Does Eating a Plant-Based Diet Decrease the Severity of COVID-19 Infections?

Two thousand eight hundred eighty-four healthcare workers (95% physicians, 70% male) from six countries (France, Germany, Italy, Spain, United Kingdom, and United States) who had had substantial exposure to COVID-19 patients completed a survey from July 17, 2020 to September 25, 2020 regarding diet, demographic characteristics, and COVID-19 outcomes. Five hundred sixty-eight of these individuals had been infected with COVID-19 (defined as having symptoms consistent with COVID-19 and/or having a positive PCR or antibody test), and 2,316 had not been infected (controls) (defined as having a negative test and/or no history of symptoms consistent with COVID-19). Among the 568 COVID-19 cases, the illness was moderate-to-severe in 138 individuals and very-mild-to-mild in 430 individuals. After adjustment for potential confounding variables (including age, sex, race/ethnicity, smoking, physical activity, body mass index, and presence of a medical condition), those who followed a plant-based diet had a 72% lower risk of having moderate-to-severe COVID-19, compared with individuals who did not follow such a diet. Participants who followed either a plant-based diet or a pescatarian diet (plant-based diet that included fish and seafood) had a 59% lower risk of having moderate-to-severe COVID-19, compared with participants who did not follow one of these diets.

Comment: In this study, people who consumed a plant-based diet, with or without fish and seafood, had less severe COVID-19 infections than people who consumed omnivorous diets. While observational studies cannot prove causation, one of the strengths of this study is that it controlled for various factors that predict outcomes in COVID-19 cases, such as age, race, body mass index, and presence of comorbid conditions. If plant-based diets decrease the severity of COVID-19 infections, one possible explanation might be that such diets contain a higher amount of vitamin C and other protective micronutrients. In addition, plant foods tend to promote less inflammation than meats and other animal foods. It is conceivable that a person with chronic low-level inflammation would be less likely to tolerate the inflammatory response to a COVID-19 infection.

Kim H, et al. Plant-based diets, pescatarian diets and COVID-19 severity: a population-based case-control study in six countries. BMJ Nutr Prev Health. 2021;4:257-266.

Ginger for Acute Gastroenteritis in Children

One hundred fifty children (aged 1-10 years; mean age, 5.5 years) with vomiting associated with acute gastroenteritis were randomly assigned to receive, in double-blind fashion, ginger or placebo. The dosage was 20 drops (containing 10 mg of ginger) every 8 hours until resolution of vomiting. Oral rehydration solution was started 30 minutes after the first dose of ginger or placebo. The primary outcome measure was the occurrence of one or more episodes of vomiting after treatment was started. The incidence of the primary outcome was 67% in the ginger group and 87% in the placebo group. This corresponded to an absolute risk reduction of 20%, indicating that for every five children treated with ginger, one child stopped vomiting who otherwise would have continued vomiting.

Comment: Most, but not all, studies have demonstrated that ginger can prevent motion sickness, nausea and vomiting of pregnancy, nausea and vomiting caused by cancer chemotherapy, and postoperative nausea and vomiting. It appears that vomiting associated with acute gastroenteritis in children can now be added to the list of conditions for which ginger is beneficial.

Nocerino R, et al. Efficacy of ginger as antiemetic in children with acute gastroenteritis: a randomised controlled trial. Aliment Pharmacol Ther. 2021;54:24-31.

Atkins Diet for Infantile Spasms

Ninety-one children (aged 9 months to 3 years) in India with infantile spasms that had failed to respond to adrenocorticotropic hormone (ACTH) or oral prednisolone and anticonvulsant medication were randomly assigned to consume a modified Atkins diet (diet group; n = 46) or their usual diet (control group; n = 45) for four weeks. On the modified Atkins diet, carbohydrate intake was restricted to 10 g per day in children aged 18 months to three years, and 5 g per day in younger children. All children continued their antiepileptic drugs. At four weeks, the proportion of children who were free of spasms was higher in the diet group than in the control group (23.9% vs. 0%; p ≤ 0.001). The median time before spasms stopped was 10 days (interquartile range, 9-20 days). Nine of the 11 children who became spasm-free had a resolution of hypsarrhythmia on electroencephalography. Thirty children (65.2%) in the diet group had a greater-than-50% reduction in spasms, whereas no child in the control group had that degree of improvement (p < 0.001). The most common side effect of the diet was constipation, which occurred in 34.8% of the children.

Comment: Infantile spasms (West syndrome) are a type of severe epilepsy characterized by recurrent seizures (spasms), an abnormal electroencephalographic pattern called hypsarrhythmia, and mental retardation. In some cases, the condition is secondary to brain damage caused by another disease, while in other cases the cause is unknown. Conventional treatments include ACTH, anticonvulsant medications, and vitamin B6.

