Vitamin A in resistance to and recovery from infection: relevance to SARS-CoV2.

SARS-CoV2 infects respiratory epithelial cells via its cellular receptor angiotensin-converting enzyme 2, causing a viral pneumonia with pronounced inflammation resulting in significant damage to the lungs and other organ systems, including the kidneys, though symptoms and disease severity are quite variable depending on the intensity of exposure and presence of underlying conditions that may affect the immune response. The resulting disease, coronavirus disease 2019 (COVID-19), can cause multi-organ system dysfunction in patients requiring hospitalisation and intensive care treatment. Serious infections like COVID-19 often negatively affect nutritional status, and the resulting nutritional deficiencies may increase disease severity and impair recovery. One example is the viral infection measles, where associated vitamin A (VA) deficiency increases disease severity and appropriately timed supplementation during recovery reduces mortality and hastens recovery. VA may play a similar role in COVID-19. First, VA is important in maintaining innate and adaptive immunity to promote clearance of a primary infection as well as minimise risks from secondary infections. Second, VA plays a unique role in the respiratory tract, minimising damaging inflammation, supporting repair of respiratory epithelium and preventing fibrosis. Third, VA deficiency may develop during COVID-19 due to specific effects on lung and liver stores caused by inflammation and impaired kidney function, suggesting that supplements may be needed to restore adequate status. Fourth, VA supplementation may counteract adverse effects of SARS-CoV2 on the angiotensin system as well as minimises adverse effects of some COVID-19 therapies. Evaluating interactions of SARS-CoV2 infection with VA metabolism may thus provide improved COVID-19 therapy.

Serum retinol, the acute phase response, and the apparent misclassification of vitamin A status in the third National Health and Nutrition Examination Survey.

BACKGROUND: Serum retinol decreases transiently during the acute phase response and can thus result in misclassification of vitamin A status. OBJECTIVE: Our objective was to determine the prevalence of acute phase response activation in a representative sample of the US population, identify the factors associated with this activation, and determine whether persons with an active acute phase response have lower serum retinol concentrations. DESIGN: Data from the third National Health and Nutrition Examination Survey (NHANES III) were analyzed. A serum C-reactive protein (CRP) concentration >/=10 mg/L indicated an active acute phase response. RESULTS: Mean serum retinol was lowest in subjects aged <10 y and increased with age. Concentrations were higher in males than in females aged 20-59 y. The prevalence of a CRP concentration >/=10 mg/L was lowest in subjects aged <20 y (/=10 mg/L also increases with age, is 2-fold greater in females than in males aged 20-69 y, and is associated with common inflammatory conditions. Thus, inflammation appeared to contribute to the misclassification of vitamin A status in the NHANES III population, and serum CRP is useful in identifying subjects who may be misclassified.

Urinary excretion of retinol in children with acute diarrhea.

Acute infections of childhood are associated with an increased of xerophthalmia, apparently due to depletion of vitamin A stores. The mechanism responsible for this is not known. Recently, it has been reported that severe infections in adult patients (ie, sepsis and pneumonia) result in excretion of large quantities of retinol in the urine. In 44 children hospitalized for treatment of acute diarrhea we found mean urinary excretions of 1.44 mumol retinol/24 h on day 1 of hospitalization, 0.62 mumol retinol/24 h on day 2, and 0.23 mumol/24 h on day 3. Healthy control subjects matched for age did not excrete measurable amounts of retinol in the urine. Retinol excretion was associated strongly with rotavirus diarrhea and presence of fever. Furthermore, serum retinol concentration was negatively associated with duration of diarrhea before hospitalization, suggesting that urinary excretion of retinol may be an important contributor to vitamin A depletion.

Predictors of serum retinol in children with shigellosis.

