74 Am J Exp Clin Res, Vol. 1, No. 4, 2014 http://www.ajecr.org American Journal of Experimental and Clinical Research Am J Exp Clin Res 2014;1(4):74-77 Case Report Vitamin D deficiency and recurrent lower respiratory tract infections: a case based discussion Cenk Aypak 1* , Özlem Türedi 1 , Sümeyye Ayöz 2 , Mehtap Acar 3 1 Dışkapı Yıldırım Beyazıt Training and Research Hospital, Department of Family Medicine, Ankara, Turkey 2 Ankara Numune Training and Research Hospital, Department of Family Medicine, Ankara, Turkey 3 Dr Sami Ulus Children's Hospital, Department of Pediatrics, Ankara, Turkey Abstract. Lower respiratory tract infections (LRTI) are among the most prevalent infectious diseases. Vitamin D deficiency has been found to be a risk factor for LRTI. We here report a case with the diagnosis of recurrent LRTI treated safely by empirical antibiotherapy and vitamin D supplementation in order to underline the importance of assessment and treatment of vitamin D deficiency in pediatric patients with the diagnosis of LRTI. Keywords: Lower Respiratory Tract Infections, Children, Rickets, Vitamin D Introduction Lower respiratory tract infections (LRTI) are among the most prevalent infectious diseases which may cause considerable morbidity and mortality during childhood [1, 2]. Development of LRTI is closely related with different risk factors including malnutrition, low socio-economic status, passive smoking and presence of systemic diseases (e.g immune deficiency, congenital heart diseases and prematurity) [3-8]. Previous studies have shown that low serum hydroxyvitamin D3 (25(OHD) status is associated with increased risk of LRTI in children [9, 10]. This issue is a particular concern because the prevalence of vitamin D deficiency is notably high in all over the world including tropical countries [9]. We here report a pediatric case with the diagnosis of recurrent LRTI treated safely by empirical antibiotherapy and vitamin D supplementation. Case Presentation A 6-month-old boy was admitted to pediatric outpatient clinic with complaints of cough and wheezing. Medical history taken from mother revealed that he was born at 39 weeks of gestation. Pregnancy, labor, and delivery were uneventful. She reported that the boy was also hospitalized with the diagnosis of LRTI one month ago. The infant was exclusively breastfed without vitamin D supplementation until the age of 6 months. His mother did not receive any vitamin D supplementation either. Upon arrival to the hospital, the patient’s vital signs were stable, with a body temperature of 37.1°C, pulse rate of 100/min, blood pressure of 90/50 mmHg, respiratory rate of 35/min, and oxygen saturation of 96% on room air. Height was 65 cm (25 percentile), weight was 7500 gr (50th percentile). At Anterior fontanel was 2x2 cm and posterior fontanel was closed. The rest of physical evaluation was normal except bilateral diffuse rhonchus and rales on chest and bilateral wrist enlargement. Initial laboratory data revealed a white blood cell count: 13.500/mm3, calcium: 7.5 mg/dL, phosphorus: 2.5 mg/dL, alkaline phosphatase: 421 IU/L, albumin: 4.5 g/dL, 25(OH)D: 11.7 ng/mL, parathyroid hormone: 70.5 pg/dL. Urine calcium excretion was normal. Anteroposterior chest radiograph showed infiltration of the right hemi-thorax (Fig. 1) and the plain radiography of the wrist showed evidence of cupping, fraying, metaphyseal widening, and demineralization of the distal radial and ulnar metaphyses (Fig. 2). According to the clinical, radiological and laboratory findings, the patient was hospitalized with the diagnosis of recurrent LRTI and rickets. The treatment was initiated with 200 mg/kg/day ampicilin-sulbactam and 50 mg/kg/day of elemental calcium therapy. One week after this therapy he was clinically recovered and the patient was discharged along with 5000 IU/day of cholecalciferol for two weeks. Calcium, phosphorus and alkaline phosphatase concentrations were normalized four weeks after initiation of vitamin D supplementation. Follow up radiographs obtained at a clinic visit 3 months after the completion of treatment were found to be normal. The patient did not have LRTI attack in during a follow up period of six month. ___________________________________________________________ * Corresponding author: Cenk Aypak, MD (cenkaypak@yahoo.com). This case report was presented as a poster communication at the 49 th Turkish Pediatric Congress, July 10-13, 2014. http://www.ajecr.org/ mailto:cenkaypak@yahoo.com 75 Am J Exp Clin Res, Vol. 1, No. 4, 2014 http://www.ajecr.org Figure 1 Chest radiography revealed infiltration of the right hemi-thorax. Figure 2 Plain radiography of the wrist showed evidence of cupping, fraying, metaphyseal widening, and demineralization of the distal radial and ulnar metaphyses. Discussion Vitamin D deficiency is a major