SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

SAN DIEGO – If a medical professional is trying to figure out the best medical treatment for a pregnant woman with headache, it may be helpful to review data from randomized clinical trials (RCTs). Well, make that data from the RCT. There’s just been one, Northwestern Medicine obstetrician-gynecologist Catherine Stika, MD, told colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

Only a single efficacy RCT has examined headache in pregnancy, said Dr. Stika. “Overall, we have very limited data in pregnancy to tell us exactly what to do,” she added.

But ob.gyns. aren’t entirely in the dark, according to medical specialists who spoke at the session. Expert opinion and fetal safety data offer insight into the best treatments, as does a new ACOG clinical practice guideline on headaches during pregnancy and post partum that was coauthored by the speakers.

And there’s some good news: Pregnancy itself is often a good treatment for headaches.

Pregnant women often find relief from one kind of headache – migraine – as their estradiol levels rise, said Laura Mercer, MD, an ob.gyn. at the University of Arizona, Phoenix. “About half of patients will report that migraines are getting better as early as the first trimester, and upwards of 83% will say that their migraines are better by the time they’re in their third trimester,” she said. “What this means for us as obstetricians is that oftentimes we can actually discontinue preventative therapies for patients during pregnancy.”

But simply discontinuing every headache treatment during pregnancy may not be the right approach, Dr. Mercer said. Instead, she said, consider the benefits and risks.

Divalproex sodium (Depakote) and topiramate (Topamax) must be avoided because of fetal risk, she said. “In fact, we will prefer that people stop these medications before they discontinue their contraception if they’re planning on getting pregnant,” she said.

Other medications, such as ACE inhibitors and the herbal remedy feverfew, should not be used at any time during pregnancy, she said.

On the other hand, calcium channel blockers and antihistamines are alright to use in pregnancy, she said. “These two should be considered first-line because there’s no known risks for them.”

Beta-blockers also may be used “with some consideration to the known risks that we’re familiar with when we use them for other indications,” she said.

There are questions about the safety of oral magnesium in pregnancy, although it’s generally considered safe, she added, and “nerve blocks and nerve stimulators seem very promising and have little known risks.”

Dr. Mercer recommended gradually tapering most medications prior to conception. But it’s crucial to stop higher-risk drugs immediately once pregnancy is confirmed, she said.

In regard to acute headache, Dr. Stika urged caution if a patient reports taking a headache medication more than twice a week. “All the medications we use for the treatment of migraine, both in and outside of pregnancy, carry the risk of what’s called medication overuse” that can lead to rebound headaches, she said.

Excedrin Tension Headache may be used for headaches in pregnancy, she said, but not Excedrin Migraine since it includes aspirin. Triptans are not recommended as first-line therapy, she added, and they “should absolutely not be used in any pregnant patient with a history of known cardiac disease or hypertension.”

Dr. Stika added that ACOG advises against the use of drugs that contain butalbital, a barbiturate that’s combined with other agents to treat headache. “Butalbital is the drug that’s most closely associated with getting people into this medication overuse headache,” she said. “It’s even worse than opioids.”

Unlike multiple other countries and the entire European Union, the United States has not banned compounds that contain butalbital, she said.

In some cases, she said, patients may present to triage with vomiting, an inability to keep food down, and persistent headache despite treatment. “This is a really classic presentation.”

The ACOG clinical practice guideline offers a flow chart about what to do, she said. Hydration is key, she said, and various treatment options can help. A referral to neurology may be needed in extreme cases, she said. But “most of the time, you’re able to get rid of her headache.”

Dr. Mercer and Dr. Stika report no disclosures.

Bronchoscopic lung volume reduction significantly increased survival in patients with severe chronic obstructive pulmonary disease, based on data from more than 1,400 individuals.

Previous studies have shown that patients with severe chronic obstructive pulmonary disease (COPD) can benefit from treatment with bronchoscopic lung volume reduction (BLVR) involving lung volume reduction coils or endobronchial valves (EBVs) in terms of improved pulmonary function, lung volume, exercise capacity, and quality of life.

However, data on the impact of the procedure on patient survival are limited, and most previous studies have been small, wrote Jorine E. Hartman, MD, of the University of Groningen, the Netherlands, and colleagues.

In a study published in Respiratory Medicine, the researchers reviewed data from 1,471 patients with severe COPD who had consultations for BLVR at a single center between June 2006 and July 2019. Of these, 483 (33%) underwent a BLVR treatment.

The follow-up period ranged from 633 days to 5,401 days. During this time, 531 patients died (35%); 165 of these (34%) were in the BLVR group.

Overall, the median survival of BLVR patients was significantly longer, compared with those who did not have the procedure, for a difference of approximately 1.7 years (3,133 days vs. 2,503 days, P < .001). No significant differences in survival were noted in BLVR patients treated with coils or EBVs.

The average age of the study population at baseline was 61 years, and 63% were women. Overall, patients treated with BLVR were more likely to be younger and female, with fewer COPD exacerbations but worse pulmonary function, as well as lower body mass index and more evidence of emphysema than the untreated patients, the researchers noted. Patients treated with BLVR also were more likely than untreated patients to have a history of myocardial infarction, percutaneous coronary intervention, or stroke.

However, BLVR was a significant independent predictor of survival after controlling for multiple variables, including age, sex, and disease severity, the researchers noted.

The current study supports existing literature on the value of BLVR for severe COPD but stands out from previous studies by comparing patients who underwent BLVR with those who did not, the researchers noted in their discussion of the findings.

The study findings were limited by several factors, including the fact that the non-treated patients were not eligible for treatment for various reasons that might have impacted survival, the researchers noted. Another limitation was the lack of data on cause of death and other medical events and treatments during the follow-up period, they said.

However, the results were strengthened by the large sample size and long-term follow-up and suggest that “reducing lung volume in patients with COPD and severe hyperinflation and reduced life expectancy may lead to a survival benefit,” they concluded.

The study received no outside funding. Dr. Hartman had no financial conflicts to disclose.

Bronchoscopic lung volume reduction significantly increased survival in patients with severe chronic obstructive pulmonary disease, based on data from more than 1,400 individuals.

Previous studies have shown that patients with severe chronic obstructive pulmonary disease (COPD) can benefit from treatment with bronchoscopic lung volume reduction (BLVR) involving lung volume reduction coils or endobronchial valves (EBVs) in terms of improved pulmonary function, lung volume, exercise capacity, and quality of life.

However, data on the impact of the procedure on patient survival are limited, and most previous studies have been small, wrote Jorine E. Hartman, MD, of the University of Groningen, the Netherlands, and colleagues.

In a study published in Respiratory Medicine, the researchers reviewed data from 1,471 patients with severe COPD who had consultations for BLVR at a single center between June 2006 and July 2019. Of these, 483 (33%) underwent a BLVR treatment.

The follow-up period ranged from 633 days to 5,401 days. During this time, 531 patients died (35%); 165 of these (34%) were in the BLVR group.

Overall, the median survival of BLVR patients was significantly longer, compared with those who did not have the procedure, for a difference of approximately 1.7 years (3,133 days vs. 2,503 days, P < .001). No significant differences in survival were noted in BLVR patients treated with coils or EBVs.

The average age of the study population at baseline was 61 years, and 63% were women. Overall, patients treated with BLVR were more likely to be younger and female, with fewer COPD exacerbations but worse pulmonary function, as well as lower body mass index and more evidence of emphysema than the untreated patients, the researchers noted. Patients treated with BLVR also were more likely than untreated patients to have a history of myocardial infarction, percutaneous coronary intervention, or stroke.

However, BLVR was a significant independent predictor of survival after controlling for multiple variables, including age, sex, and disease severity, the researchers noted.

The current study supports existing literature on the value of BLVR for severe COPD but stands out from previous studies by comparing patients who underwent BLVR with those who did not, the researchers noted in their discussion of the findings.

The study findings were limited by several factors, including the fact that the non-treated patients were not eligible for treatment for various reasons that might have impacted survival, the researchers noted. Another limitation was the lack of data on cause of death and other medical events and treatments during the follow-up period, they said.

However, the results were strengthened by the large sample size and long-term follow-up and suggest that “reducing lung volume in patients with COPD and severe hyperinflation and reduced life expectancy may lead to a survival benefit,” they concluded.

The study received no outside funding. Dr. Hartman had no financial conflicts to disclose.

Bronchoscopic lung volume reduction significantly increased survival in patients with severe chronic obstructive pulmonary disease, based on data from more than 1,400 individuals.

Previous studies have shown that patients with severe chronic obstructive pulmonary disease (COPD) can benefit from treatment with bronchoscopic lung volume reduction (BLVR) involving lung volume reduction coils or endobronchial valves (EBVs) in terms of improved pulmonary function, lung volume, exercise capacity, and quality of life.

However, data on the impact of the procedure on patient survival are limited, and most previous studies have been small, wrote Jorine E. Hartman, MD, of the University of Groningen, the Netherlands, and colleagues.

