Medical case reports are as old as the healing profession itself.¹ These ancient medical stories have a modern definition: “A case report is a narrative that describes, for medical, scientific or educational purposes, a medical problem experienced by one or more patients.”² Case report experts describe the 3-fold purposes of this type of research: as a mainstay of education; a harbinger of emerging illnesses; and an appraiser of new interventions. Case-based education has long been a pillar of health professions education: Nurses, doctors, and allied health professionals are taught and learn through reading and discussing with their teachers and each other about cases of their own patients and of those in the literature.³ Case reports also have helped identify and raise awareness of new diseases and rare conditions, such as HIV.⁴ Finally, case reports have alerted regulatory agencies and the medical community about medication adverse effects, such as birth defects from thalidomide.⁵

Case reports also have been criticized on both scientific and ethical grounds. Critics argue that many case reports often lack the rigor and consistency of other types of research.⁶ Three recent trends in medical publication have strengthened the validity of these criticisms: the increase in the popularity of case reports; the corresponding increase in submissions to journals, including Federal Practitioner; and the rise of predatory publishers.^7,8

The ethical scrutiny of case reports discussed in this column focuses on the tension between providing readers with adequate, accurate information to fulfil the goals of case reports while also protecting patient confidentiality. The latter issue during most of the history of medicine was not considered by health care professionals when the prevailing paternalism supported a professional-oriented approach to health care. The rise of bioethics in the 1960s and 1970s began the shift toward patient autonomy in medical decision making and patient rights to control their protected health information that rendered case reports ethically problematic.

To address both changes in ethical standards and scientific limitations, a committee of clinicians, researchers, and journal editors formed the Case Report (CARE) group.^2,8 The group undertook an effort to improve the quality of case reports. From 2011 to 2012, they developed the CARE guidelines for clinical case reporting. The guidance took the form of a Statement and Checklist presented at the 2013 International Congress on Peer Review and Biomedical Publication. Since their presentation, multiple prestigious medical journals in many countries have implemented these recommendations.

As part of an overall effort to raise the ethical caliber of our own journal, Federal Practitioner will begin to implement the CARE guidelines for case reports for all future submissions. Use of the CARE recommendations will help prospective authors enhance the scientific value and ethical caliber of case reports submitted to the journal as well as assist the Federal Practitioner editorial team, editorial board, and peer reviewers to evaluate submissions more judiciously.

An essential part of the CARE guidelines is that the patient who is the subject of the case report provide informed consent for the publication of their personal narrative. The CARE group considers this an “ethical duty” of authors and editors alike. In “exceptional circumstances” such as if the patient is a minor or permanently incapacitated, a guardian or relative may grant consent. In the rare event that even with exhaustive attempts, if informed consent cannot be obtained from a patient or their representative, then the authors of the case report must submit a statement to this effect.⁴ Some journals may require that the authors obtain the approval of an institutional review board or the permission of an ethics or other institutional committee or a privacy officer.²

Requesting the patient’s consent is an extension of the shared decision making that is now a best practice in clinical care into the arena of research, making the patient or their representative a partner in the work. Ethicists have recommended inviting patients or relatives to read a draft of the case report and agree to its publication or request specific modifications to the manuscript. The CARE group rightly points out that with the rise of open notes in medical documentation, patients increasingly have access to their charts in near or real time.² Gone are the days of Sir William Osler when only doctors read medical journals and all of these technical developments as well as standards of research and social changes in the practitioner-patient relationship make it imperative that writers and editors join together to make case reports more transparent, accurate, and consistent.⁷

An additional step to protect patient privacy is the requirement that authors either de-identify potentially identifiable health information, such as age, birth, death, admission, and discharge dates, or in some instances obtain separate consent for the release of that protected data.⁸ These restrictions constitute a challenge to case report authors who in some instances may consider these same facts critical to the integrity of the case presentation that have made some scholars doubt their continued viability. After all, the contribution of the case to the medical literature often lies in its very particularity. Conversely, no matter how frustrated we might become during writing a case report, we would not want to see our own protected health information or that of our family on a website or in print without our knowledge or approval. Indeed, the International Committee of Medical Journal Editors states that “If identifying characteristics are de-identified, authors should provide assurance, and editors should so note, that such changes do not distort scientific meaning.”⁹

However, the exponential growth of the internet, the spread of social media, and the ubiquity of a plethora of electronic devices, which prior generations of writers and readers could not even imagine, make these limitations necessary to protect patient privacy and the public’s trust in health care professionals. The CARE guidelines can help authors of case reports hone the art of anonymizing the protected health information of subjects of case reports, such as ethnicity and occupation, while accurately conveying the clinical specifics of the case that make it valuable to students and colleagues.

We at Federal Practitioner recognize there is a real tension between truth-telling in case report publication and respect for patient confidentiality that will never be perfectly achieved, but is one that is important for medical knowledge, making it worthy of the continuous efforts of authors and editors to negotiate.

Medical case reports are as old as the healing profession itself.¹ These ancient medical stories have a modern definition: “A case report is a narrative that describes, for medical, scientific or educational purposes, a medical problem experienced by one or more patients.”² Case report experts describe the 3-fold purposes of this type of research: as a mainstay of education; a harbinger of emerging illnesses; and an appraiser of new interventions. Case-based education has long been a pillar of health professions education: Nurses, doctors, and allied health professionals are taught and learn through reading and discussing with their teachers and each other about cases of their own patients and of those in the literature.³ Case reports also have helped identify and raise awareness of new diseases and rare conditions, such as HIV.⁴ Finally, case reports have alerted regulatory agencies and the medical community about medication adverse effects, such as birth defects from thalidomide.⁵

Case reports also have been criticized on both scientific and ethical grounds. Critics argue that many case reports often lack the rigor and consistency of other types of research.⁶ Three recent trends in medical publication have strengthened the validity of these criticisms: the increase in the popularity of case reports; the corresponding increase in submissions to journals, including Federal Practitioner; and the rise of predatory publishers.^7,8

The ethical scrutiny of case reports discussed in this column focuses on the tension between providing readers with adequate, accurate information to fulfil the goals of case reports while also protecting patient confidentiality. The latter issue during most of the history of medicine was not considered by health care professionals when the prevailing paternalism supported a professional-oriented approach to health care. The rise of bioethics in the 1960s and 1970s began the shift toward patient autonomy in medical decision making and patient rights to control their protected health information that rendered case reports ethically problematic.

To address both changes in ethical standards and scientific limitations, a committee of clinicians, researchers, and journal editors formed the Case Report (CARE) group.^2,8 The group undertook an effort to improve the quality of case reports. From 2011 to 2012, they developed the CARE guidelines for clinical case reporting. The guidance took the form of a Statement and Checklist presented at the 2013 International Congress on Peer Review and Biomedical Publication. Since their presentation, multiple prestigious medical journals in many countries have implemented these recommendations.

As part of an overall effort to raise the ethical caliber of our own journal, Federal Practitioner will begin to implement the CARE guidelines for case reports for all future submissions. Use of the CARE recommendations will help prospective authors enhance the scientific value and ethical caliber of case reports submitted to the journal as well as assist the Federal Practitioner editorial team, editorial board, and peer reviewers to evaluate submissions more judiciously.

An essential part of the CARE guidelines is that the patient who is the subject of the case report provide informed consent for the publication of their personal narrative. The CARE group considers this an “ethical duty” of authors and editors alike. In “exceptional circumstances” such as if the patient is a minor or permanently incapacitated, a guardian or relative may grant consent. In the rare event that even with exhaustive attempts, if informed consent cannot be obtained from a patient or their representative, then the authors of the case report must submit a statement to this effect.⁴ Some journals may require that the authors obtain the approval of an institutional review board or the permission of an ethics or other institutional committee or a privacy officer.²

Requesting the patient’s consent is an extension of the shared decision making that is now a best practice in clinical care into the arena of research, making the patient or their representative a partner in the work. Ethicists have recommended inviting patients or relatives to read a draft of the case report and agree to its publication or request specific modifications to the manuscript. The CARE group rightly points out that with the rise of open notes in medical documentation, patients increasingly have access to their charts in near or real time.² Gone are the days of Sir William Osler when only doctors read medical journals and all of these technical developments as well as standards of research and social changes in the practitioner-patient relationship make it imperative that writers and editors join together to make case reports more transparent, accurate, and consistent.⁷

An additional step to protect patient privacy is the requirement that authors either de-identify potentially identifiable health information, such as age, birth, death, admission, and discharge dates, or in some instances obtain separate consent for the release of that protected data.⁸ These restrictions constitute a challenge to case report authors who in some instances may consider these same facts critical to the integrity of the case presentation that have made some scholars doubt their continued viability. After all, the contribution of the case to the medical literature often lies in its very particularity. Conversely, no matter how frustrated we might become during writing a case report, we would not want to see our own protected health information or that of our family on a website or in print without our knowledge or approval. Indeed, the International Committee of Medical Journal Editors states that “If identifying characteristics are de-identified, authors should provide assurance, and editors should so note, that such changes do not distort scientific meaning.”⁹

However, the exponential growth of the internet, the spread of social media, and the ubiquity of a plethora of electronic devices, which prior generations of writers and readers could not even imagine, make these limitations necessary to protect patient privacy and the public’s trust in health care professionals. The CARE guidelines can help authors of case reports hone the art of anonymizing the protected health information of subjects of case reports, such as ethnicity and occupation, while accurately conveying the clinical specifics of the case that make it valuable to students and colleagues.

We at Federal Practitioner recognize there is a real tension between truth-telling in case report publication and respect for patient confidentiality that will never be perfectly achieved, but is one that is important for medical knowledge, making it worthy of the continuous efforts of authors and editors to negotiate.

Medical case reports are as old as the healing profession itself.¹ These ancient medical stories have a modern definition: “A case report is a narrative that describes, for medical, scientific or educational purposes, a medical problem experienced by one or more patients.”² Case report experts describe the 3-fold purposes of this type of research: as a mainstay of education; a harbinger of emerging illnesses; and an appraiser of new interventions. Case-based education has long been a pillar of health professions education: Nurses, doctors, and allied health professionals are taught and learn through reading and discussing with their teachers and each other about cases of their own patients and of those in the literature.³ Case reports also have helped identify and raise awareness of new diseases and rare conditions, such as HIV.⁴ Finally, case reports have alerted regulatory agencies and the medical community about medication adverse effects, such as birth defects from thalidomide.⁵

Case reports also have been criticized on both scientific and ethical grounds. Critics argue that many case reports often lack the rigor and consistency of other types of research.⁶ Three recent trends in medical publication have strengthened the validity of these criticisms: the increase in the popularity of case reports; the corresponding increase in submissions to journals, including Federal Practitioner; and the rise of predatory publishers.^7,8

The ethical scrutiny of case reports discussed in this column focuses on the tension between providing readers with adequate, accurate information to fulfil the goals of case reports while also protecting patient confidentiality. The latter issue during most of the history of medicine was not considered by health care professionals when the prevailing paternalism supported a professional-oriented approach to health care. The rise of bioethics in the 1960s and 1970s began the shift toward patient autonomy in medical decision making and patient rights to control their protected health information that rendered case reports ethically problematic.

To address both changes in ethical standards and scientific limitations, a committee of clinicians, researchers, and journal editors formed the Case Report (CARE) group.^2,8 The group undertook an effort to improve the quality of case reports. From 2011 to 2012, they developed the CARE guidelines for clinical case reporting. The guidance took the form of a Statement and Checklist presented at the 2013 International Congress on Peer Review and Biomedical Publication. Since their presentation, multiple prestigious medical journals in many countries have implemented these recommendations.

As part of an overall effort to raise the ethical caliber of our own journal, Federal Practitioner will begin to implement the CARE guidelines for case reports for all future submissions. Use of the CARE recommendations will help prospective authors enhance the scientific value and ethical caliber of case reports submitted to the journal as well as assist the Federal Practitioner editorial team, editorial board, and peer reviewers to evaluate submissions more judiciously.

An essential part of the CARE guidelines is that the patient who is the subject of the case report provide informed consent for the publication of their personal narrative. The CARE group considers this an “ethical duty” of authors and editors alike. In “exceptional circumstances” such as if the patient is a minor or permanently incapacitated, a guardian or relative may grant consent. In the rare event that even with exhaustive attempts, if informed consent cannot be obtained from a patient or their representative, then the authors of the case report must submit a statement to this effect.⁴ Some journals may require that the authors obtain the approval of an institutional review board or the permission of an ethics or other institutional committee or a privacy officer.²

Requesting the patient’s consent is an extension of the shared decision making that is now a best practice in clinical care into the arena of research, making the patient or their representative a partner in the work. Ethicists have recommended inviting patients or relatives to read a draft of the case report and agree to its publication or request specific modifications to the manuscript. The CARE group rightly points out that with the rise of open notes in medical documentation, patients increasingly have access to their charts in near or real time.² Gone are the days of Sir William Osler when only doctors read medical journals and all of these technical developments as well as standards of research and social changes in the practitioner-patient relationship make it imperative that writers and editors join together to make case reports more transparent, accurate, and consistent.⁷

An additional step to protect patient privacy is the requirement that authors either de-identify potentially identifiable health information, such as age, birth, death, admission, and discharge dates, or in some instances obtain separate consent for the release of that protected data.⁸ These restrictions constitute a challenge to case report authors who in some instances may consider these same facts critical to the integrity of the case presentation that have made some scholars doubt their continued viability. After all, the contribution of the case to the medical literature often lies in its very particularity. Conversely, no matter how frustrated we might become during writing a case report, we would not want to see our own protected health information or that of our family on a website or in print without our knowledge or approval. Indeed, the International Committee of Medical Journal Editors states that “If identifying characteristics are de-identified, authors should provide assurance, and editors should so note, that such changes do not distort scientific meaning.”⁹

However, the exponential growth of the internet, the spread of social media, and the ubiquity of a plethora of electronic devices, which prior generations of writers and readers could not even imagine, make these limitations necessary to protect patient privacy and the public’s trust in health care professionals. The CARE guidelines can help authors of case reports hone the art of anonymizing the protected health information of subjects of case reports, such as ethnicity and occupation, while accurately conveying the clinical specifics of the case that make it valuable to students and colleagues.

We at Federal Practitioner recognize there is a real tension between truth-telling in case report publication and respect for patient confidentiality that will never be perfectly achieved, but is one that is important for medical knowledge, making it worthy of the continuous efforts of authors and editors to negotiate.

Automated urine cultures (UCs) following urinalysis (UA) are often used in emergency departments (EDs) to identify urinary tract infections (UTIs). The fast-paced environment of the ED makes this method of proactive collection and facilitation of UC favorable. However, results are often reported as no organism growth or the growth of clinically insignificant organisms, leading to the overdetection and overtreatment of asymptomatic bacteriuria (ASB).^1-3 An estimated 30 to 60% of patients with ASB receive unwarranted antibiotic treatment, which is associated with an increased risk of developing Clostridioides difficile infection and contributes to the development of antimicrobial resistance.^4-10 The costs associated with UC are an important consideration given the use of resources, the time and effort required to collect and process large numbers of negative cultures, and further efforts devoted to the follow-up of ED culture results.

Changes in traditional testing involving testing of both a UA and UC to reflex testing where urine specimens undergo culture only if they meet certain criteria have been described.^11-14 This change in traditional testing aims to reduce the number of potentially unnecessary cultures performed without compromising clinical care. Leukocyte quantity in the UA has been shown to be a reliable predictor of true infection.^11,15 Fok and colleagues demonstrated that reflex urine testing in ambulatory male urology patients in which cultures were done on only urine specimens with > 5 white blood cells per high-power field (WBC/HPF) would have missed only 7% of positive UCs, while avoiding 69% of cultures.¹¹

At the Edward Hines, Jr Veterans Affairs Hospital (Hines VA), inappropriate UC ordering and treatment for ASB has been identified as an area needing improvement. An evaluation was conducted at the facility to determine the population of inpatient veterans with a positive UC who were appropriately managed. Of the 113 study patients with a positive UC included in this review, 77 (68%) had a diagnosis of ASB, with > 80% of patients with ASB (and no other suspected infections) receiving antimicrobial therapy.⁸ A subsequent evaluation was conducted at the Hines VA ED to evaluate UTI treatment and follow-up. Of the 173 ED patients included, 23% received antibiotic therapy for an ASB and 60% had a UA and UC collected but did not report symptoms.⁹ Finally, a review by the Hines VA laboratory showed that in May 2017, of 359 UCs sent from various locations of the hospital, 38% were obtained in the setting of a negative UA.

A multidisciplinary group with representation from primary care, infectious diseases, pharmacy, nursing, laboratory, and informatics was created with a goal to improve the workup and management of UTIs. In addition to periodic education for the clinicians regarding appropriate use and interpretation of UA and UC along with judicious use of antimicrobials especially in the setting of ASB, a UA to reflex culture process change was implemented. This allowed for automatic cancellation of a UC in the setting of a negative UA, which was designed to help facilitate appropriate UC ordering.

Methods

The primary objective of this study was to compare the frequency of inappropriate UC use and inappropriate antibiotic prescribing pre- and postimplementation of this UA to reflex culture process change. An inappropriate UC was defined as a UC ordered despite a negative UA in asymptomatic patients. Inappropriate antibiotic prescribing was defined as treatment of patients with ASB. The secondary objective evaluated postintervention data to assess the frequency of outpatient, ED, and hospital visits for UTI-related symptoms in the group of patients that had a UC cancelled as a result of the new process change (within a 7-day period of the initial UA) to determine whether patients with true infections were missed due to the process change.

Study Design and Setting

This pre-post quality improvement (QI) study analyzed the UC-ordering practices for UTIs sent from the ED at the Hines VA. This VA is a 483-bed tertiary care hospital in Chicago, Illinois, and serves > 57,000 veterans and about 23,000 ED visits annually. This study was approved by the Edward Hines, Jr VA Institutional Review Board as a quality assurance/QI proposal prior to data collection.

Patient Selection

All patients who received a UA with or without a UC sent from the ED between October 17, 2017 and January 17, 2018 were identified by the microbiology laboratory and a list was generated. Postintervention data were compared with data from a previous analysis performed at the Hines VA in 2015 (baseline data), which found that UCs were collected frequently despite negative UA, and often resulted in the prescribing of unnecessary antibiotics.⁹

When comparing postintervention data with preintervention data for the primary study objective, the same exclusion criteria from the 2015 study were applied to the present study, which excluded ED patients who were admitted for inpatient care, concurrent antibiotic therapy for a non-UTI indication, duplicate cultures, and use of chronic bladder management devices. All patients identified as receiving a UA during the specified postintervention study period were included for evaluation of the secondary study objective.

Interventions

After physician education, an ED process change was implemented on October 3, 2017. This process change involved the creation of new order sets in the EHR that allowed clinicians to order a UA only, a UA with culture that would be cancelled by laboratory personnel if the UA did not result in > 5 WBC/HPF, and a UA with culture designated as do not cancel, where the UC was processed regardless of the UA results. The scenarios in which the latter option was considered appropriate were listed on the ordering screen and included pregnancy, a genitourinary procedure with necessary preoperative culture, and neutropenia.

Measurements

Postimplementation, all UAs were reviewed and grouped as follows: (1) positive UA with subsequent UC; (2) negative UA, culture cancelled; (3) only UA ordered (no culture); or (4) do not cancel UC ordered. Of the UAs that were analyzed, the following data were collected: demographics, comorbidities, concurrent medications for benign prostatic hyperplasia (BPH) and/or overactive bladder (OAB), documented allergies/adverse drug reactions to antibiotics, date of ED visit, documented UTI signs/symptoms (defined as frequency, urgency, dysuria, fever, suprapubic pain, or altered mental status in patients unable to verbalize urinary symptoms), UC results and susceptibilities, number of UCs repeated within 7 days after initial UA, requirement of antibiotic for UTI within 7 days of initial UA, antibiotic prescribed, duration of antibiotic therapy, and outpatient visits, ED visits, or need for hospital admission within 7 days of the initial UA for UTI-related symptoms. Other relevant UA and UC data that could not be obtained from the EHR were collected by generating a report using the Veterans Information Systems and Technology Architecture (VistA).

Analysis

Statistical analysis was performed using SAS v9.4. Independent t tests and Fisher exact tests were used to describe difference pre- and postintervention. Statistical significance was considered for P < .05. Based on results from the previous study conducted at this facility in addition to a literature review, it was determined that 92 patients in each group (pre- and postintervention) would be necessary to detect a 15% increase in percentage of patients appropriately treated for a UTI.

Results

There were 684 UAs evaluated from ED visits, 429 preintervention and 255 postintervention. The 255 patients were evaluated for the secondary objective of the study. Of the 255 patients with UAs identified postintervention, 150 were excluded based on the predefined exclusion criteria, and the remaining 105 were compared with the 173 patients from the preintervention group and were included in the analysis for the primary objective (Figure 1).

Patients in the postintervention group were younger than those in the preintervention group (P < .02): otherwise the groups were similar (Table 1). Inappropriate antibiotics for ASB decreased from 10.2% preintervention to 1.9% postintervention (odds ratio, 0.17; P = .01) (Table 2). UC processing despite a negative UA significantly decreased from 100% preintervention to 38.6% postintervention (P < .001) (Table 3). In patients with a negative UA, antibiotic prescribing decreased by 25.3% postintervention, but this difference was not statistically significant.

Discussion

A simple process change at the Hines VA resulted in benefits related to antimicrobial stewardship without conferring adverse outcomes on patient safety. Both UC processing despite a negative UA and inappropriate antibiotic prescribing for ASB were reduced significantly postintervention. This process change was piloted in the ED where UCs are often included as part of the initial diagnostic testing in patients who may not report UTI-related symptoms but for whom a UC is often bundled with other infectious workup, depending on the patient presentation.

Reflex testing of urine specimens has been described in the literature, both in an exploratory nature where impact of a reflex UC cancellation protocol based on certain UA criteria is measured by percent reduction of UCs processed as well as results of such interventions implemented into clinical practice.^11-13 A retrospective study performed at the University of North Carolina Medical Center evaluated patients who presented to the ED during a 6-month period and had both an automated UA and UC collected. UC processing was restricted to UA that was positive for nitrites, leukocyte esterase, bacteria, or > 10 WBC/HPF. Use of this reflex culture cancellation protocol could have eliminated 604 of the 1546 (39.1%) cultures processed. However, 11 of the 314 (3.5%) positive cultures could have been missed.¹³ This same protocol was externally validated at another large academic ED setting, where similar results were found.¹⁴

Limitations

This single-center, pre-post QI study was not without limitations. Manual chart reviews were required, and accuracy of information was dependent on clinician documentation and assessment of UTI-related symptoms. The population studied was predominately older males; thus, results may not be applicable to females or young adults. Additionally, recognition of a negative UA and subsequent cancellation of the UC was dependent on laboratory personnel. As noted in the patient group with a positive UA, some of these UAs were negative and may have been overlooked; therefore, subsequent UCs were inappropriately processed. However, this occurred infrequently and confirmed the low probability of true UTI in the setting of a negative UA. Follow-up for UTI-related symptoms may not have been captured if a patient had presented to an outside facility. Last, definitions of a positive UA differed slightly between the pre- and postintervention groups. The preintervention study defined a positive UA as a WBC count > 5 WBC/HPF and positive leukocyte esterase, whereas the present study defined a positive UA with a WBC count > 5. This may have resulted in an overestimation of positive UA in the postintervention group.