The ketogenic diet has been used successfully in some children with infantile spasms. The Atkins diet is a low-carbohydrate, high-fat diet that has been used by millions of people for weight loss. Like the ketogenic diet, the Atkins diet can induce a state of ketosis, but it is less restrictive with respect to calorie and protein intake. In addition, unlike the ketogenic diet, the Atkins diet does not require fluid restriction and does not need to be started in the hospital. The improvements in the present study were similar to those seen with the ketogenic diet in children with infantile spasms. Because it is less restrictive, the modified Atkins diet may be considered as an alternative to the ketogenic diet in children with infantile spasms refractory to conventional therapy.

Sharma S, et al. Evaluation of the modified Atkins diet for the treatment of epileptic spasms refractory to hormonal therapy: a randomized controlled trial. J Child Neurol. 2021;36:686-691.

Low-Carbohydrate, Low-Glycemic-Index Diet for Children with Epilepsy

Forty children (aged 2-8 years; mean age, 3.9 years) in India with drug-resistant epilepsy were randomly assigned to consume a low-carbohydrate, low-glycemic-index diet for three months (n = 20) or to a control group that did not receive dietary advice (n = 20). On the intervention diet, carbohydrate intake was restricted to 10% of calories, or a maximum of 40-60 g per day. All children continued their antiepileptic drugs. The proportion of children who had more than a 50% reduction in seizure frequency (responders) was 30% in the diet group and 0% in the control group (p = 0.02). Of the six responders in the diet group, one was completely free of seizures during a follow-up period of 12 months and one had more than a 90% reduction in seizure frequency during a follow-up period of 10 months. Five patients successfully continued the diet after the study, for a total median treatment period of 8 months (range, 4-12 months). Three children on the diet had non-serious side effects (2 with lethargy, 1 with vomiting).

Comment: A classic ketogenic diet is effective in children with drug-resistant epilepsy, but it is not well tolerated. The results of the present study suggest that a low-carbohydrate, low-glycemic-index diet, which is less restrictive than a ketogenic diet, is also effective for some children and is reasonably well tolerated.

Lakshminarayanan K, et al. Efficacy of low glycemic index diet therapy (LGIT) in children aged 2-8 years with drug-resistant epilepsy: A randomized controlled trial. Epilepsy Res. 2021;171:106574.

Riboflavin for Pediatric Migraines

The authors of this study retrospectively reviewed data from 68 Japanese children (aged 6-15 years) with migraines, of whom 52 also experienced another type of headache. The children received 10 mg or 40 mg per day of riboflavin, based mostly on age. Migraine frequency per month was lower after three months of riboflavin supplementation than at baseline (median [interquartile range]: 4.0 [2-5] vs. 5.2 [3-7]; p < 0.01). Twenty-five children (36.7%) had a 50%-or-greater reduction in episode frequency (responders), while 18 (26.5%) had a 25-50% reduction. Children who had less than a 50% reduction in migraine frequency were classified as nonresponders. There was no significant difference between responders and nonresponders with respect to riboflavin dose, presence or absence of aura, age at headache onset, or age at consultation. However, nonresponders were more likely to have co-morbid non-migraine headaches (odds ratio = 4.11; p = 0.02), particularly tension headaches.

Comment: As the precursor of flavin adenine dinucleotide (FAD), a coenzyme involved in the electron-transport chain, riboflavin plays a role in mitochondrial energy production, which appears to be impaired in migraine patients. Riboflavin has repeatedly been shown to decrease migraine frequency in adults, but the results in children have been less clear. In an uncontrolled trial, of 41 children and adolescents with migraines who received 200 mg or 400 mg per day of riboflavin for up to six months, 68% had at least a 50% reduction in attack frequency.¹ However, in two double-blind studies in children and adolescents, supplementation with 50 mg or 200 mg per day of riboflavin for 12-16 weeks did not decrease the frequency or severity of migraines compared with placebo.^{2 3} The results of the present study suggest that riboflavin is beneficial for children with migraines, especially if they do not also have tension headaches or other types of headaches. Perhaps the conflicting findings in children could be resolved by conducting a randomized trial in which children with co-morbid headaches are excluded.

Yamanaka G, et al. Effectiveness of low-dose riboflavin as a prophylactic agent in pediatric migraine. Brain Dev. 2020;42:523-528.

N-Acetylcysteine Shrinks Uterine Fibroids, or More Iranian Research Fraud?