In a study published in Respiratory Medicine, the researchers reviewed data from 1,471 patients with severe COPD who had consultations for BLVR at a single center between June 2006 and July 2019. Of these, 483 (33%) underwent a BLVR treatment.

The follow-up period ranged from 633 days to 5,401 days. During this time, 531 patients died (35%); 165 of these (34%) were in the BLVR group.

Overall, the median survival of BLVR patients was significantly longer, compared with those who did not have the procedure, for a difference of approximately 1.7 years (3,133 days vs. 2,503 days, P < .001). No significant differences in survival were noted in BLVR patients treated with coils or EBVs.

The average age of the study population at baseline was 61 years, and 63% were women. Overall, patients treated with BLVR were more likely to be younger and female, with fewer COPD exacerbations but worse pulmonary function, as well as lower body mass index and more evidence of emphysema than the untreated patients, the researchers noted. Patients treated with BLVR also were more likely than untreated patients to have a history of myocardial infarction, percutaneous coronary intervention, or stroke.

However, BLVR was a significant independent predictor of survival after controlling for multiple variables, including age, sex, and disease severity, the researchers noted.

The current study supports existing literature on the value of BLVR for severe COPD but stands out from previous studies by comparing patients who underwent BLVR with those who did not, the researchers noted in their discussion of the findings.

The study findings were limited by several factors, including the fact that the non-treated patients were not eligible for treatment for various reasons that might have impacted survival, the researchers noted. Another limitation was the lack of data on cause of death and other medical events and treatments during the follow-up period, they said.

However, the results were strengthened by the large sample size and long-term follow-up and suggest that “reducing lung volume in patients with COPD and severe hyperinflation and reduced life expectancy may lead to a survival benefit,” they concluded.

The study received no outside funding. Dr. Hartman had no financial conflicts to disclose.

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; [email protected]

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; [email protected]

Advances in Alzheimer disease (AD) genes and biomarkers now allow older adults to undergo testing and learn about their risk for AD.¹ Current routes for doing so include testing in cardiology, screening for enrollment in secondary prevention trials (which use these tests to determine trial eligibility),² and direct-to-consumer (DTC) services that provide these results as part of large panels.³ Patients may also obtain apolipoprotein (APOE) genotype information as part of an assessment of the risks and benefits of treatment with aducanumab (Aduhelm) or other anti-amyloid therapies that have been developed to stop or slow the progression of AD pathologies.

Expanded access to testing, in combination with limited guidance from DTC companies, suggests more older adults may consult their primary care physicians about this testing. In this narrative review, we use a vignette-driven approach to summarize the current scientific knowledge of the topic and to offer guidance on provider-patient discussions and follow-up.

First, a look at APOE genotyping

In cognitively unimpaired older adults, the APOE gene is a known risk factor for mild cognitive impairment (MCI) or AD.³ A person has 2 alleles of the APOE gene, which has 3 variants: ε2, ε3, and ε4. The combination of alleles conveys varying levels of risk for developing clinical symptoms (TABLE 1⁴), with ε4 increasing risk and ε2 decreasing risk compared to the more common ε3; thus the ε4/ε4 genotype conveys the most risk and the ε2/ε2 the least.

The APOE gene differs from other genes that have been identified in early-onset familial AD. These other genes, which include APP, PSEN1, and PSEN2, are deterministic genes that are fully penetrant. The APOE gene is not deterministic, meaning there is no combination of APOE alleles that are necessary or sufficient to cause late-onset AD dementia.

In clinical trials of amyloid-modifying therapies, the APOE gene has been shown to convey a risk of amyloid-related imaging abnormalities (ARIA).⁵ That is, in addition to conveying a risk for AD, the gene also conveys a risk for adverse effects of emerging treatments that can result in serious injury or death. This includes the drug aducanumab that was recently approved by the US Food and Drug Administration (FDA).⁶ In this review, we focus primarily on common clinical scenarios related to APOE. However, in light of the recent controversy over aducanumab and whether the drug should be offered to patients,^7-9 we also describe how a patient’s APOE genotype may factor into drug candidacy decisions.

Testing, in clinic and “at home.” To date, practice guidelines have consistently recommended against APOE genetic testing in routine clinical practice. This is primarily due to low clinical prognostic utility and the lack of actionable results. Furthermore, no lifestyle or pharmaceutical interventions based on APOE genotype currently exist (although trials are underway¹⁰).

In 2017, the FDA approved marketing of DTC testing for the APOE gene.¹¹ While DTC companies tend to issue standardized test result reports, the content and quality can vary widely. In fact, some provide risk estimates that are too high and too definitive and may not reflect the most recent science.¹²

Continue to: 7 clinical scenarios and how to approach them

7 clinical scenarios and how to approach them

Six of the following vignettes describe common clinical scenarios in which patients seek medical advice regarding APOE test results. The seventh vignette describes a patient whose APOE genotype may play a role in possible disease-modifying treatments down the road. Each vignette is designed to guide your approach to patient discussions and follow-up. Recommendations and considerations are also summarized in TABLE 2^13-16.

Vignette 1

Janet W, age 65, comes to the clinic for a new patient visit. She has no concerns about her memory but recently purchased DTC genetic testing to learn about her genetic health risks. Her results showed an APOE ε4/ε4 genotype. She is now concerned about developing AD. Her mother was diagnosed with AD in her 70s.

Several important pieces of information can be conveyed by the primary care physician. First, patients such as Ms. W should be told that the APOE gene is not deterministic; many people, even those with 2 ε4 alleles, never develop dementia. Second, no specific preventive measures or treatments exist based on an individual’s APOE genotype (see Vignette 5 for additional discussion).

In this scenario, patients may ask for numeric quantification of their risk for dementia (see TABLE 1⁴ for estimates). When conveying probabilistic risk, consider using simple percentages or pictographs (eg, out of 100 individuals with an ε4/ε4 genotype, 30 to 55 develop MCI or AD). Additionally, because people tend to exhibit confirmatory bias in thinking about probabilistic risk, providing opposing interpretations of an estimate may help them to consider alternative possibilities.¹⁷ For example, ε4/ε4 individuals have a 30% to 55% risk for MCI or AD. Alternatively, they have a 45% to 70% risk of not developing MCI or AD.

There are important caveats to the interpretation of APOE risk estimates. Because APOE risk estimates are probabilistic and averaged across a broader spectrum of people in large population cohorts,⁴ estimates may not accurately reflect a given individual’s risk. The ranges reflect the uncertainty in the estimates. The uncertainty arises from relatively small samples, the rareness of some genotypes (notably ε4/ε4) even in large samples, and variations in methods and sampling that can lead to differences in estimates beyond statistical variation.

Vignette 2

Eric J, age 85, presents for a new patient visit accompanied by his daughter. He lives independently, volunteers at a senior center several times a week, and exercises regularly, and neither he nor his daughter has any concerns about his memory. As a gift, he recently underwent DTC genetic testing and unexpectedly learned his APOE result, which is ε4/ε4. He wants to know about his chances of developing AD.

Risk conveyed by APOE genotype can be modified by a patient’s age. At age 85, Mr. J is healthy, highly functional, and cognitively unimpaired. Given his age, Mr. J has likely “outlived” much of the risk for dementia attributable to the ε4/ε4 genotype. His risk for dementia remains high, but this risk is likely driven more by age than by his APOE genotype. Data for individuals older than age 80 are limited, and thus risk estimates lack precision. Given Mr. J’s good health and functional status, his physician may want to perform a brief cognitive screening test to serve as a baseline for future evaluations.

Continue to: Vignette 3

Vignette 3

Audrey S is a 60-year-old African American woman who comes to the clinic for her annual visit. Because her father had AD, she recently purchased DTC genetic testing to learn about her APOE genotype and risk for AD. Her results are ε3/ε4. She is wondering what this may mean for her future.

Lack of diversity in research cohorts often limits the generalizability of estimates. For example, both the frequency and impact of APOE ε4 differ across racial groups.¹⁸ But most of the data on APOE lifetime risk estimates are from largely White patient samples. While APOE ε4 seems to confer increased risk for AD across sociocultural groups, these effects may be attenuated in African American and Hispanic populations.^19,20 If Ms. S is interested in numeric risk estimates, the physician can provide the estimate for ε3/ε4 (20%-25% lifetime risk), with the important caveat that this estimate may not be reflective of her individual risk.

Both the frequency and impact of APOE ε4 differ across racial groups, but most of the data on APOE lifetime risk estimates are from largely White patient samples.

It may be prudent to determine whether Ms. S, at age 60, has subjective memory concerns and if she does, to perform a brief cognitive exam to serve as a baseline for future evaluations. Additionally, while the Genetic Information Nondiscrimination Act (GINA, 2008) prohibits health insurers and employers from discriminating based on genetic testing results, no legal provisions exist regarding long-term care, disability, or life insurance. Documented conversations about APOE test results in the medical record may become part of patients’ applications for these insurance products, and physicians should be cautious before documenting such discussions in the medical record.

