Reply to Jakovac; Severity of COVID-19 infection in patients with phenylketonuria: is vitamin D status protective?

to the editor: In his outstanding article, Jakovac (7) highlighted the relevance of vitamin D in coronavirus disease (COVID-19) context. In fact, this seems an important metabolic explanation for the higher vulnerability for severe forms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the patients with obesity and hypertension or older patients. There are no published intervention studies to prove that vitamin D supplementation could help with COVID-19 outcomes. However, our group specializing in phenylketonuria (PKU; McKusick #261600) are unaware of any reported deaths from COVID-19 in this patient group. Could it be that patients with PKU are spared from COVID-19 severe outcomes? A proof of concept that vitamin D status could effectively help infected individuals with the new coronavirus might be fostered from this observation.

In fact, for many patients with PKU, a phenylalanine-restricted diet remains the only management strategy, despite emerging pharmacological treatments. It is established that stringent dietary treatment accomplishes near-normal outcomes (14). Dietary management involves a controlled phenylalanine intake, supplemented with a low phenylalanine protein substitute, usually containing micronutrients (12). Initially, nutritional requirements were not fully understood, and unpalatable medical formulas without rigorous supplementation led to nutritional deficiencies (10). In recent years, the quality of dietary treatment has considerably improved, protein substitutes are fortified with micronutrients to meet requirements, and there are few reports of micronutrient inadequacy in PKU (8). Balanced nutrition is required for optimal cell function with vitamins A, B6, B12, C, D, E, folate, trace elements, and essential fatty acids important and complementary in supporting the immune system (1).

Although vitamin D deficiency is common in the general population, several recent studies reported good or improved vitamin D status in patients with PKU, dependent on the amount of protein substitute being consumed. A patient, taking 60 g/day protein equivalent from protein substitute will receive around 13 to 30 µg/day of vitamin D compared with a requirement varying between 10 to 15 µg/day for adults (3, 15). In the United Kingdom, Daly et al. (2) reported median 25-hydroxy-vitamin D levels above 80 nmol/L in 50 PKU diet-treated patients aged 5 to 16 yr. At the end of 1 yr intervention, no patient had a vitamin D concentration of ≤50 nmol/L. Also, in adults with PKU, the vitamin D intake was significantly higher in diet-adherent compared with nonadherent patients (25.8 ± 8.96 vs. 4.16 ± 5.31 μg/day, respectively; P < 0.001) (6). Thiele et al. (16) showed in patients with PKU that vitamin D intake decreased to less than requirements when protein substitute intake was lowered as a consequence of pharmacological treatment. A recent, retrospective study from early treated adults with PKU patients from 17 European centers highlighted a low number (n = 32 of 173) of patients with low vitamin D status (25-OH vitamin D <50 nmol/L) (9). Experience from Portugal comparing a group of patients with PKU with healthy controls showed vitamin D inadequacy was more prevalent in the control group (13).

Although there is no direct evidence that vitamin D will prevent or treat COVID-19, vitamin D may help (5). Data from the University of Turin, Italy, indicated a high prevalence of hypovitaminosis D in hospitalized patients with COVID-19 (4). In PKU, associated with the nutrient supplementation in protein substitutes, it is possible that satisfactory vitamin D status offers protection against COVID-19. This, of course, is speculation, and COVID-19 incidence in patients with PKU within and between countries is not reported. To understand if nutritional status may influence acute respiratory infection rate in COVID-19, it seems important to study the occurrence of COVID-19 in adolescent and adult patients with PKU and compare outcome with their treatment status. In addition, individual susceptibility to vitamin D deficiency and dose response of supplementation strategies should be based on assessing single nucleotide polymorphisms (SNPs) in vitamin D metabolism (11, 17).

DISCLOSURES

J. C. Rocha is member of the European Nutrition Expert Panel (Biomarin) and of the advisory boards of Applied Pharma Research and Nutricia. He has received speaker’s fees from Applied Pharma Research, Merck Serono, BioMarin, Nutricia, Vitaflo, Cambrooke, PIAM, and Lifediet. A. MacDonald has received research funding and honoraria from Nutricia, Vitaflo International and Merck Serono. She is a member of the European Nutritionist Expert Panel (Biomarin), a member of Sapropterin Advisory Board (Biomarin), a member of the advisory board entitled ELEMENT (Danone-Nutricia), and a member of an advisory board for Arla and Applied Pharma Research. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.

AUTHOR CONTRIBUTIONS

J.C.R. drafted manuscript; J.C.R., C.C., and A.M. edited and revised manuscript; J.C.R., C.C., and A.M. approved final version of manuscript.