# Periprosthetic Joint Infection: What Patients Need to Know About Infections After Joint Replacement

Periprosthetic joint infection (PJI) is an infection that develops around an artificial joint, such as a hip or knee replacement. This review article explains how bacteria form protective films on implants, why these infections are hard to treat, and how doctors diagnose and prevent them. The article reports that hip and knee PJI occurred in 2.1% and 2.3% of replacements in the United States in 2017. Hospital costs reach approximately $89,000 for hip PJI and $116,000 for knee PJI per episode. It also details risk factors, prevention strategies, diagnostic criteria, and the economic burden of this rare but serious complication.

# Periprosthetic Joint Infection: What Patients Need to Know About Infections After Joint Replacement

## Table of Contents

- Key Points
- Background: What Is Periprosthetic Joint Infection?
- Clinical Presentation: Symptoms and Signs
- Microbiologic Features: What Causes These Infections
- Epidemiology: How Common Are These Infections
- Economic Considerations: The Cost of Treatment
- Risk Factors: Who Is at Higher Risk
- Prevention: Strategies to Reduce Risk
- Diagnosis: How Doctors Identify PJI
- Frequently Asked Questions
- Source Information

## Key Points

- PJI is a rare infection around an artificial joint; bacteria form biofilms on the implant that resist many antibiotics and the immune system.
- In the U.S. in 2017, PJI occurred in 2.1% of hip replacements and 2.3% of knee replacements, but rates vary across studies.
- Common symptoms include joint pain, redness, swelling, and warmth; fever is often absent, and a draining sinus confirms PJI.
- Diagnosis may involve blood tests, joint fluid aspiration, and tissue cultures; imaging cannot identify the causative organism.
- Hospital costs per episode are about $89,000 for hip PJI and $116,000 for knee PJI; prevention focuses on modifiable risk factors and surgical precautions.

## Background: What Is Periprosthetic Joint Infection?

Periprosthetic joint infection (PJI) is an infection that occurs around an artificial joint. The condition is rare, and it is clinically distinct from infection in a native bone or joint. PJI involves complex interactions between microorganisms, the implant, and the patient's immune system.

A small quantity of microorganisms can cause PJI. Bacteria, and in rare cases fungi, adhere to the surfaces of the artificial joint. These microorganisms then form biofilms on the arthroplasty surfaces. A biofilm is a community of microorganisms that stick together and produce a protective matrix.

Biofilms tend to be refractory to many antimicrobial agents and to the host immune system. This means that standard antibiotics often cannot clear the infection, and the body's natural defenses cannot eliminate it either.

The causative microorganisms are often skin microbiota that are inoculated at the time of placement. In other words, bacteria normally living on the skin enter the surgical site during the joint replacement procedure. However, implants may also be seeded after placement. This can happen hematogenously (through the bloodstream) or through compromised local tissues.

## Clinical Presentation: Symptoms and Signs

The most common symptom of PJI is joint pain. In some cases, local signs of infection may be present. These local signs include erythema (redness), swelling, and warmth of the joint. Fever is often absent.

With chronic infection, there may be pain alone. This pain sometimes occurs together with prosthetic loosening and a draining sinus tract. A draining sinus tract is a channel that allows fluid to drain from the joint to the skin surface.

The presence of a draining sinus is pathognomonic for PJI. This means that if a draining sinus is present, the diagnosis of PJI is confirmed. However, many cases are not associated with draining sinuses.

In some cases, it may be challenging to differentiate PJI from noninfectious causes of arthroplasty failure. This distinction is important because it informs surgical and medical management. The choice of treatment depends on whether an infection is present.

## Microbiologic Features: What Causes These Infections

A myriad of bacteria, as well as some fungi in rare cases, can cause PJI. In a study involving 1,651 patients with 2,067 hip or knee PJIs, researchers identified the most common microorganism groups.

The most common microorganism group was coagulase-negative staphylococci, especially Staphylococcus epidermidis. This was followed by S. aureus, streptococcus species, enterococcus species, cutibacterium species, and Enterobacterales.

This study was performed at a single tertiary referral center. Findings may be different at other institutions. Of the PJIs in this study, 70% were monomicrobial (caused by a single organism) and 25% were polymicrobial (caused by multiple organisms).

Culture-negative rates vary among studies. This variation reflects differences in diagnostic strategies, antibiotic pretreatment, and definitions of culture positivity. Reported culture-negative rates are up to 45%.