Vignette 4

Tina L, age 60, comes to the clinic for a routine wellness visit. She recently developed an interest in genealogy and purchased a DNA testing kit to learn more about her family tree. As part of this testing, she unexpectedly learned that she has an APOE ε4/ε4 genotype. She describes feeling distraught and anxious about what the result means for her future.

Ms. L’s reaction to receiving unexpected genetic results highlights a concern of DTC APOE testing. Her experience is quite different from individuals undergoing medically recommended genetic testing or those who are participating in research studies. They receive comprehensive pre-test counseling by licensed genetic counselors. The counseling includes psychological assessment, education, and discussion of expectations.²

In Ms. L’s case, it may be helpful to explain the limits of APOE lifetime risk estimates (see Vignettes 1-3). But it’s also important to address her concerns. There are behavior scales that can aid the assessment and monitoring of an individual’s well-being. The Impact of Genetic Testing for Alzheimer’s Disease (IGT-AD) scale is a tool that assesses psychological impact. It can help physicians to identify, monitor, and address concerns.²¹ Other useful tools include the Patient Health Questionnaire-9 (PHQ-9) and the Geriatric Depression Scale (GDS) for depression, and a suicide or self-harm assessment.^2,22,23 Finally, a follow-up visit at 2 to 4 weeks may be useful to reassess psychological well-being.

Vignette 4 (cont’d)

Ms. L returns to the clinic 2 weeks later, reporting continued anxiety about her APOE test result and feelings of hopelessness and despair.

Continue to: Some patients struggle...

Some patients struggle with knowing their APOE test result. Test result–related distress is often a combination of depression (as with Ms. L), anger, confusion, and grief.²⁴ Cognitions often include worries about uncertainty, stereotyped threat, and internalized stigma.^25,26 These issues can spill over to patient concerns about sharing an APOE test result with others.²⁷

Intolerance of uncertainty is a transdiagnostic risk factor that can influence psychological suffering.²⁸ Brief cognitive behavioral interventions that reinforce routines and encourage healthy and mindful practices may help alleviate patient distress from unexpected genetic test results.²⁹ Interventions that personalize and validate an individual’s experience can help address internalized stigma.³⁰ Referral to a psychologist or psychiatrist could be warranted. Additionally, referral to a genetic counselor may help provide patients with access to added expertise and guidance; useful web-based resources for identifying an appropriate referral include https://medlineplus.gov/genetics/­understanding/consult/findingprofessional/ and https://findageneticcounselor.nsgc.org/.

Vignette 5

Bob K, age 65, comes to the clinic for his annual exam. He is a current smoker and says he’s hoping to be more physically active now that he is retired. He says that his mother and grandmother both had AD. He recently purchased DTC genetic testing to learn more about his risk for AD. His learned his APOE genotype is ε3/ε4 and is wondering what he can do to decrease his chances of developing AD.

Mr. K likely would have benefited from pre-test counseling regarding the lack of current therapies to modify one’s genetic risk for AD. A pre-test counseling session often includes education about APOE testing and a brief evaluation to assess psychological readiness to undergo testing. Posttest educational information may help Mr. K avoid predatory advertising of products claiming—without scientific evidence—to modify risk for cognitive decline or to improve cognitive function.

Emerging evidence from RCTs suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.

There are several important pieces of information that should be communicated to Mr. K. Emerging evidence from randomized controlled trials suggests that healthy lifestyle modifications may benefit cognition in individuals with APOE ε4 alleles.³¹ It would be prudent to address proper blood pressure control³² and counsel Mr. K on how he may be able to avoid diabetes through exercise and weight maintenance. Lifestyle recommendations for Mr. K could include: smoking cessation, regular aerobic exercise (eg, 150 min/wk), and a brain-healthy diet (eg, the Mediterranean-DASH Intervention for Neurodegenerative Delay [MIND] diet).^13,14 Moreover, dementia prevention also includes appropriately managing depression and chronic illnesses and preventing social isolation and hearing loss.^15,16 This information should be thoughtfully conveyed, as these interventions can improve overall (especially cardiovascular) health, as well as mitigating one’s personal risk for AD.

Vignette 6

Juan L, age 45, comes in for his annual physical exam. He has a strong family history of heart disease. His cardiologist recently ordered lipid disorder genetic testing for familial hypercholesterolemia. This panel included APOE testing and showed Mr. L’s genotype is ε2/ε4. He read that the APOE gene can be associated with an increased AD risk and asks for information about his genotype.

Mr. L received genetic testing results that were ordered by a physician for another health purpose. Current recommendations for genetic testing in cardiology advise pre-test genetic counseling.³³ But this counseling may not include discussion of the relationship of APOE and risk for MCI or AD. This additional information may be unexpected for Mr. L. Moreover, its significance in the context of his present concerns about cardiovascular disease may influence his reaction.

Continue to: The ε2/ε4 genotype...

The ε2/ε4 genotype is rare. One study showed that in healthy adults, the frequency was 7 in 210 (0.02 [0.01-0.04]).³⁴ Given the rarity of the ε2/ε4 genotype, data about it are sparse. However, since the ε4 allele increases risk but the ε2 allele decreases risk, it is likely that any increase in risk is more modest than with ε3/ε4. In addition, it would help Mr. L to know that AD occurs infrequently before age 60.³⁵ Given his relatively young age, he is unlikely to develop AD any time in the near future. In addition, particularly if he starts early, he might be able to mitigate any increased risk through some of the advice provided to Mr. K in Vignette 5.

Vignette 7

Joe J, age 65, comes to the clinic for a new patient visit. He has no concerns about his memory but has a family history of dementia and recently purchased DTC genetic testing to learn about his genetic health risks. His results showed an APOE ε4/ε4 genotype. He is concerned about developing AD. He heard on the news that there is a drug that can treat AD and wants to know if he is a candidate for this treatment.

Mr. J would benefit from the education provided to Ms. W in Vignette 1. Patients such as Mr. J should be advised that while an APOE ε4/ε4 genotype conveys an increased risk for AD, it is not deterministic of the disease. While there are no specific preventive measures or treatments based on APOE genotype, careful medical care and lifestyle factors can offset some of the risk (see Vignette 5 for discussion).

One reason for the aducanumab controversy is that the drug has potenially severe adverse effects.

Recently (and controversially), the FDA approved aducanumab, a drug that targets amyloid.^6,36 Of note, brain amyloid is more common in individuals with the APOE ε4/ε4 genotype, such as Mr. J. However, there would be no point in testing Mr. J for brain amyloid because at present the drug is only indicated in symptomatic individuals—and, even in this setting, it is controversial. One reason for the controversy is that aducanumab has potentially severe adverse effects. Patients with the ε4/ε4 genotype should know that this genotype carries increased risk for the most serious adverse event, ARIA—which can include brain edema and microhemorrhages.

What lies ahead?

More research is needed to explore the impact that greater AD gene and biomarker testing will have on the health system and workforce development. In addition, graduate schools and training programs will need to prepare clinicians to address probabilistic risk estimates for common diseases, such as AD. Finally, health systems and medical groups that employ clinicians may want to offer simulated training—similar to the vignettes in this article—as a practice requirement or as continuing medical education. This may also allow health systems or medical groups to put in place frameworks that support clinicians in proactively answering questions for patients and families about APOE and other emerging markers of disease risk.

CORRESPONDENCE
Shana Stites, University of Pennsylvania, 3615 Chestnut Street, Philadelphia, PA 19104; [email protected]

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.

Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.

1995 Indian stamp; photo in public domain

Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.

Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
 

‘Yella,’ folic acid, and a paradigm shift

No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”

As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)

Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.

In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.

Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.

By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
 

Discoveries pile up, but credit and fame prove elusive

Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”

Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”

Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)

Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
 

Rise of methotrexate and fall of leukemia

In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.

Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.

Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.

Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
 

Death takes the doctor, but his legacy remains

In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”

It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”

Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”

During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
 

A career cut short, and a lasting legacy

In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.

Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.

Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.

Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”

By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.

In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.

Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.

Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.

“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”

Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”

In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”

“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”

The research was published online in Gastroenterology.
 

Looking at the big picture of PPIs in people with cirrhosis

The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.

However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.

To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.

They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.

In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).

Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.

Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.

Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.

However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).

Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).

The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
 

Large study suggests limited protective PPI indication

Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.

“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.

“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”

“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.

Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”

In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”

Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.

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

In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.

Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.

Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.

“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”

Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”

In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”

“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”

The research was published online in Gastroenterology.
 

Looking at the big picture of PPIs in people with cirrhosis

The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.

However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.

To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.

They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.

In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).

Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.

Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.

Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.

However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).

Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).

The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
 

Large study suggests limited protective PPI indication

Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.

“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.

“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”

“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.

Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”

In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”

Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.

