Letter to the editor concerning the article ‘Safety of vaccines administration in hereditary fructose intolerance’

ABSTRACT

The most important approach for the management of hereditary fructose intolerance is a strict avoidance of fructose, sucrose and sorbitol from the diet and medications. A safe threshold of 2.4 mg/kg/dose was recently established by the Instituto Superiore di Sanità of Italy for both oral and parenteral routes, thus shouldering a safe administration of a majority of vaccines in these patients. This would not include, Rotarix® pre-established oral suspension and Rotateq® vaccines, which are indeed contraindicated. Moreover, Rotarix® white powder and solvent for oral suspension would only be safely administered at a weight above 9.3 kg.

Overall, these recommendations to avoid rotavirus vaccination are difficult to implement because these vaccines are given during exclusive breastfeeding, prior to fructose-containing food introduction.

KEYWORDS:

• Rotavirus
• vaccine
• safety
• hereditary fructose intolerance

Sr Editor,

In a recent issue of Orphanet J Rare Dis, Mariorana et al.¹ published that, according to a recommendation of the Instituto Superiore di Sanità of Italy,² a majority of vaccines can be safely administered in children with Hereditary fructose intolerance (HFI) (OMIM 229600), considering a limit of 2.4 mg/kg/dose as a safe threshold for oral and parenteral route.

M-M-RVAXPRO, Proquad, Priorix, Priorix tetra and Varilrix contain sorbitol up to 16 mg and sucrose traces. All of these vaccines, according to the manufacturer, should not be administered to children aged less than 9 months. Therefore, they can be administered with reasonable safety, whenever a threshold of 2.4 mg/kg/dose will not be exceeded (assumption: lower than 3rd percentile of weight-for-age in females at 9 months: 6.6 kg according to WHO Multicentre Study Growth Reference Study Group, 2006). However, this would not include the Rotateq® vaccine and Rotarix® pre-established oral suspension vaccine, that contain 1080 mg and 1073 mg of sucrose/dose, respectively, and are thus contraindicated in HFI. Regarding the Rotarix® white powder and solvent for oral suspension, containing 9 mg of sucrose and 13.5 mg of sorbitol, it should only be administered in HFI children with a weight above 9.3 kg. All other vaccines do not contain fructose or contain fructose and analogs in traces up to 10 mg. Therefore, according to the above recommendations, they can be safely administered.

We wish to highlight several important points about this article:

First, the weight of 9.3 kg corresponds to a 97th percentile of weight-for-age in males at 5 months and females at 6 months, according to the WHO Multicentre Study Growth, 2006. Rotarix®, according to the manufacturer, is administered in 2 doses with an interval of at least 4 weeks between doses, the first dose would be given to infants ≥6 weeks of age and the second dose prior to 24 weeks of age.³ This implies that this vaccine could only be safely given in very few cases of children with HFI.

These age restrictions are due to concerns about intussusception risk. Natural intussusception rarely occurs before 3 months of age, but its incidence increases ten-fold between 3 and 6 months of age.⁴ Therefore, any vaccine associated with an increased risk of intussusception should be theoretically avoided. This is particularly pointed with the first rotavirus vaccine dose, which has been primarily associated with a slightly increased risk of intussusception (~1–6 per 100000 infants vaccinated).⁵ Models have shown that 44 rotavirus diarrhea deaths would be prevented for every one potential intussusception death if children were eligible to receive rotavirus vaccination up to 1 y of age. Therefore, WHO recommends administering rotavirus vaccine to children up to 24 months of age concomitantly with diphtheria-tetanus-pertussis vaccine.⁶ Furthermore, WHO also recommends administering the first dose of rotavirus vaccine as soon as possible after 6 weeks of age, to ensure induction of protection prior to natural rotavirus infection.⁶

In conclusion, Rotavirus is a significant cause of diarrheal hospitalization and death among children <5 years old worldwide. Whether to vaccinate or not children with HFI and a weight above 9.3 kg should be based on an individualized assessment of the potential risks and benefits.

Second, HFI is a rare inborn error of carbohydrate metabolism. It is an autosomal recessive metabolic disorder caused by aldolase B deficiency and encoded by the ALDOB (9q22.3) gene. Affected individuals fail to metabolize fructose completely in the liver, small intestine and kidneys, leading to intracellular accumulation of the toxic substrate fructose-1-phosphate and subsequent depletion of adenosine triphosphate.^7,8 HFI patients are asymptomatic, having normal growth and development during exclusive breastfeeding. First symptoms appear after weaning, when fructose, sucrose or sorbitol-containing foods are introduced. Clinical onset of HFI prior to complementary feeding would basically be linked to infant formulas containing these types of sugar, especially soy-based formulas.⁹ Even a single day of excess fructose, sucrose or sorbitol uptake can lead to morbidity. Affected subjects suffer abdominal pain, vomiting, pallor, jaundice and/or metabolic disturbances (hypoglycemia, lactic acidemia, hypophosphatemia, hyperuricemia, hypermagnesemia and/or hyperalaninemia). Continued ingestion of these sugars, even at low doses, causes hepatic and renal injury and failure to thrive and eventually leads to liver cirrhosis and sometimes death, particularly in small infants. The most important approach for the management of HFI is a strict elimination of fructose, sucrose and sorbitol from the diet and drugs. Due to properties as viscosity modifiers, sweeteners and protein stabilizers, sucrose and sorbitol are also used as excipients in some medical products and they can also be found in vaccine formulations like rotavirus vaccines.^1,7,8 However, most individuals with HFI are not suspected when rotavirus vaccines are administered, as these vaccines are given prior to complementary feeding. The only exception would be newborns diagnosed by presymptomatic genetic testing for HFI disease, following previous detection of ALDOB mutations in an affected family member. Thus, recommendations to avoid rotavirus vaccination in babies with HFI published by Mariorana et al.,¹ are not easy to follow.

For this reason, we want to report an unusual case of HFI in a male infant, with first symptoms appearing at 2 months of age, during exclusive breastfeeding. Two hours after rotavirus oral vaccine administration (Rotarix® pre-established oral suspension vaccine), the patient presented with pallor, sweating and hypotonia. Capillary blood glucose test revealed hypoglycemia (52 mg/dL). The clinical picture disappeared after glucose oral administration. Similar symptoms appeared 90 minutes after eating his first fruit at 5 months of age. Following this second episode, the introduction of other fruits was delayed. Gluten-free cereals, some vegetables and chicken were introduced without issues. At the age of 7 months, the patient was referred to a Gastroenterology and Liver Pediatric Unit for the evaluation of a moderate hepatosplenomegaly without hypertransaminasemia and cholestasis. From his medical history, HFI was suspected, and elevated carbohydrate-deficient transferrin levels were found (5.6%; normal <1.5%). Diagnosis of HFI was established after the detection of ALDOB gene mutations [c.448 G > C (p.Ala150Pro); 360_363del (p Asn120Lysfs*32)].

In conclusion, recommendations to avoid rotavirus vaccination in HFI patients are very difficult to implement and rotavirus vaccines will be inevitably given to HFI patients. Therefore, the combination of hypoglycemia, pallor, hypotonia and/or sweating after Rotarix® or Rotateq® vaccine administration should make us consider HFI. This clinical alert would help to avoid the metabolic disturbances, failure to thrive, hepatic and renal injury, secondary to the introduction of fructose, sucrose and sorbitol in these infants after weaning.

Disclosure of potential conflicts of interest

The authors report no conflict of interest. There are no financial interests