BACKGROUND: Low serum retinol can be useful as an indicator of depleted liver vitamin A stores, particularly in population-based studies. However, serum retinol concentrations decrease transiently during infection, independent of any changes in liver stores. The magnitude of the decrease in serum retinol is often proportional to indicators of disease severity. OBJECTIVE: We examined the relation of serum retinol in children with culture-positive shigellosis with severity of illness, anthropometric indicators of nutritional status, urinary retinol excretion, and serum concentrations of C-reactive protein, alpha1-acid glycoprotein, retinol binding protein, and transthyretin. DESIGN: This was a prospective study assessing the clinical and laboratory measurements at admission and recovery of 90 children with dysentery (66 with shigellosis) hospitalized in Bangladesh. RESULTS: Serum retinol concentrations were low at admission but were significantly greater at discharge even though no vitamin A supplements were given during the illness (0.36 +/- 0.22 compared with 1.15 +/- 0.50 micromol/L, P < 0.001). Serum retinol concentrations were lower in children with Shigella dysenteriae type 1 infection than in children with shigellosis due to less virulent strains of Shigella. Low serum retinol was independently associated with S. dysenteriae type 1, high serum C-reactive protein concentrations, and low weight-forage in multiple regression analysis. CONCLUSIONS: This study showed that shigellosis was associated with a significant, transient decrease in serum retinol concentrations of approximately 0.8 micromol/L, and that this change was significantly associated with severity of disease and poor underlying nutritional status, particularly low weight-for-age.

Vitamin A is excreted in the urine during acute infection.

Episodes of acute infection are thought to deplete body stores of vitamin A. The mechanism by which this might occur is not known, but increased metabolic requirements are presumed to play a role. We have found, however, that significant amounts of retinol and retinol-binding protein (RBP) were excreted in the urine during serious infections, whereas only trace amounts were found in the urine of healthy control subjects. The geometric mean excretion rate in 29 subjects with pneumonia and sepsis was 0.78 mumol retinol/d. Subjects with fever (temperature > or = 38.3 degrees C) excreted significantly more retinol (geometric mean = 1.67 mumol/d) than did those without fever (0.18 mumol/d; t = 3.53, P < 0.0015). Aminoglycoside administration and low glomerular filtration rates (< 35 mL/min) were also associated with higher rates of urinary retinol excretion. Thirty-four percent of patients excreted > 1.75 mumol retinol/d, equivalent to 50% of the US recommended dietary allowance. These data show that vitamin A requirements are substantially increased during serious infections because of excretion of retinol in the urine, and suggest that these losses are due to pathologic changes associated with the febrile response.

Urinary retinol excretion and kidney function in children with shigellosis.

BACKGROUND: Acute infections, including diarrhea, are associated with an increased risk of vitamin A deficiency. Urinary retinol excretion during such infections may contribute to this risk. The mechanism accounting for urinary retinol loss has not been clearly defined. OBJECTIVE: This study attempted to determine whether urinary retinol loss in children with acute infection is associated with impaired kidney function, particularly impaired tubular protein reabsorption. DESIGN: Urinary retinol excretion and kidney function were examined in 66 hospitalized children 5 mo to 5 y of age with acute Shigella dysentery. RESULTS: Urinary retinol loss occurred in 59% of children and was substantial (>0.1 micromol/d) in 8% of them. Children with more severe disease excreted higher concentrations of urinary retinol; those with a body temperature > or =40 degrees C excreted a mean of 0.10 +/- 0.18 micromol/d compared with 0.005 +/- 0.008 micromol/d for other children (P < 0.0001). Children with more severe disease also had impaired tubular reabsorption of low-molecular-weight proteins beta2-microglobulin and retinol binding protein (RBP)], although other measures of tubular and glomerular function were not similarly impaired. In multiple regression analysis, severity of disease indicators were the best predictors of tubular reabsorption of beta2-microglobulin (R2 = 0.53) whereas tubular reabsorption of beta2-microglobulin and RBP were found to be the best predictors of urinary retinol loss (R2 = 0.69). CONCLUSIONS: A significant amount of retinol was excreted in the urine in children with shigellosis: 8% excreted >0.10 micromol/d (15% of the daily metabolic requirement). Impaired tubular reabsorption of low-molecular-weight proteins, such as RBP transporting retinol, appeared to be the cause of this urinary retinol loss.

Phylogenetic analysis of a highly conserved region of the polymerase gene from 11 coronaviruses and development of a consensus polymerase chain reaction assay.