Cutibacterium acnes accounts for approximately 44% of cases of shoulder PJI. This is a specific finding for shoulder replacements.

The table below summarizes the microorganisms identified in hip and knee PJI from the single tertiary referral center study:

- Aerobic gram-positive bacteria: 82% frequency

- Coagulase-negative staphylococcus species (other than S. lugdunensis): 37%
- S. aureus: 24%
- S. lugdunensis: 4%
- Streptococcus species: 14%
- Enterococcus species: 8%
- Corynebacterium species: 5%

- Aerobic gram-negative bacteria: 11% frequency

- Enterobacterales: 7%
- Pseudomonas species: 3%

- Anaerobic bacteria: 13% frequency

- Cutibacterium species: 8%
- Other species: 5%

- Fungi: 3%
- Mycobacteria: 0.5%

Pathogen distributions may vary from institution to institution. The percentages listed above are from a single tertiary referral center.

## Epidemiology: How Common Are These Infections

The joint replacements most commonly performed in the United States are knee replacements, followed by hip replacements. Shoulder, elbow, wrist, ankle, and metacarpophalangeal and interphalangeal joint replacements are less commonly performed.

Total hip and total knee arthroplasty numbers in the United States have increased over time. These numbers are projected to continue to increase. Parallel increases in hip and knee PJI numbers have occurred, and these are also projected to continue to rise.

The incidence of hip and knee PJI in the United States was 2.1% and 2.3%, respectively, in 2017. Similar rates have been reported in Korea.

The reported incidence varies across studies, however. This variation is due to differences in populations, definitions, and the duration of follow-up. For example, in a study of 36,494 primary total hip arthroplasties at an institution in the United States, PJI occurred in 0.4%.

Although the risk of PJI is highest in the early postoperative period, the risk persists for the lifetime of the joint. A significant proportion of infections manifest after 1 year.

In a Canadian population-based study and a New Zealand registry study, the incidence of knee PJI increased from 0.5% and 0.8% at 1 year to 1.7% and 2.0%, respectively, at 15 years. In another Canadian population-based study, the incidence of hip PJI was 0.5% at 1 year and 1.4% at 15 years.

Earlier studies reported polyethylene wear as the top cause of failure of total knee arthroplasty. However, improvements in materials have made PJI the main cause of failure of total knee arthroplasty.

## Economic Considerations: The Cost of Treatment

The treatment of PJI is expensive, time-consuming, and resource-intensive. Hospital costs per episode are approximately $89,000 and $116,000 for hip and knee PJI, respectively.

In the first 5 years after total hip arthroplasty is performed, the cost of a revision for PJI is high. The cost of a revision for PJI is more than 5 times as high as the cost of revisions for other reasons. This finding is based on data from hospital admissions. PJI of the hip ultimately costs approximately $391,000 over the course of a lifetime.

Hospital costs in the United States for PJI of the hip and knee will amount to an estimated $1.85 billion annually by 2030.

Surgical strategy affects cost. The cost of a two-stage revision is 2 to 4 times as high as the cost of treatment with débridement, antibiotics, and implant retention (DAIR). A two-stage revision involves prosthesis removal, administration of systemic antibiotics, and subsequent implantation of a new prosthesis.

DAIR, in turn, is approximately twice the cost of a partial component exchange in the absence of infection.

Medicare reimbursement for PJI management is considered inadequate. It requires updating to account for these high costs. This updating is needed to ensure sustainable access to treatment and high-quality care for patients with PJI. Reimbursement gaps may limit access by underserved populations.

## Risk Factors: Who Is at Higher Risk

Numerous risk factors for PJI have been identified. Only some of these risk factors are potentially modifiable. The modifiable risk factors include anemia, injection drug use, malnutrition, obesity, poor glycemic control (with diabetes), and tobacco use.

Many surgeons attempt to address these factors before performing arthroplasty. An online tool for predicting the risk of death among patients with PJI of the hip is available at https://erikbulow.shinyapps.io/prediction_model/.

Arthroplasty procedures should be deferred when there is active infection elsewhere, such as pneumonia. Receipt of injections into affected joints 3 months or less before total knee arthroplasty or total hip arthroplasty is a risk factor for PJI. These injections include glucocorticoids, hyaluronic acid, or anesthetics.

