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.
NEPHROLOGY AND HYPERTENSION (June 2022)
Oral glucocorticoids for immunoglobulin A (IgA) nephropathy
●For patients with IgA nephropathy who are considered to be at high risk of disease progression (ie, proteinuria ≥1 g/day despite at least three months of optimized supportive care), we suggest treatment with glucocorticoids plus supportive care rather than supportive care alone (Grade 2B).
In patients with immunoglobulin A (IgA) nephropathy who are at high risk for progressive disease, the effect of glucocorticoids on clinical outcomes has been uncertain. In a randomized trial of over 500 patients with IgA nephropathy, proteinuria ≥1 g/day, and an estimated glomerular filtration rate of 20 to 120 mL/min per 1.73 m2 after at least three months of supportive therapy, the addition of oral glucocorticoids (full- or reduced-dose) to supportive therapy slowed the decline of kidney function and reduced the risk of end-stage kidney disease compared with supportive therapy alone (19 versus 27 percent) . Serious adverse events were more frequent with glucocorticoids than with placebo but occurred primarily among those receiving full rather than reduced doses of glucocorticoids. Based on these results, we now suggest use of glucocorticoids in most high-risk patients with IgA nephropathy. (See "IgA nephropathy: Treatment and prognosis", section on 'Glucocorticoid therapy'.)
INFECTIOUS DISEASES (June 2022)
COVID-19 vaccination in children 6 months and older
●For children aged 6 months to 11 years old, we recommend COVID-19 vaccination (Grade 1B).
As of June 2022, the US Food and Drug Administration (FDA) has authorized BNT162b2 (Pfizer COVID-19 vaccine) and mRNA-1273 (Moderna COVID-19 vaccine) for use in children 6 months and older. Trials in children 6 months to 11 years have demonstrated that these vaccines, given at lower doses, elicit neutralizing immune responses comparable to those in adolescents and adults following standard doses [2-4]. Vaccination also reduces the risk of symptomatic COVID-19 in these populations, although the estimates of effect vary, in part because of different variants prevalent during the trials. There were no cases of vaccine-associated myocarditis in the trials; the precise risk is uncertain but 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 or mRNA-1273 to children ages 6 months to 11 years. Clinicians should be aware that the dose and formulation used for children are different than those for adolescents and adults (table 1). (See "COVID-19: Vaccines", section on 'Summary and recommendations'.)
INFECTIOUS DISEASES (October 2021, Modified May 2022)
Booster doses of COVID-19 vaccines for individuals five years or older
●For individuals ≥5 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 and Prevention recommends a booster dose for all individuals five years or older [5-8]. The booster dose is given five months after a primary BNT162b2 (Pfizer) or mRNA-1273 (Moderna) series for most patients (or three months after the primary series for immunocompromised patients) and two months after a primary Ad26.COV2.S (Johnson and Johnson) series. Any vaccine authorized for the patient's age group can be used for the booster dose, regardless of the vaccine used for the primary series; we favor one of the mRNA vaccines over Ad26.COV2.S. We recommend booster doses for eligible individuals, based on trials and observational evidence suggesting improved vaccine efficacy following a booster dose. (See "COVID-19: Vaccines", section on 'Role of booster vaccinations/waning efficacy'.)
INFECTIOUS DISEASES (February 2022, Modified May 2022)
Updated recommendations for pneumococcal vaccination in adults
●For all adults with an indication for pneumococcal vaccination (table 1), we suggest PCV20 rather than other vaccines (Grade 2C). For patients with immunocompromising conditions or risk for meningitis, some UpToDate authors also favor administering PPSV23 ≥8 weeks following the PCV20 dose.
In early 2022, the Advisory Committee on Immunization Practices (ACIP) updated guidance on pneumococcal vaccination to recommend either :
•20-valent pneumococcal conjugate vaccine (PCV20) alone (newly available), or
•The combination of 15-valent pneumococcal conjugate vaccine (PCV15; newly available) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) at least a year afterward, except in high-risk individuals (eg, immunocompromising conditions, cochlear implant, or cerebrospinal fluid leak), in whom a shorter interval of ≥8 weeks may be used to maximize protection more quickly
Based largely on convenience, we now suggest PCV20 for all adults with indications for pneumococcal vaccination (table 2). Although the ACIP does not require it, some UpToDate authors also favor giving PPSV23 ≥8 weeks after PSV20 for immunocompromised patients and those with increased risk for meningitis in order to provide protection against serotypes present in PPSV23 that are absent from PCV20. (See "Pneumococcal vaccination in adults".)
