INTRODUCTION — This section highlights selected specific new recommendations and/or updates that we anticipate may change usual clinical practice. Practice Changing UpDates focus on changes that may have significant and broad impact on practice, and therefore do not represent all updates that affect practice. These Practice Changing UpDates, reflecting important changes to UpToDate over the past year, are presented chronologically, and are discussed in greater detail in the identified topic reviews.
INFECTIOUS DISEASES (November 2021)
COVID-19 vaccination in children 5 years and older
●For children ages 5 to 11 years, we recommend COVID-19 vaccination (Grade 1B).
In October 2021, the US Food and Drug Administration authorized BNT162b2 (Pfizer vaccine) for individuals 5 to 11 years old based on data from randomized trials in over 2000 children in this age group, which demonstrated 91 percent vaccine efficacy against symptomatic COVID-19 and immunogenicity similar to that in adolescents and young adults . There were no cases of vaccine-associated myocarditis in the trials; although the precise risk is uncertain, it is expected to be lower than that seen in older individuals. We agree with recommendations from the Centers for Disease Control and Prevention to give BNT162b2 to children ages 5 to 11 years. Clinicians should be aware that the dose and formulation used for children are different than those for adolescents and adults. (See "COVID-19: Vaccines to prevent SARS-CoV-2 infection", section on 'Summary and recommendations'.)
EMERGENCY MEDICINE (ADULT AND PEDIATRIC) (November 2021)
New threshold for elevated blood lead in United States children
●For children younger than six years of age in the United States, the reference value for an elevated blood level is 3.5 mcg/L (0.17 micromol/L).
Detectable blood lead levels (BLLs) are associated with neurocognitive deficits in infants and children <6 years old, and targeted screening of at-risk children is recommended. The Centers for Disease Control and Prevention has lowered the blood lead level (BLL) threshold for action to 3.5 mcg/dL (0.17 micromol/L) from the previous level of 5.0 mcg/dL (0.24 micromol/L) [2,3]. At or above this threshold, specific interventions should be taken based upon the degree of BLL elevation (table 1). For children with BLLs below 3.5 mcg/dL, the limit of detection for lead varies by laboratory, and the actual blood lead value may be close to or above the threshold. Thus, some children may need to be retested depending upon age or other risk factors. (See "Childhood lead poisoning: Management", section on 'Approach'.)
INFECTIOUS DISEASES (October 2021)
Booster doses of COVID-19 vaccines for individuals 16 years or older
●For individuals ≥16 years of age who received a primary series of a COVID-19 vaccine, we recommend booster vaccination (Grade 1B).
Several countries have introduced booster doses of COVID-19 vaccines because of potentially attenuated vaccine effectiveness due to waning efficacy and variants. The US Food and Drug Administration has authorized and the Centers for Disease Control (CDC) suggests a booster dose for all individuals 16 years or older [4-7]. For those who received BNT162b2 (Pfizer) or mRNA-1273 (Moderna) vaccines, the booster dose should be given at least six months after the primary series. For those who received Ad26.COV2.S (Johnson & Johnson), the booster dose should be given at least two months after the primary series. Any authorized vaccine can be used for the booster dose, regardless of the vaccine used for the primary series. We now recommend booster doses for eligible individuals, based on trials and observational evidence suggesting improved vaccine efficacy following a booster dose. (See "COVID-19: Vaccines to prevent SARS-CoV-2 infection", section on 'Role of booster vaccinations/waning efficacy'.)
NEPHROLOGY AND HYPERTENSION (September 2021)
Glomerular filtration rate estimation without inclusion of a race coefficient
●We suggest using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation to estimate glomerular filtration rate (GFR) for the general population (calculator 1).
Previously, the chronic kidney disease epidemiology (CKD-EPI) equation used to estimate glomerular filtration rate (GFR) included a term for race such that, for any given age, sex, and serum creatinine, a Black individual would have a higher estimated GFR. The American Society of Nephrology and National Kidney Foundation reevaluated the inclusion of race in estimating GFR and determined that a revised creatinine-based equation (ie, the 2021 CKD-EPI equation) that did not include race was sufficiently accurate for clinical use . We now suggest using the 2021 revised CKD-EPI equation to estimate GFR (calculator 1). The equation applies to people with stable kidney function. (See "Assessment of kidney function", section on 'Estimation of GFR'.)