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

In a retrospective study to evaluate the impact of proton pump inhibitors (PPIs) on all-cause mortality in patients with cirrhosis, researchers found reduced mortality only in those hospitalized for gastrointestinal bleeding. They reported increased liver-related mortality associated with PPIs in all other patients with cirrhosis.

Patients on PPIs had an 18% reduction in all-cause mortality versus other patients if they had gastrointestinal bleeding. But in those without bleeding, PPIs were associated with a 23% increase in liver-related mortality.

Further analysis suggested that the mortality increase could be related to a 21% increased risk for severe infection with PPI exposure in patients with cirrhosis, as well as a 64% increased risk for decompensation.

“My takeaway from this study is that there should be a nuanced understanding of PPIs and cirrhosis,” corresponding author Nadim Mahmud, MD, MS, University of Pennsylvania, Philadelphia, said in an interview, adding that, if they are to be used in this setting, there should be “a very compelling indication.”

Based on the new analysis, Dr. Mahmud explained, in a patient with cirrhosis hospitalized with a potentially ulcer-related upper gastrointestinal bleed, “we shouldn’t be afraid” to use PPIs “out of fear of potential infection or decompensation because our data demonstrate pretty strongly that that sort of patient may have a mortality benefit.”

In contrast, patients with cirrhosis and “vague abdominal discomfort” are often started on a PPI “just to see if that helps,” Dr. Mahmud said, and they may stay on the medication “in perpetuity, just because they’re so ubiquitously prescribed.”

“In that patient, we should recognize that there is a potential risk of increased infection and decompensation,” he said. There “should be an active effort to deprescribe the PPI or at the very least reduce it to the minimum dose needed for efficacy, if it’s treating a symptom.”

The research was published online in Gastroenterology.
 

Looking at the big picture of PPIs in people with cirrhosis

The authors noted that the half-life of PPIs is “prolonged in patients with cirrhosis” and that alterations in the gastrointestinal microbiota as a result of gastric acid suppression “may allow for bacterial overgrowth and translocation,” thus increasing the risk for infections.

However, studies of the impact of PPIs on adverse outcomes in patients with cirrhosis have often been hampered by numerous limitations, such as small sample sizes, a “limited ability to control for complex confounding,” or a “narrow focus” on hospitalized patients.

To overcome these problems, the team retrospectively examined data from the Veterans Outcomes and Costs Associated with Liver Diseases cohort, including all adults with incident cirrhosis between January 2008 and June 2021.

They excluded patients with Fibrosis-4 scores less than 1.45 at baseline, as well as those with prior liver transplantation, decompensated cirrhosis at baseline, a diagnosis of hepatocellular carcinoma within 6 months of the index date, and less than 6 months of follow-up.

In all, 76,251 patients with incident cirrhosis met the inclusion criteria, 21% of whom were on a PPI at baseline. The most commonly used PPIs were omeprazole (76.7%), followed by pantoprazole (22.2%) and lansoprazole (0.1%).

Those taking the drugs were more likely than other patients to be White, have metabolic and cardiovascular comorbidities, have a higher median body mass index, and were more likely to have cirrhosis because of alcohol-related liver disease or metabolic-associated fatty liver disease.

Over 49 months of follow-up, all-cause mortality was recorded for 37.5% of patients, of whom 59% experienced non–liver-related death and 41% liver-related mortality.

Multivariate analysis revealed that PPI exposure was not associated with all-cause mortality overall but was significantly associated with reduced all-cause mortality in patients with hospitalization for gastrointestinal bleeding, at a hazard ratio of 0.88.

However, PPI exposure in patients without gastrointestinal bleeding was associated with an increased risk for liver-related mortality (HR, 1.23), but a reduced risk for non–liver-related mortality (HR, 0.88).

Dr. Mahmud and colleagues found that PPI exposure was significantly associated with severe infection (HR, 1.21) and cirrhosis decompensation (HR, 1.64).

The authors suggested that these increased risks “may mediate the observed increased in liver-related mortality.”
 

Large study suggests limited protective PPI indication

Nancy S. Reau, MD, chair of hepatology at Rush Medical College, Chicago, said that “multiple studies” point to a link between PPI exposure and infection in cirrhosis.

“Although this is a retrospective study, it is very large so we should give credit to the associations,” she said in an interview. She was not involved with the current study.

“The most important message is that we need to be judicious with our therapy,” Dr. Reau added, qualifying that “everything is a risk-benefit ratio.”

“PPI use in cirrhosis has a role but should not overstep its boundary,” she explained. “More simply, if the PPI is indicated, you should not avoid it in a patient with cirrhosis. On the other hand, if you have a patient with advanced liver disease who is chronically taking a PPI, you should question its indication.

Paul Martin, MD, chief of the division of hepatology, University of Miami Health Systems, said in an interview that, when it comes to PPI use in patients with cirrhosis, “judicious is the right word. They should be clearly used if there’s a bona fide indication ... and probably for a finite period of time.”

In a common scenario, “a patient is put on a PPI after they’ve undergone endoscopy with obliteration of varices, and the thought is that PPIs help the ulcers induced by the banding to heal,” said Dr. Martin, who was not associated with the research. “This paper didn’t specifically tease out whether that’s beneficial or not, but it certainly suggests, in patients with a history of gastrointestinal bleeding, that PPIs are still beneficial.”

Dr. Mahmud is supported by the National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor is supported by a National Institutes of Health K23 grant; another is supported by a VA Merit Grant and by a National Cancer Institute R01; a third has received unrelated support from Gilead, Glycotest, and Bayer and also is supported by VA Merit Grants. Dr. Reau and Dr. Martin disclosed no relevant financial relationships.

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

Good solutions have great road maps. 

For HIV preexposure prophylaxis (PrEP), the road map might just be that of contraceptive care. Once an onerous process, over time contraceptive care exploded into a range of options across a broad landscape in terms of approach and accessibility.

How then do organizations help vulnerable patients navigate their PrEP journeys using the contraceptive road map as a guide?

That’s what researchers at the University of Washington were intent on demonstrating, according to Julie Dombrowski, MD, MPH, an infectious disease specialist at the University of Washington, Seattle, and deputy director of the HIV/STD Program, Public Health for the city of Seattle and King County, Wash.

“The same sorts of things that happened with oral contraceptive pills – which initially required you to see a gynecologist and get a Pap smear – over time, became much more available,” said Dr. Dombrowski, coauthor of a new study published online in the Journal of Acquired Immune Deficiency Syndrome.

“The basic idea is that PrEP is not medically complicated; it can be easily protocolized,” she told this news organization.
 

Decentralizing HIV PrEP

In addition to her responsibilities at University of Washington, Dr. Dombrowski provides clinical services at the Public Health Sexual Health Clinic (PHSKC) at Seattle’s Harborview Medical Center – a dual-county center that provides confidential STI and HIV evaluation, screening, testing, and treatment on a walk-in basis for a sliding fee.

Sexual health clinics are ideal environments for reaching large numbers of patients, but strategies for integrating PrEP successfully into what are commonly one-time appointments have not been well-described or broadly adopted. 

“Sexual health clinics in general are STD specialty clinics with walk-in access to care; often, patients come into a clinic, get seen, diagnosed, and treated, and they don’t necessarily come back,” said Dr. Dombrowski. 

She said that, because most operations have been set up around same-day treatment, to offer PrEP and successfully change outcomes, there needs to be a shift in the current model toward one that promotes an ongoing relationship with the patients.

So, she and her colleagues decided to see what would happen if they implemented a decentralized PrEP model in their clinic over a 6-year period. They established a protocol that moves from an initial consultation with a clinician to review risk behaviors, ascertain HIV status, and acquire a PrEP prescription, to ongoing interactions with an STI and PrEP-trained disease intervention specialist (DIS).

As the clinic’s PrEP program coordinators, these specialists enroll patients in PrEP drug assistance programs, verify prescription fills, provide follow-up visits and adherence and adverse events assessments, and collect specimens.

“[Disease intervention specialists] are frontline public health workers who ensure that people diagnosed with HIV or an STI – or who’ve been exposed – get necessary testing and treatment,” explained Dr. Dombrowski. “They’re very similar to patient navigators.”

At the same time, clinicians remain the key providers for annual appointments, new symptoms, STI diagnoses, adverse drug reactions, and missed doses. Licensed medical providers review all labs.
 

Shifting responsibilities, better PrEP initiation, retention rates

After establishing the PrEP services protocol, the University of Washington team then assessed retention rates among PrEP patients who attended an initial visit (1,387) from October 2014 to December 2019. Follow-up continued through February 2020. (For study purposes, PrEP discontinuation was defined as either stopping PrEP after initiation or as lost to follow-up, i.e., either not attending a follow-up visit or not responding to more than three DIS calls or text messages).

Just over half of the participants were aged 20-29 years, and a third were aged 30-39. More than 9 out of 10 (93%) were men who sleep with men (MSM), 55% White, 26% Hispanic/Latinx, and 10% Black. 