OBSTETRICS, GYNECOLOGY AND WOMEN'S HEALTH (April 2022)
Treatment of chronic hypertension in pregnancy
●For pregnant patients with nonsevere chronic hypertension (based on medical history or systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or both on at least two occasions at least four hours apart before 20 weeks of gestation), we recommend antihypertensive treatment (Grade 1B).
Traditionally, only severe chronic hypertension (blood pressure [BP] ≥160/110 mmHg) has been treated in pregnancy because of fetal safety concerns and lack of evidence of maternal benefit. In the Chronic Hypertension and Pregnancy (CHAP) trial, over 2400 pregnant people with nonsevere chronic hypertension (≥140/90 mmHg) were randomly assigned to active treatment (initiating/continuing antihypertensive treatment to keep BP <140/90 mmHg) or usual care (antihypertensive treatment only for BP ≥160/105 mmHg) . Active treatment resulted in an 18 percent relative reduction in a composite adverse pregnancy outcome, including preeclampsia with severe features (23.3 versus 29.1 percent) and medically indicated preterm birth <35 weeks (12.2 versus 16.7 percent), with no adverse fetal effects. Based on this trial, we now recommend antihypertensive treatment for pregnant patients with chronic hypertension to keep BP <140/90 mmHg. We prefer labetalol or extended-release nifedipine. (See "Treatment of hypertension in pregnant and postpartum patients", section on 'Background'.)
ONCOLOGY (April 2022)
First-line therapy for high-risk, high-volume metastatic hormone-sensitive prostate cancer
●For most patients with metastatic hormone-sensitive, high-risk, high-volume prostate cancer who are candidates for docetaxel, we recommend androgen deprivation therapy (ADT) plus docetaxel and darolutamide rather than ADT plus docetaxel alone (Grade 1B). Abiraterone is a reasonable alternative to darolutamide with promising but currently less robust data, particularly in those with metachronous metastatic disease.
Docetaxel plus androgen deprivation therapy (ADT) is a standard approach for initial treatment of patients with hormone-sensitive, high-risk, high-volume metastatic prostate cancer. Two trials now demonstrate an overall survival benefit from the addition of a second systemic agent to ADT plus docetaxel. In the ARASENS trial, the addition of darolutamide to ADT plus docetaxel improved overall survival and all secondary endpoints without worsening treatment-related toxicity in men with metastatic castration-sensitive prostate cancer (CSPC), and the benefits were similar in most subgroups . In the PEACE-1 trial, the addition of abiraterone to ADT plus docetaxel also improved survival over ADT plus docetaxel alone in patients with de novo metastatic CSPC . (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)
INFECTIOUS DISEASES (August 2021, Modified February 2022)
Additional COVID-19 vaccine primary series dose for immunocompromised individuals
●For individuals with certain immunocompromising conditions (table 1), we suggest administering a three-dose primary mRNA vaccine series rather than a two-dose series (Grade 2C). Similarly, we suggest an additional mRNA vaccine dose for such individuals who previously received a single Ad26.COV2.S dose (Grade 2C).
COVID-19 vaccines are less effective among patients with certain immunocompromising conditions than in the general population; additional vaccine doses have been associated with improved effectiveness in this population. We agree with recommendations from the Advisory Committee on Immunization Practices (ACIP) in the United States that individuals with such conditions (table 3) receive an additional mRNA vaccine dose as part of their primary COVID-19 vaccine series (eg, following two doses of an mRNA vaccine or one dose of Ad26.COV2.S vaccine) (figure 1) [13,14]. This additional primary series dose is distinct from the booster dose, which such patients should additionally receive, although at a shorter interval than recommended for the general population. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)
INFECTIOUS DISEASES (February 2022)
Tenofovir alafenamide now a preferred NRTI agent for pregnant individuals with HIV
●For most treatment-naïve individuals with HIV who are initiating antiretroviral therapy during pregnancy, we suggest tenofovir alafenamide-emtricitabine plus dolutegravir rather than other preferred three-drug combination regimens (Grade 2C).
Recommended antiretroviral regimens for individuals with HIV initiating treatment during pregnancy include two nucleoside reverse transcriptase inhibitor (NRTI) agents in conjunction with either an integrase inhibitor or a booster protease inhibitor. Based on accumulating safety and efficacy data in this population, the United States Department of Health and Human Services has added tenofovir alafenamide (TAF) to the list of preferred NRTIs to use for pregnant individuals with HIV . In a recent trial, regimens containing TAF versus tenofovir disoproxil fumarate (TDF) resulted in similar virologic suppression rates, but TAF was associated with fewer adverse pregnancy outcomes. We generally initiate the NRTI combination of TAF-emtricitabine in this patient population unless there is significant concern for excessive gestational weight gain, in which case a TAF-containing regimen can be used. (See "Antiretroviral selection and management in pregnant women with HIV in resource-rich settings", section on 'Selecting the NRTI backbone'.)