INFECTIOUS DISEASES (August 2021)
Third dose of COVID-19 mRNA vaccine for immunocompromised individuals
The US Food and Drug Administration has authorized a third dose of the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 mRNA vaccines for individuals who have certain immunocompromising conditions, such as active chemotherapy for cancer, hematopoietic cell or solid organ transplant recipients, immunosuppressive therapy (eg, rituximab and other biologic agents, antimetabolites, alkylating agents, prednisone ≥20 mg daily), and advanced or untreated HIV [4,5]. The authorization is based upon studies showing that the immune response to a two-dose mRNA vaccine series is suboptimal and that administration of a third dose may improve the immune response without causing short-term adverse events [9-13]. In agreement with the Advisory Committee on Immunization Practices, we now suggest giving the mRNA vaccines as a three-dose primary series in patients with any of the conditions listed in the table (table 2). (See "COVID-19: Vaccines to prevent SARS-CoV-2 infection", section on 'Immunocompromised individuals'.)
PEDIATRICS (August 2021)
Direct oral anticoagulants for venous thromboembolism in children ≥2 years
●For most adolescents (≥12 years) with venous thromboembolism, after at least five days of initial parenteral therapy, we suggest a direct oral anticoagulant (DOAC; eg, dabigatran or rivaroxaban) rather than other agents (Grade 2B). For children ages 2 to <12 years old, either a DOAC or low molecular weight heparin is reasonable.
In 2021, the US Food and Drug Administration approved dabigatran, a direct oral anticoagulant (DOAC), for treatment of venous thrombosis and thromboembolism (VTE) in children ≥3 months old ; another DOAC, rivaroxaban, has been approved in children in Canada and Europe . These regulatory approvals were based upon two large multicenter pediatric trials demonstrating that dabigatran and rivaroxaban have similar efficacy and bleeding risk compared with low molecular weight heparin (LMWH) and warfarin [16,17]. Adolescents made up most of the trial populations, and children <2 years were underrepresented. DOACs are an attractive option since they are orally administered and do not require drug monitoring. We now suggest one of the approved DOACs (dabigatran or rivaroxaban) for treatment of VTE in adolescents, after at least five days of initial parenteral therapy. For children ages 2 to 11 years, either a DOAC or LMWH is acceptable. For infants and children <2 years, the efficacy and safety of DOACs remain uncertain, and we continue to suggest LMWH. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Direct oral anticoagulants'.)
INFECTIOUS DISEASES (July 2021)
Approaches to reduce recurrent Clostridioides difficile infection
●For patients with nonfulminant Clostridioides difficile infection (CDI), we suggest fidaxomicin over vancomycin (Grade 2C). For patients with recurrent CDI within six months of a prior episode, we suggest bezlotoxumab in addition to antibiotics (Grade 2C). For patients with multiply recurrent CDI who are not candidates for fecal microbiota transplant, we suggest suppressive oral vancomycin following treatment of an acute episode (Grade 2C).
New guidelines on management of Clostridioides difficile infection (CDI) were issued by the Infectious Disease Society of America (IDSA) and American College of Gastroenterology (ACG) in June 2021 [18,19]. For patients with nonfulminant CDI, the IDSA guidelines favor use of fidaxomicin over vancomycin; in addition, for patients with recurrent CDI and prior episode in the last six months, the IDSA guidelines favor use of adjunctive bezlotoxumab (with a standard antibiotic regimen). For patients with recurrent CDI who are not fecal microbiota transplantation candidates, the ACG guidelines suggest use of suppressive oral vancomycin following completion of treatment. We are in agreement with these approaches, which have been associated with a modest reduction in risk for recurrent CDI; in the setting of cost constraints, we prioritize them for patients at highest risk of recurrent CDI (age ≥65 years, history of severe CDI, or immunosuppression). (See "Clostridioides difficile infection in adults: Treatment and prevention", section on 'Nonsevere disease'.)