Conclusions

Better selective use of UC testing may improve stewardship resources and reduce costs impacting both ED and clinical laboratories. Furthermore, benefits can include a reduction in the use of time and resources required to collect samples for culture, use of test supplies, the time and effort required to process the large number of negative cultures, and resources devoted to the follow-up of these ED culture results. The described UA to reflex culture process change demonstrated a significant reduction in the processing of inappropriate UC and unnecessary antibiotics for ASB. There were no missed UTIs or other adverse patient outcomes noted. This process change has been implemented in all departments at the Hines VA and additional data will be collected to ensure consistent outcomes.

Automated urine cultures (UCs) following urinalysis (UA) are often used in emergency departments (EDs) to identify urinary tract infections (UTIs). The fast-paced environment of the ED makes this method of proactive collection and facilitation of UC favorable. However, results are often reported as no organism growth or the growth of clinically insignificant organisms, leading to the overdetection and overtreatment of asymptomatic bacteriuria (ASB).^1-3 An estimated 30 to 60% of patients with ASB receive unwarranted antibiotic treatment, which is associated with an increased risk of developing Clostridioides difficile infection and contributes to the development of antimicrobial resistance.^4-10 The costs associated with UC are an important consideration given the use of resources, the time and effort required to collect and process large numbers of negative cultures, and further efforts devoted to the follow-up of ED culture results.

Changes in traditional testing involving testing of both a UA and UC to reflex testing where urine specimens undergo culture only if they meet certain criteria have been described.^11-14 This change in traditional testing aims to reduce the number of potentially unnecessary cultures performed without compromising clinical care. Leukocyte quantity in the UA has been shown to be a reliable predictor of true infection.^11,15 Fok and colleagues demonstrated that reflex urine testing in ambulatory male urology patients in which cultures were done on only urine specimens with > 5 white blood cells per high-power field (WBC/HPF) would have missed only 7% of positive UCs, while avoiding 69% of cultures.¹¹

At the Edward Hines, Jr Veterans Affairs Hospital (Hines VA), inappropriate UC ordering and treatment for ASB has been identified as an area needing improvement. An evaluation was conducted at the facility to determine the population of inpatient veterans with a positive UC who were appropriately managed. Of the 113 study patients with a positive UC included in this review, 77 (68%) had a diagnosis of ASB, with > 80% of patients with ASB (and no other suspected infections) receiving antimicrobial therapy.⁸ A subsequent evaluation was conducted at the Hines VA ED to evaluate UTI treatment and follow-up. Of the 173 ED patients included, 23% received antibiotic therapy for an ASB and 60% had a UA and UC collected but did not report symptoms.⁹ Finally, a review by the Hines VA laboratory showed that in May 2017, of 359 UCs sent from various locations of the hospital, 38% were obtained in the setting of a negative UA.

A multidisciplinary group with representation from primary care, infectious diseases, pharmacy, nursing, laboratory, and informatics was created with a goal to improve the workup and management of UTIs. In addition to periodic education for the clinicians regarding appropriate use and interpretation of UA and UC along with judicious use of antimicrobials especially in the setting of ASB, a UA to reflex culture process change was implemented. This allowed for automatic cancellation of a UC in the setting of a negative UA, which was designed to help facilitate appropriate UC ordering.

Methods

The primary objective of this study was to compare the frequency of inappropriate UC use and inappropriate antibiotic prescribing pre- and postimplementation of this UA to reflex culture process change. An inappropriate UC was defined as a UC ordered despite a negative UA in asymptomatic patients. Inappropriate antibiotic prescribing was defined as treatment of patients with ASB. The secondary objective evaluated postintervention data to assess the frequency of outpatient, ED, and hospital visits for UTI-related symptoms in the group of patients that had a UC cancelled as a result of the new process change (within a 7-day period of the initial UA) to determine whether patients with true infections were missed due to the process change.

Study Design and Setting

This pre-post quality improvement (QI) study analyzed the UC-ordering practices for UTIs sent from the ED at the Hines VA. This VA is a 483-bed tertiary care hospital in Chicago, Illinois, and serves > 57,000 veterans and about 23,000 ED visits annually. This study was approved by the Edward Hines, Jr VA Institutional Review Board as a quality assurance/QI proposal prior to data collection.

Patient Selection

All patients who received a UA with or without a UC sent from the ED between October 17, 2017 and January 17, 2018 were identified by the microbiology laboratory and a list was generated. Postintervention data were compared with data from a previous analysis performed at the Hines VA in 2015 (baseline data), which found that UCs were collected frequently despite negative UA, and often resulted in the prescribing of unnecessary antibiotics.⁹

When comparing postintervention data with preintervention data for the primary study objective, the same exclusion criteria from the 2015 study were applied to the present study, which excluded ED patients who were admitted for inpatient care, concurrent antibiotic therapy for a non-UTI indication, duplicate cultures, and use of chronic bladder management devices. All patients identified as receiving a UA during the specified postintervention study period were included for evaluation of the secondary study objective.

Interventions

After physician education, an ED process change was implemented on October 3, 2017. This process change involved the creation of new order sets in the EHR that allowed clinicians to order a UA only, a UA with culture that would be cancelled by laboratory personnel if the UA did not result in > 5 WBC/HPF, and a UA with culture designated as do not cancel, where the UC was processed regardless of the UA results. The scenarios in which the latter option was considered appropriate were listed on the ordering screen and included pregnancy, a genitourinary procedure with necessary preoperative culture, and neutropenia.

Measurements

Postimplementation, all UAs were reviewed and grouped as follows: (1) positive UA with subsequent UC; (2) negative UA, culture cancelled; (3) only UA ordered (no culture); or (4) do not cancel UC ordered. Of the UAs that were analyzed, the following data were collected: demographics, comorbidities, concurrent medications for benign prostatic hyperplasia (BPH) and/or overactive bladder (OAB), documented allergies/adverse drug reactions to antibiotics, date of ED visit, documented UTI signs/symptoms (defined as frequency, urgency, dysuria, fever, suprapubic pain, or altered mental status in patients unable to verbalize urinary symptoms), UC results and susceptibilities, number of UCs repeated within 7 days after initial UA, requirement of antibiotic for UTI within 7 days of initial UA, antibiotic prescribed, duration of antibiotic therapy, and outpatient visits, ED visits, or need for hospital admission within 7 days of the initial UA for UTI-related symptoms. Other relevant UA and UC data that could not be obtained from the EHR were collected by generating a report using the Veterans Information Systems and Technology Architecture (VistA).

Analysis

Statistical analysis was performed using SAS v9.4. Independent t tests and Fisher exact tests were used to describe difference pre- and postintervention. Statistical significance was considered for P < .05. Based on results from the previous study conducted at this facility in addition to a literature review, it was determined that 92 patients in each group (pre- and postintervention) would be necessary to detect a 15% increase in percentage of patients appropriately treated for a UTI.

Results

There were 684 UAs evaluated from ED visits, 429 preintervention and 255 postintervention. The 255 patients were evaluated for the secondary objective of the study. Of the 255 patients with UAs identified postintervention, 150 were excluded based on the predefined exclusion criteria, and the remaining 105 were compared with the 173 patients from the preintervention group and were included in the analysis for the primary objective (Figure 1).

Patients in the postintervention group were younger than those in the preintervention group (P < .02): otherwise the groups were similar (Table 1). Inappropriate antibiotics for ASB decreased from 10.2% preintervention to 1.9% postintervention (odds ratio, 0.17; P = .01) (Table 2). UC processing despite a negative UA significantly decreased from 100% preintervention to 38.6% postintervention (P < .001) (Table 3). In patients with a negative UA, antibiotic prescribing decreased by 25.3% postintervention, but this difference was not statistically significant.

Discussion

A simple process change at the Hines VA resulted in benefits related to antimicrobial stewardship without conferring adverse outcomes on patient safety. Both UC processing despite a negative UA and inappropriate antibiotic prescribing for ASB were reduced significantly postintervention. This process change was piloted in the ED where UCs are often included as part of the initial diagnostic testing in patients who may not report UTI-related symptoms but for whom a UC is often bundled with other infectious workup, depending on the patient presentation.

Reflex testing of urine specimens has been described in the literature, both in an exploratory nature where impact of a reflex UC cancellation protocol based on certain UA criteria is measured by percent reduction of UCs processed as well as results of such interventions implemented into clinical practice.^11-13 A retrospective study performed at the University of North Carolina Medical Center evaluated patients who presented to the ED during a 6-month period and had both an automated UA and UC collected. UC processing was restricted to UA that was positive for nitrites, leukocyte esterase, bacteria, or > 10 WBC/HPF. Use of this reflex culture cancellation protocol could have eliminated 604 of the 1546 (39.1%) cultures processed. However, 11 of the 314 (3.5%) positive cultures could have been missed.¹³ This same protocol was externally validated at another large academic ED setting, where similar results were found.¹⁴

Limitations

This single-center, pre-post QI study was not without limitations. Manual chart reviews were required, and accuracy of information was dependent on clinician documentation and assessment of UTI-related symptoms. The population studied was predominately older males; thus, results may not be applicable to females or young adults. Additionally, recognition of a negative UA and subsequent cancellation of the UC was dependent on laboratory personnel. As noted in the patient group with a positive UA, some of these UAs were negative and may have been overlooked; therefore, subsequent UCs were inappropriately processed. However, this occurred infrequently and confirmed the low probability of true UTI in the setting of a negative UA. Follow-up for UTI-related symptoms may not have been captured if a patient had presented to an outside facility. Last, definitions of a positive UA differed slightly between the pre- and postintervention groups. The preintervention study defined a positive UA as a WBC count > 5 WBC/HPF and positive leukocyte esterase, whereas the present study defined a positive UA with a WBC count > 5. This may have resulted in an overestimation of positive UA in the postintervention group.

Conclusions

Better selective use of UC testing may improve stewardship resources and reduce costs impacting both ED and clinical laboratories. Furthermore, benefits can include a reduction in the use of time and resources required to collect samples for culture, use of test supplies, the time and effort required to process the large number of negative cultures, and resources devoted to the follow-up of these ED culture results. The described UA to reflex culture process change demonstrated a significant reduction in the processing of inappropriate UC and unnecessary antibiotics for ASB. There were no missed UTIs or other adverse patient outcomes noted. This process change has been implemented in all departments at the Hines VA and additional data will be collected to ensure consistent outcomes.

Automated urine cultures (UCs) following urinalysis (UA) are often used in emergency departments (EDs) to identify urinary tract infections (UTIs). The fast-paced environment of the ED makes this method of proactive collection and facilitation of UC favorable. However, results are often reported as no organism growth or the growth of clinically insignificant organisms, leading to the overdetection and overtreatment of asymptomatic bacteriuria (ASB).^1-3 An estimated 30 to 60% of patients with ASB receive unwarranted antibiotic treatment, which is associated with an increased risk of developing Clostridioides difficile infection and contributes to the development of antimicrobial resistance.^4-10 The costs associated with UC are an important consideration given the use of resources, the time and effort required to collect and process large numbers of negative cultures, and further efforts devoted to the follow-up of ED culture results.

Changes in traditional testing involving testing of both a UA and UC to reflex testing where urine specimens undergo culture only if they meet certain criteria have been described.^11-14 This change in traditional testing aims to reduce the number of potentially unnecessary cultures performed without compromising clinical care. Leukocyte quantity in the UA has been shown to be a reliable predictor of true infection.^11,15 Fok and colleagues demonstrated that reflex urine testing in ambulatory male urology patients in which cultures were done on only urine specimens with > 5 white blood cells per high-power field (WBC/HPF) would have missed only 7% of positive UCs, while avoiding 69% of cultures.¹¹

At the Edward Hines, Jr Veterans Affairs Hospital (Hines VA), inappropriate UC ordering and treatment for ASB has been identified as an area needing improvement. An evaluation was conducted at the facility to determine the population of inpatient veterans with a positive UC who were appropriately managed. Of the 113 study patients with a positive UC included in this review, 77 (68%) had a diagnosis of ASB, with > 80% of patients with ASB (and no other suspected infections) receiving antimicrobial therapy.⁸ A subsequent evaluation was conducted at the Hines VA ED to evaluate UTI treatment and follow-up. Of the 173 ED patients included, 23% received antibiotic therapy for an ASB and 60% had a UA and UC collected but did not report symptoms.⁹ Finally, a review by the Hines VA laboratory showed that in May 2017, of 359 UCs sent from various locations of the hospital, 38% were obtained in the setting of a negative UA.

A multidisciplinary group with representation from primary care, infectious diseases, pharmacy, nursing, laboratory, and informatics was created with a goal to improve the workup and management of UTIs. In addition to periodic education for the clinicians regarding appropriate use and interpretation of UA and UC along with judicious use of antimicrobials especially in the setting of ASB, a UA to reflex culture process change was implemented. This allowed for automatic cancellation of a UC in the setting of a negative UA, which was designed to help facilitate appropriate UC ordering.

Methods

The primary objective of this study was to compare the frequency of inappropriate UC use and inappropriate antibiotic prescribing pre- and postimplementation of this UA to reflex culture process change. An inappropriate UC was defined as a UC ordered despite a negative UA in asymptomatic patients. Inappropriate antibiotic prescribing was defined as treatment of patients with ASB. The secondary objective evaluated postintervention data to assess the frequency of outpatient, ED, and hospital visits for UTI-related symptoms in the group of patients that had a UC cancelled as a result of the new process change (within a 7-day period of the initial UA) to determine whether patients with true infections were missed due to the process change.

Study Design and Setting

This pre-post quality improvement (QI) study analyzed the UC-ordering practices for UTIs sent from the ED at the Hines VA. This VA is a 483-bed tertiary care hospital in Chicago, Illinois, and serves > 57,000 veterans and about 23,000 ED visits annually. This study was approved by the Edward Hines, Jr VA Institutional Review Board as a quality assurance/QI proposal prior to data collection.

Patient Selection

All patients who received a UA with or without a UC sent from the ED between October 17, 2017 and January 17, 2018 were identified by the microbiology laboratory and a list was generated. Postintervention data were compared with data from a previous analysis performed at the Hines VA in 2015 (baseline data), which found that UCs were collected frequently despite negative UA, and often resulted in the prescribing of unnecessary antibiotics.⁹

When comparing postintervention data with preintervention data for the primary study objective, the same exclusion criteria from the 2015 study were applied to the present study, which excluded ED patients who were admitted for inpatient care, concurrent antibiotic therapy for a non-UTI indication, duplicate cultures, and use of chronic bladder management devices. All patients identified as receiving a UA during the specified postintervention study period were included for evaluation of the secondary study objective.

Interventions

After physician education, an ED process change was implemented on October 3, 2017. This process change involved the creation of new order sets in the EHR that allowed clinicians to order a UA only, a UA with culture that would be cancelled by laboratory personnel if the UA did not result in > 5 WBC/HPF, and a UA with culture designated as do not cancel, where the UC was processed regardless of the UA results. The scenarios in which the latter option was considered appropriate were listed on the ordering screen and included pregnancy, a genitourinary procedure with necessary preoperative culture, and neutropenia.

Measurements

Postimplementation, all UAs were reviewed and grouped as follows: (1) positive UA with subsequent UC; (2) negative UA, culture cancelled; (3) only UA ordered (no culture); or (4) do not cancel UC ordered. Of the UAs that were analyzed, the following data were collected: demographics, comorbidities, concurrent medications for benign prostatic hyperplasia (BPH) and/or overactive bladder (OAB), documented allergies/adverse drug reactions to antibiotics, date of ED visit, documented UTI signs/symptoms (defined as frequency, urgency, dysuria, fever, suprapubic pain, or altered mental status in patients unable to verbalize urinary symptoms), UC results and susceptibilities, number of UCs repeated within 7 days after initial UA, requirement of antibiotic for UTI within 7 days of initial UA, antibiotic prescribed, duration of antibiotic therapy, and outpatient visits, ED visits, or need for hospital admission within 7 days of the initial UA for UTI-related symptoms. Other relevant UA and UC data that could not be obtained from the EHR were collected by generating a report using the Veterans Information Systems and Technology Architecture (VistA).

Analysis

Statistical analysis was performed using SAS v9.4. Independent t tests and Fisher exact tests were used to describe difference pre- and postintervention. Statistical significance was considered for P < .05. Based on results from the previous study conducted at this facility in addition to a literature review, it was determined that 92 patients in each group (pre- and postintervention) would be necessary to detect a 15% increase in percentage of patients appropriately treated for a UTI.

Results

There were 684 UAs evaluated from ED visits, 429 preintervention and 255 postintervention. The 255 patients were evaluated for the secondary objective of the study. Of the 255 patients with UAs identified postintervention, 150 were excluded based on the predefined exclusion criteria, and the remaining 105 were compared with the 173 patients from the preintervention group and were included in the analysis for the primary objective (Figure 1).

Patients in the postintervention group were younger than those in the preintervention group (P < .02): otherwise the groups were similar (Table 1). Inappropriate antibiotics for ASB decreased from 10.2% preintervention to 1.9% postintervention (odds ratio, 0.17; P = .01) (Table 2). UC processing despite a negative UA significantly decreased from 100% preintervention to 38.6% postintervention (P < .001) (Table 3). In patients with a negative UA, antibiotic prescribing decreased by 25.3% postintervention, but this difference was not statistically significant.

Discussion

A simple process change at the Hines VA resulted in benefits related to antimicrobial stewardship without conferring adverse outcomes on patient safety. Both UC processing despite a negative UA and inappropriate antibiotic prescribing for ASB were reduced significantly postintervention. This process change was piloted in the ED where UCs are often included as part of the initial diagnostic testing in patients who may not report UTI-related symptoms but for whom a UC is often bundled with other infectious workup, depending on the patient presentation.

Reflex testing of urine specimens has been described in the literature, both in an exploratory nature where impact of a reflex UC cancellation protocol based on certain UA criteria is measured by percent reduction of UCs processed as well as results of such interventions implemented into clinical practice.^11-13 A retrospective study performed at the University of North Carolina Medical Center evaluated patients who presented to the ED during a 6-month period and had both an automated UA and UC collected. UC processing was restricted to UA that was positive for nitrites, leukocyte esterase, bacteria, or > 10 WBC/HPF. Use of this reflex culture cancellation protocol could have eliminated 604 of the 1546 (39.1%) cultures processed. However, 11 of the 314 (3.5%) positive cultures could have been missed.¹³ This same protocol was externally validated at another large academic ED setting, where similar results were found.¹⁴

Limitations

This single-center, pre-post QI study was not without limitations. Manual chart reviews were required, and accuracy of information was dependent on clinician documentation and assessment of UTI-related symptoms. The population studied was predominately older males; thus, results may not be applicable to females or young adults. Additionally, recognition of a negative UA and subsequent cancellation of the UC was dependent on laboratory personnel. As noted in the patient group with a positive UA, some of these UAs were negative and may have been overlooked; therefore, subsequent UCs were inappropriately processed. However, this occurred infrequently and confirmed the low probability of true UTI in the setting of a negative UA. Follow-up for UTI-related symptoms may not have been captured if a patient had presented to an outside facility. Last, definitions of a positive UA differed slightly between the pre- and postintervention groups. The preintervention study defined a positive UA as a WBC count > 5 WBC/HPF and positive leukocyte esterase, whereas the present study defined a positive UA with a WBC count > 5. This may have resulted in an overestimation of positive UA in the postintervention group.

Conclusions

Better selective use of UC testing may improve stewardship resources and reduce costs impacting both ED and clinical laboratories. Furthermore, benefits can include a reduction in the use of time and resources required to collect samples for culture, use of test supplies, the time and effort required to process the large number of negative cultures, and resources devoted to the follow-up of these ED culture results. The described UA to reflex culture process change demonstrated a significant reduction in the processing of inappropriate UC and unnecessary antibiotics for ASB. There were no missed UTIs or other adverse patient outcomes noted. This process change has been implemented in all departments at the Hines VA and additional data will be collected to ensure consistent outcomes.

The American Heart Association (AHA) draws attention to the important bidirectional link between cardiovascular health and brain health in its annual statistical update on heart disease and stroke.

“For several years now, the AHA and the scientific community have increasingly recognized the connections between cardiovascular health and brain health, so it was time for us to cement this into its own chapter, which we highlight as the brain health chapter,” Connie W. Tsao, MD, MPH, chair of the statistical update writing group, with Harvard Medical School, Boston, said in an AHA podcast.

“The global rate of brain disease is quickly outpacing heart disease,” Mitchell S. V. Elkind, MD, immediate past president of the AHA, added in a news release.

“The rate of deaths from Alzheimer’s disease and other dementias rose more than twice as much in the past decade compared to the rate of deaths from heart disease, and that is something we must address,” said Dr. Elkind, with Columbia University Vagelos College of Physicians and Surgeons in New York.

“It’s becoming more evident that reducing vascular disease risk factors can make a real difference in helping people live longer, healthier lives, free of heart disease and brain disease,” Dr. Elkind added.

The AHA’s Heart Disease and Stroke Statistics – 2022 Update was published online January 26 in Circulation).

The report highlights some of the research connecting heart and brain health, including the following:

• A meta-analysis of 139 studies showed that people with midlife hypertension were five times more likely to experience impairment on global cognition and about twice as likely to experience reduced executive function, dementia, and Alzheimer’s disease.
• A meta-analysis of four longitudinal studies found that the risk for dementia associated with heart failure was increased nearly twofold.
• In the large prospective Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study, atrial fibrillation was associated with greater cognitive decline and dementia over 20 years.
• A meta-analysis of 10 prospective studies (including 24,801 participants) showed that coronary heart disease (CHD) was associated with a 40% increased risk of poor cognitive outcomes, including dementia, cognitive impairment, or cognitive decline.

“This new chapter on brain health was a critical one to add,” Dr. Tsao said in the news release.

“The data we’ve collected brings to light the strong correlations between heart health and brain health and makes it an easy story to tell -- what’s good for the heart is good for the brain,” Dr. Tsao added.

Along with the new chapter on brain health, the 2022 statistical update provides the latest statistics and heart disease and stroke. Among the highlights:

• Cardiovascular disease (CVD) remains the leading cause of death worldwide. In the United States in 2019, CVD, listed as the underlying cause of death, accounted for 874,613 deaths, about 2,396 deaths each day. On average, someone dies of CVD every 36 seconds.
• CVD claims more lives each year in the United States than all forms of cancer and chronic lower respiratory disease combined.
• In 2019, CHD was the leading cause (41.3%) of deaths attributable to CVD, followed by other CVD (17.3%), stroke (17.2%), hypertension (11.7%), heart failure (9.9%), and diseases of the arteries (2.8%).
• In 2019, stroke accounted for roughly 1 in every 19 deaths in the United States. On average, someone in the United States has a stroke every 40 seconds and someone dies of stroke every 3 minutes 30 seconds. When considered separately from other CVD, stroke ranks number five among all causes of death in the United States.

