Vitamin D and periprosthetic infection: Review of literature (Preprint)

Abstract

Infections are rare events in arthroplasty surgeries, occurring in only 0.5% to 2% of procedures. It significantly impacts all involved parts (patient, surgeon, and the funding source, whether public or private), and the cost of infections in arthroplasties is estimated at US$ 1.6 billion in 2020, with an expectation of an increase in the coming years (1). Despite improvements with hip prostheses' articular surfaces, we cannot significantly observe a reduction in the number of revision arthroplasties. On the other hand, even though an increase in the number of infection cases is noted (2), this probably happens as a reflect of the greater attention that this problem has been receiving in recent years, and the improvement of the diagnostic criteria for infection in arthroplasty (3). In parallel to the acknowledging the problem, the scientific community seeks strategies to prevent and reduce the risk of infection after hip arthroplasties. Some of these scenarios are well-established and effective, such as improving glycemic control, correcting malnutrition, and treating obesity (4). Still, we have a long path to grow and learn novel treatments to tackle postoperative hip prosthetic surgery.

Even though a rare event, the postoperative infection of a joint prosthesis is still an inconvenient complication in the orthopedic surgeon's daily routine and can present as significant damage to the patient if not treated accordingly. For this reason, we are always examining modifiable risk factors for this problem (5). In this context, some authors have assessed the association between vitamin D levels and the chances of developing Staphylococcus aureus infection. Olsen et al.(6) discovered that the lower the colonization rates, the higher the vitamin D levels. Matheson et al. (7) found a higher chance of patients with vitamin D deficiency having multi-resistant Staphylococcus aureus. Many authors state that vitamin D insufficiency is consistently associated with severe sepsis (8–10). Our goal is to verify if there is a viable correlation between low serum vitamin D levels and periprosthetic infections.

We reviewed PubMed and Scielo databases using the following terms: "vitamin D," "arthroplasty," and "infection." Our focus is to search for evidence of the association of vitamin D with periprosthetic infection. We selected several articles, systematic reviews, consensus, retrospective, and prospective case-control studies. We only included articles in English, Spanish, and Portuguese in this review. We seek to investigate the effects of vitamin D on the body, mainly concentrating on the immune system and infections. As we focus on orthopedics, especially hip surgery, we are very interested in finding new ways to reduce periprosthetic infection risk.