Viruses in the genus Coronavirus are currently placed in three groups based on antigenic cross-reactivity and sequence analysis of structural protein genes. Consensus polymerase chain reaction (PCR) primers were used to obtain cDNA, then cloned and sequenced a highly conserved 922 nucleotide region in open reading frame (ORF) 1b of the polymerase (pol) gene from eight coronaviruses. These sequences were compared with published sequences for three additional coronaviruses. In this comparison, it was found that nucleotide substitution frequencies (per 100 nucleotides) varied from 46.40 to 50.13 when viruses were compared among the traditional coronavirus groups and, with one exception (the human coronavirus (HCV) 229E), varied from 2.54 to 15.89 when compared within these groups. (The substitution frequency for 229E, as compared to other members of the same group, varied from 35.37 to 35.72.) Phylogenetic analysis of these pol gene sequences resulted in groupings which correspond closely with the previously described groupings, including recent data which places the two avian coronaviruses--infectious bronchitis virus (IBV) of chickens and turkey coronavirus (TCV)--in the same group [Guy, J.S., Barnes, H.J., Smith L.G., Breslin, J., 1997. Avian Dis. 41:583-590]. A single pair of degenerate primers was identified which amplify a 251 bp region from coronaviruses of all three groups using the same reaction conditions. This consensus PCR assay for the genus Coronavirus may be useful in identifying as yet unknown coronaviruses.

Low gastric acid as a risk factor for cholera transmission: application of a new non-invasive gastric acid field test.

Although gastric acid is thought to be an important host defense against certain enteric infections, field studies of the role of gastric acid in preventing enteric infections have been hampered by the lack of a suitable non-invasive test. Because low gastric acid output (GAO) is an established risk factor for cholera, we assessed after validation, whether a new non-invasive test which estimates GAO by measuring breath hydrogen excess after ingestion of magnesium and a stimulant of gastric acid secretion, could discriminate between persons at high and at low risk of developing cholera. Fifteen age-matched pairs, participants in the field trial of two oral cholera vaccines in rural Bangladesh, were tested. In each pair the "case" was a person who had recovered from severe cholera at least 6 months before testing and the "control" was a person who resided in the home of a cholera patient but remained uninfected. The stimulated breath hydrogen was higher in controls (median hydrogen excess = 369 mumol/80 min) than in cases (median hydrogen excess = 150 mumol/80 min) (p less than 0.05) and was higher in controls in 12 out of 15 pairs. The results, which are consistent with past invasive assessments of the association between hypochlorhydria and cholera, suggest that this non-invasive test may be useful in evaluating GAO in epidemiological field studies.

Age distribution of lymphocytic choriomeningitis virus serum antibody in Birmingham, Alabama: evidence of a decreased risk of infection.

Lymphocytic choriomeningitis virus (LCMV) is an arenavirus that causes human disease ranging from a mild, flu-like illness to meningitis. Infections occur principally in and around the home due to contact with infected mice. Data on the incidence of LCMV infection in the United States are scarce but suggest that the risk of infection may have decreased over the past 30-40 years. To examine this hypothesis, sera from an age-stratified sample of hospital patients in Birmingham, Alabama were tested for LCMV antibody by ELISA. The overall prevalence of LCMV-specific IgG was 3.5% (56 of 1,600). The prevalence of antibody among those < 30 years of age was 0.3% (2 of 600), while the prevalence among those 30 years of age and older was 5.4% (P < 0.0001). Multiple logistic regression was used to identify risk factors for LCMV seropositivity. Age was positively associated (P < 0.0001) and socioeconomic status was negatively associated with a positive antibody test result (P < 0.03). These data are consistent with a decreased incidence of human LCMV infection in Birmingham over the past 30-40 years.

Interferon alters intracellular transport of vesicular stomatitis virus glycoprotein.