Patients who have undergone multiple arthroplasties and present with PJI in one joint have up to a 20% risk of infection in another joint. This infection can occur synchronously (at the same time) or metachronously (at different times, possibly years later).

In one study, women and patients with methicillin-resistant S. aureus (MRSA) PJI were more likely than men and patients without MRSA to have metachronous PJI in another joint. Patients with rheumatoid arthritis and those with bacteremia also had an increased likelihood of infection in another joint, either synchronous or metachronous.

Patients with Medicaid as a primary payer are at increased risk for PJI. This increased risk persists even with adjustment for educational level and household income. An increased rate of above-knee amputation after knee PJI and Girdlestone resection after hip PJI among poorer patients and patients with Medicare or Medicaid insurance has been reported.

In one study, first-degree relatives of patients with PJI and first- and second-degree relatives combined were at greater risk for PJI after adjustment for socioeconomic factors. A possible genetic predisposition requires further study.

Prolonged operative time increases the risk. In one study, operative times exceeding 90 minutes were associated with a risk of PJI that was increased by a factor of 1.6, as compared with operative times of less than 60 minutes.

The table below lists risk factors for PJI, organized by category:

-
**Potentially modifiable presurgical risk factors:**

- Anemia
- Injection-drug use
- Malnutrition
- Obesity
- Receipt of intraarticular injection in prior 3 months
- Tobacco use

-
**Nonmodifiable presurgical risk factors:**

- Cardiovascular disease (arrhythmia, coronary artery disease, pulmonary hypertension, congestive heart failure, or peripheral vascular disease)
- Diabetes (especially with poor glycemic control)
- Immunocompromised status (owing to cancer or receipt of a transplant)
- Inflammatory arthritis
- Kidney or liver disease (hepatitis or cirrhosis)
- Male sex
- Medicaid as primary payer
- Mental health disorder (depression or alcohol use)
- Relative with PJI
- Patellar resurfacing and post-traumatic arthritis (knees)
- Prior native joint infection
- Prior PJI of same or different joint
- Prior revision arthroplasty
- Younger age

-
**Operative risk factors:**

- Allogeneic blood transfusion
- Prolonged operative time
- Simultaneous bilateral arthroplasty

-
**Postoperative risk factors:**

- Discharge to rehabilitation or convalescent care
- Prolonged hospitalization
- S. aureus bacteremia
- Wound-healing complications (including superficial skin infection)

Improved glycemic control can be achieved presurgically for patients with diabetes.

## Prevention: Strategies to Reduce Risk

Beyond mitigating the modifiable risk factors, several strategies help prevent PJI. Since complications are more likely when arthroplasty is performed at low-volume hospitals by low-volume surgeons, management at specialized centers should be considered.

Preoperative screening for S. aureus carriage, with decolonization of carriers, or universal decolonization, should be considered. Meta-analyses comparing surgical-site infection and PJI in patients undergoing elective total knee arthroplasty or total hip arthroplasty have shown an increased risk of any infection in the absence of decolonization. These meta-analyses also showed increased risks of S. aureus or MRSA infection in the absence of decolonization. There was little difference in risk according to whether universal decolonization or screening-based decolonization was performed.

Patients undergoing elective surgery should cleanse their skin with chlorhexidine cloths or soap and water on at least the night before surgery.

Cefazolin, administered within 60 minutes before incision and infused before tourniquet inflation, should be used as antibiotic prophylaxis. As compared with cefazolin, alternative agents such as vancomycin and clindamycin are associated with a higher risk of PJI of the hip, knee, and shoulder.

Most patients with reported penicillin allergies are candidates to receive cefazolin. This applies in the absence of a history of anaphylaxis or the Stevens–Johnson syndrome. Some practitioners recommend allergy evaluation, such as skin testing.

For patients colonized with MRSA, some clinicians recommend adding vancomycin to cefazolin. A randomized, controlled trial of prophylaxis with cefazolin plus vancomycin as compared with cefazolin alone is in progress (Australian New Zealand Clinical Trials Registry number, ACTRN12618000642280).

Although the duration of prophylaxis has historically varied, the current recommendation is to stop prophylaxis by the time the incision is closed. A retrospective review looked at data from patients undergoing primary total knee arthroplasty or total hip arthroplasty. The review showed no significant differences in PJI rates between those receiving single-dose preoperative prophylaxis and those receiving 24-hour prophylaxis.