health problem especially in pregnant women, infants and adolescents. It has been estimated that one billion people worldwide have vitamin D deficiency or insufficiency [11, 12]. The causes of vitamin D deficiency are; increased skin pigmentation, living at higher latitudes, aging, winter time, poor vitamin D nutrition, low maternal vitamin D (in only breast-fed infants), obesity (increased sequestration of 25(OH)D in fat tissue), malabsorption (including chronic liver disease and cystic fibrosis), drugs (phenobarbital, carbamazepine, phenytoin, valproic acid, and rifampicin) [13-21]. Symptomatic vitamin D deficiency (i.e. rickets) is more frequently reported in infancy and adolescence than in childhood. This is due to the increased calcium demand secondary to the rapid growth velocity during these two periods. It is well known that severe vitamin D deficiency impairs bone mineralization, leading to clinical manifestations such as rickets in children and osteomalacia in adults [22]. Patients with rickets like our patient have skeletal alterations such as, cupping, fraying and irregularity of the metaphyseal regions, loss of definition of the epiphyses, widening of the epiphyseal-metaphyseal junctions, and in severe cases, pathologic fractures [23]. Although 25(OH)D is primarily responsible for the regulation of calcium and bone metabolism, vitamin D receptor (VDR) and the vitamin D activating enzyme 1-α- hydroxylase (CYP0B1) are expressed in many cell types such as intestine, pancreas, prostate and cells of the immune system [12, 24]. Previous studies have suggested that vitamin D deficiency and insufficiency not only have negative consequences on bone health but are also likely to be a risk for many acute and chronic illnesses including autoimmune diseases (Type 1 diabetes, multiple sclerosis), cardiovascular diseases, type 2 diabetes mellitus, several types of cancer (Non-Hodgkin lymphoma, colorectal, prostate, oesophagus and breast cancer), neurocognitive dysfunction and mental illness, infertility, adverse pregnancy-birth outcomes and infectious diseases [25-39]. Vitamin D stimulates the production of antibodies and has positive effect on phagocyte activity of macrophages [40, 41]. Data have shown that low 25(OH)D status was related to the increased risk of developing LRTI [9, 10, 26, 42)] Therefore, it was assumed that the repletion/ supplementation of vitamin D along with antibiotherapy in LRTI, would reduce the length of hospital stay and possibility of recurrence of LRTI over the next 3-months period of discharge [43]. However, many questions remain. What is the optimal dose of vitamin D? What is the 25(OH)D threshold for an anti-infective effect? How long does it take for vitamin D to become effective? Are daily doses required or will weekly or monthly doses prevent infections? In order to prevent vitamin D deficiency and related health problems, the American Academy of Pediatrics (AAP) recommends that all infants, children and adolescent have a minimum intake of 400UI of vitamin D per day [44], but it was shown that most US infants were not consuming adequate amounts of vitamin D according to the 2008 AAP recommendation [45]. Unfortunately the use of vitamin D may be neglected by the families and this might be overlooked during routine follow-up if not carefully questioned and physically examined. As vitamin D deficiency is a risk factor for recurrent LRTI, all children with the diagnosis of LRTI should be checked for 25(OH)D status and should receive repletion therapy in addition to antibiotic treatment if they found to be vitamin D deficient. Conflicts of Interest The authors declare no conflicts of interest. http://www.ajecr.org/ 76 Am J Exp Clin Res, Vol. 1, No. 4, 2014 http://www.ajecr.org References 1. UNICEF/WHO. Pneumonia: The Forgotten Killer of Children. Geneva: WHO, 2006. 2. Mulholland K. Magnitude of the problem of childhood pneumoniae. Lancet 354:590-592, 1999. 3. Whitney CG, Harper SA. Lower respiratory tract infections: prevention using vaccines. Infect Dis Clin North Am 18:899-917, 2004. 4. Nielsen HE, Siersma V, Andersen S, et al. Respiratory syncytial virus infection risk factors for hospital admission: a case-control study. Acta Paediatr 92:1314-21, 2003. 5. Welliver RC. Review of epidemiology and clinical risk factors for severe respiratory syncytial virus (RSV) infection. J Pediatr 143:112-117, 2003. 6. Marrie TJ, Carriere KC, Jin Y, Johnson DH. Hospitalization for community-acquired pneumonia in Alberta First Nations Aboriginals compared with non-First Nations Albertans. Can Respir J 11:336-342, 2004. 7. Chantry CJ, Howard CR, Auinger P. Full breastfeeding duration and associated decrease in respiratory tract infection in US children. Pediatrics 117:425-432, 2006. 8. Hassan MK, Al-Sadoon I. Risk factors for severe pneumonia in children in Basrah. Trop Doct 31:139-141, 2001. 