While the annual statistics update aims to be a contemporary update of annual heart disease and stroke statistics over the past year, it also examines trends over time, Dr. Tsao explains in the podcast.

“One noteworthy point is that we saw a decline in the rate of cardiovascular mortality over the past three decades or so until about 2010. But over the past decade now, we’re also seeing a rise in these numbers,” she said.

This could be due to rising rates of obesity, diabetes, and poor hypertension control, as well as other lifestyle behaviors, Tsao said.
 

Key risk factor data

Each year, the statistical update gauges the cardiovascular health of Americans by tracking seven key health factors and behaviors that increase risk for heart disease and stroke. Below is a snapshot of the latest risk factor data.

Smoking

In 2019, smoking was the leading risk factor for years of life lost to premature death and the third leading risk factor for years of life lived with disability or injury.

According to the 2020 surgeon general’s report on smoking cessation, more than 480,000 Americans die as a result of cigarette smoking, and more than 41,000 die of secondhand smoke exposure each year (roughly 1 in 5 deaths annually).

One in 7 adults are current smokers, 1 in 6 female adults are current smokers, and 1 in 5 high school students use e-cigarettes.
 

Physical inactivity

In 2018, 25.4% of U.S. adults did not engage in leisure-time physical activity, and only 24.0% met the 2018 Physical Activity Guidelines for Americans for both aerobic and muscle strengthening.

Among U.S. high school students in 2019, only 44.1% were physically active for 60 minutes or more on at least 5 days of the week.
 

Nutrition

While there is some evidence that Americans are improving their diet, fewer than 10% of U.S. adults met guidelines for whole grain, whole fruit, and nonstarchy vegetable consumption each day in 2017–2018.

Overweight/obesity

The prevalence of obesity among adults increased from 1999–2000 through 2017–2018 from 30.5% to 42.4%. Overall prevalence of obesity and severe obesity in U.S. youth 2 to 19 years of age increased from 13.9% to 19.3% and 2.6% to 6.1% between 1999–2000 and 2017–2018.

Cholesterol

Close to 94 million (38.1%) U.S. adults have total cholesterol of 200 mg/dL or higher, according to 2015–2018 data; about 28.0 million (11.5%) have total cholesterol of 240 mg/dL or higher; and 27.8% have high levels of low-density lipoprotein cholesterol (130 mg/dL or higher).

Diabetes

In 2019, 87,647 U.S. deaths were attributed to diabetes; data show that 9.8 million U.S. adults have undiagnosed diabetes, 28.2 million have diagnosed diabetes, and 113.6 million have prediabetes.

Hypertension

A total of 121.5 million (47.3%) U.S. adults have hypertension, based on 2015–2018 data. In 2019, 102,072 U.S. deaths were primarily attributable to hypertension.

This statistical update was prepared by a volunteer writing group on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Disclosures for the writing committee are listed with the original article.



A version of this article first appeared on Medscape.com.

The American Heart Association (AHA) draws attention to the important bidirectional link between cardiovascular health and brain health in its annual statistical update on heart disease and stroke.

“For several years now, the AHA and the scientific community have increasingly recognized the connections between cardiovascular health and brain health, so it was time for us to cement this into its own chapter, which we highlight as the brain health chapter,” Connie W. Tsao, MD, MPH, chair of the statistical update writing group, with Harvard Medical School, Boston, said in an AHA podcast.

“The global rate of brain disease is quickly outpacing heart disease,” Mitchell S. V. Elkind, MD, immediate past president of the AHA, added in a news release.

“The rate of deaths from Alzheimer’s disease and other dementias rose more than twice as much in the past decade compared to the rate of deaths from heart disease, and that is something we must address,” said Dr. Elkind, with Columbia University Vagelos College of Physicians and Surgeons in New York.

“It’s becoming more evident that reducing vascular disease risk factors can make a real difference in helping people live longer, healthier lives, free of heart disease and brain disease,” Dr. Elkind added.

The AHA’s Heart Disease and Stroke Statistics – 2022 Update was published online January 26 in Circulation).

The report highlights some of the research connecting heart and brain health, including the following:

• A meta-analysis of 139 studies showed that people with midlife hypertension were five times more likely to experience impairment on global cognition and about twice as likely to experience reduced executive function, dementia, and Alzheimer’s disease.
• A meta-analysis of four longitudinal studies found that the risk for dementia associated with heart failure was increased nearly twofold.
• In the large prospective Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study, atrial fibrillation was associated with greater cognitive decline and dementia over 20 years.
• A meta-analysis of 10 prospective studies (including 24,801 participants) showed that coronary heart disease (CHD) was associated with a 40% increased risk of poor cognitive outcomes, including dementia, cognitive impairment, or cognitive decline.

“This new chapter on brain health was a critical one to add,” Dr. Tsao said in the news release.

“The data we’ve collected brings to light the strong correlations between heart health and brain health and makes it an easy story to tell -- what’s good for the heart is good for the brain,” Dr. Tsao added.

Along with the new chapter on brain health, the 2022 statistical update provides the latest statistics and heart disease and stroke. Among the highlights:

• Cardiovascular disease (CVD) remains the leading cause of death worldwide. In the United States in 2019, CVD, listed as the underlying cause of death, accounted for 874,613 deaths, about 2,396 deaths each day. On average, someone dies of CVD every 36 seconds.
• CVD claims more lives each year in the United States than all forms of cancer and chronic lower respiratory disease combined.
• In 2019, CHD was the leading cause (41.3%) of deaths attributable to CVD, followed by other CVD (17.3%), stroke (17.2%), hypertension (11.7%), heart failure (9.9%), and diseases of the arteries (2.8%).
• In 2019, stroke accounted for roughly 1 in every 19 deaths in the United States. On average, someone in the United States has a stroke every 40 seconds and someone dies of stroke every 3 minutes 30 seconds. When considered separately from other CVD, stroke ranks number five among all causes of death in the United States.

While the annual statistics update aims to be a contemporary update of annual heart disease and stroke statistics over the past year, it also examines trends over time, Dr. Tsao explains in the podcast.

“One noteworthy point is that we saw a decline in the rate of cardiovascular mortality over the past three decades or so until about 2010. But over the past decade now, we’re also seeing a rise in these numbers,” she said.

This could be due to rising rates of obesity, diabetes, and poor hypertension control, as well as other lifestyle behaviors, Tsao said.
 

Key risk factor data

Each year, the statistical update gauges the cardiovascular health of Americans by tracking seven key health factors and behaviors that increase risk for heart disease and stroke. Below is a snapshot of the latest risk factor data.

Smoking

In 2019, smoking was the leading risk factor for years of life lost to premature death and the third leading risk factor for years of life lived with disability or injury.

According to the 2020 surgeon general’s report on smoking cessation, more than 480,000 Americans die as a result of cigarette smoking, and more than 41,000 die of secondhand smoke exposure each year (roughly 1 in 5 deaths annually).

One in 7 adults are current smokers, 1 in 6 female adults are current smokers, and 1 in 5 high school students use e-cigarettes.
 

Physical inactivity

In 2018, 25.4% of U.S. adults did not engage in leisure-time physical activity, and only 24.0% met the 2018 Physical Activity Guidelines for Americans for both aerobic and muscle strengthening.

Among U.S. high school students in 2019, only 44.1% were physically active for 60 minutes or more on at least 5 days of the week.
 

Nutrition

While there is some evidence that Americans are improving their diet, fewer than 10% of U.S. adults met guidelines for whole grain, whole fruit, and nonstarchy vegetable consumption each day in 2017–2018.

Overweight/obesity

The prevalence of obesity among adults increased from 1999–2000 through 2017–2018 from 30.5% to 42.4%. Overall prevalence of obesity and severe obesity in U.S. youth 2 to 19 years of age increased from 13.9% to 19.3% and 2.6% to 6.1% between 1999–2000 and 2017–2018.

Cholesterol

Close to 94 million (38.1%) U.S. adults have total cholesterol of 200 mg/dL or higher, according to 2015–2018 data; about 28.0 million (11.5%) have total cholesterol of 240 mg/dL or higher; and 27.8% have high levels of low-density lipoprotein cholesterol (130 mg/dL or higher).

Diabetes

In 2019, 87,647 U.S. deaths were attributed to diabetes; data show that 9.8 million U.S. adults have undiagnosed diabetes, 28.2 million have diagnosed diabetes, and 113.6 million have prediabetes.

Hypertension

A total of 121.5 million (47.3%) U.S. adults have hypertension, based on 2015–2018 data. In 2019, 102,072 U.S. deaths were primarily attributable to hypertension.

This statistical update was prepared by a volunteer writing group on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Disclosures for the writing committee are listed with the original article.



A version of this article first appeared on Medscape.com.

The American Heart Association (AHA) draws attention to the important bidirectional link between cardiovascular health and brain health in its annual statistical update on heart disease and stroke.

“For several years now, the AHA and the scientific community have increasingly recognized the connections between cardiovascular health and brain health, so it was time for us to cement this into its own chapter, which we highlight as the brain health chapter,” Connie W. Tsao, MD, MPH, chair of the statistical update writing group, with Harvard Medical School, Boston, said in an AHA podcast.

“The global rate of brain disease is quickly outpacing heart disease,” Mitchell S. V. Elkind, MD, immediate past president of the AHA, added in a news release.

“The rate of deaths from Alzheimer’s disease and other dementias rose more than twice as much in the past decade compared to the rate of deaths from heart disease, and that is something we must address,” said Dr. Elkind, with Columbia University Vagelos College of Physicians and Surgeons in New York.

“It’s becoming more evident that reducing vascular disease risk factors can make a real difference in helping people live longer, healthier lives, free of heart disease and brain disease,” Dr. Elkind added.

The AHA’s Heart Disease and Stroke Statistics – 2022 Update was published online January 26 in Circulation).

The report highlights some of the research connecting heart and brain health, including the following:

• A meta-analysis of 139 studies showed that people with midlife hypertension were five times more likely to experience impairment on global cognition and about twice as likely to experience reduced executive function, dementia, and Alzheimer’s disease.
• A meta-analysis of four longitudinal studies found that the risk for dementia associated with heart failure was increased nearly twofold.
• In the large prospective Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study, atrial fibrillation was associated with greater cognitive decline and dementia over 20 years.
• A meta-analysis of 10 prospective studies (including 24,801 participants) showed that coronary heart disease (CHD) was associated with a 40% increased risk of poor cognitive outcomes, including dementia, cognitive impairment, or cognitive decline.

“This new chapter on brain health was a critical one to add,” Dr. Tsao said in the news release.

“The data we’ve collected brings to light the strong correlations between heart health and brain health and makes it an easy story to tell -- what’s good for the heart is good for the brain,” Dr. Tsao added.

Along with the new chapter on brain health, the 2022 statistical update provides the latest statistics and heart disease and stroke. Among the highlights:

• Cardiovascular disease (CVD) remains the leading cause of death worldwide. In the United States in 2019, CVD, listed as the underlying cause of death, accounted for 874,613 deaths, about 2,396 deaths each day. On average, someone dies of CVD every 36 seconds.
• CVD claims more lives each year in the United States than all forms of cancer and chronic lower respiratory disease combined.
• In 2019, CHD was the leading cause (41.3%) of deaths attributable to CVD, followed by other CVD (17.3%), stroke (17.2%), hypertension (11.7%), heart failure (9.9%), and diseases of the arteries (2.8%).
• In 2019, stroke accounted for roughly 1 in every 19 deaths in the United States. On average, someone in the United States has a stroke every 40 seconds and someone dies of stroke every 3 minutes 30 seconds. When considered separately from other CVD, stroke ranks number five among all causes of death in the United States.

While the annual statistics update aims to be a contemporary update of annual heart disease and stroke statistics over the past year, it also examines trends over time, Dr. Tsao explains in the podcast.

“One noteworthy point is that we saw a decline in the rate of cardiovascular mortality over the past three decades or so until about 2010. But over the past decade now, we’re also seeing a rise in these numbers,” she said.

This could be due to rising rates of obesity, diabetes, and poor hypertension control, as well as other lifestyle behaviors, Tsao said.
 

Key risk factor data

Each year, the statistical update gauges the cardiovascular health of Americans by tracking seven key health factors and behaviors that increase risk for heart disease and stroke. Below is a snapshot of the latest risk factor data.

Smoking

In 2019, smoking was the leading risk factor for years of life lost to premature death and the third leading risk factor for years of life lived with disability or injury.

According to the 2020 surgeon general’s report on smoking cessation, more than 480,000 Americans die as a result of cigarette smoking, and more than 41,000 die of secondhand smoke exposure each year (roughly 1 in 5 deaths annually).

One in 7 adults are current smokers, 1 in 6 female adults are current smokers, and 1 in 5 high school students use e-cigarettes.
 

Physical inactivity

In 2018, 25.4% of U.S. adults did not engage in leisure-time physical activity, and only 24.0% met the 2018 Physical Activity Guidelines for Americans for both aerobic and muscle strengthening.

Among U.S. high school students in 2019, only 44.1% were physically active for 60 minutes or more on at least 5 days of the week.
 

Nutrition

While there is some evidence that Americans are improving their diet, fewer than 10% of U.S. adults met guidelines for whole grain, whole fruit, and nonstarchy vegetable consumption each day in 2017–2018.

Overweight/obesity

The prevalence of obesity among adults increased from 1999–2000 through 2017–2018 from 30.5% to 42.4%. Overall prevalence of obesity and severe obesity in U.S. youth 2 to 19 years of age increased from 13.9% to 19.3% and 2.6% to 6.1% between 1999–2000 and 2017–2018.

Cholesterol

Close to 94 million (38.1%) U.S. adults have total cholesterol of 200 mg/dL or higher, according to 2015–2018 data; about 28.0 million (11.5%) have total cholesterol of 240 mg/dL or higher; and 27.8% have high levels of low-density lipoprotein cholesterol (130 mg/dL or higher).

Diabetes

In 2019, 87,647 U.S. deaths were attributed to diabetes; data show that 9.8 million U.S. adults have undiagnosed diabetes, 28.2 million have diagnosed diabetes, and 113.6 million have prediabetes.

Hypertension

A total of 121.5 million (47.3%) U.S. adults have hypertension, based on 2015–2018 data. In 2019, 102,072 U.S. deaths were primarily attributable to hypertension.

This statistical update was prepared by a volunteer writing group on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Disclosures for the writing committee are listed with the original article.



A version of this article first appeared on Medscape.com.

The increase in cardiovascular disease caused by chronic stress is related to biologic mechanisms (metabolic, hormonal, inflammatory) and to behavioral mechanisms (lifestyle). There is a popular saying that “stress speeds up aging,” which makes sense if we consider the age-old idea that “our age corresponds to that of our arteries.”

The study of the mechanisms of psychosocial risk factors is of major relevance to the creation of the individual and communal preventive strategies that ensure longevity and maintain quality of life.

The following hypotheses were proposed by a group of researchers from Yale University, in New Haven, Conn., in a recent study:

1. Stress is positively associated with accelerated biologic aging, and this relationship will be mediated by stress-related physiologic changes, such as insulin and hypothalamic-pituitary-adrenal (HPA) signaling.

2. Strong factors associated with psychologic resilience will be protective against the negative consequences of stress on aging. (These relationships are predictive, not causative, as this study is cross-sectional.)
 

The study

In their study, the team assessed 444 adults with no chronic medical conditions or psychiatric disorders who were 18-50 years of age and living in the greater New Haven area. Levels of obesity and alcohol consumption in the study cohort were generally in line with those in a community population, so alcohol use and body mass index were used as covariates to account for their impact on the results.

The team also used the latest “epigenetic clock,” known as GrimAge. In recent years, several methods of determining biologic age have been developed that trace chemical changes in the DNA that are natural to the aging process but occur at different moments in different people. The epigenetic clocks have proved to be better predictors of longevity and health than chronologic age, and GrimAge predicts mortality better than other epigenetic clocks.
 

Results

1. Cumulative stress was associated with the acceleration of GrimAge and stress-related physiologic measures of adrenal sensitivity (cortisol/ACTH ratio) and insulin resistance (HOMA). After the researchers controlled for demographic and behavioral factors, HOMA was correlated with GrimAge acceleration.

2. Psychologic resilience factors moderated the association between stress and aging, such that with worse regulation of emotions, there was greater stress-related age acceleration, and with stronger regulation of emotions, any significant effect of stress on GrimAge was prevented. Self-control moderated the relationship between stress and insulin resistance, with high self-control blunting this relationship.

3. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge acceleration, even when demographic, physiologic, and behavioral covariates were accounted for.
 

Implications

These results elegantly demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.

Even after adjustment for demographic and behavioral factors – such as smoking, body mass index, race, and income – people with high chronic stress scores showed markers of accelerated aging and physiologic changes, such as increased insulin resistance.

However, individuals with high scores on two psychologic resilience measures – emotion regulation and self-control – were more resilient to the effects of stress on aging and insulin resistance.

These results support the popular notion that stress ages (and sickens) us, and suggest a viable way of minimizing the adverse consequences of stress by strengthening the regulation of emotion and self-control.

In other words, the greater the psychologic resilience, the more likely the individual is to live a long and healthy life. “We like to feel as if we have some sovereignty over our destiny and, therefore, it is worth emphasizing to people (and healthcare providers) that it is important to invest in mental health,” said one of the study researchers.

With all the stress we face these days, it is essential to remember that there is no health without mental health. Above all, if we can achieve greater psychologic resilience, we will have a better chance of delaying aging.

A version of this article first appeared on Medscape.com.

The increase in cardiovascular disease caused by chronic stress is related to biologic mechanisms (metabolic, hormonal, inflammatory) and to behavioral mechanisms (lifestyle). There is a popular saying that “stress speeds up aging,” which makes sense if we consider the age-old idea that “our age corresponds to that of our arteries.”

The study of the mechanisms of psychosocial risk factors is of major relevance to the creation of the individual and communal preventive strategies that ensure longevity and maintain quality of life.

The following hypotheses were proposed by a group of researchers from Yale University, in New Haven, Conn., in a recent study:

1. Stress is positively associated with accelerated biologic aging, and this relationship will be mediated by stress-related physiologic changes, such as insulin and hypothalamic-pituitary-adrenal (HPA) signaling.

2. Strong factors associated with psychologic resilience will be protective against the negative consequences of stress on aging. (These relationships are predictive, not causative, as this study is cross-sectional.)
 

The study

In their study, the team assessed 444 adults with no chronic medical conditions or psychiatric disorders who were 18-50 years of age and living in the greater New Haven area. Levels of obesity and alcohol consumption in the study cohort were generally in line with those in a community population, so alcohol use and body mass index were used as covariates to account for their impact on the results.

The team also used the latest “epigenetic clock,” known as GrimAge. In recent years, several methods of determining biologic age have been developed that trace chemical changes in the DNA that are natural to the aging process but occur at different moments in different people. The epigenetic clocks have proved to be better predictors of longevity and health than chronologic age, and GrimAge predicts mortality better than other epigenetic clocks.
 

Results

1. Cumulative stress was associated with the acceleration of GrimAge and stress-related physiologic measures of adrenal sensitivity (cortisol/ACTH ratio) and insulin resistance (HOMA). After the researchers controlled for demographic and behavioral factors, HOMA was correlated with GrimAge acceleration.

2. Psychologic resilience factors moderated the association between stress and aging, such that with worse regulation of emotions, there was greater stress-related age acceleration, and with stronger regulation of emotions, any significant effect of stress on GrimAge was prevented. Self-control moderated the relationship between stress and insulin resistance, with high self-control blunting this relationship.

3. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge acceleration, even when demographic, physiologic, and behavioral covariates were accounted for.
 

Implications

These results elegantly demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.

Even after adjustment for demographic and behavioral factors – such as smoking, body mass index, race, and income – people with high chronic stress scores showed markers of accelerated aging and physiologic changes, such as increased insulin resistance.

However, individuals with high scores on two psychologic resilience measures – emotion regulation and self-control – were more resilient to the effects of stress on aging and insulin resistance.

These results support the popular notion that stress ages (and sickens) us, and suggest a viable way of minimizing the adverse consequences of stress by strengthening the regulation of emotion and self-control.

In other words, the greater the psychologic resilience, the more likely the individual is to live a long and healthy life. “We like to feel as if we have some sovereignty over our destiny and, therefore, it is worth emphasizing to people (and healthcare providers) that it is important to invest in mental health,” said one of the study researchers.

With all the stress we face these days, it is essential to remember that there is no health without mental health. Above all, if we can achieve greater psychologic resilience, we will have a better chance of delaying aging.

A version of this article first appeared on Medscape.com.

The increase in cardiovascular disease caused by chronic stress is related to biologic mechanisms (metabolic, hormonal, inflammatory) and to behavioral mechanisms (lifestyle). There is a popular saying that “stress speeds up aging,” which makes sense if we consider the age-old idea that “our age corresponds to that of our arteries.”

The study of the mechanisms of psychosocial risk factors is of major relevance to the creation of the individual and communal preventive strategies that ensure longevity and maintain quality of life.

The following hypotheses were proposed by a group of researchers from Yale University, in New Haven, Conn., in a recent study:

1. Stress is positively associated with accelerated biologic aging, and this relationship will be mediated by stress-related physiologic changes, such as insulin and hypothalamic-pituitary-adrenal (HPA) signaling.

2. Strong factors associated with psychologic resilience will be protective against the negative consequences of stress on aging. (These relationships are predictive, not causative, as this study is cross-sectional.)
 

The study

In their study, the team assessed 444 adults with no chronic medical conditions or psychiatric disorders who were 18-50 years of age and living in the greater New Haven area. Levels of obesity and alcohol consumption in the study cohort were generally in line with those in a community population, so alcohol use and body mass index were used as covariates to account for their impact on the results.

The team also used the latest “epigenetic clock,” known as GrimAge. In recent years, several methods of determining biologic age have been developed that trace chemical changes in the DNA that are natural to the aging process but occur at different moments in different people. The epigenetic clocks have proved to be better predictors of longevity and health than chronologic age, and GrimAge predicts mortality better than other epigenetic clocks.
 

Results

1. Cumulative stress was associated with the acceleration of GrimAge and stress-related physiologic measures of adrenal sensitivity (cortisol/ACTH ratio) and insulin resistance (HOMA). After the researchers controlled for demographic and behavioral factors, HOMA was correlated with GrimAge acceleration.

2. Psychologic resilience factors moderated the association between stress and aging, such that with worse regulation of emotions, there was greater stress-related age acceleration, and with stronger regulation of emotions, any significant effect of stress on GrimAge was prevented. Self-control moderated the relationship between stress and insulin resistance, with high self-control blunting this relationship.

3. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge acceleration, even when demographic, physiologic, and behavioral covariates were accounted for.
 

Implications

These results elegantly demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.

Even after adjustment for demographic and behavioral factors – such as smoking, body mass index, race, and income – people with high chronic stress scores showed markers of accelerated aging and physiologic changes, such as increased insulin resistance.

However, individuals with high scores on two psychologic resilience measures – emotion regulation and self-control – were more resilient to the effects of stress on aging and insulin resistance.

These results support the popular notion that stress ages (and sickens) us, and suggest a viable way of minimizing the adverse consequences of stress by strengthening the regulation of emotion and self-control.

In other words, the greater the psychologic resilience, the more likely the individual is to live a long and healthy life. “We like to feel as if we have some sovereignty over our destiny and, therefore, it is worth emphasizing to people (and healthcare providers) that it is important to invest in mental health,” said one of the study researchers.

With all the stress we face these days, it is essential to remember that there is no health without mental health. Above all, if we can achieve greater psychologic resilience, we will have a better chance of delaying aging.

A version of this article first appeared on Medscape.com.

It is a great mystery of infectious disease: Why are some people seemingly unaffected by illness that harms others? During the COVID-19 pandemic, we’ve seen this play out time and time again when whole families get sick except for one or two fortunate family members. And at so-called superspreader events that infect many, a lucky few typically walk away with their health intact. Did the virus never enter their bodies? Or do some people have natural resistance to pathogens they’ve never been exposed to before encoded in their genes?

Resistance to infectious disease is much more than a scientific curiosity and studying how it works can be a path to curb future outbreaks.

“In the event that we could identify what makes some people resistant, that immediately opens avenues for therapeutics that we could apply in all those other people who do suffer from the disease,” says András Spaan, MD, a microbiologist at Rockefeller University in New York.

Dr. Spaan is part of an international effort to identify genetic variations that spare people from becoming infected with SARS-CoV-2, the virus that causes COVID-19.

There’s far more research on what drives the tendency to get infectious diseases than on resistance to them. But a few researchers are investigating resistance to some of the world’s most common and deadly infectious diseases, and in a few cases, they’ve already translated these insights into treatments.

Perhaps the strongest example of how odd genes of just a few people can inspire treatments to help many comes from research on the human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome (AIDS).
 

A genetic quirk

In the mid-1990s, several groups of researchers independently identified a mutation in a gene called CCR5 linked to resistance to HIV infection.

The gene encodes a protein on the surface of some white blood cells that helps set up the movement of other immune cells to fight infections. HIV, meanwhile, uses the CCR5 protein to help it enter the white blood cells that it infects.

The mutation, known as delta 32, results in a shorter than usual protein that doesn’t reach the surface of the cell. People who carry two copies of the delta 32 form of CCR5 do not have any CCR5 protein on the outside of their white blood cells.

Researchers, led by molecular immunologist Philip Murphy, MD, at the National Institute of Allergy and Infectious Diseases in Bethesda, Md, showed in 1997 that people with two copies of the mutation were unusually common among a group of men who were at especially high risk of HIV exposure, but had never contracted the virus. And out of more than 700 HIV-positive people, none carried two copies of CCR5 delta 32.

Pharmaceutical companies used these insights to develop drugs to block CCR5 and delay the development of AIDS. For instance, the drug maraviroc, marketed by Pfizer, was approved for use in HIV-positive people in 2007.

Only a few examples of this kind of inborn, genetically determined complete resistance to infection have ever been heard of. All of them involve cell-surface molecules that are believed to help a virus or other pathogen gain entry to the cell.
 

Locking out illness

“The first step for any intracellular pathogen is getting inside the cell. And if you’re missing the doorway, then the virus can’t accomplish the first step in its life cycle,” Dr. Murphy says. “Getting inside is fundamental.”

Changes in cell-surface molecules can also make someone more likely to have an infection or severe disease. One such group of cell-surface molecules that have been linked to both increasing and decreasing the risk of various infections are histo-blood group antigens. The most familiar members of this group are the molecules that define blood types A, B, and O.

Scientists have also identified one example of total resistance to infection involving these molecules. In 2003, researchers showed that people who lack a functional copy of a gene known as FUT2 cannot be infected with Norwalk virus, one of more than 30 viruses in the norovirus family that cause illness in the digestive tract.

The gene FUT2 encodes an enzyme that determines whether or not blood group antigens are found in a person’s saliva and other body fluids as well as on their red blood cells.

“It didn’t matter how many virus particles we challenged an individual with, if they did not have that first enzyme, they did not get infected,” says researcher Lisa Lindesmith, a virologist at the University of North Carolina in Chapel Hill.
 

No norovirus

Norwalk is a relatively rare type of norovirus. But FUT2 deficiency also provides some protection against the most common strains of norovirus, known as GII.4, which have periodically swept across the world over the past quarter-century. These illnesses take an especially heavy toll on children in the developing world, causing malnutrition and contributing to infant and child deaths.

But progress in translating these insights about genetic resistance into drugs or other things that could reduce the burden of noroviruses has been slow.

“The biggest barrier here is lack of ability to study the virus outside of humans,” Lindesmith says.

Noroviruses are very difficult to grow in the lab, “and there’s no small animal model of gastrointestinal illness caused by the viruses.”

We are clearly making giant strides in improving those skills,” says Lindesmith. “But we are just not quite there yet.”

In the years before COVID-19 emerged, tuberculosis was responsible for the largest number of annual worldwide deaths from an infectious disease. It’s a lung disease caused by the bacterium Mycobacterium tuberculosis, and it has been a pandemic for thousands of years.

Some 85%-95% of people with intact immune systems who are infected with TB control the infection and never get active lung disease. And some people who have intense, continuing exposure to the bacterium, which is spread through droplets and aerosols from people with active lung disease, apparently never become infected at all.
 

Thwarting uberculosis

Understanding the ways of these different forms of resistance could help in the search for vaccines, treatments, and other ways to fight tuberculosis, says Elouise Kroon, MD, a graduate student at Stellenbosch University in Cape Town, South Africa.

“What makes it particularly hard to study is the fact that there is no gold standard to measure infection,” she says. “So, what we do is infer infection from two different types of tests” -- a skin test and a blood test that measure different kinds of immune response to molecules from the bacterium.

Dr. Kroon and other researchers have studied resistance to infection by following people living in the same household as those with active lung disease or people who live and work in crowded conditions in high-risk communities. But not all such studies have used the same definition of so-called resisters, documented exposure in the same way, or followed up to ensure that people continue to test negative over the long term.

The best clue that has emerged from studies so far links resistance to infection to certain variations in immune molecules known as HLA class II antigens, says Marlo Möller, PhD, a professor in the TB Host Genetics Research Group at Stellenbosch University.

“That always seems to pop up everywhere. But the rest is not so obvious,” she says. “A lot of the studies don’t find the same thing. It’s different in different populations,” which may be a result of the long evolutionary history between tuberculosis and humans, as well as the fact that different strains of the bacterium are prevalent in different parts of the world.

COVID-19 is a much newer infectious disease, but teasing out how it contributes to both severe illness and resistance to infection is still a major task.
 

Overcoming COVID

Early in the pandemic, research by the COVID Human Genetic Effort, the international consortium that Dr. Spaan is part of, linked severe COVID-19 pneumonia to the lack of immune molecules known as type I interferons and to antibodies produced by the body that destroy these molecules. Together, these mechanisms explain about one-fifth of severe COVID-19 cases, the researchers reported in 2021.

A few studies by other groups have explored resistance to COVID-19 infection, suggesting that reduced risk of contracting the virus is tied to certain blood group factors. People with Type O blood appear to be at slightly reduced risk of infection, for example.

But the studies done so far are designed to find common genetic variations, which generally have a small effect on resistance. Now, genetic researchers are launching an effort to identify genetic resistance factors with a big effect, even if they are vanishingly rare.

The group is recruiting people who did not become infected with COVID-19 despite heavy exposure, such as those living in households where all the other members got sick or people who were exposed to a superspreader event but did not become ill. As with tuberculosis, being certain that someone has not been infected with the virus can be tricky, but the team is using several blood tests to home in on the people most likely to have escaped infection.

They plan to sequence the genomes of these people to identify things that strongly affect infection risk, then do more laboratory studies to try to tease out the means of resistance.

Their work is inspired by earlier efforts to uncover inborn resistance to infections, Dr. Spaan says. Despite the lack of known examples of such resistance, he is optimistic about the possibilities. Those earlier efforts took place in “a different epoch,” before there were rapid sequencing technologies, Dr. Spaan says.

“Now we have modern technologies to do this more systematically.”

The emergence of viral variants such as the Delta and Omicron COVID strains raises the stakes of the work, he continues.

“The need to unravel these inborn mechanisms of resistance to COVID has become even more important because of these new variants and the anticipation that we will have COVID with us for years.”

A version of this article first appeared on WebMD.com.

It is a great mystery of infectious disease: Why are some people seemingly unaffected by illness that harms others? During the COVID-19 pandemic, we’ve seen this play out time and time again when whole families get sick except for one or two fortunate family members. And at so-called superspreader events that infect many, a lucky few typically walk away with their health intact. Did the virus never enter their bodies? Or do some people have natural resistance to pathogens they’ve never been exposed to before encoded in their genes?

Resistance to infectious disease is much more than a scientific curiosity and studying how it works can be a path to curb future outbreaks.

“In the event that we could identify what makes some people resistant, that immediately opens avenues for therapeutics that we could apply in all those other people who do suffer from the disease,” says András Spaan, MD, a microbiologist at Rockefeller University in New York.

Dr. Spaan is part of an international effort to identify genetic variations that spare people from becoming infected with SARS-CoV-2, the virus that causes COVID-19.

There’s far more research on what drives the tendency to get infectious diseases than on resistance to them. But a few researchers are investigating resistance to some of the world’s most common and deadly infectious diseases, and in a few cases, they’ve already translated these insights into treatments.

Perhaps the strongest example of how odd genes of just a few people can inspire treatments to help many comes from research on the human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome (AIDS).
 

A genetic quirk

In the mid-1990s, several groups of researchers independently identified a mutation in a gene called CCR5 linked to resistance to HIV infection.

The gene encodes a protein on the surface of some white blood cells that helps set up the movement of other immune cells to fight infections. HIV, meanwhile, uses the CCR5 protein to help it enter the white blood cells that it infects.

The mutation, known as delta 32, results in a shorter than usual protein that doesn’t reach the surface of the cell. People who carry two copies of the delta 32 form of CCR5 do not have any CCR5 protein on the outside of their white blood cells.

Researchers, led by molecular immunologist Philip Murphy, MD, at the National Institute of Allergy and Infectious Diseases in Bethesda, Md, showed in 1997 that people with two copies of the mutation were unusually common among a group of men who were at especially high risk of HIV exposure, but had never contracted the virus. And out of more than 700 HIV-positive people, none carried two copies of CCR5 delta 32.

Pharmaceutical companies used these insights to develop drugs to block CCR5 and delay the development of AIDS. For instance, the drug maraviroc, marketed by Pfizer, was approved for use in HIV-positive people in 2007.

Only a few examples of this kind of inborn, genetically determined complete resistance to infection have ever been heard of. All of them involve cell-surface molecules that are believed to help a virus or other pathogen gain entry to the cell.
 

Locking out illness

“The first step for any intracellular pathogen is getting inside the cell. And if you’re missing the doorway, then the virus can’t accomplish the first step in its life cycle,” Dr. Murphy says. “Getting inside is fundamental.”

Changes in cell-surface molecules can also make someone more likely to have an infection or severe disease. One such group of cell-surface molecules that have been linked to both increasing and decreasing the risk of various infections are histo-blood group antigens. The most familiar members of this group are the molecules that define blood types A, B, and O.

Scientists have also identified one example of total resistance to infection involving these molecules. In 2003, researchers showed that people who lack a functional copy of a gene known as FUT2 cannot be infected with Norwalk virus, one of more than 30 viruses in the norovirus family that cause illness in the digestive tract.

The gene FUT2 encodes an enzyme that determines whether or not blood group antigens are found in a person’s saliva and other body fluids as well as on their red blood cells.

“It didn’t matter how many virus particles we challenged an individual with, if they did not have that first enzyme, they did not get infected,” says researcher Lisa Lindesmith, a virologist at the University of North Carolina in Chapel Hill.
 

No norovirus

Norwalk is a relatively rare type of norovirus. But FUT2 deficiency also provides some protection against the most common strains of norovirus, known as GII.4, which have periodically swept across the world over the past quarter-century. These illnesses take an especially heavy toll on children in the developing world, causing malnutrition and contributing to infant and child deaths.

But progress in translating these insights about genetic resistance into drugs or other things that could reduce the burden of noroviruses has been slow.

“The biggest barrier here is lack of ability to study the virus outside of humans,” Lindesmith says.

Noroviruses are very difficult to grow in the lab, “and there’s no small animal model of gastrointestinal illness caused by the viruses.”

We are clearly making giant strides in improving those skills,” says Lindesmith. “But we are just not quite there yet.”

In the years before COVID-19 emerged, tuberculosis was responsible for the largest number of annual worldwide deaths from an infectious disease. It’s a lung disease caused by the bacterium Mycobacterium tuberculosis, and it has been a pandemic for thousands of years.

Some 85%-95% of people with intact immune systems who are infected with TB control the infection and never get active lung disease. And some people who have intense, continuing exposure to the bacterium, which is spread through droplets and aerosols from people with active lung disease, apparently never become infected at all.
 

Thwarting uberculosis

Understanding the ways of these different forms of resistance could help in the search for vaccines, treatments, and other ways to fight tuberculosis, says Elouise Kroon, MD, a graduate student at Stellenbosch University in Cape Town, South Africa.

“What makes it particularly hard to study is the fact that there is no gold standard to measure infection,” she says. “So, what we do is infer infection from two different types of tests” -- a skin test and a blood test that measure different kinds of immune response to molecules from the bacterium.

Dr. Kroon and other researchers have studied resistance to infection by following people living in the same household as those with active lung disease or people who live and work in crowded conditions in high-risk communities. But not all such studies have used the same definition of so-called resisters, documented exposure in the same way, or followed up to ensure that people continue to test negative over the long term.

The best clue that has emerged from studies so far links resistance to infection to certain variations in immune molecules known as HLA class II antigens, says Marlo Möller, PhD, a professor in the TB Host Genetics Research Group at Stellenbosch University.

“That always seems to pop up everywhere. But the rest is not so obvious,” she says. “A lot of the studies don’t find the same thing. It’s different in different populations,” which may be a result of the long evolutionary history between tuberculosis and humans, as well as the fact that different strains of the bacterium are prevalent in different parts of the world.

COVID-19 is a much newer infectious disease, but teasing out how it contributes to both severe illness and resistance to infection is still a major task.
 

Overcoming COVID

Early in the pandemic, research by the COVID Human Genetic Effort, the international consortium that Dr. Spaan is part of, linked severe COVID-19 pneumonia to the lack of immune molecules known as type I interferons and to antibodies produced by the body that destroy these molecules. Together, these mechanisms explain about one-fifth of severe COVID-19 cases, the researchers reported in 2021.

A few studies by other groups have explored resistance to COVID-19 infection, suggesting that reduced risk of contracting the virus is tied to certain blood group factors. People with Type O blood appear to be at slightly reduced risk of infection, for example.

But the studies done so far are designed to find common genetic variations, which generally have a small effect on resistance. Now, genetic researchers are launching an effort to identify genetic resistance factors with a big effect, even if they are vanishingly rare.

The group is recruiting people who did not become infected with COVID-19 despite heavy exposure, such as those living in households where all the other members got sick or people who were exposed to a superspreader event but did not become ill. As with tuberculosis, being certain that someone has not been infected with the virus can be tricky, but the team is using several blood tests to home in on the people most likely to have escaped infection.

They plan to sequence the genomes of these people to identify things that strongly affect infection risk, then do more laboratory studies to try to tease out the means of resistance.

Their work is inspired by earlier efforts to uncover inborn resistance to infections, Dr. Spaan says. Despite the lack of known examples of such resistance, he is optimistic about the possibilities. Those earlier efforts took place in “a different epoch,” before there were rapid sequencing technologies, Dr. Spaan says.

“Now we have modern technologies to do this more systematically.”

The emergence of viral variants such as the Delta and Omicron COVID strains raises the stakes of the work, he continues.

“The need to unravel these inborn mechanisms of resistance to COVID has become even more important because of these new variants and the anticipation that we will have COVID with us for years.”

A version of this article first appeared on WebMD.com.

It is a great mystery of infectious disease: Why are some people seemingly unaffected by illness that harms others? During the COVID-19 pandemic, we’ve seen this play out time and time again when whole families get sick except for one or two fortunate family members. And at so-called superspreader events that infect many, a lucky few typically walk away with their health intact. Did the virus never enter their bodies? Or do some people have natural resistance to pathogens they’ve never been exposed to before encoded in their genes?

Resistance to infectious disease is much more than a scientific curiosity and studying how it works can be a path to curb future outbreaks.

“In the event that we could identify what makes some people resistant, that immediately opens avenues for therapeutics that we could apply in all those other people who do suffer from the disease,” says András Spaan, MD, a microbiologist at Rockefeller University in New York.

Dr. Spaan is part of an international effort to identify genetic variations that spare people from becoming infected with SARS-CoV-2, the virus that causes COVID-19.

There’s far more research on what drives the tendency to get infectious diseases than on resistance to them. But a few researchers are investigating resistance to some of the world’s most common and deadly infectious diseases, and in a few cases, they’ve already translated these insights into treatments.

Perhaps the strongest example of how odd genes of just a few people can inspire treatments to help many comes from research on the human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome (AIDS).
 

A genetic quirk

In the mid-1990s, several groups of researchers independently identified a mutation in a gene called CCR5 linked to resistance to HIV infection.

The gene encodes a protein on the surface of some white blood cells that helps set up the movement of other immune cells to fight infections. HIV, meanwhile, uses the CCR5 protein to help it enter the white blood cells that it infects.

The mutation, known as delta 32, results in a shorter than usual protein that doesn’t reach the surface of the cell. People who carry two copies of the delta 32 form of CCR5 do not have any CCR5 protein on the outside of their white blood cells.

Researchers, led by molecular immunologist Philip Murphy, MD, at the National Institute of Allergy and Infectious Diseases in Bethesda, Md, showed in 1997 that people with two copies of the mutation were unusually common among a group of men who were at especially high risk of HIV exposure, but had never contracted the virus. And out of more than 700 HIV-positive people, none carried two copies of CCR5 delta 32.

Pharmaceutical companies used these insights to develop drugs to block CCR5 and delay the development of AIDS. For instance, the drug maraviroc, marketed by Pfizer, was approved for use in HIV-positive people in 2007.

Only a few examples of this kind of inborn, genetically determined complete resistance to infection have ever been heard of. All of them involve cell-surface molecules that are believed to help a virus or other pathogen gain entry to the cell.
 

Locking out illness

“The first step for any intracellular pathogen is getting inside the cell. And if you’re missing the doorway, then the virus can’t accomplish the first step in its life cycle,” Dr. Murphy says. “Getting inside is fundamental.”

Changes in cell-surface molecules can also make someone more likely to have an infection or severe disease. One such group of cell-surface molecules that have been linked to both increasing and decreasing the risk of various infections are histo-blood group antigens. The most familiar members of this group are the molecules that define blood types A, B, and O.

Scientists have also identified one example of total resistance to infection involving these molecules. In 2003, researchers showed that people who lack a functional copy of a gene known as FUT2 cannot be infected with Norwalk virus, one of more than 30 viruses in the norovirus family that cause illness in the digestive tract.

The gene FUT2 encodes an enzyme that determines whether or not blood group antigens are found in a person’s saliva and other body fluids as well as on their red blood cells.

“It didn’t matter how many virus particles we challenged an individual with, if they did not have that first enzyme, they did not get infected,” says researcher Lisa Lindesmith, a virologist at the University of North Carolina in Chapel Hill.
 

No norovirus

Norwalk is a relatively rare type of norovirus. But FUT2 deficiency also provides some protection against the most common strains of norovirus, known as GII.4, which have periodically swept across the world over the past quarter-century. These illnesses take an especially heavy toll on children in the developing world, causing malnutrition and contributing to infant and child deaths.

But progress in translating these insights about genetic resistance into drugs or other things that could reduce the burden of noroviruses has been slow.

“The biggest barrier here is lack of ability to study the virus outside of humans,” Lindesmith says.

Noroviruses are very difficult to grow in the lab, “and there’s no small animal model of gastrointestinal illness caused by the viruses.”

We are clearly making giant strides in improving those skills,” says Lindesmith. “But we are just not quite there yet.”

In the years before COVID-19 emerged, tuberculosis was responsible for the largest number of annual worldwide deaths from an infectious disease. It’s a lung disease caused by the bacterium Mycobacterium tuberculosis, and it has been a pandemic for thousands of years.

Some 85%-95% of people with intact immune systems who are infected with TB control the infection and never get active lung disease. And some people who have intense, continuing exposure to the bacterium, which is spread through droplets and aerosols from people with active lung disease, apparently never become infected at all.
 

Thwarting uberculosis

Understanding the ways of these different forms of resistance could help in the search for vaccines, treatments, and other ways to fight tuberculosis, says Elouise Kroon, MD, a graduate student at Stellenbosch University in Cape Town, South Africa.

“What makes it particularly hard to study is the fact that there is no gold standard to measure infection,” she says. “So, what we do is infer infection from two different types of tests” -- a skin test and a blood test that measure different kinds of immune response to molecules from the bacterium.

Dr. Kroon and other researchers have studied resistance to infection by following people living in the same household as those with active lung disease or people who live and work in crowded conditions in high-risk communities. But not all such studies have used the same definition of so-called resisters, documented exposure in the same way, or followed up to ensure that people continue to test negative over the long term.

The best clue that has emerged from studies so far links resistance to infection to certain variations in immune molecules known as HLA class II antigens, says Marlo Möller, PhD, a professor in the TB Host Genetics Research Group at Stellenbosch University.

“That always seems to pop up everywhere. But the rest is not so obvious,” she says. “A lot of the studies don’t find the same thing. It’s different in different populations,” which may be a result of the long evolutionary history between tuberculosis and humans, as well as the fact that different strains of the bacterium are prevalent in different parts of the world.

COVID-19 is a much newer infectious disease, but teasing out how it contributes to both severe illness and resistance to infection is still a major task.
 

Overcoming COVID

Early in the pandemic, research by the COVID Human Genetic Effort, the international consortium that Dr. Spaan is part of, linked severe COVID-19 pneumonia to the lack of immune molecules known as type I interferons and to antibodies produced by the body that destroy these molecules. Together, these mechanisms explain about one-fifth of severe COVID-19 cases, the researchers reported in 2021.