A randomized clinical trial comparing one dose of cefazolin with three doses in patients undergoing total knee arthroplasty is in progress (ClinicalTrials.gov number, NCT03283878). A randomized trial addresses a possible need for prolonged prophylaxis in high-risk patients. The trial compares the effect of oral antibiotic prophylaxis for 7 days versus standard care. The trial compares the effect on the incidence of PJI after total hip arthroplasty or total knee arthroplasty in a high-risk patient population (NCT04297592).

Appropriate surgical-site preparation is indicated at surgery. Antimicrobial-impregnated incise drapes are not useful. These drapes are constructed of transparent film and are designed to prevent surgical-site infections. Operating-room traffic should be curbed. Aggressive anticoagulation should be avoided. Tranexamic acid lowers hip and knee PJI rates.

Local delivery of an antimicrobial agent into the wound site may be considered, with caveats. The American Academy of Orthopaedic Surgeons suggests that dilute povidone–iodine lavage be used in total hip arthroplasty and total knee arthroplasty to reduce the risk of infection.

Studies have shown that dilute povidone–iodine lavage has had no effect in patients undergoing primary or revision surgery as compared with various control groups. However, a subgroup analysis of studies with a saline control group suggested an effect in preventing PJI.

In another study, PJI rates did not differ significantly between patients undergoing chlorhexidine gluconate lavage and those undergoing dilute povidone–iodine lavage. This comparison was before primary total knee arthroplasty or total hip arthroplasty.

Although some surgeons apply vancomycin powder, its benefit is unproved. There is potential harm, such as aseptic postoperative wound complications. A multicenter, randomized, controlled trial of vancomycin powder is under way.

## Diagnosis: How Doctors Identify PJI

Definitions of PJI have evolved over time. They progressed from the 2012 Infectious Diseases Society of America guidelines and the Musculoskeletal Infection Society criteria (2011). They progressed to the International Consensus on Orthopedic Infections definition (2018), the definition proposed by Parvizi et al. (2018), and the European Bone and Joint Infection Society definition (2021). These evolving definitions may be helpful starting points for the diagnosis of PJI.

Accurate diagnosis is important because the management of PJI differs from that of noninfectious joint failure. If PJI is present, identification of the microbial cause informs surgical management and the selection of antimicrobial agents.

Establishing a diagnosis of acute infection, or in the case of a draining sinus, chronic infection, is straightforward. In these situations, testing may be restricted to that needed for microbiologic diagnosis. Localized joint pain alone may pose more of a diagnostic challenge and necessitate further testing.

Blood tests may be helpful. These include C-reactive protein measurement, and to a lesser extent, interleukin-6, erythrocyte sedimentation rate, or d-dimer assessment. However, the test results are not diagnostic alone. They may be redundant with one another and do not provide microbiologic information.

Diagnostic tests and associated scoring systems can be helpful when the diagnosis is unclear. Blood cultures are positive in approximately 25% of cases, most often in cases of acute PJI. However, the isolated organisms do not always correlate with those found in joint specimens.

Arthrocentesis is a highly recommended mainstay of PJI diagnosis. Arthrocentesis is the aspiration of joint fluid with a needle. Aspiration should be performed with avoidance of overlying cellulitis. Aspiration of a joint other than the knee, especially the hip, may require imaging guidance, ideally ultrasonographic guidance.

The volume of aspirate should be at least 3.5 ml for typical microorganisms. Synovial fluid should be submitted for assessment of the leukocyte count and neutrophil percentage and for culture. Normal laboratory-reported values and those for septic arthritis of a native joint do not apply to the leukocyte count and neutrophil percentage. PJI-specific interpretive criteria are used, which vary according to the definition used and the interval between arthroplasty and the development of infection.

Alpha-defensin (Synovasure, Zimmer Biomet), C-reactive protein, leukocyte esterase, and calprotectin can be assayed in synovial fluid. There is some redundancy in the diagnostic information provided by each of these tests, as compared with the leukocyte count and neutrophil percentage. These four tests are typically reserved for challenging cases.

Synovial fluid should be cultured aerobically and anaerobically, ideally in blood culture bottles. Anaerobic cultures should be incubated for 14 days. If an organism of uncertain clinical significance is detected, repeat aspiration should be considered. Alternatively, the results should be interpreted in the context of intraoperative cultures. Gram's staining is not recommended.