Double-label immunofluorescence staining studies in virus-infected subclone 11 of LB cells indicated that almost all of the vesicular stomatitis virus (VSV) glycoprotein (G) was plasma membrane-associated during the logarithmic phase of virus replication. In contrast, treatment with interferon (IFN) resulted in inhibition of VSV-G transport, so that almost all of the G remained associated with the Golgi complex (GC) at comparable times after infection. In both IFN-treated and control cells, G was resistant to treatment with the enzyme endo-beta-N-acetylglucosamine H (endo H) indicating that the bulk of the G had reached the trans compartment of the GC.

[Detection of pyloric Campylobacter in patients with gastroduodenal diseases]. / Detección del Campylobacter pilórico en pacientes con enfermedades gastroduodenales.

We report a study of 127 patients examined with esophago-gastroduodenoscopy and with a diagnosis of chronic gastritis (by biopsy), and gastric peptic ulcer and duodenal peptic ulcer (endoscopically). Brushing samples and biopsies were taken from the esophagus, stomach, and duodenum. Gram stains of brush-collected samples, culture of brush samples and biopsies were performed in order to detect the presence of PC. In cases of chronic active gastritis, PC was found in 91% of patients. It was found in 73% and 84%, respectively, of cases of gastric and duodenal ulcer. PC was found with equal frequency in the cardia and body as in the antrum of infected individuals, but no confirmed cases of colonization of the esophagus or duodenum were found. The most efficient methods for identifying PC colonization were (in descending order of efficiency), silver stain of biopsies, Gram stain of brushings, hematoxylin-eosin stain of biopsies, culture of biopsies, and culture of brushings. In some cases, we have identified PC in the esophagus and duodenum by gram stain and culture, but no not by silver stain or H&E stain of biopsies, suggesting that contamination from other areas of the stomach may be an occasional problem in sampling these areas for PC.

Associations of obesity with triglycerides and C-reactive protein are attenuated in adults with high red blood cell eicosapentaenoic and docosahexaenoic acids.

BACKGROUND: N-3 fatty acids are associated with favorable, and obesity with unfavorable, concentrations of chronic disease risk biomarkers. OBJECTIVE: We examined whether high eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid intakes, measured as percentages of total red blood cell (RBC) fatty acids, modify associations of obesity with chronic disease risk biomarkers. METHODS: In a cross-sectional study of 330 Yup'ik Eskimos, generalized additive models (GAM) and linear and quadratic regression models were used to examine associations of BMI with biomarkers across RBC EPA and DHA categories. RESULTS: Median (5th-95th percentile) RBC EPA and DHA were 2.6% (0.5-5.9%) and 7.3% (3.3-8.9%), respectively. In regression models, associations of BMI with triglycerides, glucose, insulin, C-reactive protein (CRP) and leptin differed significantly by RBC EPA and DHA. The GAM confirmed regression results for triglycerides and CRP: at low RBC EPA and RBC DHA, the predicted increases in triglycerides and CRP concentrations associated with a BMI increase from 25 to 35 were 99.5±45.3 mg/dl (106%) and 137.8±71.0 mg/dl (156%), respectively, for triglycerides and 1.2±0.7 mg/l (61%) and 0.8±1.0 mg/l (35%), respectively, for CRP. At high RBC EPA and RBC DHA, these predicted increases were 13.9±8.1 mg/dl (23%) and 12.0±12.3 mg/dl (18%), respectively, for triglycerides and 0.5±0.5 mg/l (50%) and -0.5±0.6 mg/l (-34%), respectively, for CRP. CONCLUSIONS: In this population, high RBC EPA and DHA were associated with attenuated dyslipidemia and low-grade systemic inflammation among overweight and obese persons. This may help inform recommendations for n-3 fatty acid intakes in the reduction of obesity-related disease risk.

Vitamin A, infection, and immune function.