Over the course of the study, 6,887 PrEP visits were recorded. Quarterly visits increased concurrently with the program expansion, from 31 visits in 2014 to 623 in the fourth quarter (Q4) of 2019. Likewise, while 57% of visits overall were with a clinician, DIS visits increased from 3% in Q4 of 2014 to 45% in Q4 of 2019, an increase of 1,400% in 5 years.

Significant numbers of patients also initiated PrEP in the clinic, especially when prescribing practices were expanded to be part of routine, walk-in visits.

Retention rates also improved, with 43% (510/1,190) of patients still on PrEP at the end of the analysis period. Forty-one percent (490) discontinued PrEP, 21% within 3 months of initiation, and 72% within a year; another 16% moved, transferred care, or tested positive, and were considered “censored.” However, as of July 31, 2021, 54% (265) of the 490 patients who had discontinued PrEP returned to the clinic for a restart visit, 93% of whom refilled their restart prescription.

“This is really basic preventative care and is actually quite easy to do,” noted Sarah Schmalzle, MD, assistant professor of medicine and medical director of the Thrive Program at the Institute of Human Virology at the University of Maryland, Baltimore. Dr. Schmalzle was not involved in the study. 

Dr. Schmalzle practices in inner-city Baltimore, so she and her colleagues have been thorough in terms of setting up PrEP (and postexposure prophylaxis, PEP) programs to ensure that patients access PrEP wherever they want to. But she also said that PrEP is only a part of the sexual wellness and prevention toolbox, and ideally, part of a whole prevention program. 

“Focusing on how to get the prescription out is great but the rest is having ongoing and accurate sexual health conversations, healthy conversations about sex and prevention, to have [an] algorithm in place that says, ‘Here’s your PrEP, this is the next time that you need an appointment, the next time you need labs, I’m going to check your adherence, etc.’ ”

Both Dr. Dombrowski and Dr. Schmalzle emphasized that decentralization is not a one-size model; flexibility is key, especially when it comes to who is providing PrEP 

“People overcomplicate PrEP and clinicians do this too,” said Dr. Dombrowski. “If we are going to successfully increase PrEP and improve the patient experience, we need to decrease the requirement for clinician involvement.”

Dr. Dombrowski has disclosed no relevant financial relationships. Dr. Schmalzle receives grant funding from Gilead Sciences.

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

Good solutions have great road maps. 

For HIV preexposure prophylaxis (PrEP), the road map might just be that of contraceptive care. Once an onerous process, over time contraceptive care exploded into a range of options across a broad landscape in terms of approach and accessibility.

How then do organizations help vulnerable patients navigate their PrEP journeys using the contraceptive road map as a guide?

That’s what researchers at the University of Washington were intent on demonstrating, according to Julie Dombrowski, MD, MPH, an infectious disease specialist at the University of Washington, Seattle, and deputy director of the HIV/STD Program, Public Health for the city of Seattle and King County, Wash.

“The same sorts of things that happened with oral contraceptive pills – which initially required you to see a gynecologist and get a Pap smear – over time, became much more available,” said Dr. Dombrowski, coauthor of a new study published online in the Journal of Acquired Immune Deficiency Syndrome.

“The basic idea is that PrEP is not medically complicated; it can be easily protocolized,” she told this news organization.
 

Decentralizing HIV PrEP

In addition to her responsibilities at University of Washington, Dr. Dombrowski provides clinical services at the Public Health Sexual Health Clinic (PHSKC) at Seattle’s Harborview Medical Center – a dual-county center that provides confidential STI and HIV evaluation, screening, testing, and treatment on a walk-in basis for a sliding fee.

Sexual health clinics are ideal environments for reaching large numbers of patients, but strategies for integrating PrEP successfully into what are commonly one-time appointments have not been well-described or broadly adopted. 

“Sexual health clinics in general are STD specialty clinics with walk-in access to care; often, patients come into a clinic, get seen, diagnosed, and treated, and they don’t necessarily come back,” said Dr. Dombrowski. 

She said that, because most operations have been set up around same-day treatment, to offer PrEP and successfully change outcomes, there needs to be a shift in the current model toward one that promotes an ongoing relationship with the patients.

So, she and her colleagues decided to see what would happen if they implemented a decentralized PrEP model in their clinic over a 6-year period. They established a protocol that moves from an initial consultation with a clinician to review risk behaviors, ascertain HIV status, and acquire a PrEP prescription, to ongoing interactions with an STI and PrEP-trained disease intervention specialist (DIS).

As the clinic’s PrEP program coordinators, these specialists enroll patients in PrEP drug assistance programs, verify prescription fills, provide follow-up visits and adherence and adverse events assessments, and collect specimens.

“[Disease intervention specialists] are frontline public health workers who ensure that people diagnosed with HIV or an STI – or who’ve been exposed – get necessary testing and treatment,” explained Dr. Dombrowski. “They’re very similar to patient navigators.”

At the same time, clinicians remain the key providers for annual appointments, new symptoms, STI diagnoses, adverse drug reactions, and missed doses. Licensed medical providers review all labs.
 

Shifting responsibilities, better PrEP initiation, retention rates

After establishing the PrEP services protocol, the University of Washington team then assessed retention rates among PrEP patients who attended an initial visit (1,387) from October 2014 to December 2019. Follow-up continued through February 2020. (For study purposes, PrEP discontinuation was defined as either stopping PrEP after initiation or as lost to follow-up, i.e., either not attending a follow-up visit or not responding to more than three DIS calls or text messages).

Just over half of the participants were aged 20-29 years, and a third were aged 30-39. More than 9 out of 10 (93%) were men who sleep with men (MSM), 55% White, 26% Hispanic/Latinx, and 10% Black. 

Over the course of the study, 6,887 PrEP visits were recorded. Quarterly visits increased concurrently with the program expansion, from 31 visits in 2014 to 623 in the fourth quarter (Q4) of 2019. Likewise, while 57% of visits overall were with a clinician, DIS visits increased from 3% in Q4 of 2014 to 45% in Q4 of 2019, an increase of 1,400% in 5 years.

Significant numbers of patients also initiated PrEP in the clinic, especially when prescribing practices were expanded to be part of routine, walk-in visits.

Retention rates also improved, with 43% (510/1,190) of patients still on PrEP at the end of the analysis period. Forty-one percent (490) discontinued PrEP, 21% within 3 months of initiation, and 72% within a year; another 16% moved, transferred care, or tested positive, and were considered “censored.” However, as of July 31, 2021, 54% (265) of the 490 patients who had discontinued PrEP returned to the clinic for a restart visit, 93% of whom refilled their restart prescription.

“This is really basic preventative care and is actually quite easy to do,” noted Sarah Schmalzle, MD, assistant professor of medicine and medical director of the Thrive Program at the Institute of Human Virology at the University of Maryland, Baltimore. Dr. Schmalzle was not involved in the study. 

Dr. Schmalzle practices in inner-city Baltimore, so she and her colleagues have been thorough in terms of setting up PrEP (and postexposure prophylaxis, PEP) programs to ensure that patients access PrEP wherever they want to. But she also said that PrEP is only a part of the sexual wellness and prevention toolbox, and ideally, part of a whole prevention program. 

“Focusing on how to get the prescription out is great but the rest is having ongoing and accurate sexual health conversations, healthy conversations about sex and prevention, to have [an] algorithm in place that says, ‘Here’s your PrEP, this is the next time that you need an appointment, the next time you need labs, I’m going to check your adherence, etc.’ ”

Both Dr. Dombrowski and Dr. Schmalzle emphasized that decentralization is not a one-size model; flexibility is key, especially when it comes to who is providing PrEP 

“People overcomplicate PrEP and clinicians do this too,” said Dr. Dombrowski. “If we are going to successfully increase PrEP and improve the patient experience, we need to decrease the requirement for clinician involvement.”

Dr. Dombrowski has disclosed no relevant financial relationships. Dr. Schmalzle receives grant funding from Gilead Sciences.

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

Good solutions have great road maps. 

For HIV preexposure prophylaxis (PrEP), the road map might just be that of contraceptive care. Once an onerous process, over time contraceptive care exploded into a range of options across a broad landscape in terms of approach and accessibility.

How then do organizations help vulnerable patients navigate their PrEP journeys using the contraceptive road map as a guide?

That’s what researchers at the University of Washington were intent on demonstrating, according to Julie Dombrowski, MD, MPH, an infectious disease specialist at the University of Washington, Seattle, and deputy director of the HIV/STD Program, Public Health for the city of Seattle and King County, Wash.

“The same sorts of things that happened with oral contraceptive pills – which initially required you to see a gynecologist and get a Pap smear – over time, became much more available,” said Dr. Dombrowski, coauthor of a new study published online in the Journal of Acquired Immune Deficiency Syndrome.

“The basic idea is that PrEP is not medically complicated; it can be easily protocolized,” she told this news organization.
 