INFECTIOUS DISEASES; EMERGENCY MEDICINE (ADULT AND PEDIATRIC) (February 2021, Modified June 2021)
Adjunctive baricitinib or tocilizumab for COVID-19
●For hospitalized adults with COVID-19 who have initiated mechanical ventilation in the prior 24 to 48 hours, we suggest adding tocilizumab to usual care (which includes dexamethasone) (Grade 2B). For hospitalized adults with COVID-19 who have initiated high-flow supplemental oxygen or noninvasive ventilation within the prior 24 to 48 hours, we suggest adding baricitinib or tocilizumab to usual care (Grade 2B). For hospitalized adults with COVID-19 who are receiving low-flow supplemental oxygen and have both progressively increasing oxygen requirements despite dexamethasone and significantly elevated inflammatory markers, we suggest adding baricitinib or tocilizumab to usual care (Grade 2C). However, if availability of these agents is limited, we prioritize them for patients on higher levels of oxygen support.
Results from recent randomized trials suggest adjunctive use of the Janus kinase inhibitor baricitinib or the interleukin-6 pathway inhibitor tocilizumab has a survival benefit in hospitalized adults with severe COVID-19.
•In one unpublished randomized trial of patients who were not receiving invasive mechanical ventilation, adding baricitinib to standard of care reduced 28-day mortality; among those on high-flow oxygen or noninvasive ventilation at baseline, mortality was 17.5 versus 29.4 percent with placebo .
•In two open-label trials that included patients on oxygen support with a C-reactive protein level ≥75 mg/L or patients who had recently started high-flow oxygen or more intensive respiratory support, adding tocilizumab reduced 28-day mortality (28 to 29 percent versus 33 to 36 percent with usual care alone) [21,22].
In the majority of patients, usual care included dexamethasone. Baricitinib and tocilizumab have not been compared directly or studied together. We suggest either baricitinib or tocilizumab as an adjunct to dexamethasone for select patients with severe or critical COVID-19. (See "COVID-19: Management in hospitalized adults", section on 'IL-6 pathway inhibitors (eg, tocilizumab)'.)
PEDIATRICS (June 2021)
Elexacaftor-tezacaftor-ivacaftor for children ≥6 years with cystic fibrosis
●For patients ≥6 years old with cystic fibrosis who are homozygous for the F508del variant, we recommend triple therapy (elexacaftor-tezacaftor-ivacaftor) rather than dual therapy (tezacaftor-ivacaftor or lumacaftor-ivacaftor) (Grade 1B). For patients ≥6 years old who have one F508del mutation (heterozygotes) or other eligible mutation based on in vitro data, we suggest triple therapy rather than dual therapy or monotherapy (ivacaftor) (Grade 2C).
Elexacaftor-tezacaftor-ivacaftor is an important therapy for most patients with cystic fibrosis (CF), but its use has been limited to adolescents and adults. The drug combination was evaluated in a 24-week open-label study in 66 children 6 to 11 years old who were homozygous for F508del or heterozygous for F508del with a second minimal function mutation . The safety profile and pharmacokinetics were similar to that in older individuals, and patients experienced improvement in pulmonary function (change in FEV1, 10.2 percentage points; 95% CI 7.9-12.6); respiratory symptoms; sweat chloride; and body weight. On the basis of this study, the US Food and Drug Administration approved this drug for children ≥6 years with CF and eligible genotypes (algorithm 1), and we now recommend treatment in eligible patients starting at the age of six years. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Efficacy'.)
ONCOLOGY (June 2021)
Adjuvant olaparib for BRCA carriers with early breast cancer
Although poly (ADP-ribose) polymerase (PARP) inhibitors are used for individuals with germline pathogenic variants in BRCA1 or BRCA2 and advanced breast cancer, their role in early breast cancer was previously undefined. A randomized trial (OlympiA) was conducted in over 1800 patients with high risk, HER2-negative early breast cancer with BRCA1 or BRCA2 variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy . Patients assigned to the olaparib group had an improvement in three-year disease-free survival relative to the placebo group (86 versus 77 percent). The benefit was observed irrespective of hormone receptor status, and olaparib was generally well tolerated. For BRCA carriers with high-risk disease as defined by criteria from the OlympiA trial (table 3), we now suggest adjuvant olaparib rather than observation. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Supporting data'.)