A few studies by other groups have explored resistance to COVID-19 infection, suggesting that reduced risk of contracting the virus is tied to certain blood group factors. People with Type O blood appear to be at slightly reduced risk of infection, for example.

But the studies done so far are designed to find common genetic variations, which generally have a small effect on resistance. Now, genetic researchers are launching an effort to identify genetic resistance factors with a big effect, even if they are vanishingly rare.

The group is recruiting people who did not become infected with COVID-19 despite heavy exposure, such as those living in households where all the other members got sick or people who were exposed to a superspreader event but did not become ill. As with tuberculosis, being certain that someone has not been infected with the virus can be tricky, but the team is using several blood tests to home in on the people most likely to have escaped infection.

They plan to sequence the genomes of these people to identify things that strongly affect infection risk, then do more laboratory studies to try to tease out the means of resistance.

Their work is inspired by earlier efforts to uncover inborn resistance to infections, Dr. Spaan says. Despite the lack of known examples of such resistance, he is optimistic about the possibilities. Those earlier efforts took place in “a different epoch,” before there were rapid sequencing technologies, Dr. Spaan says.

“Now we have modern technologies to do this more systematically.”

The emergence of viral variants such as the Delta and Omicron COVID strains raises the stakes of the work, he continues.

“The need to unravel these inborn mechanisms of resistance to COVID has become even more important because of these new variants and the anticipation that we will have COVID with us for years.”

A version of this article first appeared on WebMD.com.

Americans who have received a COVID-19 booster shot are 97 times less likely to die from the coronavirus than those who aren’t vaccinated, according to a new update from the CDC.

In addition, fully vaccinated Americans — meaning those with up to two doses, but no booster — are 14 times less likely to die from COVID-19 than unvaccinated people.

“These data confirm that vaccination and boosting continues to protect against severe illness and hospitalization, even during the Omicron surge,” Rochelle Walensky, MD, director of the CDC, said during a briefing by the White House COVID-19 Response Team.

“If you are not up to date on your COVID-19 vaccinations, you have not optimized your protection against severe disease and death, and you should get vaccinated and boosted if you are eligible,” she said.

Dr. Walensky presented the latest numbers on Feb. 2 based on reports from 25 jurisdictions in early December. The number of average weekly deaths for those who were unvaccinated was 9.7 per 100,000 people, as compared with 0.7 of those who were vaccinated and 0.1 of those who had received a booster.

“The data are really stunningly obvious why a booster is really very important,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said during the briefing.

Dr. Fauci also encouraged vaccination for those who are pregnant and couples who may want to conceive in the near feature. He highlighted two recent studies that found vaccination in either partner didn’t affect fertility, including in vitro fertilization.

Meanwhile, fertility fell temporarily among men who were infected with the coronavirus. Couples were 18% less likely to conceive if the male partner had contracted the coronavirus within 60 days before a menstrual cycle.

“New data adds to previous studies that indicate that COVID-19 vaccination does not negatively impact fertility,” Dr. Fauci said. “Vaccination is recommended for people who are trying to get pregnant now or might become pregnant in the future, as well as their partners.”

About 80% of eligible Americans have received at least one vaccine dose, and 68% are fully vaccinated, according to the latest CDC data. About 51% of those who are eligible for a booster dose have received one.

The FDA could authorize the Pfizer vaccine for children under age 5 later this month. When that happens, about 18 million children will qualify for a shot, Jeff Zients, coordinator of the White House COVID-19 Response Team, said during the briefing. The Biden administration is already working on distribution plans for the shot for young kids, he added.

“We’ll be ready to start getting shots in arms soon after FDA and CDC make their decisions,” he said.

A version of this article first appeared on WebMD.com.

Americans who have received a COVID-19 booster shot are 97 times less likely to die from the coronavirus than those who aren’t vaccinated, according to a new update from the CDC.

In addition, fully vaccinated Americans — meaning those with up to two doses, but no booster — are 14 times less likely to die from COVID-19 than unvaccinated people.

“These data confirm that vaccination and boosting continues to protect against severe illness and hospitalization, even during the Omicron surge,” Rochelle Walensky, MD, director of the CDC, said during a briefing by the White House COVID-19 Response Team.

“If you are not up to date on your COVID-19 vaccinations, you have not optimized your protection against severe disease and death, and you should get vaccinated and boosted if you are eligible,” she said.

Dr. Walensky presented the latest numbers on Feb. 2 based on reports from 25 jurisdictions in early December. The number of average weekly deaths for those who were unvaccinated was 9.7 per 100,000 people, as compared with 0.7 of those who were vaccinated and 0.1 of those who had received a booster.

“The data are really stunningly obvious why a booster is really very important,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said during the briefing.

Dr. Fauci also encouraged vaccination for those who are pregnant and couples who may want to conceive in the near feature. He highlighted two recent studies that found vaccination in either partner didn’t affect fertility, including in vitro fertilization.

Meanwhile, fertility fell temporarily among men who were infected with the coronavirus. Couples were 18% less likely to conceive if the male partner had contracted the coronavirus within 60 days before a menstrual cycle.

“New data adds to previous studies that indicate that COVID-19 vaccination does not negatively impact fertility,” Dr. Fauci said. “Vaccination is recommended for people who are trying to get pregnant now or might become pregnant in the future, as well as their partners.”

About 80% of eligible Americans have received at least one vaccine dose, and 68% are fully vaccinated, according to the latest CDC data. About 51% of those who are eligible for a booster dose have received one.

The FDA could authorize the Pfizer vaccine for children under age 5 later this month. When that happens, about 18 million children will qualify for a shot, Jeff Zients, coordinator of the White House COVID-19 Response Team, said during the briefing. The Biden administration is already working on distribution plans for the shot for young kids, he added.

“We’ll be ready to start getting shots in arms soon after FDA and CDC make their decisions,” he said.

A version of this article first appeared on WebMD.com.

Americans who have received a COVID-19 booster shot are 97 times less likely to die from the coronavirus than those who aren’t vaccinated, according to a new update from the CDC.

In addition, fully vaccinated Americans — meaning those with up to two doses, but no booster — are 14 times less likely to die from COVID-19 than unvaccinated people.

“These data confirm that vaccination and boosting continues to protect against severe illness and hospitalization, even during the Omicron surge,” Rochelle Walensky, MD, director of the CDC, said during a briefing by the White House COVID-19 Response Team.

“If you are not up to date on your COVID-19 vaccinations, you have not optimized your protection against severe disease and death, and you should get vaccinated and boosted if you are eligible,” she said.

Dr. Walensky presented the latest numbers on Feb. 2 based on reports from 25 jurisdictions in early December. The number of average weekly deaths for those who were unvaccinated was 9.7 per 100,000 people, as compared with 0.7 of those who were vaccinated and 0.1 of those who had received a booster.

“The data are really stunningly obvious why a booster is really very important,” Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, said during the briefing.

Dr. Fauci also encouraged vaccination for those who are pregnant and couples who may want to conceive in the near feature. He highlighted two recent studies that found vaccination in either partner didn’t affect fertility, including in vitro fertilization.

Meanwhile, fertility fell temporarily among men who were infected with the coronavirus. Couples were 18% less likely to conceive if the male partner had contracted the coronavirus within 60 days before a menstrual cycle.

“New data adds to previous studies that indicate that COVID-19 vaccination does not negatively impact fertility,” Dr. Fauci said. “Vaccination is recommended for people who are trying to get pregnant now or might become pregnant in the future, as well as their partners.”

About 80% of eligible Americans have received at least one vaccine dose, and 68% are fully vaccinated, according to the latest CDC data. About 51% of those who are eligible for a booster dose have received one.

The FDA could authorize the Pfizer vaccine for children under age 5 later this month. When that happens, about 18 million children will qualify for a shot, Jeff Zients, coordinator of the White House COVID-19 Response Team, said during the briefing. The Biden administration is already working on distribution plans for the shot for young kids, he added.

“We’ll be ready to start getting shots in arms soon after FDA and CDC make their decisions,” he said.

A version of this article first appeared on WebMD.com.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease that involves the skin. Cutaneous lupus erythematosus can be classified into various subtypes.¹ These include, but are not limited to, acute CLE, subacute CLE, chronic CLE, intermittent CLE, lupus tumidus, and lupus profundus.^1,2 The CLE subtypes have variable associations with systemic lupus erythematosus. For instance, some subtypes, such as acute CLE, are more strongly associated with systemic lupus erythematosus.

Treatment of CLE is similar to other autoimmune disorders. Although the US Food and Drug Administration (FDA) has not approved any treatments for CLE,^3,4 the most common therapeutic options are disease-modifying antirheumatic drugs. Unfortunately, many of these treatments carry teratogenic effects. Because CLE predominantly affects women, particularly those of childbearing age, it is imperative to understand the available treatment options for those who are pregnant or considering pregnancy for an informed discussion with patients.⁵

For years, the gold standard when considering a medication during pregnancy was the FDA’s classification system. According to this system, medications were classified into 5 letter categories based on their potential teratogenicity, including A (no fetal risk), B (potential animal risk but inconclusive human studies), C (risk cannot be ruled out), D (evidence of fetal risk), and X (contraindicated in pregnancy). In 2014, the FDA decided to no longer use this classification system for medications approved after 2000.⁶ However, because many proposed treatment options for CLE were approved prior to 2001, we have summarized the commonly prescribed medications for CLE according to their prior FDA letter categories.

Treatment Options for CLE During Pregnancy

Prior to initiating systemic medications for the treatment of CLE, topical medications should be considered. Recommended treatment options include corticosteroids and calcineurin inhibitors.⁷ Compared with systemic medications, topical treatments carry minimal side effects, such as skin atrophy, that typically remain localized to areas of application.⁸ Moreover, even with extensive application, no correlation has been found between topical corticosteroid use and fetal growth,⁹ which suggests that topical steroids are safe in pregnancy and should be considered as a first-line treatment option for CLE. Calcineurin inhibitors also are considered safe based on their low level of absorption through the skin and are considered second-line topical treatment options in pregnancy.¹⁰

Although topical medications are effective for the treatment of CLE, many patients require the administration of systemic therapeutics for severe or refractory disease. Based on previously published reports, Figure 1 describes the current recommended systemic treatment options for CLE.¹¹ Unfortunately, many of these medications carry teratogenic risks during pregnancy. The risks and side effects of the medications are described in detail in the following sections and summarized in the eTable.

Category B

Systemic Steroids—Systemic steroids are one of the most prescribed medications during pregnancy.¹² Oral steroids have been associated with fast symptom relief, making this class of medications particularly effective during CLE flares; however, long-term management is not recommended because of the side effects, which include osteoporosis and impaired glucose metabolism.¹³

With low transmission across the placenta, there are 3 glucocorticoids that carry the safest profile in pregnancy: prednisone, cortisone, and hydrocortisone.¹⁴ Dexamethasone and betamethasone should be avoided, as both readily cross the placenta and increase fetal exposure.¹⁵ Although teratogenic effects have been associated with steroid use, most studies involving pregnant patients have inconclusive results. For instance, one study described an association between cleft lip/palate with in utero glucocorticoid exposure.¹⁶ However, multiple follow-up studies found no association between the two.^17,18 Studies investigating the relationship between steroids and miscarriages or steroids and low birth weight also are inconclusive. Of note, if used throughout pregnancy, administration of a loading dose of glucocorticoids prior to delivery is recommended because of the increased stress brought on during labor.¹⁹

Sulfasalazine—Sulfasalazine is an immunomodulator commonly used for the treatment of inflammatory bowel disease and rheumatoid arthritis. However, studies also have shown that sulfasalazine is an effective treatment of CLE if standard treatments have failed.^20,21

During pregnancy, patients exposed to sulfasalazine experienced minimal side effects despite transportation across the placenta.²² In comparison with control, pregnant women taking sulfasalazine experienced no increased risk for low fetal weight,²³ congenital abnormalities,²⁴ or spontaneous abortions.²⁵ Of note, sulfasalazine can affect sperm, so male patients also should be counselled.

Category C

Hydroxychloroquine—Hydroxychloroquine is considered a first-line medication for those with CLE based on a symptomatic relief rate of 50% to 70%.²⁶ For those taking hydroxychloroquine during pregnancy, the majority of studies have shown no association between the medication and adverse fetal events, including congenital abnormalities, prematurity, or spontaneous abortions.^27-29 Therefore, hydroxychloroquine is considered safe in pregnancy, and those on the medication should continue standard monitoring, including retinopathy screening.³⁰

Of note, hydroxychloroquine can be stored in tissue for weeks to months after discontinuation.⁵ Therefore, if patients wish to avoid hydroxychloroquine in pregnancy, one should stop taking the medication several months prior to conception.

Dapsone—Dapsone, a medication with both antimicrobial and immunomodulatory properties, is an effective second-line therapy for CLE.³¹ Although large-scale human trials have not been performed, multiple case reports and observational studies have supported the safe use of dapsone in pregnancy.^32-34 However, there are notable side effects, including dose-dependent hemolysis, methemoglobinemia, and hypersensitivity reactions.¹³ Therefore, once treatment is initiated or continued, folic acid supplementation (5 mg daily) and regular serum analysis, including complete blood cell counts, are recommended in pregnant patients.¹⁹

Rituximab—Recent studies have demonstrated that rituximab can be an effective treatment of subacute and chronic CLE.^35,36 Through inhibition of CD20, rituximab causes a decrease in circulating B cells and a reduced immune response. Therefore, experts recommend discontinuation of rituximab for 12 months prior to conception to reduce potential side effects to the fetus, which may include a transient reduction of circulating fetal B cells.³⁷

If continued during pregnancy, most studies suggest discontinuation of rituximab during the third trimester, as it has been associated with neonatal infections and congenital abnormalities.^19,37 However, these results are based on limited case reports, and thus robust research is needed to better understand the effect of rituximab in utero.

Intravenous Immunoglobulin Infusion—Intravenous immunoglobulin (IVIG) infusion is a well-tolerated treatment for many autoimmune disorders.³⁸ Although not first line, limited case studies have demonstrated remission of refractory CLE following IVIG.^39,40 Although no studies have directly investigated the effect of IVIG on fetal development, it has been frequently administered and well tolerated during pregnancy, especially in those with multiple sclerosis or antiphospholipid syndrome.⁴¹ Commonly reported side effects include headache and fatigue, and a rare associated side effect to be aware of is embolic events.^42,43

Cyclosporine—Cyclosporine rarely is used in the treatment of localized CLE due to its extensive side-effect profile, most notably nephrotoxicity.⁴⁴ However, studies have shown that cyclosporine may be efficacious if symptoms extend beyond the skin, involve multiple organs, and/or other treatments have failed.³⁹ For those who are pregnant and wish to continue cyclosporine use, studies have associated low birth weight and premature delivery with its exposure in utero.⁴⁴

Category D

Mycophenolate Mofetil—In conjunction with standard therapy, mycophenolate mofetil (MMF) is an adequate treatment of refractory CLE.⁴⁵ Unfortunately, case reports have demonstrated an increased risk for fetal congenital abnormalities and first-trimester spontaneous abortion with use of MMF during pregnancy.^46,47 Therefore, it is recommended that patients on MMF discontinue the medication at least 6 weeks prior to conception.⁴⁶

Azathioprine—Although azathioprine has been shown to provide relief of discoid lupus erythematosus symptoms,⁴⁸ it currently is only utilized for refractory disease, largely due to notable side effects that particularly affect the gastrointestinal tract and liver.⁴ Moreover, azathioprine use during pregnancy has been associated with prematurity, congenital anomalies, fetal cytopenia, and low birth weight.⁴⁹ With that said, and although not recommended, if patients decide to continue treatment, experts recommend limiting the dose to 2 mg/kg daily to reduce potential adverse events.

Category X

Oral Retinoids—According to the American Academy of Dermatology, retinoids such as isotretinoin and acitretin are considered second-line therapy for CLE.⁵⁰ With that being said, there are well-documented effects on fetal development associated with oral retinoid use, including central nervous system, cardiovascular system, and craniofacial abnormalities.⁵¹ Therefore, its use is contraindicated during pregnancy. To prevent pregnancy while taking isotretinoin, patients must enroll in an online monitoring program called iPLEDGE. This program requires monthly updates by both the physician and the patient, including a negative pregnancy test every month for female patients actively taking the medication.⁵²

The half-lives of the oral retinoids isotretinoin and acitretin are 10 to 20 hours and 50 to 60 hours, respectively.^53,54 However, alcohol consumption converts acitretin into the metabolite etretinate, which can remain in tissue for up to 120 days.^54,55 Therefore, women are advised to avoid alcohol while taking acitretin and avoid conception for 2 to 3 years after cessation of the medication.⁵⁵ For those wishing to restart retinoids after pregnancy, studies show the medication can be safely reinstated 35 days after delivery for those interested in continued treatment.⁵⁶

Thalidomide—Although low-dose thalidomide can treat refractory CLE, its use is restricted because of its known teratogenicity, most notably limb deformities.⁵⁷ If prescribed thalidomide, women will need to enroll in the System for Thalidomide Education and Prescribing Safety program, similar to the iPLEDGE program, and use 2 forms of contraception when sexually active.⁵⁸ Contraception should be continued for 4 weeks following the last dose of thalidomide. After this point, conception is considered safe.⁵⁹

Methotrexate—For nonpregnant patients, low-dose methotrexate (MTX) with folate supplementation is a treatment option for CLE.⁶⁰ However, for those who are pregnant, low-dose MTX is an abortive agent and has been associated with aminopterin syndrome, which includes skull deficits, craniofacial abnormalities, and limb deformities in live births.^19,61 Therefore, MTX is not recommended in pregnancy. Of note, MTX can affect sperm; male patients also should be counselled.

Overall, it is recommended to limit medication use as much as possible in pregnancy. To reduce these exposures, it is imperative to reduce triggers that may lead to symptomatic flares of CLE. Because CLE can be triggered by sun exposure, we advise topical sunscreen to prevent CLE flares that may require additional oral medication.^62,63

Various medications are considered safe for the treatment of CLE in pregnant patients (Figure 2). Based on studies in animal and clinical trials, hydroxychloroquine is considered a safe and effective medication for CLE in pregnancy and is a first-line therapy in nonpregnant patients.^26,27 If flares occur, IVIG or a short course of oral steroids should be considered to manage symptoms.^13,39 For those with severe flares, treatment is difficult, and personalized approaches may be necessary.

Part of the question for the childbearing population is when a patient would like to conceive. For severe cases when hydroxychloroquine is not effective as monotherapy, using a treatment that can encourage remission prior to conception attempts can be a beneficial strategy. Rituximab is an excellent example of such a therapy, as the therapeutic effect outlasts the immunosuppressive effect and therefore is unlikely to affect a future fetus.⁶⁴ Thalidomide also is a potential option prior to conception, based on its short washout period and its ability to achieve notable remission rates in patients with CLE.^57,59 Regardless, patients with CLE should still consult their dermatologist and rheumatologist (if applicable) prior to conception.

Patients of childbearing potential represent a population in which discussion about life goals greatly affects medication options. Having these discussions early and often allows for an open, more successful approach so that treatment regimens are not derailed at the time of conception.

When I finished my dermatology training in 1986, the only moving parts in the skin that I recall were keratinocytes moving upward from the basal layer of the epidermis until they were desquamated 4 or 5 weeks later and hairs growing within their follicles until they were shed. Now we are learning about countless cytokines, chemokines, interleukins, antibodies, receptors, enzymes, and cell types, as well as their associated pathways, at an endless pace. Every day I am looking in my inbox to sign up for the “Cytokine of the Month” club! Despite the challenges of sorting through what is relevant clinically, it is a very exciting time. Coupled with this myriad of fundamental science is the emergence of newer therapies that are more directly targeting specific disease states and dramatically changing the lives of patients. We see prominent examples of these therapeutic results every day in patients we treat, especially with psoriasis and atopic dermatitis. Importantly, there also is hope for patients with notoriously refractory skin disorders, such as hidradenitis suppurativa, alopecia areata, and vitiligo, as newer therapies are being thoroughly studied in clinical trials.

Despite the best advances in therapy that we currently have available and those anticipated in the foreseeable future, patients with chronic dermatoses such as psoriasis and atopic dermatitis still require prolonged constant or frequently used intermittent therapies to adequately control their disease. Fortunately, as dermatologists we understand the importance of proper skin care and topical medications as well as how to incorporate them in the management plan. To date, specifically with psoriasis, we have a variety of brand and generic topical corticosteroids, calcipotriene (vitamin D analogue), and tazarotene (retinoid), as well as combination formulations, in our toolbox to help manage localized areas of involvement.¹ This includes both patients with more limited psoriasis and those responding favorably to systemic therapy but who still develop some new or persistent areas of localized psoriatic lesions. New data with the brand formulation of calcipotriene–betamethasone dipropionate (Cal-BDP) foam applied once daily shows that after adequate control is achieved, continued application to the affected sites twice weekly is superior to vehicle in preventing relapse of psoriasis.² A highly cosmetically acceptable Cal-BDP cream incorporating a unique vehicle technology has been US Food and Drug Administration (FDA) approved for once-daily use for plaque psoriasis, overcoming the compatibility difficulties encountered in combining both active ingredients in an aqueous-based formulation and also optimizing the delivery of the active ingredients into the skin. This Cal-BDP cream demonstrated efficacy superior to a brand Cal-BDP suspension, rapid reduction in pruritus, and favorable tolerability and safety.³ Another combination formulation that is FDA approved for plaque psoriasis with once-daily application that has been shown to be effective and safe is halobetasol propionate–tazarotene lotion. This formulation contains lower concentrations of both active ingredients than those normally used in a barrier-friendly polymeric emulsion vehicle, allowing for augmented delivery of both active ingredients into the skin than with the individual agents applied separately and sequentially.^4,5 In the best of circumstances, most patients with psoriasis still require use of topical therapy and appreciate its availability. Just like on any menu, it is good to have multiple good options.

What else does this psoriasis management story need? A pipeline! I am happy to tell you that with topical therapy, 2 nonsteroidal agents are under development with completion of phase 2 and phase 3 trials submitted to the FDA to evaluate for approval for psoriasis. They are tapinarof cream, an aryl hydrocarbon receptor agonist, and roflumilast cream, a phosphodiesterase 4 (PDE4) inhibitor. Both of these modes of action involve intracellular pathways that are highly conserved in humans and are ubiquitously present in structural and hematopoietic cells.