Arthroscopy with biopsy may be considered if no organism is found, the PJI diagnosis remains unconfirmed, and surgery is not planned.

Plain radiographs have low sensitivity and specificity. Periprosthetic radiolucent lines, osteolysis, implant migration, or a combination of these findings may be present with infection or aseptic loosening. White-cell scintigraphy may provide evidence of potential PJI.

Computed tomography (CT) or 18F-fluorodeoxyglucose or 18F–sodium fluoride positron-emission tomography–CT may be considered if the diagnosis of PJI is unclear. This is especially relevant if revision surgery is not otherwise planned. Magnetic resonance imaging provides good resolution for soft-tissue abnormalities associated with nonferromagnetic implants, such as titanium and tantalum. However, no imaging study can be used to identify causative pathogens.

At surgery, tissue should be collected for histopathological evaluation, unless the diagnosis of PJI has already been established. Multiple tissue specimens should be collected for aerobic and anaerobic culture. This is done given the poor sensitivity of single cultures and to discern contaminants from pathogens. Swab cultures, sinus tract cultures, and Gram's staining of tissue are not recommended.

The culture yield is likely to be higher when antibiotics are withheld for at least 2 weeks before culture. However, prophylactic preoperative antibiotic therapy does not reduce the culture yield and should therefore be administered. Frozen-section analysis for acute inflammation permits intraoperative assessment. Multiple sites and tissue types should be sampled for culture. Even if culture of the preoperative synovial fluid is positive, tissue cultures should be collected.

The table below lists the criteria for diagnosis of hip or knee PJI according to two definitions:

-
**European Bone and Joint Infection Society (EBJIS) "Confirmatory" Single Criteria:**

- Two positive cultures (includes synovial fluid, tissue, and sonicate-fluid cultures) for the same microorganism
- Sinus tract with communication to joint or prosthesis
- Synovial fluid leukocyte count, greater than 3,000 per ml
- Synovial fluid neutrophils, greater than 80%
- Synovial fluid alpha-defensin positive
- Sonicate-fluid culture, greater than 50 CFU/ml for any organism (greater than 200 CFU/ml if centrifuged)
- Histopathological assessment (high-power field, 400× magnification) showing 5 or more neutrophils in 5 or more high-power fields (or visible microorganisms)

-
**2018 Parvizi et al. "Major" Single Criteria:**

- Two positive cultures (includes synovial fluid, tissue, and sonicate-fluid cultures) for the same microorganism
- Sinus tract with communication to joint or prosthesis

"Single" indicates that only one of the listed criteria is needed to confirm the diagnosis. CFU denotes colony-forming units.

Some criteria require cautious interpretation. The synovial fluid leukocyte count and neutrophil percentage should be interpreted with caution in the early postoperative period or when other possible causes of inflammation are present. These other causes include metallosis, hemarthrosis, crystal arthropathy, active inflammatory joint disease (such as rheumatoid arthritis), or periprosthetic fracture. These measures are valid only with clear fluid and no lavage. The volume should be more than 250 μl (ideally, 1 ml), collected in an EDTA tube and analyzed in less than 1 hour, if possible, with the use of automated techniques. With viscous samples, hyaluronidase pretreatment improves accuracy for automated or optical techniques. For bloody samples, the following formula is used: adjusted synovial white-cell count = synovial white-cell count observed − (white-cell count in blood ÷ red-cell count in blood × red-cell count in synovial fluid).

The alpha-defensin criterion is not valid with an underlying adverse local tissue reaction, hematoma, acute inflammatory arthritis, or crystal arthropathy. Bémer et al. propose a threshold of 23 neutrophils in 10 high-power fields for the histopathological criterion.

New diagnostic markers, such as presepsin, are being evaluated. New diagnostic methods for microbial detection and characterization include 16S ribosomal RNA gene polymerase chain reaction (PCR). New diagnostic methods also include either Sanger sequencing or next-generation sequencing (that is, targeted metagenomic sequencing [TMS]) or both. These methods are performed on synovial fluid, sonicate fluid, or periprosthetic tissue. Shotgun metagenomic sequencing (SMS) is another new method. TMS and SMS have performed similarly when assessed on sonicate fluid.