CARDIOVASCULAR MEDICINE (June 2021)
Surgical left atrial appendage occlusion for patients undergoing cardiac surgery
●For patients who are undergoing cardiac surgery for another indication who have atrial fibrillation and a CHA2DS2-VASc risk score (table 1) of at least 2, we recommend concomitant surgical left atrial appendage occlusion (Grade 1B).
The left atrial appendage (LAA) is the primary source of thromboembolism in patients with atrial fibrillation (AF). When patients with AF undergo cardiac surgery, LAA occlusion is commonly performed with limited supporting evidence. The effects of surgical LAA occlusion were studied in a trial enrolling nearly 4800 patients with AF (with ≥2 risk factors for thromboembolism) undergoing cardiac surgery, in which patients were randomly assigned to surgical LAA occlusion or no occlusion and most continued oral anticoagulation after the procedure . At nearly four years of follow-up, stroke or systemic embolism was about one-third less frequent in the occlusion group than in the no-occlusion group, and perioperative complications were similar in the two groups. These results support use of surgical LAA occlusion as an adjunct to long-term anticoagulation for patients undergoing cardiac surgery for another indication who have AF and a CHA2DS2-VASc risk score (table 4) of at least 2. (See "Atrial fibrillation: Left atrial appendage occlusion", section on 'For patients without contraindication to long-term anticoagulation'.)
NEUROLOGY (April 2021)
Second course of IVIG not beneficial for patients with severe Guillain-Barré syndrome
●For patients with Guillain-Barré syndrome treated initially with IVIG who show further deterioration or no improvement, we suggest against retreating with IVIG because it exposes patients to adverse risks without additional benefit (Grade 2C).
For patients with severe Guillain-Barré syndrome (GBS) whose symptoms worsen or fail to improve after a course of intravenous immune globulin (IVIG), a repeat course has sometimes been given, despite uncertain benefit. In a randomized trial of 93 patients with GBS and a poor predicted outcome, those assigned to a second course of IVIG (given two to four days after completion of the first course) had similar disability but more adverse effects, including thromboembolic complications, than those who were assigned to placebo . Based on these data, we suggest against retreating with a second course of IVIG for patients with GBS. (See "Guillain-Barré syndrome in adults: Treatment and prognosis", section on 'Approach to patients who relapse or worsen'.)
ONCOLOGY (April 2021)
Postoperative nivolumab after initial chemoradiotherapy for esophageal and esophagogastric junction cancer
●For patients with localized esophageal or esophagogastric junction cancer who have residual disease in the surgical specimen after initial chemoradiotherapy, we suggest nivolumab for one year (Grade 2B), although we discontinue it if disease recurs during treatment.
Patients with localized esophageal or esophagogastric junction (EGJ) cancer who are treated with neoadjuvant chemoradiotherapy and have residual disease at the time of resection remain at high risk for recurrence and death from cancer, yet optimal postoperative management is unknown. In the CheckMate 577 trial of nearly 800 such patients, adjuvant nivolumab for up to one year doubled median disease-free survival compared with placebo (22.4 versus 11 months) without adversely affecting health-related quality of life . Benefits were seen across all patient subgroups (histology, location, initial and posttreatment disease stage) and did not depend on programmed cell death ligand-1 status. Overall survival data are not yet mature. Despite the lack of data on survival, given the morbidity of disease recurrence, we now suggest one year of adjuvant nivolumab for patients with resected esophageal or EGJ cancer who have residual disease in the surgical specimen after initial chemoradiotherapy. This approach has been endorsed by an updated guideline on the treatment of locally advanced esophageal carcinoma . (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus", section on 'After preoperative therapy'.)
OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (February 2021)
Low-dose aspirin for those with previous pregnancy loss (miscarriage)
While low-dose aspirin (LDA; 81 mg) improves pregnancy outcomes for individuals at high risk for preeclampsia or with antiphospholipid syndrome, LDA did not show statistically significant benefits in a placebo-controlled trial in over 1200 patients with one or two previous pregnancy losses. A limitation of the trial was the low rate of adherence. In a new analysis of this trial using detailed adherence data and adjustment for confounders, LDA started preconception and continued throughout pregnancy was associated with approximately 30 percent fewer pregnancy losses and 30 percent more live births compared with placebo . Based on these findings and the safety profile of LDA in other pregnant populations, we now suggest preconception initiation of LDA for individuals who have experienced one or two pregnancy losses, but not for those who are nulliparous or who have not had a prior loss. (See "Pregnancy loss (miscarriage): Comparison of treatment options and discussion of related care", section on 'Review of data'.)
EMERGENCY MEDICINE (ADULT AND PEDIATRIC); OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (February 2021)
Levonorgestrel intrauterine device for emergency contraception
Until now, the copper TCu380A intrauterine device (copper IUD) was the only IUD option for use as emergency contraception (EC). In a randomized, noninferiority trial in 711 females who presented within five days of unprotected intercourse and had a negative urine pregnancy test, the copper IUD and the levonorgestrel intrauterine device 52 mg (LNG 52) resulted in similar pregnancy rates (0.0 and 0.3 percent, respectively) . Based on this trial, we now suggest either the copper IUD or the LNG 52 IUD to individuals who desire an IUD for EC. Some patients may prefer the lighter menstrual bleeding or amenorrhea associated with LNG 52 IUD use. Use of the LNG 52 IUD represents off-label use for this indication. (See "Emergency contraception".)
INFECTIOUS DISEASES; OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH; PRIMARY CARE (ADULT); FAMILY MEDICINE AND GENERAL PRACTICE; EMERGENCY MEDICINE (ADULT AND PEDIATRIC) (January 2021)
Anaerobic coverage for treatment of pelvic inflammatory disease
Anaerobic bacteria are frequently recovered from the upper genital tract of women with acute pelvic inflammatory disease (PID), but whether antibiotic regimens for PID should include anaerobic coverage has been controversial. In a trial of 233 women with mild to moderate PID who were treated with ceftriaxone and doxycycline and randomly assigned to additionally receive either metronidazole (500 mg twice daily) or placebo for 14 days, clinical improvement rates at three days were similar in the two groups . However, at 30 days, women in the metronidazole group had a lower rate of pelvic tenderness (9 versus 20 percent) and a nonsignificant trend towards a higher 30-day clinical cure rate (96 versus 90 percent). Adherence was similar in both groups. Given the potential additional benefits of anaerobic coverage, we now add metronidazole to standard outpatient therapy for PID. (See "Pelvic inflammatory disease: Treatment in adults and adolescents", section on 'Anaerobic bacteria'.)
INFECTIOUS DISEASES; PRIMARY CARE (ADULT); FAMILY MEDICINE AND GENERAL PRACTICE; OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (January 2021)
Single-dose ceftriaxone for treatment of gonococcal infections
●For suspected or confirmed uncomplicated urogenital or anorectal gonococcal infection, we suggest ceftriaxone in a single 500 mg intramuscular dose rather than other regimens (Grade 2C). For individuals who weigh ≥150 kg, we give a 1 g dose.
In the United States, the Centers for Disease Control and Prevention updated its guidance on treatment of gonococcal infections to recommend ceftriaxone as the preferred regimen, given as a single intramuscular dose of 500 mg for individuals who weigh <150 kg or 1 g for individuals who weigh ≥150 kg . Previous recommendations were for combination therapy with a lower dose of ceftriaxone plus azithromycin. However, the previous preference for combination therapy was based on a theoretical benefit, which is now outweighed by decreasing susceptibility to azithromycin in Neisseria gonorrhoeae. A higher dose of ceftriaxone is recommended because of concern that lower doses are unlikely to be effective against isolates with higher minimum inhibitory concentrations to ceftriaxone, which have increased in prevalence. Presumptive treatment of chlamydia with doxycycline is warranted if chlamydia coinfection has not been ruled out. We agree with these updated guidelines. (See "Treatment of uncomplicated Neisseria gonorrhoeae infections", section on '"High" dose intramuscular ceftriaxone'.)