Topical application of tapinarof cream once daily has been shown to be effective and safe for plaque psoriasis, is well tolerated with some reports of folliculitis observed that did not typically interfere with use, exhibits a remittive effect in patients achieving clearance on therapy, and is devoid of any systemic safety signals with both short-term and long-term use.^6-8 It also is currently under evaluation for atopic dermatitis. Topical roflumilast cream once daily has been shown to be effective and safe for plaque psoriasis as well as intertriginous psoriasis; is well tolerated including negligible rates of skin tolerability reactions such as stinging and burning; and is devoid of systemic safety signals, including those often observed with oral PDE4 inhibitor therapy (apremilast).^9,10 In addition, roflumilast has been shown to be more inherently potent in PDE4 inhibition activity than crisaborole and apremilast.¹¹ Roflumilast cream also is being studied for atopic dermatitis and a foam formulation is being evaluated for seborrheic dermatitis. Importantly, both tapinarof and roflumilast are not corticosteroids and are not associated with adverse effects observed with topical corticosteroid therapy, such as atrophy, striae, telangiectasia, and hypothalamic-pituitary-adrenal axis suppression. This provides a sense of comfort for clinicians and patients, as potential side effects associated with more prolonged topical corticosteroid therapy are common and lingering concerns.

To summarize, topical therapy for psoriasis is here to stay, just like all the rock and roll we have more access to than ever through expanded modern-day radio access and several music streaming sources, most of which are on demand. Also available to us are some viable current options, including a few newer brand formulations. New nonsteroidal agents with favorable data thus far are on the horizon, providing their own inherent efficacy and safety, which appear to be advantageous thus far. As the late Ric Ocasek of the Cars sang, “Let the good times roll.”

When I finished my dermatology training in 1986, the only moving parts in the skin that I recall were keratinocytes moving upward from the basal layer of the epidermis until they were desquamated 4 or 5 weeks later and hairs growing within their follicles until they were shed. Now we are learning about countless cytokines, chemokines, interleukins, antibodies, receptors, enzymes, and cell types, as well as their associated pathways, at an endless pace. Every day I am looking in my inbox to sign up for the “Cytokine of the Month” club! Despite the challenges of sorting through what is relevant clinically, it is a very exciting time. Coupled with this myriad of fundamental science is the emergence of newer therapies that are more directly targeting specific disease states and dramatically changing the lives of patients. We see prominent examples of these therapeutic results every day in patients we treat, especially with psoriasis and atopic dermatitis. Importantly, there also is hope for patients with notoriously refractory skin disorders, such as hidradenitis suppurativa, alopecia areata, and vitiligo, as newer therapies are being thoroughly studied in clinical trials.

Despite the best advances in therapy that we currently have available and those anticipated in the foreseeable future, patients with chronic dermatoses such as psoriasis and atopic dermatitis still require prolonged constant or frequently used intermittent therapies to adequately control their disease. Fortunately, as dermatologists we understand the importance of proper skin care and topical medications as well as how to incorporate them in the management plan. To date, specifically with psoriasis, we have a variety of brand and generic topical corticosteroids, calcipotriene (vitamin D analogue), and tazarotene (retinoid), as well as combination formulations, in our toolbox to help manage localized areas of involvement.¹ This includes both patients with more limited psoriasis and those responding favorably to systemic therapy but who still develop some new or persistent areas of localized psoriatic lesions. New data with the brand formulation of calcipotriene–betamethasone dipropionate (Cal-BDP) foam applied once daily shows that after adequate control is achieved, continued application to the affected sites twice weekly is superior to vehicle in preventing relapse of psoriasis.² A highly cosmetically acceptable Cal-BDP cream incorporating a unique vehicle technology has been US Food and Drug Administration (FDA) approved for once-daily use for plaque psoriasis, overcoming the compatibility difficulties encountered in combining both active ingredients in an aqueous-based formulation and also optimizing the delivery of the active ingredients into the skin. This Cal-BDP cream demonstrated efficacy superior to a brand Cal-BDP suspension, rapid reduction in pruritus, and favorable tolerability and safety.³ Another combination formulation that is FDA approved for plaque psoriasis with once-daily application that has been shown to be effective and safe is halobetasol propionate–tazarotene lotion. This formulation contains lower concentrations of both active ingredients than those normally used in a barrier-friendly polymeric emulsion vehicle, allowing for augmented delivery of both active ingredients into the skin than with the individual agents applied separately and sequentially.^4,5 In the best of circumstances, most patients with psoriasis still require use of topical therapy and appreciate its availability. Just like on any menu, it is good to have multiple good options.

What else does this psoriasis management story need? A pipeline! I am happy to tell you that with topical therapy, 2 nonsteroidal agents are under development with completion of phase 2 and phase 3 trials submitted to the FDA to evaluate for approval for psoriasis. They are tapinarof cream, an aryl hydrocarbon receptor agonist, and roflumilast cream, a phosphodiesterase 4 (PDE4) inhibitor. Both of these modes of action involve intracellular pathways that are highly conserved in humans and are ubiquitously present in structural and hematopoietic cells.

Topical application of tapinarof cream once daily has been shown to be effective and safe for plaque psoriasis, is well tolerated with some reports of folliculitis observed that did not typically interfere with use, exhibits a remittive effect in patients achieving clearance on therapy, and is devoid of any systemic safety signals with both short-term and long-term use.^6-8 It also is currently under evaluation for atopic dermatitis. Topical roflumilast cream once daily has been shown to be effective and safe for plaque psoriasis as well as intertriginous psoriasis; is well tolerated including negligible rates of skin tolerability reactions such as stinging and burning; and is devoid of systemic safety signals, including those often observed with oral PDE4 inhibitor therapy (apremilast).^9,10 In addition, roflumilast has been shown to be more inherently potent in PDE4 inhibition activity than crisaborole and apremilast.¹¹ Roflumilast cream also is being studied for atopic dermatitis and a foam formulation is being evaluated for seborrheic dermatitis. Importantly, both tapinarof and roflumilast are not corticosteroids and are not associated with adverse effects observed with topical corticosteroid therapy, such as atrophy, striae, telangiectasia, and hypothalamic-pituitary-adrenal axis suppression. This provides a sense of comfort for clinicians and patients, as potential side effects associated with more prolonged topical corticosteroid therapy are common and lingering concerns.

To summarize, topical therapy for psoriasis is here to stay, just like all the rock and roll we have more access to than ever through expanded modern-day radio access and several music streaming sources, most of which are on demand. Also available to us are some viable current options, including a few newer brand formulations. New nonsteroidal agents with favorable data thus far are on the horizon, providing their own inherent efficacy and safety, which appear to be advantageous thus far. As the late Ric Ocasek of the Cars sang, “Let the good times roll.”

When I finished my dermatology training in 1986, the only moving parts in the skin that I recall were keratinocytes moving upward from the basal layer of the epidermis until they were desquamated 4 or 5 weeks later and hairs growing within their follicles until they were shed. Now we are learning about countless cytokines, chemokines, interleukins, antibodies, receptors, enzymes, and cell types, as well as their associated pathways, at an endless pace. Every day I am looking in my inbox to sign up for the “Cytokine of the Month” club! Despite the challenges of sorting through what is relevant clinically, it is a very exciting time. Coupled with this myriad of fundamental science is the emergence of newer therapies that are more directly targeting specific disease states and dramatically changing the lives of patients. We see prominent examples of these therapeutic results every day in patients we treat, especially with psoriasis and atopic dermatitis. Importantly, there also is hope for patients with notoriously refractory skin disorders, such as hidradenitis suppurativa, alopecia areata, and vitiligo, as newer therapies are being thoroughly studied in clinical trials.

Despite the best advances in therapy that we currently have available and those anticipated in the foreseeable future, patients with chronic dermatoses such as psoriasis and atopic dermatitis still require prolonged constant or frequently used intermittent therapies to adequately control their disease. Fortunately, as dermatologists we understand the importance of proper skin care and topical medications as well as how to incorporate them in the management plan. To date, specifically with psoriasis, we have a variety of brand and generic topical corticosteroids, calcipotriene (vitamin D analogue), and tazarotene (retinoid), as well as combination formulations, in our toolbox to help manage localized areas of involvement.¹ This includes both patients with more limited psoriasis and those responding favorably to systemic therapy but who still develop some new or persistent areas of localized psoriatic lesions. New data with the brand formulation of calcipotriene–betamethasone dipropionate (Cal-BDP) foam applied once daily shows that after adequate control is achieved, continued application to the affected sites twice weekly is superior to vehicle in preventing relapse of psoriasis.² A highly cosmetically acceptable Cal-BDP cream incorporating a unique vehicle technology has been US Food and Drug Administration (FDA) approved for once-daily use for plaque psoriasis, overcoming the compatibility difficulties encountered in combining both active ingredients in an aqueous-based formulation and also optimizing the delivery of the active ingredients into the skin. This Cal-BDP cream demonstrated efficacy superior to a brand Cal-BDP suspension, rapid reduction in pruritus, and favorable tolerability and safety.³ Another combination formulation that is FDA approved for plaque psoriasis with once-daily application that has been shown to be effective and safe is halobetasol propionate–tazarotene lotion. This formulation contains lower concentrations of both active ingredients than those normally used in a barrier-friendly polymeric emulsion vehicle, allowing for augmented delivery of both active ingredients into the skin than with the individual agents applied separately and sequentially.^4,5 In the best of circumstances, most patients with psoriasis still require use of topical therapy and appreciate its availability. Just like on any menu, it is good to have multiple good options.

What else does this psoriasis management story need? A pipeline! I am happy to tell you that with topical therapy, 2 nonsteroidal agents are under development with completion of phase 2 and phase 3 trials submitted to the FDA to evaluate for approval for psoriasis. They are tapinarof cream, an aryl hydrocarbon receptor agonist, and roflumilast cream, a phosphodiesterase 4 (PDE4) inhibitor. Both of these modes of action involve intracellular pathways that are highly conserved in humans and are ubiquitously present in structural and hematopoietic cells.

Topical application of tapinarof cream once daily has been shown to be effective and safe for plaque psoriasis, is well tolerated with some reports of folliculitis observed that did not typically interfere with use, exhibits a remittive effect in patients achieving clearance on therapy, and is devoid of any systemic safety signals with both short-term and long-term use.^6-8 It also is currently under evaluation for atopic dermatitis. Topical roflumilast cream once daily has been shown to be effective and safe for plaque psoriasis as well as intertriginous psoriasis; is well tolerated including negligible rates of skin tolerability reactions such as stinging and burning; and is devoid of systemic safety signals, including those often observed with oral PDE4 inhibitor therapy (apremilast).^9,10 In addition, roflumilast has been shown to be more inherently potent in PDE4 inhibition activity than crisaborole and apremilast.¹¹ Roflumilast cream also is being studied for atopic dermatitis and a foam formulation is being evaluated for seborrheic dermatitis. Importantly, both tapinarof and roflumilast are not corticosteroids and are not associated with adverse effects observed with topical corticosteroid therapy, such as atrophy, striae, telangiectasia, and hypothalamic-pituitary-adrenal axis suppression. This provides a sense of comfort for clinicians and patients, as potential side effects associated with more prolonged topical corticosteroid therapy are common and lingering concerns.

To summarize, topical therapy for psoriasis is here to stay, just like all the rock and roll we have more access to than ever through expanded modern-day radio access and several music streaming sources, most of which are on demand. Also available to us are some viable current options, including a few newer brand formulations. New nonsteroidal agents with favorable data thus far are on the horizon, providing their own inherent efficacy and safety, which appear to be advantageous thus far. As the late Ric Ocasek of the Cars sang, “Let the good times roll.”

Psoriasis is a common chronic immunologic skin disease that affects approximately 7.4 million adults in the United States¹ and more than 100 million individuals worldwide.² Patients with psoriasis have a potentially heightened risk for cardiometabolic diseases, psychiatric disorders, and psoriatic arthritis,³ as well as impaired quality of life (QOL).⁴ Psoriasis also is associated with increased health care costs⁵ and may result in substantial socioeconomic repercussions for affected patients.^6,7

Psoriasis treatments focus on relieving symptoms and improving patient QOL. Systemic therapy has been the mainstay of treatment for moderate to severe psoriasis.⁸ Although topical therapy usually is applied to treat mild symptoms, it also can be used as an adjunct to enhance efficacy of other treatment approaches.⁹ The National Psoriasis Foundation (NPF) recommends a treat-to-target (TTT) strategy for plaque psoriasis, the most common form of psoriasis, with a target response of attaining affected body surface area (BSA) of 1% or lower at 3 months after treatment initiation, allowing for regular assessments of treatment responses.¹⁰

Not all patients with moderate to severe psoriasis can achieve a satisfactory response with systemic biologic monotherapy.¹¹ Switching to a new biologic improves responses in some but not all cases¹² and could be associated with new safety issues and additional costs. Combinations of biologics with phototherapy, nonbiologic systemic agents, or topical medications were found to be more effective than biologics alone,^9,11 though long-term safety studies are needed for biologics combined with other systemic inverventions.¹¹

A lotion containing a fixed combination of halobetasol propionate (HP) 0.01%, a corticosteroid, and tazarotene (TAZ) 0.045%, a retinoid, is indicated for plaque psoriasis in adults.¹³ Two randomized, controlled, phase 3 trials demonstrated the rapid and sustained efficacy of HP-TAZ in treating moderate to severe plaque psoriasis without any safety concerns.^14,15 However, combining HP-TAZ lotion with biologics has not been examined yet, to our knowledge.

This open-label study evaluated the effectiveness and safety of adjunctive HP-TAZ lotion in adult patients with moderate to severe plaque psoriasis who were being treated with biologics in a real-world setting. Potential cost savings with the addition of topical HP-TAZ to ongoing biologics vs switching to a new biologic also were assessed.

Methods

Study Design and Participants—A single-center, institutional review board–approved, open-label study evaluated adjunctive therapy with HP 0.01%–TAZ 0.045% lotion in patients with psoriasis being treated with biologic agents. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with Good Clinical Practices. All patients provided written informed consent before enrollment.

Male and nonpregnant female patients (aged ≥18 years)with moderate to severe chronic plaque psoriasis and a BSA of 2% to 10% who were being treated with biologics for at least 24 weeks at baseline were enrolled. Patients were excluded if they had used oral systemic medications for psoriasis (≤4 weeks), other topical antipsoriatic therapies (≤14 days), UVB phototherapy (≤2 weeks), and psoralen plus UVA phototherapy (≤4 weeks) prior to study initiation. Concomitant use of steroid-free topical emollients or low-potency topical steroids and appropriate interventions deemed necessary by the investigator were allowed.

Although participants maintained their prescribed biologics for the duration of the study, HP-TAZ lotion also was applied once daily for 8 weeks, followed by once every other day for an additional 4 weeks. Participants then continued with biologics only for the last 4 weeks of the study.

Study Outcome Measures—Disease severity and treatment efficacy were assessed by affected BSA, Physician Global Assessment (PGA) score, composite BSA×PGA score, and participant-reported Dermatology Life Quality Index (DLQI). The primary end point was the proportion of participants achieving a BSA of 0% to 1% (NPF TTT status) at week 8. Secondary end points included the proportions of participants with BSA of 0% to 1% at weeks 12 and 16; BSA×PGA score at weeks 8, 12, and 16; and improvements in BSA, PGA, and DLQI at weeks 8, 12, and 16.

Adverse events (AEs) that occurred after the signing of the informed consent and for the duration of the participant’s participation were recorded, regardless of causality. Physical examinations were performed at screening; baseline; and weeks 8, 12, and 16 to document any clinically significant abnormalities. Localized skin reactions were assessed for tolerability of the study drug, with any reaction requiring concomitant therapy recorded as an AE.

The likelihood of switching to a new biologic regimen was assessed by the investigator for each participant at baseline and weeks 8, 12, and 16. Participants with unacceptable responses to their treatments (BSA >3%) were reported as likely to be considered for switching biologics by the investigator.

Pharmacoeconomic Evaluation—Potential cost savings were evaluated for the addition of HP-TAZ lotion to ongoing biologics vs switching to a new biologic. Cost comparisons were made in participants for whom the investigator would likely have switched biologics at baseline but not at the end of the study. For maintaining the same biologic with adjunctive topical HP-TAZ, total cost was estimated by adding the cost for 12 weeks (once daily for 8 weeks and once every other day for 4 weeks) of the HP-TAZ lotion to that of 16-week maintenance dosing with the biologic. The projected cost for switching to a new biologic for 16 weeks of treatment was based on both induction and maintenance dosing as recommended in its product label. Prices were obtained from the 2020 average wholesale price specialty pharmacy reports (BioPlus Specialty Pharmacy Services [https://www.bioplusrx.com]).

Data Handling—Enrollment of approximately 25 participants was desired for the study. Data on disease severity and participant-reported outcomes were assessed using descriptive statistics. Adverse events were summarized descriptively by incidence, severity, and relationship to the study drug. All participants with data available at a measured time point were included in the analyses for that time point.

Results

Participant Disposition and Demographics—Twenty-five participants (15 male and 10 female) were included in the study (Table 1). Seven participants discontinued the study for the following reasons: AEs (n=4), patient choice (n=2), and noncompliance (n=1).

The average age of the participants was 50 years, the majority were White (76.0% [19/25]) andnon-Hispanic (88.0% [22/25]), and the mean duration of chronic plaque psoriasis was 18.9 years (Table 1). Participants had been receiving biologic monotherapy for at least 24 weeks prior to enrollment, most commonly ustekinumab (32.0% [8/25])(Table 1). None had achieved the NPF TTT status with their biologics. At baseline, mean (SD) affected BSA, PGA, BSA×PGA, and participant-reported DLQI were 4.16% (2.04%), 2.84 (0.55), 11.88 (6.39), and 4.00 (4.74), respectively.

Efficacy Assessment—Application of HP-TAZ lotion in addition to the participants’ existing biologic therapy reduced severity of the disease, as evidenced by the reductions in mean BSA, PGA, and BSA×PGA. After 8 weeks of once-daily concomitant HP-TAZ use with biologic, mean BSA and PGA dropped by approximately 40% and 37%, respectively (Figures 1A and 1B). A greater reduction (54%) was found for mean BSA×PGA (Figure 1C). Disease severity continued to improve when the application schedule for HP-TAZ was changed to once every other day for 4 weeks, as mean BSA, PGA, and BSA×PGA decreased further at week 12. These beneficial effects were sustained during the last 4 weeks of the study after HP-TAZ was discontinued, with reductions of 57%, 43%, and 70% from baseline for mean BSA, PGA, and BSA×PGA, respectively (Figure 1).

The proportion of participants who achieved NPF TTT status increased from 0% at baseline to 20.0% (5/20) at week 8 with once-daily use of HP-TAZ plus biologic for 8 weeks (Figure 2). At week 12, more participants (64.7% [11/17]) achieved the treatment goal after application of HP-TAZ once every other day with biologic for 4 weeks. Most participants maintained NPF TTT status after HP-TAZ was discontinued; at week 16, 50.0% (9/18) attained the NPF treatment goal (Figure 2).

The mean DLQI score decreased from 4.00 at baseline to 2.45 after 8 weeks of concomitant use of once-daily HP-TAZ with biologic, reflecting a 39% score reduction. An additional 4 weeks of adjunctive HP-TAZ applied once every other day with biologic further decreased the DLQI score to 2.18 at week 12. Mean DLQI remained similar (2.33) after another 4 weeks of biologics alone. The proportion of participants reporting a DLQI score of 0 to 1 increased from 40% (10/25) at baseline to 60% (12/20) at week 8 and 76.5% (13/17) at week 12 with adjunctive HP-TAZ lotion use with biologic. At week 16, a DLQI score of 0 to 1 was reported in 61.1% (11/18) of participants after receiving only biologics for 4 weeks.

Safety Assessment—A total of 19 AEs were reported in 11 participants during the study; 16 AEs were considered treatment related in 8 participants (Table 2). The most common AEs were retinoid dermatitis (28% [7/25]), burning at the application site (8% [2/25]), and pruritus at the application site (8% [2/25]), all of which were considered related to the treatment. Among all AEs, 12 were mild in severity, and the remaining 7 were moderate. Adverse events led to early study termination in 4 participants, all with retinoid dermatitis as the primary reason.

Likelihood of Switching Biologics—At baseline, almost 90% (22/25) of participants were rated as likely to switch biologics by the investigator due to unacceptable responses to their currently prescribed biologics (BSA >3%)(Figure 3). The likelihood was greatly reduced by concomitant HP-TAZ, as the proportion of participants defined as nonresponders to their biologic decreased to 35% (7/20) with 8-week adjunctive application of once-daily HP-TAZ with biologic and further decreased to 23.5% (4/17) with another 4 weeks of adjunctive HP-TAZ applied every other day plus biologic. At week 16, after 4 weeks of biologics alone, the proportion was maintained at 33.3% (6/18).

Pharmacoeconomics of Adding Topical HP-TAZ vs Switching Biologics—In the participants whom the investigator reported as likely to switch biologics at baseline, 9 had improvements in disease control such that switching biologics was no longer considered necessary for them at week 16. Potential cost savings with adjunctive therapy of HP-TAZ plus biologic vs switching biologics were therefore evaluated in these 9 participants, who were receiving ustekinumab, adalimumab, guselkumab, ixekizumab, and secukinumab during the study (Table 3). The estimated total cost of 16-week maintenance dosing of biologics plus adjunct HP-TAZ lotion ranged from $14,675 (ustekinumab 45 mg) to $54,025 (secukinumab 300 mg), while switching to other most commonly prescribed biologics for 16 weeks would cost an estimated $33,340 to $106,400 (induction and subsequent maintenance phases)(Table 3). Most biologic plus HP-TAZ combinations were estimated to cost less than $30,000, potentially saving $4816 to $91,725 compared with switching to any of the other 7 biologics (Table 3). The relatively more expensive maintenance combination containing secukinumab plus HP-TAZ ($54,025) appeared to be a less expensive option when compared with switching to ustekinumab (90 mg)($83,097), ixekizumab (80 mg)($61,452), or risankizumab (150 mg)($57,030) as an alternative biologic.

Comment

Adjunctive Use of HP-TAZ Lotion—In the present study, we showed that adjunctive HP-TAZ lotion improved biologic treatment response and reduced disease severity in participants with moderate to severe psoriasis whose symptoms could not be adequately controlled by 24 weeks or more of biologic monotherapy in a real-world setting. Disease activity decreased as evidenced by reductions in all assessed effectiveness variables, including BSA involvement, PGA score, composite BSA×PGA score, and participant-reported DLQI score. Half of the participants achieved NPF TTT status at the end of the study. The treatment was well tolerated with no unexpected safety concerns. Compared with switching to a new biologic, adding topical HP-TAZ to ongoing biologics appeared to be a more cost-effective approach to enhance treatment effects. Our results suggest that adjunctive use of HP-TAZ lotion may be a safe, effective, and economical option for patients with psoriasis who are failing their ongoing biologic monotherapy.