PEDIATRICS (February 2022)
Duration of anticoagulation for low-risk provoked venous thromboembolism in pediatric patients
●For pediatric patients with provoked venous thromboembolism who meet low-risk criteria, we suggest six weeks of anticoagulant therapy rather than observation or shorter or longer courses of treatment (Grade 2C).
The optimal duration of anticoagulant therapy for children with venous thromboembolism (VTE) is uncertain. Usual practice has been to treat for three months based largely upon evidence from adult studies. However, a recent clinical trial suggests that six weeks of therapy is sufficient for most pediatric patients with low-risk provoked VTE (ie, attributable to a transient risk factor) . The trial enrolled 417 children with provoked VTE (catheter-associated in 50 percent; infection-related in 30 percent; surgery- or trauma-related in 20 percent) who were randomly assigned to six weeks or three months of anticoagulant therapy. At one year, rates of VTE recurrence were similarly low in both groups (1.1 and 1.6 percent, respectively). Based upon these findings, we now suggest a six-week course of treatment for pediatric patients with provoked VTE who met all of the following low-risk criteria:
•No prior history of VTE
•The VTE is not severe or life-threatening
•The provoking risk factor resolves within six weeks
•The thrombus resolves or is nonocclusive within six weeks
For patients with provoked VTE who do not meet these criteria, we continue to suggest three months of therapy. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Provoked VTE'.)
HEMATOLOGY (January 2022)
Chimeric antigen receptor-T cell therapy for early relapse or refractory diffuse large B cell lymphoma
●For patients with early first relapse of diffuse large B cell lymphoma or primary refractory disease, we recommend CD19-directed chimeric antigen receptor-T cell therapy using lisocabtagene maraleucel or axicabtagene ciloleucel, rather than autologous hematopoietic cell transplantation (Grade 1B).
Although autologous hematopoietic cell transplantation (HCT) has long been standard treatment in medically-fit patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), recent phase 3 trials compared transplantation with CD19-directed chimeric antigen receptor (CAR)-T products in these settings. In patients with early first relapse (<12 months after initial therapy) or primary refractory DLBCL, lisocabtagene maraleucel (liso-cel) and axicabtagene ciloleucel (axi-cel) improved event-free and overall survival relative to autologous HCT, with acceptable toxicity [17,18]. By contrast, another CD-19 CAR-T cell product, tisagenlecleucel, did not improve outcomes or toxicity relative to HCT . CAR-T cell therapy is restricted to approved institutions and can be associated with life-threatening cytokine release syndrome and neurologic toxicity. We now recommend liso-cel or axi-cel for early relapsed or primary refractory DLBCL, when available; note that this guidance does not apply to later relapses (≥12 months). (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in medically-fit patients", section on 'Relapse <12 months or primary refractory DLBCL'.)
GENERAL SURGERY (December 2021)
No benefit of antibiotics for outpatient treatment of uncomplicated acute diverticulitis
●For patients who meet criteria for outpatient treatment of acute colonic diverticulitis, we suggest not administering antibiotics (Grade 2B).
Antibiotics have been the cornerstone of diverticulitis treatment based upon retrospective studies and clinical experience. In a randomized trial (DINAMO) of 480 patients with imaging-confirmed uncomplicated acute diverticulitis who met criteria for outpatient treatment and whose symptoms were adequately controlled in the emergency department, supportive treatment (pain control and liquid diet) with or without antibiotics resulted in similarly low rates of unscheduled return visits (6.7 versus 7 percent) or hospitalizations (6 versus 3 percent) . Based on this and two other similar trials, we now suggest not prescribing antibiotics when treating outpatients with uncomplicated acute diverticulitis (ie, nonsevere diverticular disease and no serious comorbidities) (algorithm 1). (See "Acute colonic diverticulitis: Medical management", section on 'No oral antibiotics'.)
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) [21,22]. At or above this threshold, specific interventions should be taken based upon the degree of BLL elevation (table 4). 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'.)
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".)
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 two direct oral anticoagulants (DOACs), dabigatran and rivaroxaban, for treatment of venous thrombosis and thromboembolism (VTE) in children [24,25]. 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 [26,27]. 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 a third or subsequent CDI recurrence 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 [28,29]. 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'.)
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 2), 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 5), 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 6) of at least 2. (See "Atrial fibrillation: Left atrial appendage occlusion", section on 'For patients without contraindication to long-term anticoagulation'.)