VITAMIN D ROLES IN THE HUMAN BODY Vitamin D has pleiotropic functions that include cardioprotection, immunomodulatory effects, and antimicrobial action improvement (11). Its action also extends to the immune system (11,12), playing a vital role in innate and adaptive responses, with receptors expressed in T cells, activated B cells, and dendritic cells. Vitamin D also participates in the release of chemotactic mediators, production of proinflammatory cytokines, macrocytic phagocytosis, and lipopolysaccharides neutralization (9–11,13). Current studies have linked vitamin D deficiency to several autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM), multiple sclerosis (MS), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Given these associations, it is suggested that vitamin D acts as an extrinsic factor that affects the prevalence of autoimmune diseases (14). Vitamin D presents an important link between the activation of toll-like receptors (TLR), leukocyte accumulation, local inflammation, and antimicrobial response via the immune system. It also regulates the feedback control pathways, restraining possible inflammatory damage caused by excessive immune response activation. The systemic inflammatory response is associated with decreased serum vitamin D levels (15,16). Vitamin D's connection with TLR receptors is also meaningful in innate immunity, as it regulates the expression of antimicrobial peptides called cathelicidins (LL-37) and β-defensins (17,18). Both peptides stimulate angiogenesis and attract monocytes and neutrophils to the injured site (19). In humans, cathelicidin has a broad spectrum of action against bacteria (gram-positive and gram-negative), viruses, fungi, and mycobacteria (15,16,19–23). Furthermore, it is present at the body's entrances exploited by pathogens, including skin, mouth (24), mucous membranes of the respiratory tract, and gastrointestinal tract (25). Other important antimicrobial peptides against cutaneous infections with Staphylococcus aureus are human β-defensins 2 and 3 (HBD-2 and HBD-3), which have broad-spectrum activity against bacteria and fungi (25). For example, de Filippis et al.(24) showed that vitamin D participates in the proinflammatory cytokine modulation through the production of HBD-2 and HBD-3 in the human gingival epithelium and the human periodontal ligament, present in the gums' soft tissues. In another study, Zanger et al.(26) reported that HBD-2 and HBD-3 could be found in healthy skin in low concentrations; however, their levels increase when the tissue undergoes inflammatory and bacterial stimuli. Besides, vitamin D also regulates cell differentiation, such as lymphocytes, macrophages, and natural killer cells (NK). Some of the immunomodulatory effects are listed below: 1. decreased production of interleukin-2 (IL-2), interferon-gamma (INFγ), and tumor necrosis factor (TNF); 2. inhibition of interleukin-6 (IL-6) expression; 3. inhibition of secretion and production of B lymphocytes autoantibodies(14). Vitamin D deficiency relates to the increased risk of developing viral and bacterial infections (16). In addition, injury or trauma induces a series of metabolic, inflammatory, and endocrine events, known as "surgical stress response," causing a profound change in the protein distribution between the intravascular and extravascular compartments (20,27). There is literature showing a decreased risk of infection in patients with higher vitamin D levels (28–32). Some studies even show increased global mortality rates associated with lower serum vitamin D levels (31,33). However, there are still some controversies concerning clinical applicability in various diseases (34). In addition, the heterogeneity of the studies makes it difficult to carry out a meta-analysis with higher statistical power (22,32,35). VITAMIN D AND INFECTION IN ARTHROPLASTY Some authors suggest an association of serum vitamin D levels with orthopedic infection. Traven et al. (36) carried out a retrospective case-control study on hip or knee arthroplasty patients. The case group included patients with vitamin D levels <30ng/ml. In conclusion, there is a higher percentage of patients with vitamin D deficiency with hip or knee arthroplasty revision surgery than those who underwent primary arthroplasty or in the general population. They also noted that patients who underwent review for infection were more likely to be deficient in vitamin D. Low vitamin D patients still had a higher number of new unplanned surgeries within the first 90 days. Maier et al. (31) compared three groups (primary joint prosthesis x revision of aseptic joint prosthesis x periprosthetic infection) and found a more significant number of patients with hypovitaminosis D in the group with infection. Zajonz et al. (33) also compared three different groups. The case group included patients who had an infection following knee or hip arthroplasty, while the control groups were (1) patients who underwent primary arthroplasty or (2) aseptic revision. Unlike other authors, there was no difference in vitamin D levels between groups. However, assessing whether the infection was acute or chronic within the case group found significantly lower vitamin D levels in acute infections. Still, Signori et al. (30) compared four groups: (1) septic prosthesis loosening, (2) aseptic prosthetic loosening, and (3) orthopedic infection (such as osteomyelitis and septic arthritis), and (4) other orthopedic pathologies. When comparing groups 1 and 3 versus 2 and 4, then 1 versus 2, the infected groups had significantly higher vitamin D levels. In this latest study, all septic reviews were due to chronic infection. Emara et al. (22), despite some studies mentioned above suggest, were not able to find enough literature in their systematic review to establish the association between hypovitaminosis and arthroplasty infections due to the diversity of methodology in the articles evaluated. Hernigou et al. (37) did not find studies showing the effect of vitamin supplementation on periprosthetic infections. Marschall e al. (38), in a retrospective cohort of 223 patients, investigated whether hypovitaminosis D could negatively affect the treatment of bone and joint infections, but found no association between serum vitamin D level and treatment of the infection, even with supplementation of vitamin D concomitant with antimicrobial therapy. So far, we have not found any article published on this topic. We found some guidelines that suggest vitamin D supplementation in deficient patients decreases the risk of arthroplasty infection, despite the lack of scientific evidence for this (1,3,4). Some authors have also assessed the association of vitamin D with other pre and postoperative results or scores. Patients with lower vitamin D levels present an accelerated worsening of arthrosis-related pain over time and worse preoperative arthroplasty functional scores, but most without evidence of worse postoperative functional levels (39,40). Another study suggests that lower serum vitamin D levels are an independent risk factor for cognitive impairment after arthroplasties (41).

Although the studies carried out to date try to show an association between periprosthetic infection and vitamin D, we conclude that they are still methodologically deficient and challenging to compare in a meta-analysis. Nevertheless, despite some results contrary to this association, we believe that patients with lower serum vitamin D levels have a higher risk of periprosthetic infections. We also support preoperative vitamin D supplements in patients who will undergo arthroplasty, as the risk of complications from this medication is shallow, as described in many of the articles read. Therefore, further studies are needed to evaluate the association between serum vitamin D levels and periprosthetic infection. In addition, more studies are needed to assess vitamin D supplementation as a modifiable risk factor for joint prosthesis infection. Along with these studies, there is at least one work in progress awaiting results, like Morrison et al. (42).