Treat-to-Target Status—The NPF-recommended target response to a treatment for plaque psoriasis is BSA of 1% or lower at 3 months postinitiation.¹⁰ Patients in the current study had major psoriasis activity at study entry despite being treated with a biologic for at least 24 weeks, as none had attained NPF TTT status at baseline. Because the time period of prior biologic treatment (at least 24 weeks) is much longer than the 3 months suggested by NPF, we believe that we were observing a true failure of the biologic rather than a slow onset of treatment effects in these patients at the time of enrollment. By week 12, with the addition of HP-TAZ lotion to the biologic, a high rate of participants achieved NPF TTT status (64.7%), with most participants being able to maintain this TTT status at study end after 4 weeks of biologic alone. Most participants also reported no impact of psoriasis on their QOL (DLQI, 0–1¹⁶; 76.5%) at week 12. Improvements we found in disease control with adjunctive HP-TAZ lotion plus biologic support prior reports showing enhanced responses when a topical medication was added to a biologic.^17,18 Reductions in psoriasis activity after 8 weeks of combined biologics plus once-daily HP-TAZ also are consistent with 2 phase 3 RCTs in which a monotherapy of HP-TAZ lotion used once daily for 8 weeks reduced BSA and DLQI.¹⁵ Notably, in the current study, disease severity continued to decrease when dosing of HP-TAZ was reduced to once every other day for 4 weeks, and the improvements were maintained even after the adjunct topical therapy was discontinued.

Safety Profile of HP-TAZ Lotion—The overall safety profile in our study also was consistent with that previously reported for HP-TAZ lotion,^15,19-21 with no new safety signals observed. The combination treatment was well tolerated, with most reported AEs being mild in severity. Adverse events were mostly related to application-site reactions, the most common being dermatitis (28%), which was likely attributable to the TAZ component of the topical regimen.¹⁵

Likelihood of Switching Biologics—Reduced disease activity was reflected by a decrease in the percentage of participants the investigator considered likely to change biologics, which was 88.0% at baseline but only 33.3% at the end of the study. Although switching to a different biologic agent can improve treatment effect,²² it could lead to a substantial increase in health care costs and use of resources compared with no switch.⁵ We found that switching to one of the other most commonly prescribed biologics could incur $4816 to $91,725 in additional costs in most cases when compared with the combination strategy we evaluated over the 16-week treatment period. Therefore, concomitant use of HP-TAZ lotion with the ongoing biologics would be a potentially more economical alternative for patients to achieve acceptable responses or the NPF TTT goal. Moreover, combination with an adjunctive topical medication could avoid potential risks associated with switching, such as new AEs with new biologic regimens or disease flare during any washout period sometimes adopted for switching biologics.

Study Limitations—Our estimated costs were based on average wholesale prices and did not reflect net prices paid by patients or health plans due to the lack of known discount rates. Inherent to the nature of its design, the study also had a relatively small patient population and lacked control groups. Although lack of a control group may limit the conclusions of our study, our goal was to examine real-world patient experience, and the efficacy of HP-TAZ lotion as well as the baseline disease state for each participant using a biologic was well known. Statistical inference on the differences in efficacy between biologics with and without adjunctive HP-TAZ lotion, or between combination therapy and a new biologic monotherapy, was not possible. Additionally, a longer follow-up after discontinuation of HP-TAZ is needed to evaluate the long-term maintenance of responses. Nevertheless, the results here demonstrated that participants responded better when adjunctive HP-TAZ lotion was added to the ongoing biologics in a clinical practice setting.

Conclusion

In this real-world study, patients with psoriasis that failed to respond to biologic monotherapy had improved disease control and QOL and reported no new safety concerns with adjunctive use of HP-TAZ lotion. Adding HP-TAZ to the ongoing biologics could be a more cost-effective option vs switching biologics for patients whose psoriasis symptoms could not be controlled with biologic monotherapy. Taken together, our results support the use of HP-TAZ lotion as an effective and safe adjunctive topical therapy in combination with biologics for psoriasis treatment.

Acknowledgments—We acknowledge the medical writing assistance provided by Hui Zhang, PhD, and Kathleen Ohleth, PhD, from Precise Publications LLC (Far Hills, New Jersey), which was funded by Ortho Dermatologics.

Psoriasis is a common chronic immunologic skin disease that affects approximately 7.4 million adults in the United States¹ and more than 100 million individuals worldwide.² Patients with psoriasis have a potentially heightened risk for cardiometabolic diseases, psychiatric disorders, and psoriatic arthritis,³ as well as impaired quality of life (QOL).⁴ Psoriasis also is associated with increased health care costs⁵ and may result in substantial socioeconomic repercussions for affected patients.^6,7

Psoriasis treatments focus on relieving symptoms and improving patient QOL. Systemic therapy has been the mainstay of treatment for moderate to severe psoriasis.⁸ Although topical therapy usually is applied to treat mild symptoms, it also can be used as an adjunct to enhance efficacy of other treatment approaches.⁹ The National Psoriasis Foundation (NPF) recommends a treat-to-target (TTT) strategy for plaque psoriasis, the most common form of psoriasis, with a target response of attaining affected body surface area (BSA) of 1% or lower at 3 months after treatment initiation, allowing for regular assessments of treatment responses.¹⁰

Not all patients with moderate to severe psoriasis can achieve a satisfactory response with systemic biologic monotherapy.¹¹ Switching to a new biologic improves responses in some but not all cases¹² and could be associated with new safety issues and additional costs. Combinations of biologics with phototherapy, nonbiologic systemic agents, or topical medications were found to be more effective than biologics alone,^9,11 though long-term safety studies are needed for biologics combined with other systemic inverventions.¹¹

A lotion containing a fixed combination of halobetasol propionate (HP) 0.01%, a corticosteroid, and tazarotene (TAZ) 0.045%, a retinoid, is indicated for plaque psoriasis in adults.¹³ Two randomized, controlled, phase 3 trials demonstrated the rapid and sustained efficacy of HP-TAZ in treating moderate to severe plaque psoriasis without any safety concerns.^14,15 However, combining HP-TAZ lotion with biologics has not been examined yet, to our knowledge.

This open-label study evaluated the effectiveness and safety of adjunctive HP-TAZ lotion in adult patients with moderate to severe plaque psoriasis who were being treated with biologics in a real-world setting. Potential cost savings with the addition of topical HP-TAZ to ongoing biologics vs switching to a new biologic also were assessed.

Methods

Study Design and Participants—A single-center, institutional review board–approved, open-label study evaluated adjunctive therapy with HP 0.01%–TAZ 0.045% lotion in patients with psoriasis being treated with biologic agents. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with Good Clinical Practices. All patients provided written informed consent before enrollment.

Male and nonpregnant female patients (aged ≥18 years)with moderate to severe chronic plaque psoriasis and a BSA of 2% to 10% who were being treated with biologics for at least 24 weeks at baseline were enrolled. Patients were excluded if they had used oral systemic medications for psoriasis (≤4 weeks), other topical antipsoriatic therapies (≤14 days), UVB phototherapy (≤2 weeks), and psoralen plus UVA phototherapy (≤4 weeks) prior to study initiation. Concomitant use of steroid-free topical emollients or low-potency topical steroids and appropriate interventions deemed necessary by the investigator were allowed.

Although participants maintained their prescribed biologics for the duration of the study, HP-TAZ lotion also was applied once daily for 8 weeks, followed by once every other day for an additional 4 weeks. Participants then continued with biologics only for the last 4 weeks of the study.

Study Outcome Measures—Disease severity and treatment efficacy were assessed by affected BSA, Physician Global Assessment (PGA) score, composite BSA×PGA score, and participant-reported Dermatology Life Quality Index (DLQI). The primary end point was the proportion of participants achieving a BSA of 0% to 1% (NPF TTT status) at week 8. Secondary end points included the proportions of participants with BSA of 0% to 1% at weeks 12 and 16; BSA×PGA score at weeks 8, 12, and 16; and improvements in BSA, PGA, and DLQI at weeks 8, 12, and 16.

Adverse events (AEs) that occurred after the signing of the informed consent and for the duration of the participant’s participation were recorded, regardless of causality. Physical examinations were performed at screening; baseline; and weeks 8, 12, and 16 to document any clinically significant abnormalities. Localized skin reactions were assessed for tolerability of the study drug, with any reaction requiring concomitant therapy recorded as an AE.

The likelihood of switching to a new biologic regimen was assessed by the investigator for each participant at baseline and weeks 8, 12, and 16. Participants with unacceptable responses to their treatments (BSA >3%) were reported as likely to be considered for switching biologics by the investigator.

Pharmacoeconomic Evaluation—Potential cost savings were evaluated for the addition of HP-TAZ lotion to ongoing biologics vs switching to a new biologic. Cost comparisons were made in participants for whom the investigator would likely have switched biologics at baseline but not at the end of the study. For maintaining the same biologic with adjunctive topical HP-TAZ, total cost was estimated by adding the cost for 12 weeks (once daily for 8 weeks and once every other day for 4 weeks) of the HP-TAZ lotion to that of 16-week maintenance dosing with the biologic. The projected cost for switching to a new biologic for 16 weeks of treatment was based on both induction and maintenance dosing as recommended in its product label. Prices were obtained from the 2020 average wholesale price specialty pharmacy reports (BioPlus Specialty Pharmacy Services [https://www.bioplusrx.com]).

Data Handling—Enrollment of approximately 25 participants was desired for the study. Data on disease severity and participant-reported outcomes were assessed using descriptive statistics. Adverse events were summarized descriptively by incidence, severity, and relationship to the study drug. All participants with data available at a measured time point were included in the analyses for that time point.

Results

Participant Disposition and Demographics—Twenty-five participants (15 male and 10 female) were included in the study (Table 1). Seven participants discontinued the study for the following reasons: AEs (n=4), patient choice (n=2), and noncompliance (n=1).

The average age of the participants was 50 years, the majority were White (76.0% [19/25]) andnon-Hispanic (88.0% [22/25]), and the mean duration of chronic plaque psoriasis was 18.9 years (Table 1). Participants had been receiving biologic monotherapy for at least 24 weeks prior to enrollment, most commonly ustekinumab (32.0% [8/25])(Table 1). None had achieved the NPF TTT status with their biologics. At baseline, mean (SD) affected BSA, PGA, BSA×PGA, and participant-reported DLQI were 4.16% (2.04%), 2.84 (0.55), 11.88 (6.39), and 4.00 (4.74), respectively.

Efficacy Assessment—Application of HP-TAZ lotion in addition to the participants’ existing biologic therapy reduced severity of the disease, as evidenced by the reductions in mean BSA, PGA, and BSA×PGA. After 8 weeks of once-daily concomitant HP-TAZ use with biologic, mean BSA and PGA dropped by approximately 40% and 37%, respectively (Figures 1A and 1B). A greater reduction (54%) was found for mean BSA×PGA (Figure 1C). Disease severity continued to improve when the application schedule for HP-TAZ was changed to once every other day for 4 weeks, as mean BSA, PGA, and BSA×PGA decreased further at week 12. These beneficial effects were sustained during the last 4 weeks of the study after HP-TAZ was discontinued, with reductions of 57%, 43%, and 70% from baseline for mean BSA, PGA, and BSA×PGA, respectively (Figure 1).

The proportion of participants who achieved NPF TTT status increased from 0% at baseline to 20.0% (5/20) at week 8 with once-daily use of HP-TAZ plus biologic for 8 weeks (Figure 2). At week 12, more participants (64.7% [11/17]) achieved the treatment goal after application of HP-TAZ once every other day with biologic for 4 weeks. Most participants maintained NPF TTT status after HP-TAZ was discontinued; at week 16, 50.0% (9/18) attained the NPF treatment goal (Figure 2).

The mean DLQI score decreased from 4.00 at baseline to 2.45 after 8 weeks of concomitant use of once-daily HP-TAZ with biologic, reflecting a 39% score reduction. An additional 4 weeks of adjunctive HP-TAZ applied once every other day with biologic further decreased the DLQI score to 2.18 at week 12. Mean DLQI remained similar (2.33) after another 4 weeks of biologics alone. The proportion of participants reporting a DLQI score of 0 to 1 increased from 40% (10/25) at baseline to 60% (12/20) at week 8 and 76.5% (13/17) at week 12 with adjunctive HP-TAZ lotion use with biologic. At week 16, a DLQI score of 0 to 1 was reported in 61.1% (11/18) of participants after receiving only biologics for 4 weeks.

Safety Assessment—A total of 19 AEs were reported in 11 participants during the study; 16 AEs were considered treatment related in 8 participants (Table 2). The most common AEs were retinoid dermatitis (28% [7/25]), burning at the application site (8% [2/25]), and pruritus at the application site (8% [2/25]), all of which were considered related to the treatment. Among all AEs, 12 were mild in severity, and the remaining 7 were moderate. Adverse events led to early study termination in 4 participants, all with retinoid dermatitis as the primary reason.

Likelihood of Switching Biologics—At baseline, almost 90% (22/25) of participants were rated as likely to switch biologics by the investigator due to unacceptable responses to their currently prescribed biologics (BSA >3%)(Figure 3). The likelihood was greatly reduced by concomitant HP-TAZ, as the proportion of participants defined as nonresponders to their biologic decreased to 35% (7/20) with 8-week adjunctive application of once-daily HP-TAZ with biologic and further decreased to 23.5% (4/17) with another 4 weeks of adjunctive HP-TAZ applied every other day plus biologic. At week 16, after 4 weeks of biologics alone, the proportion was maintained at 33.3% (6/18).

Pharmacoeconomics of Adding Topical HP-TAZ vs Switching Biologics—In the participants whom the investigator reported as likely to switch biologics at baseline, 9 had improvements in disease control such that switching biologics was no longer considered necessary for them at week 16. Potential cost savings with adjunctive therapy of HP-TAZ plus biologic vs switching biologics were therefore evaluated in these 9 participants, who were receiving ustekinumab, adalimumab, guselkumab, ixekizumab, and secukinumab during the study (Table 3). The estimated total cost of 16-week maintenance dosing of biologics plus adjunct HP-TAZ lotion ranged from $14,675 (ustekinumab 45 mg) to $54,025 (secukinumab 300 mg), while switching to other most commonly prescribed biologics for 16 weeks would cost an estimated $33,340 to $106,400 (induction and subsequent maintenance phases)(Table 3). Most biologic plus HP-TAZ combinations were estimated to cost less than $30,000, potentially saving $4816 to $91,725 compared with switching to any of the other 7 biologics (Table 3). The relatively more expensive maintenance combination containing secukinumab plus HP-TAZ ($54,025) appeared to be a less expensive option when compared with switching to ustekinumab (90 mg)($83,097), ixekizumab (80 mg)($61,452), or risankizumab (150 mg)($57,030) as an alternative biologic.

Comment

Adjunctive Use of HP-TAZ Lotion—In the present study, we showed that adjunctive HP-TAZ lotion improved biologic treatment response and reduced disease severity in participants with moderate to severe psoriasis whose symptoms could not be adequately controlled by 24 weeks or more of biologic monotherapy in a real-world setting. Disease activity decreased as evidenced by reductions in all assessed effectiveness variables, including BSA involvement, PGA score, composite BSA×PGA score, and participant-reported DLQI score. Half of the participants achieved NPF TTT status at the end of the study. The treatment was well tolerated with no unexpected safety concerns. Compared with switching to a new biologic, adding topical HP-TAZ to ongoing biologics appeared to be a more cost-effective approach to enhance treatment effects. Our results suggest that adjunctive use of HP-TAZ lotion may be a safe, effective, and economical option for patients with psoriasis who are failing their ongoing biologic monotherapy.

Treat-to-Target Status—The NPF-recommended target response to a treatment for plaque psoriasis is BSA of 1% or lower at 3 months postinitiation.¹⁰ Patients in the current study had major psoriasis activity at study entry despite being treated with a biologic for at least 24 weeks, as none had attained NPF TTT status at baseline. Because the time period of prior biologic treatment (at least 24 weeks) is much longer than the 3 months suggested by NPF, we believe that we were observing a true failure of the biologic rather than a slow onset of treatment effects in these patients at the time of enrollment. By week 12, with the addition of HP-TAZ lotion to the biologic, a high rate of participants achieved NPF TTT status (64.7%), with most participants being able to maintain this TTT status at study end after 4 weeks of biologic alone. Most participants also reported no impact of psoriasis on their QOL (DLQI, 0–1¹⁶; 76.5%) at week 12. Improvements we found in disease control with adjunctive HP-TAZ lotion plus biologic support prior reports showing enhanced responses when a topical medication was added to a biologic.^17,18 Reductions in psoriasis activity after 8 weeks of combined biologics plus once-daily HP-TAZ also are consistent with 2 phase 3 RCTs in which a monotherapy of HP-TAZ lotion used once daily for 8 weeks reduced BSA and DLQI.¹⁵ Notably, in the current study, disease severity continued to decrease when dosing of HP-TAZ was reduced to once every other day for 4 weeks, and the improvements were maintained even after the adjunct topical therapy was discontinued.

Safety Profile of HP-TAZ Lotion—The overall safety profile in our study also was consistent with that previously reported for HP-TAZ lotion,^15,19-21 with no new safety signals observed. The combination treatment was well tolerated, with most reported AEs being mild in severity. Adverse events were mostly related to application-site reactions, the most common being dermatitis (28%), which was likely attributable to the TAZ component of the topical regimen.¹⁵

Likelihood of Switching Biologics—Reduced disease activity was reflected by a decrease in the percentage of participants the investigator considered likely to change biologics, which was 88.0% at baseline but only 33.3% at the end of the study. Although switching to a different biologic agent can improve treatment effect,²² it could lead to a substantial increase in health care costs and use of resources compared with no switch.⁵ We found that switching to one of the other most commonly prescribed biologics could incur $4816 to $91,725 in additional costs in most cases when compared with the combination strategy we evaluated over the 16-week treatment period. Therefore, concomitant use of HP-TAZ lotion with the ongoing biologics would be a potentially more economical alternative for patients to achieve acceptable responses or the NPF TTT goal. Moreover, combination with an adjunctive topical medication could avoid potential risks associated with switching, such as new AEs with new biologic regimens or disease flare during any washout period sometimes adopted for switching biologics.

Study Limitations—Our estimated costs were based on average wholesale prices and did not reflect net prices paid by patients or health plans due to the lack of known discount rates. Inherent to the nature of its design, the study also had a relatively small patient population and lacked control groups. Although lack of a control group may limit the conclusions of our study, our goal was to examine real-world patient experience, and the efficacy of HP-TAZ lotion as well as the baseline disease state for each participant using a biologic was well known. Statistical inference on the differences in efficacy between biologics with and without adjunctive HP-TAZ lotion, or between combination therapy and a new biologic monotherapy, was not possible. Additionally, a longer follow-up after discontinuation of HP-TAZ is needed to evaluate the long-term maintenance of responses. Nevertheless, the results here demonstrated that participants responded better when adjunctive HP-TAZ lotion was added to the ongoing biologics in a clinical practice setting.

Conclusion

In this real-world study, patients with psoriasis that failed to respond to biologic monotherapy had improved disease control and QOL and reported no new safety concerns with adjunctive use of HP-TAZ lotion. Adding HP-TAZ to the ongoing biologics could be a more cost-effective option vs switching biologics for patients whose psoriasis symptoms could not be controlled with biologic monotherapy. Taken together, our results support the use of HP-TAZ lotion as an effective and safe adjunctive topical therapy in combination with biologics for psoriasis treatment.

Acknowledgments—We acknowledge the medical writing assistance provided by Hui Zhang, PhD, and Kathleen Ohleth, PhD, from Precise Publications LLC (Far Hills, New Jersey), which was funded by Ortho Dermatologics.

Psoriasis is a common chronic immunologic skin disease that affects approximately 7.4 million adults in the United States¹ and more than 100 million individuals worldwide.² Patients with psoriasis have a potentially heightened risk for cardiometabolic diseases, psychiatric disorders, and psoriatic arthritis,³ as well as impaired quality of life (QOL).⁴ Psoriasis also is associated with increased health care costs⁵ and may result in substantial socioeconomic repercussions for affected patients.^6,7

Psoriasis treatments focus on relieving symptoms and improving patient QOL. Systemic therapy has been the mainstay of treatment for moderate to severe psoriasis.⁸ Although topical therapy usually is applied to treat mild symptoms, it also can be used as an adjunct to enhance efficacy of other treatment approaches.⁹ The National Psoriasis Foundation (NPF) recommends a treat-to-target (TTT) strategy for plaque psoriasis, the most common form of psoriasis, with a target response of attaining affected body surface area (BSA) of 1% or lower at 3 months after treatment initiation, allowing for regular assessments of treatment responses.¹⁰

Not all patients with moderate to severe psoriasis can achieve a satisfactory response with systemic biologic monotherapy.¹¹ Switching to a new biologic improves responses in some but not all cases¹² and could be associated with new safety issues and additional costs. Combinations of biologics with phototherapy, nonbiologic systemic agents, or topical medications were found to be more effective than biologics alone,^9,11 though long-term safety studies are needed for biologics combined with other systemic inverventions.¹¹

A lotion containing a fixed combination of halobetasol propionate (HP) 0.01%, a corticosteroid, and tazarotene (TAZ) 0.045%, a retinoid, is indicated for plaque psoriasis in adults.¹³ Two randomized, controlled, phase 3 trials demonstrated the rapid and sustained efficacy of HP-TAZ in treating moderate to severe plaque psoriasis without any safety concerns.^14,15 However, combining HP-TAZ lotion with biologics has not been examined yet, to our knowledge.

This open-label study evaluated the effectiveness and safety of adjunctive HP-TAZ lotion in adult patients with moderate to severe plaque psoriasis who were being treated with biologics in a real-world setting. Potential cost savings with the addition of topical HP-TAZ to ongoing biologics vs switching to a new biologic also were assessed.

Methods

Study Design and Participants—A single-center, institutional review board–approved, open-label study evaluated adjunctive therapy with HP 0.01%–TAZ 0.045% lotion in patients with psoriasis being treated with biologic agents. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with Good Clinical Practices. All patients provided written informed consent before enrollment.

Male and nonpregnant female patients (aged ≥18 years)with moderate to severe chronic plaque psoriasis and a BSA of 2% to 10% who were being treated with biologics for at least 24 weeks at baseline were enrolled. Patients were excluded if they had used oral systemic medications for psoriasis (≤4 weeks), other topical antipsoriatic therapies (≤14 days), UVB phototherapy (≤2 weeks), and psoralen plus UVA phototherapy (≤4 weeks) prior to study initiation. Concomitant use of steroid-free topical emollients or low-potency topical steroids and appropriate interventions deemed necessary by the investigator were allowed.

Although participants maintained their prescribed biologics for the duration of the study, HP-TAZ lotion also was applied once daily for 8 weeks, followed by once every other day for an additional 4 weeks. Participants then continued with biologics only for the last 4 weeks of the study.

Study Outcome Measures—Disease severity and treatment efficacy were assessed by affected BSA, Physician Global Assessment (PGA) score, composite BSA×PGA score, and participant-reported Dermatology Life Quality Index (DLQI). The primary end point was the proportion of participants achieving a BSA of 0% to 1% (NPF TTT status) at week 8. Secondary end points included the proportions of participants with BSA of 0% to 1% at weeks 12 and 16; BSA×PGA score at weeks 8, 12, and 16; and improvements in BSA, PGA, and DLQI at weeks 8, 12, and 16.