Decentralizing HIV PrEP

In addition to her responsibilities at University of Washington, Dr. Dombrowski provides clinical services at the Public Health Sexual Health Clinic (PHSKC) at Seattle’s Harborview Medical Center – a dual-county center that provides confidential STI and HIV evaluation, screening, testing, and treatment on a walk-in basis for a sliding fee.

Sexual health clinics are ideal environments for reaching large numbers of patients, but strategies for integrating PrEP successfully into what are commonly one-time appointments have not been well-described or broadly adopted. 

“Sexual health clinics in general are STD specialty clinics with walk-in access to care; often, patients come into a clinic, get seen, diagnosed, and treated, and they don’t necessarily come back,” said Dr. Dombrowski. 

She said that, because most operations have been set up around same-day treatment, to offer PrEP and successfully change outcomes, there needs to be a shift in the current model toward one that promotes an ongoing relationship with the patients.

So, she and her colleagues decided to see what would happen if they implemented a decentralized PrEP model in their clinic over a 6-year period. They established a protocol that moves from an initial consultation with a clinician to review risk behaviors, ascertain HIV status, and acquire a PrEP prescription, to ongoing interactions with an STI and PrEP-trained disease intervention specialist (DIS).

As the clinic’s PrEP program coordinators, these specialists enroll patients in PrEP drug assistance programs, verify prescription fills, provide follow-up visits and adherence and adverse events assessments, and collect specimens.

“[Disease intervention specialists] are frontline public health workers who ensure that people diagnosed with HIV or an STI – or who’ve been exposed – get necessary testing and treatment,” explained Dr. Dombrowski. “They’re very similar to patient navigators.”

At the same time, clinicians remain the key providers for annual appointments, new symptoms, STI diagnoses, adverse drug reactions, and missed doses. Licensed medical providers review all labs.
 

Shifting responsibilities, better PrEP initiation, retention rates

After establishing the PrEP services protocol, the University of Washington team then assessed retention rates among PrEP patients who attended an initial visit (1,387) from October 2014 to December 2019. Follow-up continued through February 2020. (For study purposes, PrEP discontinuation was defined as either stopping PrEP after initiation or as lost to follow-up, i.e., either not attending a follow-up visit or not responding to more than three DIS calls or text messages).

Just over half of the participants were aged 20-29 years, and a third were aged 30-39. More than 9 out of 10 (93%) were men who sleep with men (MSM), 55% White, 26% Hispanic/Latinx, and 10% Black. 

Over the course of the study, 6,887 PrEP visits were recorded. Quarterly visits increased concurrently with the program expansion, from 31 visits in 2014 to 623 in the fourth quarter (Q4) of 2019. Likewise, while 57% of visits overall were with a clinician, DIS visits increased from 3% in Q4 of 2014 to 45% in Q4 of 2019, an increase of 1,400% in 5 years.

Significant numbers of patients also initiated PrEP in the clinic, especially when prescribing practices were expanded to be part of routine, walk-in visits.

Retention rates also improved, with 43% (510/1,190) of patients still on PrEP at the end of the analysis period. Forty-one percent (490) discontinued PrEP, 21% within 3 months of initiation, and 72% within a year; another 16% moved, transferred care, or tested positive, and were considered “censored.” However, as of July 31, 2021, 54% (265) of the 490 patients who had discontinued PrEP returned to the clinic for a restart visit, 93% of whom refilled their restart prescription.

“This is really basic preventative care and is actually quite easy to do,” noted Sarah Schmalzle, MD, assistant professor of medicine and medical director of the Thrive Program at the Institute of Human Virology at the University of Maryland, Baltimore. Dr. Schmalzle was not involved in the study. 

Dr. Schmalzle practices in inner-city Baltimore, so she and her colleagues have been thorough in terms of setting up PrEP (and postexposure prophylaxis, PEP) programs to ensure that patients access PrEP wherever they want to. But she also said that PrEP is only a part of the sexual wellness and prevention toolbox, and ideally, part of a whole prevention program. 

“Focusing on how to get the prescription out is great but the rest is having ongoing and accurate sexual health conversations, healthy conversations about sex and prevention, to have [an] algorithm in place that says, ‘Here’s your PrEP, this is the next time that you need an appointment, the next time you need labs, I’m going to check your adherence, etc.’ ”

Both Dr. Dombrowski and Dr. Schmalzle emphasized that decentralization is not a one-size model; flexibility is key, especially when it comes to who is providing PrEP 

“People overcomplicate PrEP and clinicians do this too,” said Dr. Dombrowski. “If we are going to successfully increase PrEP and improve the patient experience, we need to decrease the requirement for clinician involvement.”

Dr. Dombrowski has disclosed no relevant financial relationships. Dr. Schmalzle receives grant funding from Gilead Sciences.

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

Madhu Manivannan, a third-year medical student at Emory University, Atlanta, is on the vanguard of a new approach to clinical education. Ms. Manivannan, copresident of Emory Medical Students for Climate Action, was in the first class of Emory’s medical students to experience the birth of a refined curriculum – lobbied for and partially created by students themselves. The new course of study addresses the myriad ways climate affects health: from air pollution and its effects on the lungs and cardiovascular system to heat-related kidney disease.

“We have known that climate has affected health for decades,” Ms. Manivannan said in a recent interview. “The narrative used to be that icebergs were melting and in 2050 polar bears would be extinct. The piece that’s different now is people are linking climate to increases in asthma and various diseases. We have a way to directly communicate that it’s not a far-off thing. It’s happening to your friends and family right now.”

Hospitals, medical schools, and public health programs are stepping up to educate the next generation of doctors as well as veteran medical workers on one of the most widespread, insidious health threats of our time – climate change – and specific ways it could affect their patients.

Although climate change may seem to many Americans like a distant threat, Marilyn Howarth, MD, a pediatrician in Philadelphia, is trying to make sure physicians are better prepared to treat a growing number of health problems associated with global warming.

“There isn’t a lot of education for pediatricians and internists on environmental health issues. It has not been a standard part of education in medical school or residency training,” Dr. Howarth, deputy director of the new Philadelphia Regional Center for Children’s Environmental Health, said. “With increasing attention on our climate, we really recognize there’s a real gap in physician knowledge, both in pediatric and adult care.”

Scientists have found that climate change can alter just about every system within the human body. Studies show that more extreme weather events, such as heat waves, thunderstorms, and floods, can worsen asthma and produce more pollen and mold, triggering debilitating respiratory problems.

According to the American Lung Association, ultrafine particles of air pollution can be inhaled and then travel throughout the bloodstream, wreaking havoc on organs and increasing risk of heart attack and stroke. Various types of air pollution also cause changes to the climate by trapping heat in the atmosphere, which leads to problems such as rising sea levels and extreme weather. Plus, in a new study published in Nature, scientists warn that warming climates are forcing animals to migrate to different areas, raising the risk that new infectious diseases will hop from animals – such as bats – to humans, a process called “zoonotic spillover” that many researchers believe is responsible for the COVID-19 pandemic.
 

The Philadelphia Regional Center for Children’s Environmental Health

One of the latest initiatives aimed at disseminating information about children’s health to health care providers is the Philadelphia Regional Center for Children’s Environmental Health, part of Children’s Hospital of Philadelphia and Penn Medicine. CHOP and Penn Medicine are jointly funding this center’s work, which will include educating health care providers on how to better screen for climate-caused health risks and treat related conditions, such as lead poisoning and asthma.

Outreach will focus on providers who treat patients with illnesses that researchers have linked to climate change, Dr. Howarth said. The center will offer clinicians access to seminars and webinars, along with online resources to help doctors treat environmental illnesses. For example, doctors at CHOP’s Poison Control Center are developing a toolkit for physicians to treat patients with elevated levels of lead in the blood. Scientists have linked extreme weather events related to climate change to flooding that pushes metals away from river banks where they were previously contained, allowing them to more easily contaminate homes, soils, and yards.

The initiative builds on CHOP’s Community Asthma Prevention Program (CAPP), which was launched in 1997 by Tyra Bryant-Stephens, MD, its current medical director. CAPP deploys community health workers into homes armed with supplies and tips for managing asthma. The new center will use similar tactics to provide education and resources to patients. The goal is to reach as many at-risk local children as possible.
 

Future generation of doctors fuel growth in climate change education

Lisa Doggett, MD, cofounder and president of the board of directors of Texas Physicians for Social Responsibility, announced in March that the University of Texas at Austin, Baylor College of Medicine, Houston, and the University of Texas Southwestern in Dallas have all decided to begin offering a course on environmental threats. Emory’s new curriculum has become more comprehensive every year since its start – thanks in part to the input of students like Ms. Manivannan. Faculty members tasked her with approving the new additions to the curriculum on how climate affects health, which in 2019 had consisted of a few slides about issues such as extreme heat exposure and air pollution and their effects on childbirth outcomes.