In populations where vitamin A availability from food is low, infectious diseases can precipitate vitamin A deficiency by decreasing intake, decreasing absorption, and increasing excretion. Infectious diseases that induce the acute-phase response also impair the assessment of vitamin A status by transiently depressing serum retinol concentrations. Vitamin A deficiency impairs innate immunity by impeding normal regeneration of mucosal barriers damaged by infection, and by diminishing the function of neutrophils, macrophages, and natural killer cells. Vitamin A is also required for adaptive immunity and plays a role in the development of T both-helper (Th) cells and B-cells. In particular, vitamin A deficiency diminishes antibody-mediated responses directed by Th2 cells, although some aspects of Th1-mediated immunity are also diminished. These changes in mucosal epithelial regeneration and immune function presumably account for the increased mortality seen in vitamin A-deficient infants, young children, and pregnant women in many areas of the world today.

Burden of infection on growth failure.

The high prevalence of infections among children living in poor areas of developing countries impairs linear growth in these populations. Acute, invasive infections, which provoke a systemic response (e.g., dysentery and pneumonia), and chronic infections, which affect the host over a sustained period (e.g., gut helminth infections), have a substantial effect on linear growth. Such infections can diminish linear growth by affecting nutritional status. This occurs because infections may decrease food intake, impair nutrient absorption, cause direct nutrient losses, increase metabolic requirements or catabolic losses of nutrients and, possibly, impair transport of nutrients to target tissues. In addition, induction of the acute phase response and production of proinflammatory cytokines may directly affect the process of bone remodeling that is required for long bone growth. Infection of cells directly involved in bone remodeling (osteoclasts or osteoblasts) by specific viruses may also directly affect linear growth. Many interventions are possible to diminish the effect of infection on growth. Prevention of disease through sanitation, vector control, promotion of breast-feeding and vaccination is crucial. Appropriate treatment of infections (e.g., antibiotics for pneumonia) as well as supportive nutritional therapy (again including breast-feeding) during and after recovery, is also important. Targeted therapeutic interventions to decrease the prevalence of gut helminth infections may also be appropriate in areas in which such infections are widespread. Such interventions are of public health benefit not only because they reduce the incidence or severity of infections, but also because they decrease the long-term detrimental effect of malnutrition on populations.

Liberation of hydrogen from gastric acid following administration of oral magnesium.

We are in the process of developing a noninvasive test for gastric acid secretion based on the reaction of orally administered magnesium metal with gastric acid: Mg + 2HCl in equilibrium with MgCl2 + H2. We hypothesized that the hydrogen gas thus evolved could be detected in exhaled air and belches and that the amount of hydrogen released could be related to the amount of acid in the stomach. To validate this hypothesis, we gave magnesium to two groups of young adult volunteers following either betazole stimulation or cimetidine inhibition of acid secretion. In group I we gave subcutaneous betazole and gave magnesium in doses from 10 to 200 mg. In group II we gave oral betazole and used a constant dose of 150 mg of magnesium. In both groups we consistently detected significant increases in breath and belch hydrogen following magnesium in the betazole-stimulated volunteers. This response was blocked by cimetidine. The magnitude of the response was related to the magnesium dose, with 150 mg appearing to induce a maximum response. Administration of oral magnesium up to 200 mg was not associated with any untoward effects. We conclude that magnesium led to the release of hydrogen gas in vivo and that the quantity of hydrogen gas recovered was related to the amount of gastric acid. With further development, this principle might be used to develop a simple noninvasive test for gastric acid secretion.

Vitamin A and retinoids in antiviral responses.

Vitamin A deficiency results in multiple derangements that impair the response to infection. This review focuses on experimental models of specific virus infections and on cytokines and cells with cytolytic activity important to antiviral defenses. Altered specific antibody responses and greater epithelial damage in vitamin A-deficient hosts are consistent findings. The cytolytic activity of natural killer cells and various cytokine responses are altered. The inflammatory response to infection may also result in derangements in the transport and metabolism of retinol. We speculate that interaction of several factors may combine to explain the greater severity of infection seen in vitamin A-deficient animals and children. In addition to a preexisting lack of tissue vitamin A, these factors may include reduced mobilization and increased excretion of retinol during the acute phase response to infection, poor innate and specific immune response to virus, and delayed repair of damaged epithelia. Foci of vitamin A-deficient epithelia may be sites of penetration of bacteria and other agents, leading to secondary infections and contributing to an increased severity of infections and poor outcome in vitamin A-deficient animals and humans.