SMS can be performed not only on sonicate fluid but also on synovial fluid, periprosthetic tissue, or plasma. In a study of a commercial TMS assay (MicroGenDx) performed on synovial fluid or swabs, the assay did not have sensitivity or specificity that was superior to culture. In another study, a TMS-based approach performed on synovial fluid showed excellent specificity, with sensitivity that was similar to that of culture. TMS combined with culture had higher sensitivity than culture alone. A multiplex PCR panel for synovial fluid (BioFire) has also been developed.

## Frequently Asked Questions

### What is periprosthetic joint infection (PJI)?

PJI is an infection that develops around an artificial joint, such as a hip or knee replacement. It is rare and distinct from infection in a native bone or joint. Bacteria, and rarely fungi, adhere to the implant and form biofilms—protective communities that resist many antibiotics and the body's immune defenses, making the infection hard to clear.

### How common is PJI after hip or knee replacement?

In the United States in 2017, PJI occurred in 2.1% of hip replacements and 2.3% of knee replacements. However, rates vary widely across studies due to differences in populations, definitions, and follow-up. For example, one U.S. study of 36,494 primary total hip arthroplasties reported PJI in 0.4%. Risk persists for the lifetime of the joint.

### What are the symptoms of PJI?

The most common symptom is joint pain. Local signs may include redness, swelling, and warmth of the joint. Fever is often absent. With chronic infection, pain alone may occur, sometimes with prosthetic loosening and a draining sinus tract—a channel from the joint to the skin. A draining sinus confirms PJI, but many cases have no sinus.

### How do doctors diagnose PJI?

Diagnosis uses evolving criteria and may include blood tests like C-reactive protein, and arthrocentesis—aspiration of joint fluid with a needle—to check leukocyte count, neutrophil percentage, and culture. At surgery, multiple tissue samples are collected for culture and histopathology. Imaging like CT or PET-CT may help if the diagnosis is unclear, but cannot identify the causative organism.

### What risk factors increase the chance of PJI?

Modifiable risk factors include anemia, injection drug use, malnutrition, obesity, poor glycemic control with diabetes, and tobacco use. Nonmodifiable factors include prior PJI, inflammatory arthritis, kidney or liver disease, male sex, Medicaid as primary payer, and certain operative factors like prolonged surgery. Receiving joint injections within 3 months before surgery also raises risk.

### How is PJI treated and what does it cost?

Treatment is expensive and resource-intensive. Hospital costs per episode are approximately $89,000 for hip PJI and $116,000 for knee PJI. A two-stage revision costs 2 to 4 times as much as débridement, antibiotics, and implant retention (DAIR). Over a lifetime, hip PJI costs about $391,000. Medicare reimbursement is considered inadequate.

### Can PJI be prevented?

Several strategies may reduce risk. These include addressing modifiable factors like glycemic control, screening for and decolonizing S. aureus, cleansing skin with chlorhexidine before surgery, and using cefazolin prophylaxis within 60 minutes before incision. Specialized centers may be considered. Tranexamic acid lowers PJI rates. Some measures, like vancomycin powder, have unproved benefit.

### When should a patient with a periprosthetic joint infection seek a second opinion?

A second opinion is reasonable when it is unclear whether joint pain after hip or knee replacement is caused by infection or by noninfectious failure, since the two require different surgical and medical management. It is also reasonable when the diagnosis remains unconfirmed after blood tests and arthrocentesis, or when an organism of uncertain significance is found and repeat aspiration or intraoperative cultures are being considered. Because definitions of PJI have evolved and culture-negative rates reach up to 45%, an independent review of synovial fluid, tissue and imaging can help clarify the diagnosis. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article title:** Periprosthetic Joint Infection NEJM 2023

**Author:** Robin Patel, M.D.

**Author affiliation:** Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, and the Division of Public Health, Infectious Diseases, and Occupational Medicine, Department of Medicine, Mayo Clinic, Rochester, MN.

**Publication:** New England Journal of Medicine, 2023;388:251-62. DOI: 10.1056/NEJMra2203477. Copyright © 2023 Massachusetts Medical Society.

**Review Article editor:** C. Corey Hardin, M.D., Ph.D.

**Note:** This patient-friendly article is based on peer-reviewed research. The original article is a review article that summarizes and interprets findings from multiple studies. All data, statistics, and conclusions presented here are drawn from the original article. Patients should consult their own healthcare providers for personalized medical advice.


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