Material on climate change has now been woven into 13 courses. It is discussed at length in relation to pulmonology, cardiology, and gastropulmonology, for example, said Rebecca Philipsborn, MD, MPA, FAAP, faculty lead for the environmental and health curriculum at Emory.

The curriculum has only been incorporated into Emory’s program for the past 2 years. Dr. Philipsborn said the school plans to expand it to the clinical years to help trainees learn to treat conditions such as pediatric asthma.

“In the past few years, there has been so much momentum, and part of that is a testament to already seeing effects of climate change and how they affect delivery of health care,” she said.

At least one medical journal has recently ramped up its efforts to educate physicians on the links between health issues and climate change. Editors of Family Practice, from Oxford University Press, have announced that they plan to publish a special Climate Crisis and Primary Health Care issue in September.

Of course, not all climate initiatives in medicine are new. A select few have existed for decades.

But only now are physicians widely seeing the links between health and environment, according to Aaron Bernstein, MD, MPH, interim director of the Center for Climate, Health, and the Global Environment (C-CHANGE) at Harvard School of Public Health, Boston.

C-CHANGE, founded in 1996, was the first center in the world to focus on the health effects of environmental change.

“It’s taken 20 years, but what we’re seeing, I think, is the fruits of education,” Dr. Bernstein said. “There’s clearly a wave building here, and I think it really started with education and people younger than the people in charge calling them into account.”

Like the Philadelphia center, Harvard’s program conducts research on climate and health and educates people from high schoolers to health care veterans. Dr. Bernstein helps lead Climate MD, a program that aims to prepare health care workers for climate crises. The Climate MD team has published several articles in peer-reviewed journals on how to better treat patients struggling with environmental health problems. For example, an article on mapping patients in hurricane zones helped shed light on how systems can identify climate-vulnerable patients using public data.

They also developed a tool to help pediatricians provide “climate-informed primary care” – guidance on how to assess whether children are at risk of any harmful environmental exposures, a feature that is not part of standard pediatric visits.

Like the other programs, Climate MD uses community outreach to treat as many local patients as possible. Staff work with providers at more than 100 health clinics, particularly in areas where climate change disproportionately affects residents.

The next major step is to bring some of this into clinical practice, Dr. Bernstein said. In February 2020, C-CHANGE held its first symposium to address that issue.

“The key is to understand climate issues from a provider’s perspective,” he said. “Then those issues can really be brought to the bedside.”

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

Madhu Manivannan, a third-year medical student at Emory University, Atlanta, is on the vanguard of a new approach to clinical education. Ms. Manivannan, copresident of Emory Medical Students for Climate Action, was in the first class of Emory’s medical students to experience the birth of a refined curriculum – lobbied for and partially created by students themselves. The new course of study addresses the myriad ways climate affects health: from air pollution and its effects on the lungs and cardiovascular system to heat-related kidney disease.

“We have known that climate has affected health for decades,” Ms. Manivannan said in a recent interview. “The narrative used to be that icebergs were melting and in 2050 polar bears would be extinct. The piece that’s different now is people are linking climate to increases in asthma and various diseases. We have a way to directly communicate that it’s not a far-off thing. It’s happening to your friends and family right now.”

Hospitals, medical schools, and public health programs are stepping up to educate the next generation of doctors as well as veteran medical workers on one of the most widespread, insidious health threats of our time – climate change – and specific ways it could affect their patients.

Although climate change may seem to many Americans like a distant threat, Marilyn Howarth, MD, a pediatrician in Philadelphia, is trying to make sure physicians are better prepared to treat a growing number of health problems associated with global warming.

“There isn’t a lot of education for pediatricians and internists on environmental health issues. It has not been a standard part of education in medical school or residency training,” Dr. Howarth, deputy director of the new Philadelphia Regional Center for Children’s Environmental Health, said. “With increasing attention on our climate, we really recognize there’s a real gap in physician knowledge, both in pediatric and adult care.”

Scientists have found that climate change can alter just about every system within the human body. Studies show that more extreme weather events, such as heat waves, thunderstorms, and floods, can worsen asthma and produce more pollen and mold, triggering debilitating respiratory problems.

According to the American Lung Association, ultrafine particles of air pollution can be inhaled and then travel throughout the bloodstream, wreaking havoc on organs and increasing risk of heart attack and stroke. Various types of air pollution also cause changes to the climate by trapping heat in the atmosphere, which leads to problems such as rising sea levels and extreme weather. Plus, in a new study published in Nature, scientists warn that warming climates are forcing animals to migrate to different areas, raising the risk that new infectious diseases will hop from animals – such as bats – to humans, a process called “zoonotic spillover” that many researchers believe is responsible for the COVID-19 pandemic.
 

The Philadelphia Regional Center for Children’s Environmental Health

One of the latest initiatives aimed at disseminating information about children’s health to health care providers is the Philadelphia Regional Center for Children’s Environmental Health, part of Children’s Hospital of Philadelphia and Penn Medicine. CHOP and Penn Medicine are jointly funding this center’s work, which will include educating health care providers on how to better screen for climate-caused health risks and treat related conditions, such as lead poisoning and asthma.

Outreach will focus on providers who treat patients with illnesses that researchers have linked to climate change, Dr. Howarth said. The center will offer clinicians access to seminars and webinars, along with online resources to help doctors treat environmental illnesses. For example, doctors at CHOP’s Poison Control Center are developing a toolkit for physicians to treat patients with elevated levels of lead in the blood. Scientists have linked extreme weather events related to climate change to flooding that pushes metals away from river banks where they were previously contained, allowing them to more easily contaminate homes, soils, and yards.

The initiative builds on CHOP’s Community Asthma Prevention Program (CAPP), which was launched in 1997 by Tyra Bryant-Stephens, MD, its current medical director. CAPP deploys community health workers into homes armed with supplies and tips for managing asthma. The new center will use similar tactics to provide education and resources to patients. The goal is to reach as many at-risk local children as possible.
 

Future generation of doctors fuel growth in climate change education

Lisa Doggett, MD, cofounder and president of the board of directors of Texas Physicians for Social Responsibility, announced in March that the University of Texas at Austin, Baylor College of Medicine, Houston, and the University of Texas Southwestern in Dallas have all decided to begin offering a course on environmental threats. Emory’s new curriculum has become more comprehensive every year since its start – thanks in part to the input of students like Ms. Manivannan. Faculty members tasked her with approving the new additions to the curriculum on how climate affects health, which in 2019 had consisted of a few slides about issues such as extreme heat exposure and air pollution and their effects on childbirth outcomes.

Material on climate change has now been woven into 13 courses. It is discussed at length in relation to pulmonology, cardiology, and gastropulmonology, for example, said Rebecca Philipsborn, MD, MPA, FAAP, faculty lead for the environmental and health curriculum at Emory.

The curriculum has only been incorporated into Emory’s program for the past 2 years. Dr. Philipsborn said the school plans to expand it to the clinical years to help trainees learn to treat conditions such as pediatric asthma.

“In the past few years, there has been so much momentum, and part of that is a testament to already seeing effects of climate change and how they affect delivery of health care,” she said.

At least one medical journal has recently ramped up its efforts to educate physicians on the links between health issues and climate change. Editors of Family Practice, from Oxford University Press, have announced that they plan to publish a special Climate Crisis and Primary Health Care issue in September.

Of course, not all climate initiatives in medicine are new. A select few have existed for decades.

But only now are physicians widely seeing the links between health and environment, according to Aaron Bernstein, MD, MPH, interim director of the Center for Climate, Health, and the Global Environment (C-CHANGE) at Harvard School of Public Health, Boston.

C-CHANGE, founded in 1996, was the first center in the world to focus on the health effects of environmental change.

“It’s taken 20 years, but what we’re seeing, I think, is the fruits of education,” Dr. Bernstein said. “There’s clearly a wave building here, and I think it really started with education and people younger than the people in charge calling them into account.”

Like the Philadelphia center, Harvard’s program conducts research on climate and health and educates people from high schoolers to health care veterans. Dr. Bernstein helps lead Climate MD, a program that aims to prepare health care workers for climate crises. The Climate MD team has published several articles in peer-reviewed journals on how to better treat patients struggling with environmental health problems. For example, an article on mapping patients in hurricane zones helped shed light on how systems can identify climate-vulnerable patients using public data.

They also developed a tool to help pediatricians provide “climate-informed primary care” – guidance on how to assess whether children are at risk of any harmful environmental exposures, a feature that is not part of standard pediatric visits.

Like the other programs, Climate MD uses community outreach to treat as many local patients as possible. Staff work with providers at more than 100 health clinics, particularly in areas where climate change disproportionately affects residents.

The next major step is to bring some of this into clinical practice, Dr. Bernstein said. In February 2020, C-CHANGE held its first symposium to address that issue.

“The key is to understand climate issues from a provider’s perspective,” he said. “Then those issues can really be brought to the bedside.”