9. Muhe L, Lulseged S, Mason KE, Simoes EA. Case control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet 349:1801-1804, 1997. 10. Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 years. Eur J Clin Nutr 58:563-567, 2004. 11. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 87:1080-1086, 2008. 12. Holick, MF. Vitamin D deficiency. N Engl J Med 357:266-281, 2007. 13. Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1:74 -76, 1982. 14. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous synthesis of vitaminD3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 67:373- 378, 1988. 15. Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet. Lancet 2:1104-1105, 1982. 16. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr 72:690 693, 2000. 17. Zhou C, Assem M, Tay JC, et al. Steroid and xenobiotic receptor and vitamin D receptor crosstalk mediates CYP24 expression and drug induced osteomalacia. J Clin Invest 116:1703-1712, 2006. 18. Hahn TJ. Drug-induced disorders of vitamin D and mineral metabolism. Clin Endocrinol Metab 9:107-127, 1980. 19. Sotaniemi EA, Hakkarainen HK, Puranen JA, Lahti RO. Radiologic bone changes and hypocalcemia with anticonvulsant therapy in epilepsy. Ann Intern Med 77:389-394, 1972. 20. Fortenbery EJ, McDermott MT, Duncan WE. Effect of theophylline on calcium metabolism and circulating vitamin D metabolites. J Bone Miner Res 5:321-324, 1990. 21. Lehmann B, Rudolph T, Pietzsch J, Meurer M. Conversion of vitamin D3 to 1alpha,25-dihydroxyvitamin D3 in human skin equivalents. Exp Dermatol 9:97-103, 2000. 22. Pludowski P, Holick MF, Pilz S et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmun Rev 12:976-989, 2013. 23. Renton P. Radiology of rickets, osteomalacia and hyperparathyroidism. Hosp Med 59:399-403, 1998. 24. Battault S, Whiting SJ, Peltier SL, Sadrin S, Gerber G, Maixent JM. Vitamin D metabolism, functions and needs: From science to health claims. Eur J Nutr 52: 429- 441, 2013. 25. Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol 19:73-78, 2009. 26. Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med 169:384-390, 2009. 27. Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 2:1176-1178, 1989. 28. Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol 97:179 -994, 2005. 29. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality. Cancer 70:2861-2869, 1992. 30. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 94:1867-1875, 2002. 31. Grant WG, Garland CF. The association of solar ultraviolet B (UVB) with reducing risk of cancer: multifactorial ecologic analysis of geographic variation in age-adjusted cancer mortality rates. Anticancer Res 26:2687-2700, 2006. 32. Giovannucci E, Liu Y, Rimm EB, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 98:451- 459, 2006. 33. Stene LC, Ulriksen J, Magnus P, Joner G. Use of cod liver oil during pregnancy associated with lower risk of type I diabetes on the offspring. Diabetologia 43:1093- 1098, 2000. 34. Ponsonby A-L, McMichael A, van der Mei I. Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology 181-182:71-78, 2002. 35. Embry AF, Snowdon LR, Vieth R. Vitamin D and http://www.ajecr.org/ 77 Am J Exp Clin Res, Vol. 1, No. 4, 2014 http://www.ajecr.org seasonal fluctuations of gadolinium-enhancing magnetic resonance imaging lesions in multiple sclerosis. Ann Neurol 48:271-272, 2000. 36. McGrath J, Selten JP, Chant D. Long-term trends in sunshine duration and its association with schizophrenia birth rates and age at first registration–data from Australia and the Netherlands. Schizophr Res 54:199-212, 2002. 37. Gloth FM III, Alam W, Hollis B. Vitamin D vs. broad spectrum phototherapy in the treatment of seasonal effective disorder. J Nutr Health Aging 3:5-7, 1999. 38. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab 92:3517-3522, 2007. 39. Chan TYK. Vitamin D deficiency and susceptibility to tuberculosis. Calcif Tissue Int 66:476-478, 2000. 40. Kaludjerovic J, Vieth R. Relationship between vitamin D during perinatal development and health. J Midwifery Womens Health 55:550-560, 2010. 41. Garland CF, Garland FC, Gorham ED, et al. The role of vitamin D in cancer prevention. Am J Public Health. 96:252-261, 2006. 42. Laaksi I, Ruohola JP, Tuohimaa P, et al. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men. Am J Clin Nutr 86: 714-717, 2007. 43. Manaseki-Holland S, Qader G, Isaq Masher M, et al. Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial. Trop Med Int Health 15:1148-1155, 2010. 44. Wagner CL, Greer FR. American Academy of Pediatrics, Section on Breastfeeding and Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 122:1142- 1152, 2008. 45. Perrine CG, Sharma AJ, Jefferds ME, Serdula MK, Scanlon KS. Adherence to vitamin D recommendations among US infants. Pediatrics 125:627-632, 2010. http://www.ajecr.org/