Adverse events (AEs) that occurred after the signing of the informed consent and for the duration of the participant’s participation were recorded, regardless of causality. Physical examinations were performed at screening; baseline; and weeks 8, 12, and 16 to document any clinically significant abnormalities. Localized skin reactions were assessed for tolerability of the study drug, with any reaction requiring concomitant therapy recorded as an AE.

The likelihood of switching to a new biologic regimen was assessed by the investigator for each participant at baseline and weeks 8, 12, and 16. Participants with unacceptable responses to their treatments (BSA >3%) were reported as likely to be considered for switching biologics by the investigator.

Pharmacoeconomic Evaluation—Potential cost savings were evaluated for the addition of HP-TAZ lotion to ongoing biologics vs switching to a new biologic. Cost comparisons were made in participants for whom the investigator would likely have switched biologics at baseline but not at the end of the study. For maintaining the same biologic with adjunctive topical HP-TAZ, total cost was estimated by adding the cost for 12 weeks (once daily for 8 weeks and once every other day for 4 weeks) of the HP-TAZ lotion to that of 16-week maintenance dosing with the biologic. The projected cost for switching to a new biologic for 16 weeks of treatment was based on both induction and maintenance dosing as recommended in its product label. Prices were obtained from the 2020 average wholesale price specialty pharmacy reports (BioPlus Specialty Pharmacy Services [https://www.bioplusrx.com]).

Data Handling—Enrollment of approximately 25 participants was desired for the study. Data on disease severity and participant-reported outcomes were assessed using descriptive statistics. Adverse events were summarized descriptively by incidence, severity, and relationship to the study drug. All participants with data available at a measured time point were included in the analyses for that time point.

Results

Participant Disposition and Demographics—Twenty-five participants (15 male and 10 female) were included in the study (Table 1). Seven participants discontinued the study for the following reasons: AEs (n=4), patient choice (n=2), and noncompliance (n=1).

The average age of the participants was 50 years, the majority were White (76.0% [19/25]) andnon-Hispanic (88.0% [22/25]), and the mean duration of chronic plaque psoriasis was 18.9 years (Table 1). Participants had been receiving biologic monotherapy for at least 24 weeks prior to enrollment, most commonly ustekinumab (32.0% [8/25])(Table 1). None had achieved the NPF TTT status with their biologics. At baseline, mean (SD) affected BSA, PGA, BSA×PGA, and participant-reported DLQI were 4.16% (2.04%), 2.84 (0.55), 11.88 (6.39), and 4.00 (4.74), respectively.

Efficacy Assessment—Application of HP-TAZ lotion in addition to the participants’ existing biologic therapy reduced severity of the disease, as evidenced by the reductions in mean BSA, PGA, and BSA×PGA. After 8 weeks of once-daily concomitant HP-TAZ use with biologic, mean BSA and PGA dropped by approximately 40% and 37%, respectively (Figures 1A and 1B). A greater reduction (54%) was found for mean BSA×PGA (Figure 1C). Disease severity continued to improve when the application schedule for HP-TAZ was changed to once every other day for 4 weeks, as mean BSA, PGA, and BSA×PGA decreased further at week 12. These beneficial effects were sustained during the last 4 weeks of the study after HP-TAZ was discontinued, with reductions of 57%, 43%, and 70% from baseline for mean BSA, PGA, and BSA×PGA, respectively (Figure 1).

The proportion of participants who achieved NPF TTT status increased from 0% at baseline to 20.0% (5/20) at week 8 with once-daily use of HP-TAZ plus biologic for 8 weeks (Figure 2). At week 12, more participants (64.7% [11/17]) achieved the treatment goal after application of HP-TAZ once every other day with biologic for 4 weeks. Most participants maintained NPF TTT status after HP-TAZ was discontinued; at week 16, 50.0% (9/18) attained the NPF treatment goal (Figure 2).

The mean DLQI score decreased from 4.00 at baseline to 2.45 after 8 weeks of concomitant use of once-daily HP-TAZ with biologic, reflecting a 39% score reduction. An additional 4 weeks of adjunctive HP-TAZ applied once every other day with biologic further decreased the DLQI score to 2.18 at week 12. Mean DLQI remained similar (2.33) after another 4 weeks of biologics alone. The proportion of participants reporting a DLQI score of 0 to 1 increased from 40% (10/25) at baseline to 60% (12/20) at week 8 and 76.5% (13/17) at week 12 with adjunctive HP-TAZ lotion use with biologic. At week 16, a DLQI score of 0 to 1 was reported in 61.1% (11/18) of participants after receiving only biologics for 4 weeks.

Safety Assessment—A total of 19 AEs were reported in 11 participants during the study; 16 AEs were considered treatment related in 8 participants (Table 2). The most common AEs were retinoid dermatitis (28% [7/25]), burning at the application site (8% [2/25]), and pruritus at the application site (8% [2/25]), all of which were considered related to the treatment. Among all AEs, 12 were mild in severity, and the remaining 7 were moderate. Adverse events led to early study termination in 4 participants, all with retinoid dermatitis as the primary reason.

Likelihood of Switching Biologics—At baseline, almost 90% (22/25) of participants were rated as likely to switch biologics by the investigator due to unacceptable responses to their currently prescribed biologics (BSA >3%)(Figure 3). The likelihood was greatly reduced by concomitant HP-TAZ, as the proportion of participants defined as nonresponders to their biologic decreased to 35% (7/20) with 8-week adjunctive application of once-daily HP-TAZ with biologic and further decreased to 23.5% (4/17) with another 4 weeks of adjunctive HP-TAZ applied every other day plus biologic. At week 16, after 4 weeks of biologics alone, the proportion was maintained at 33.3% (6/18).

Pharmacoeconomics of Adding Topical HP-TAZ vs Switching Biologics—In the participants whom the investigator reported as likely to switch biologics at baseline, 9 had improvements in disease control such that switching biologics was no longer considered necessary for them at week 16. Potential cost savings with adjunctive therapy of HP-TAZ plus biologic vs switching biologics were therefore evaluated in these 9 participants, who were receiving ustekinumab, adalimumab, guselkumab, ixekizumab, and secukinumab during the study (Table 3). The estimated total cost of 16-week maintenance dosing of biologics plus adjunct HP-TAZ lotion ranged from $14,675 (ustekinumab 45 mg) to $54,025 (secukinumab 300 mg), while switching to other most commonly prescribed biologics for 16 weeks would cost an estimated $33,340 to $106,400 (induction and subsequent maintenance phases)(Table 3). Most biologic plus HP-TAZ combinations were estimated to cost less than $30,000, potentially saving $4816 to $91,725 compared with switching to any of the other 7 biologics (Table 3). The relatively more expensive maintenance combination containing secukinumab plus HP-TAZ ($54,025) appeared to be a less expensive option when compared with switching to ustekinumab (90 mg)($83,097), ixekizumab (80 mg)($61,452), or risankizumab (150 mg)($57,030) as an alternative biologic.

Comment

Adjunctive Use of HP-TAZ Lotion—In the present study, we showed that adjunctive HP-TAZ lotion improved biologic treatment response and reduced disease severity in participants with moderate to severe psoriasis whose symptoms could not be adequately controlled by 24 weeks or more of biologic monotherapy in a real-world setting. Disease activity decreased as evidenced by reductions in all assessed effectiveness variables, including BSA involvement, PGA score, composite BSA×PGA score, and participant-reported DLQI score. Half of the participants achieved NPF TTT status at the end of the study. The treatment was well tolerated with no unexpected safety concerns. Compared with switching to a new biologic, adding topical HP-TAZ to ongoing biologics appeared to be a more cost-effective approach to enhance treatment effects. Our results suggest that adjunctive use of HP-TAZ lotion may be a safe, effective, and economical option for patients with psoriasis who are failing their ongoing biologic monotherapy.

Treat-to-Target Status—The NPF-recommended target response to a treatment for plaque psoriasis is BSA of 1% or lower at 3 months postinitiation.¹⁰ Patients in the current study had major psoriasis activity at study entry despite being treated with a biologic for at least 24 weeks, as none had attained NPF TTT status at baseline. Because the time period of prior biologic treatment (at least 24 weeks) is much longer than the 3 months suggested by NPF, we believe that we were observing a true failure of the biologic rather than a slow onset of treatment effects in these patients at the time of enrollment. By week 12, with the addition of HP-TAZ lotion to the biologic, a high rate of participants achieved NPF TTT status (64.7%), with most participants being able to maintain this TTT status at study end after 4 weeks of biologic alone. Most participants also reported no impact of psoriasis on their QOL (DLQI, 0–1¹⁶; 76.5%) at week 12. Improvements we found in disease control with adjunctive HP-TAZ lotion plus biologic support prior reports showing enhanced responses when a topical medication was added to a biologic.^17,18 Reductions in psoriasis activity after 8 weeks of combined biologics plus once-daily HP-TAZ also are consistent with 2 phase 3 RCTs in which a monotherapy of HP-TAZ lotion used once daily for 8 weeks reduced BSA and DLQI.¹⁵ Notably, in the current study, disease severity continued to decrease when dosing of HP-TAZ was reduced to once every other day for 4 weeks, and the improvements were maintained even after the adjunct topical therapy was discontinued.

Safety Profile of HP-TAZ Lotion—The overall safety profile in our study also was consistent with that previously reported for HP-TAZ lotion,^15,19-21 with no new safety signals observed. The combination treatment was well tolerated, with most reported AEs being mild in severity. Adverse events were mostly related to application-site reactions, the most common being dermatitis (28%), which was likely attributable to the TAZ component of the topical regimen.¹⁵

Likelihood of Switching Biologics—Reduced disease activity was reflected by a decrease in the percentage of participants the investigator considered likely to change biologics, which was 88.0% at baseline but only 33.3% at the end of the study. Although switching to a different biologic agent can improve treatment effect,²² it could lead to a substantial increase in health care costs and use of resources compared with no switch.⁵ We found that switching to one of the other most commonly prescribed biologics could incur $4816 to $91,725 in additional costs in most cases when compared with the combination strategy we evaluated over the 16-week treatment period. Therefore, concomitant use of HP-TAZ lotion with the ongoing biologics would be a potentially more economical alternative for patients to achieve acceptable responses or the NPF TTT goal. Moreover, combination with an adjunctive topical medication could avoid potential risks associated with switching, such as new AEs with new biologic regimens or disease flare during any washout period sometimes adopted for switching biologics.

Study Limitations—Our estimated costs were based on average wholesale prices and did not reflect net prices paid by patients or health plans due to the lack of known discount rates. Inherent to the nature of its design, the study also had a relatively small patient population and lacked control groups. Although lack of a control group may limit the conclusions of our study, our goal was to examine real-world patient experience, and the efficacy of HP-TAZ lotion as well as the baseline disease state for each participant using a biologic was well known. Statistical inference on the differences in efficacy between biologics with and without adjunctive HP-TAZ lotion, or between combination therapy and a new biologic monotherapy, was not possible. Additionally, a longer follow-up after discontinuation of HP-TAZ is needed to evaluate the long-term maintenance of responses. Nevertheless, the results here demonstrated that participants responded better when adjunctive HP-TAZ lotion was added to the ongoing biologics in a clinical practice setting.

Conclusion

In this real-world study, patients with psoriasis that failed to respond to biologic monotherapy had improved disease control and QOL and reported no new safety concerns with adjunctive use of HP-TAZ lotion. Adding HP-TAZ to the ongoing biologics could be a more cost-effective option vs switching biologics for patients whose psoriasis symptoms could not be controlled with biologic monotherapy. Taken together, our results support the use of HP-TAZ lotion as an effective and safe adjunctive topical therapy in combination with biologics for psoriasis treatment.

Acknowledgments—We acknowledge the medical writing assistance provided by Hui Zhang, PhD, and Kathleen Ohleth, PhD, from Precise Publications LLC (Far Hills, New Jersey), which was funded by Ortho Dermatologics.

Psoriasis is an inflammatory skin condition affecting 1% to 5% of the world population. ¹ Guttate psoriasis is a subgroup of psoriasis that most commonly presents as raindroplike, erythematous, silvery, scaly papules. There have been limited reports of guttate psoriasis caused by rhinovirus and COVID-19 infection, but a PubMed search of articles indexed for MEDLINE using the term COVID-19 guttate psoriasis yielded only 3 documented cases of a psoriatic flare secondary to SARS-CoV-2 infection. ^1-4 Herein, we detail a case in which a patient with mild SARS-CoV-2 infection who did not have a personal or family history of psoriasis experienced a moderate psoriatic flare 3 weeks after diagnosis of COVID-19.

Case Report

A 55-year-old woman was diagnosed with COVID-19 after SARS-CoV-2 RNA was detected from a nasopharyngeal swab. She reported moderate fatigue but no other symptoms. At the time of infection, she was not taking medications and reported neither a personal nor family history of psoriasis.

Three weeks after the COVID-19 diagnosis, she reported erythematous scaly papules only on the trunk and backs of the legs. Two months after the COVID-19 diagnosis, she was evaluated in our practice and diagnosed with guttate psoriasis. The patient refused biopsy. Physical examination revealed that the affected body surface area had increased to 5%; erythematous, silvery, scaly papules were found on the trunk, anterior and posterior legs, and lateral thighs (Figure). At the time of evaluation, she did not report joint pain or nail changes.

The patient was treated with triamcinolone acetonide cream 0.1% twice daily for 2 to 4 weeks. The guttate psoriasis resolved.

Comment

A sudden psoriatic flare can be linked to dysregulation of the innate immune response. Guttate psoriasis and generalized plaque-type psoriasis are postulated to have similar pathogenetic mechanisms, but guttate psoriasis is the only type of psoriasis that originates from viral infection. Initially, viral RNA will stimulate the toll-like receptor 3 protein, leading to increased production of the pathogenic cytokine IL-36γ and pathogenic chemokine CXCL8 (also known as IL-8), both of which are biomarkers for psoriasis.¹ Specifically, IL-36γ and CXCL8 are known to further stimulate the proinflammatory cascade during the innate immune response displayed in guttate psoriasis.^5,6

Our patient had a mild case of COVID-19, and she first reported the erythematous and scaly papules 3 weeks after infection. Dysregulation of proinflammatory cytokines must have started in the initial stages—within 7 days—of the viral infection. Guttate psoriasis arises within 3 weeks of infection with other viral and bacterial triggers, most commonly with streptococcal infections.¹

Rodríguez et al⁷ described a phenomenon in which both SARS-CoV-2 and Middle East respiratory syndrome, both caused by a coronavirus, can lead to a reduction of type I interferon, which in turn leads to failure of control of viral replication during initial stages of a viral infection. This triggers an increase in proinflammatory cytokines and chemokines, including IL‐36γ and CXCL8. This pathologic mechanism might apply to SARS-CoV-2, as demonstrated in our patient’s sudden psoriatic flare 3 weeks after the COVID-19 diagnosis. However, further investigation and quantification of the putatively involved cytokines is necessary for confirmation.

Psoriasis, a chronic inflammatory skin condition, has been linked predominantly to genetic and environmental factors. Guttate psoriasis as a secondary reaction after streptococcal tonsillar and respiratory infections has been reported.¹

Our case is the fourth documented case of guttate psoriasis secondary to COVID-19 infection.^2-4 However, it is the second documented case of a patient with a diagnosis of guttate psoriasis secondary to COVID-19 infection who had neither a personal nor family history of psoriasis.

Because SARS-CoV-2 is a novel virus, the long-term effects of COVID-19 remain unclear. We report this case and its findings to introduce a novel clinical manifestation of SARS-CoV-2 infection. 

Psoriasis is an inflammatory skin condition affecting 1% to 5% of the world population. ¹ Guttate psoriasis is a subgroup of psoriasis that most commonly presents as raindroplike, erythematous, silvery, scaly papules. There have been limited reports of guttate psoriasis caused by rhinovirus and COVID-19 infection, but a PubMed search of articles indexed for MEDLINE using the term COVID-19 guttate psoriasis yielded only 3 documented cases of a psoriatic flare secondary to SARS-CoV-2 infection. ^1-4 Herein, we detail a case in which a patient with mild SARS-CoV-2 infection who did not have a personal or family history of psoriasis experienced a moderate psoriatic flare 3 weeks after diagnosis of COVID-19.

Case Report

A 55-year-old woman was diagnosed with COVID-19 after SARS-CoV-2 RNA was detected from a nasopharyngeal swab. She reported moderate fatigue but no other symptoms. At the time of infection, she was not taking medications and reported neither a personal nor family history of psoriasis.

Three weeks after the COVID-19 diagnosis, she reported erythematous scaly papules only on the trunk and backs of the legs. Two months after the COVID-19 diagnosis, she was evaluated in our practice and diagnosed with guttate psoriasis. The patient refused biopsy. Physical examination revealed that the affected body surface area had increased to 5%; erythematous, silvery, scaly papules were found on the trunk, anterior and posterior legs, and lateral thighs (Figure). At the time of evaluation, she did not report joint pain or nail changes.

The patient was treated with triamcinolone acetonide cream 0.1% twice daily for 2 to 4 weeks. The guttate psoriasis resolved.

Comment

A sudden psoriatic flare can be linked to dysregulation of the innate immune response. Guttate psoriasis and generalized plaque-type psoriasis are postulated to have similar pathogenetic mechanisms, but guttate psoriasis is the only type of psoriasis that originates from viral infection. Initially, viral RNA will stimulate the toll-like receptor 3 protein, leading to increased production of the pathogenic cytokine IL-36γ and pathogenic chemokine CXCL8 (also known as IL-8), both of which are biomarkers for psoriasis.¹ Specifically, IL-36γ and CXCL8 are known to further stimulate the proinflammatory cascade during the innate immune response displayed in guttate psoriasis.^5,6

Our patient had a mild case of COVID-19, and she first reported the erythematous and scaly papules 3 weeks after infection. Dysregulation of proinflammatory cytokines must have started in the initial stages—within 7 days—of the viral infection. Guttate psoriasis arises within 3 weeks of infection with other viral and bacterial triggers, most commonly with streptococcal infections.¹

Rodríguez et al⁷ described a phenomenon in which both SARS-CoV-2 and Middle East respiratory syndrome, both caused by a coronavirus, can lead to a reduction of type I interferon, which in turn leads to failure of control of viral replication during initial stages of a viral infection. This triggers an increase in proinflammatory cytokines and chemokines, including IL‐36γ and CXCL8. This pathologic mechanism might apply to SARS-CoV-2, as demonstrated in our patient’s sudden psoriatic flare 3 weeks after the COVID-19 diagnosis. However, further investigation and quantification of the putatively involved cytokines is necessary for confirmation.

Psoriasis, a chronic inflammatory skin condition, has been linked predominantly to genetic and environmental factors. Guttate psoriasis as a secondary reaction after streptococcal tonsillar and respiratory infections has been reported.¹

Our case is the fourth documented case of guttate psoriasis secondary to COVID-19 infection.^2-4 However, it is the second documented case of a patient with a diagnosis of guttate psoriasis secondary to COVID-19 infection who had neither a personal nor family history of psoriasis.

Because SARS-CoV-2 is a novel virus, the long-term effects of COVID-19 remain unclear. We report this case and its findings to introduce a novel clinical manifestation of SARS-CoV-2 infection. 

Psoriasis is an inflammatory skin condition affecting 1% to 5% of the world population. ¹ Guttate psoriasis is a subgroup of psoriasis that most commonly presents as raindroplike, erythematous, silvery, scaly papules. There have been limited reports of guttate psoriasis caused by rhinovirus and COVID-19 infection, but a PubMed search of articles indexed for MEDLINE using the term COVID-19 guttate psoriasis yielded only 3 documented cases of a psoriatic flare secondary to SARS-CoV-2 infection. ^1-4 Herein, we detail a case in which a patient with mild SARS-CoV-2 infection who did not have a personal or family history of psoriasis experienced a moderate psoriatic flare 3 weeks after diagnosis of COVID-19.

Case Report

A 55-year-old woman was diagnosed with COVID-19 after SARS-CoV-2 RNA was detected from a nasopharyngeal swab. She reported moderate fatigue but no other symptoms. At the time of infection, she was not taking medications and reported neither a personal nor family history of psoriasis.

Three weeks after the COVID-19 diagnosis, she reported erythematous scaly papules only on the trunk and backs of the legs. Two months after the COVID-19 diagnosis, she was evaluated in our practice and diagnosed with guttate psoriasis. The patient refused biopsy. Physical examination revealed that the affected body surface area had increased to 5%; erythematous, silvery, scaly papules were found on the trunk, anterior and posterior legs, and lateral thighs (Figure). At the time of evaluation, she did not report joint pain or nail changes.

The patient was treated with triamcinolone acetonide cream 0.1% twice daily for 2 to 4 weeks. The guttate psoriasis resolved.

Comment

A sudden psoriatic flare can be linked to dysregulation of the innate immune response. Guttate psoriasis and generalized plaque-type psoriasis are postulated to have similar pathogenetic mechanisms, but guttate psoriasis is the only type of psoriasis that originates from viral infection. Initially, viral RNA will stimulate the toll-like receptor 3 protein, leading to increased production of the pathogenic cytokine IL-36γ and pathogenic chemokine CXCL8 (also known as IL-8), both of which are biomarkers for psoriasis.¹ Specifically, IL-36γ and CXCL8 are known to further stimulate the proinflammatory cascade during the innate immune response displayed in guttate psoriasis.^5,6

Our patient had a mild case of COVID-19, and she first reported the erythematous and scaly papules 3 weeks after infection. Dysregulation of proinflammatory cytokines must have started in the initial stages—within 7 days—of the viral infection. Guttate psoriasis arises within 3 weeks of infection with other viral and bacterial triggers, most commonly with streptococcal infections.¹

Rodríguez et al⁷ described a phenomenon in which both SARS-CoV-2 and Middle East respiratory syndrome, both caused by a coronavirus, can lead to a reduction of type I interferon, which in turn leads to failure of control of viral replication during initial stages of a viral infection. This triggers an increase in proinflammatory cytokines and chemokines, including IL‐36γ and CXCL8. This pathologic mechanism might apply to SARS-CoV-2, as demonstrated in our patient’s sudden psoriatic flare 3 weeks after the COVID-19 diagnosis. However, further investigation and quantification of the putatively involved cytokines is necessary for confirmation.

Psoriasis, a chronic inflammatory skin condition, has been linked predominantly to genetic and environmental factors. Guttate psoriasis as a secondary reaction after streptococcal tonsillar and respiratory infections has been reported.¹

Our case is the fourth documented case of guttate psoriasis secondary to COVID-19 infection.^2-4 However, it is the second documented case of a patient with a diagnosis of guttate psoriasis secondary to COVID-19 infection who had neither a personal nor family history of psoriasis.

Because SARS-CoV-2 is a novel virus, the long-term effects of COVID-19 remain unclear. We report this case and its findings to introduce a novel clinical manifestation of SARS-CoV-2 infection.