Fifty women in Semnan, Iran, with uterine fibroids (leiomyomas) were randomly assigned to receive, in double-blind fashion, 600 mg per day of N-acetylcysteine (NAC) or placebo for 12 weeks. The mean decrease in fibroid volume was greater in the NAC group than in the placebo group (25.25% vs. 1.08%; p < 0.004).

Comments: As Townsend Letter readers know, I have been concerned that a large percentage of the nutrition research coming from Iran appears to be fraudulent. The present study has a number of problems.

1. Discrepancy regarding trial dates: The paper stated that the study was conducted in 2017-2019. The Iranian Registry of Clinical Trials (IRCT) document, which was registered on August 26, 2019, stated that the expected recruitment start date was February 7, 2018. The IRCT document also stated both “Registered while recruiting” and “Recruitment complete.” Both of those cannot be true.

2. Discrepancy regarding funding: No funding source was listed in the paper. The IRCT document stated that the study was funded by Semnan University of Medical Sciences.

3. Ethical issue: The Ethics Committee approved the study on February 6, 2018. If the study began in 2017, as was stated in the paper, then it was begun before being approved by the Ethics Committee.

4. Discrepancy regarding inclusion criterion: The paper stated that the largest diameter of the fibroid had to be greater than 8 cm. The IRCT document stated that the leiomyoma had to be 3 to 8 cm in diameter.

5. Discrepancy regarding diagnostic methods: The paper stated that leiomyomas were diagnosed by transvaginal sonography. The IRCT document stated that the diagnosis was made by ultrasound, CT, or MRI.

6. Implausible baseline data: Although the women in the study had “recently presented with severe bleeding,” all participants had a normal hemoglobin concentration. In contrast, a paper published in J Family Reprod Health. 2013;7(3):139-144 stated that the prevalence of anemia is 33% among women of reproductive age in urban and rural areas of Iran. Therefore, it is not plausible that all 50 women in this study with severe bleeding had a normal hemoglobin concentration.

7. Double-blind trials are expensive, and it is unusual to for researchers to conduct (or funding sources to fund) a double-blind trial when there is no prior evidence to suggest the treatment is effective (such as uncontrolled trials or case reports). In the paper cited above, the researchers stated, “To the best of our knowledge, there is no other article addressing the role of NAC in leiomyoma.”

Aghaamoo S, et al. The effect of N-acetyl cysteine on the volume of uterine leiomyoma: A randomized clinical trial. Int J Gynaecol Obstet. 2021;154:521-525.

Vitamin D for Primary Dysmenorrhea, or More Iranian Research Fraud?

One hundred sixteen Iranian university students with primary dysmenorrhea and a serum 25-hydroxyvitamin D level below 30 ng/ml (mean, 19.75 ng/ml) were randomly assigned to receive, in double-blind fashion, 50,000 IU of vitamin D3 or placebo once a week for eight weeks. Compared with placebo, vitamin D decreased pain intensity at four and eight weeks, decreased the number of days with pain at four and eight weeks, and decreased number of pain medications used at four and eight weeks (p < 0.001 for each comparison).

Comment: Primary dysmenorrhea is a common condition characterized by pelvic or back pain during menstruation, often in association with headaches, nausea, or other symptoms. It is not uncommon for dysmenorrhea to be severe enough to cause absence from work or school. Vitamin D would be a welcomed advance in the treatment of primary dysmenorrhea, if it can be proven to be effective. One small double-blind trial conducted in Italy found that a single dose of 300,000 IU of vitamin D₃, given five days before the expected onset of menstruation, significantly decreased menstrual pain, compared with placebo, during the next two cycles.⁴ (My impressions regarding nutrition research from Italy are discussed below in relation to the study on alpha-lipoic acid.) Three other double-blind trials, all conducted in Iran, also found vitamin D to be beneficial. As I have stated repeatedly, I have doubts about the credibility of many studies coming from Iran. I have several concerns about the study reviewed above.

1. Discrepancies regarding inclusion criteria: The paper stated that the women had to be 18-32 years old to participate, whereas the Iranian Registry of Clinical trials (IRCT) document stated that they had to be 18-30 years old. The paper stated that the women had to have menstrual cycles of 22 to 35 days in order to participate, whereas the IRCT document stated that the cycles had to be 22 to 32 days.

2. Implausible baseline data: In Table 1, the mean menstrual cycle length was 23.2 ± 2.9 days in the vitamin D group and 23.9 ± 3.3 days in the placebo group. Assuming a normal (Gaussian) distribution, approximately 16% of the study participants would have had menstrual cycles lasting 20.45 days or less. However, women were ineligible to participate in the trial if their cycle length was less than 22 days.

