reduce its use.
Our study was insufficiently powered to examine differences in specific morbidities (eg, pneumonia), or mortality given the rarity of these outcomes as identified in previous studies.4 Because of the administrative nature of the PHIS database, potential reasons (e.g., clinician decision-making) for non-use are unknown. There has been no validation for measles-coded hospitalizations in the PHIS database and thus there is the potential for miscoding. As the PHIS database provides pharmacy billing data, it is possible that vitamin A use was over-estimated if a dose was dispensed but not administered or underestimated if a dose was not billed for during the hospitalization. It is possible that patients received vitamin A at another facility before admission to the PHIS hospital.
As many regions of the United States continue to see an increased number of measles cases, we must refresh our knowledge in caring for patients with this preventable disease. This study highlights a concerning gap between recommendations and actual practice for vitamin A use in children hospitalized with measles in the United States. Further studies examining risks and benefits of vitamin A use in patients hospitalized in the United States or other high-income economy countries are warranted. Additional interventions would include clarification of statements from leading organizations surrounding when and how to use vitamin A. Additional provider education on management of measles and indications for vitamin A use would also be beneficial.
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