3. Discrepancy regarding funding: The paper stated that there was no funding source, whereas the IRCT document stated that the study was funded by the School of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences.

It is hoped that additional studies will be conducted by reputable researchers, to determine whether vitamin D is an effective treatment for primary dysmenorrhea.

Rahnemaei FA, et al. Vitamin D supplementation for primary dysmenorrhea: a double-blind, randomized, placebo-controlled trial. Obstet Gynecol Sci. 2021;64:353-363.

Alpha-Lipoic Acid Improves Idiopathic Pain

Two hundred ten nondiabetic Italian adults with idiopathic pain (57 with neuropathic pain, 141 with arthralgia, and 12 with myalgia) who could not or did not want to take analgesic medication were randomly assigned to receive, in double-blind fashion, alpha-lipoic acid (ALA; 400 mg or 800 mg per day) or placebo for two months. Outcomes were assessed using the Numeric Rating Scale (0 to 10, with 0 indicating no pain and 10 indicating the worst pain imaginable) and the Visual Analog Scale (0 to 100, with 0 indicating no pain and 100 indicating the worst pain imaginable). In the group receiving 800 mg per day of ALA, the mean Numeric Rating Scale score improved from 6.2 (range, 3-10) at baseline to 1.7 (range, 0-4) after two months (mean improvement, 73%; p < 0.001). In that group, the mean Visual Analog Scale score improved from 57.7 (range, 10-100) at baseline to 6.6 (range, 0-30) after two months (mean improvement, 89%; p < 0.001). Similar (though somewhat less pronounced) improvements were seen in the group receiving 400 mg per day of ALA. No improvement was seen in the placebo group.

Comment: In this study, treatment with ALA produced marked improvement of pain in people with idiopathic arthralgia, myalgia, or neuropathic pain. If this study is believable, it represents a major advance in the treatment of chronic pain. However, I’m not so sure I believe it.

I have written a lot about the questionable and apparently fraudulent research coming from Iran, Egypt, and a few other countries. I have not written much about studies from Italy, but over the past 10 years there have been a number Italian studies in which a nutritional treatment produced a surprisingly large beneficial effect. Some of the treatments that were found to be effective had not been investigated previously and have not since been confirmed by other investigators. For some studies, there was no clear biochemical basis for expecting the treatment would be beneficial. Few of the Italian studies have had the types of blatant irregularities that are often seen in Iranian studies, but a significant amount of the Italian research has left me with an uneasy feeling. There are a few noteworthy issues regarding the study cited above.

1. Discrepancy regarding funding: The paper stated that the research received no external funding. However, the document registered with the International Standard Randomised Controlled Trial Number (ISRCTN) Registry stated that the study was funded by the Italian Association of Health Products and Manufacturers.

2. Issues regarding the timing of the study: The ISRCTN document stated that the trial start date was September 9, 2020 and the end date was July 30, 2021. However, the ISRCTN document also stated that the recruitment start date was May 27, 2021 and the recruitment end date was June 10, 2021. Both of those statements cannot be true. If the recruitment period was indeed May 27 to June 10, 2021, that would mean that 210 patients were enrolled in 15 days. Such rapid enrollment of so many patients would be unusual for a clinical trial

3. Issue regarding the date the paper was submitted: The paper was received by the journal on August 29, 2021. The process of submitting the paper included collecting and analyzing the data, writing the paper, circulating the first draft to all nine authors, incorporating their changes into the final paper (it was stated that all 9 authors made revisions), returning the revised paper to the authors, and receiving final approval from each author. If the recruitment end date was indeed June 10, 2021, the study would have been completed on August 10, 2021 at the earliest, and there would have been only 19 days for the authors to complete the process described above. That would have been an unusually rapid turnaround time. If the trial start date was indeed September 9, 2020, then the trial was started before it was approved by the ethics committee on November 19, 2020.

4. Low dropout rate: Of the 210 participants, none dropped out and all completed the two-month study. It is quite unusual to have 100% of a relatively large number of participants complete a study.

5. Unusually large effect size: It is rare for a nutritional supplement to produce an improvement averaging as high as 73%.

Let’s see if any other researchers can confirm the results of this study. And, Townsend Letter readers, if you have personal or clinical experience demonstrating that ALA is dramatically effective for pain, please let me know (drgaby@earthlink.net).

Esposito C, et al. Safety and efficacy of alpha-lipoic acid oral supplementation in the reduction of pain with unknown etiology: A monocentric, randomized, double-blind, placebo-controlled clinical trial. Biomed Pharmacother. 2021;144:112308.