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

Madhu Manivannan, a third-year medical student at Emory University, Atlanta, is on the vanguard of a new approach to clinical education. Ms. Manivannan, copresident of Emory Medical Students for Climate Action, was in the first class of Emory’s medical students to experience the birth of a refined curriculum – lobbied for and partially created by students themselves. The new course of study addresses the myriad ways climate affects health: from air pollution and its effects on the lungs and cardiovascular system to heat-related kidney disease.

“We have known that climate has affected health for decades,” Ms. Manivannan said in a recent interview. “The narrative used to be that icebergs were melting and in 2050 polar bears would be extinct. The piece that’s different now is people are linking climate to increases in asthma and various diseases. We have a way to directly communicate that it’s not a far-off thing. It’s happening to your friends and family right now.”

Hospitals, medical schools, and public health programs are stepping up to educate the next generation of doctors as well as veteran medical workers on one of the most widespread, insidious health threats of our time – climate change – and specific ways it could affect their patients.

Although climate change may seem to many Americans like a distant threat, Marilyn Howarth, MD, a pediatrician in Philadelphia, is trying to make sure physicians are better prepared to treat a growing number of health problems associated with global warming.

“There isn’t a lot of education for pediatricians and internists on environmental health issues. It has not been a standard part of education in medical school or residency training,” Dr. Howarth, deputy director of the new Philadelphia Regional Center for Children’s Environmental Health, said. “With increasing attention on our climate, we really recognize there’s a real gap in physician knowledge, both in pediatric and adult care.”

Scientists have found that climate change can alter just about every system within the human body. Studies show that more extreme weather events, such as heat waves, thunderstorms, and floods, can worsen asthma and produce more pollen and mold, triggering debilitating respiratory problems.

According to the American Lung Association, ultrafine particles of air pollution can be inhaled and then travel throughout the bloodstream, wreaking havoc on organs and increasing risk of heart attack and stroke. Various types of air pollution also cause changes to the climate by trapping heat in the atmosphere, which leads to problems such as rising sea levels and extreme weather. Plus, in a new study published in Nature, scientists warn that warming climates are forcing animals to migrate to different areas, raising the risk that new infectious diseases will hop from animals – such as bats – to humans, a process called “zoonotic spillover” that many researchers believe is responsible for the COVID-19 pandemic.
 

The Philadelphia Regional Center for Children’s Environmental Health

One of the latest initiatives aimed at disseminating information about children’s health to health care providers is the Philadelphia Regional Center for Children’s Environmental Health, part of Children’s Hospital of Philadelphia and Penn Medicine. CHOP and Penn Medicine are jointly funding this center’s work, which will include educating health care providers on how to better screen for climate-caused health risks and treat related conditions, such as lead poisoning and asthma.

Outreach will focus on providers who treat patients with illnesses that researchers have linked to climate change, Dr. Howarth said. The center will offer clinicians access to seminars and webinars, along with online resources to help doctors treat environmental illnesses. For example, doctors at CHOP’s Poison Control Center are developing a toolkit for physicians to treat patients with elevated levels of lead in the blood. Scientists have linked extreme weather events related to climate change to flooding that pushes metals away from river banks where they were previously contained, allowing them to more easily contaminate homes, soils, and yards.

The initiative builds on CHOP’s Community Asthma Prevention Program (CAPP), which was launched in 1997 by Tyra Bryant-Stephens, MD, its current medical director. CAPP deploys community health workers into homes armed with supplies and tips for managing asthma. The new center will use similar tactics to provide education and resources to patients. The goal is to reach as many at-risk local children as possible.
 

Future generation of doctors fuel growth in climate change education

Lisa Doggett, MD, cofounder and president of the board of directors of Texas Physicians for Social Responsibility, announced in March that the University of Texas at Austin, Baylor College of Medicine, Houston, and the University of Texas Southwestern in Dallas have all decided to begin offering a course on environmental threats. Emory’s new curriculum has become more comprehensive every year since its start – thanks in part to the input of students like Ms. Manivannan. Faculty members tasked her with approving the new additions to the curriculum on how climate affects health, which in 2019 had consisted of a few slides about issues such as extreme heat exposure and air pollution and their effects on childbirth outcomes.

Material on climate change has now been woven into 13 courses. It is discussed at length in relation to pulmonology, cardiology, and gastropulmonology, for example, said Rebecca Philipsborn, MD, MPA, FAAP, faculty lead for the environmental and health curriculum at Emory.

The curriculum has only been incorporated into Emory’s program for the past 2 years. Dr. Philipsborn said the school plans to expand it to the clinical years to help trainees learn to treat conditions such as pediatric asthma.

“In the past few years, there has been so much momentum, and part of that is a testament to already seeing effects of climate change and how they affect delivery of health care,” she said.

At least one medical journal has recently ramped up its efforts to educate physicians on the links between health issues and climate change. Editors of Family Practice, from Oxford University Press, have announced that they plan to publish a special Climate Crisis and Primary Health Care issue in September.

Of course, not all climate initiatives in medicine are new. A select few have existed for decades.

But only now are physicians widely seeing the links between health and environment, according to Aaron Bernstein, MD, MPH, interim director of the Center for Climate, Health, and the Global Environment (C-CHANGE) at Harvard School of Public Health, Boston.

C-CHANGE, founded in 1996, was the first center in the world to focus on the health effects of environmental change.

“It’s taken 20 years, but what we’re seeing, I think, is the fruits of education,” Dr. Bernstein said. “There’s clearly a wave building here, and I think it really started with education and people younger than the people in charge calling them into account.”

Like the Philadelphia center, Harvard’s program conducts research on climate and health and educates people from high schoolers to health care veterans. Dr. Bernstein helps lead Climate MD, a program that aims to prepare health care workers for climate crises. The Climate MD team has published several articles in peer-reviewed journals on how to better treat patients struggling with environmental health problems. For example, an article on mapping patients in hurricane zones helped shed light on how systems can identify climate-vulnerable patients using public data.

They also developed a tool to help pediatricians provide “climate-informed primary care” – guidance on how to assess whether children are at risk of any harmful environmental exposures, a feature that is not part of standard pediatric visits.

Like the other programs, Climate MD uses community outreach to treat as many local patients as possible. Staff work with providers at more than 100 health clinics, particularly in areas where climate change disproportionately affects residents.

The next major step is to bring some of this into clinical practice, Dr. Bernstein said. In February 2020, C-CHANGE held its first symposium to address that issue.

“The key is to understand climate issues from a provider’s perspective,” he said. “Then those issues can really be brought to the bedside.”

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

SAN DIEGO – The end of the legal standards set by Roe v. Wade will likely lead to bans in as many as 26 states and send a flood of abortion seekers to the remaining states that still allow the procedure, an obstetrician-gynecologist warned colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

“The blue states neighboring those states will likely see an outpouring of patients among those who can travel,” Kristyn Brandi, MD, of New Jersey Medical School, Newark, said in a presentation about legal threats to abortion rights. “These will likely flood the health care systems and delay care for everyone. Make no mistake: Virtually all ob.gyns. across the country have the potential to be impacted.”

Indeed, research suggests that thousands more Texans than usual are heading out of state for abortions each month in the wake of a new, strict antiabortion law there.

Only three sessions at the 3-day ACOG meeting directly addressed abortion. But the topic was clearly on the minds of attendees in the wake of the release of a leaked draft of a Supreme Court ruling that would eliminate federal protection for abortion rights.

The 57,000-member ACOG organization firmly supports abortion rights and declares on its website that “Abortion Is Healthcare.”

In a workshop on challenges to abortion, ACOG chief of staff Dorothea Calvano Lindquist said “we remain your steadfast partner in advocacy and guidance on all levels.”

Ivana S. Thompson, MD, an ob.gyn. at Vanderbilt University, Nashville, Tenn., explained in a presentation that Roe v. Wade established a framework for regulations around abortion; they may not be regulated during the first trimester, but states may impose rules in the second semester that are related to health. “And then in the third trimester, once the fetus reaches viability, the state may regulate abortions or even prohibit them entirely, so long as there are exceptions for medical emergencies,” she said.

The Supreme Court ruling in the 1992 case of Planned Parenthood v. Casey did away with the trimester framework, Dr. Thompson said, and declared that abortion regulations could not place an “undue burden” on women.

This change allowed laws that “are purposely designed to trap providers and clinics and to restrict their ability to provide abortions, not due to health concerns but really just to prevent pregnant people from accessing care,” she said.

In 2018, Mississippi passed a law – which never went into effect and is now challenged before the Supreme Court – that makes most abortions illegal after 15 weeks. And in September 2021, a Texas law went into effect that outlaws abortions after a fetal heartbeat is detected.

What happens if Roe is overturned and laws that ban or severely limit abortion go into effect in states across the country? In Nashville, Dr. Thompson said, patients will have to travel to Illinois – more than 300 miles away – to reach the nearest abortion clinic.

“When I think about my own clinical practice over the last year, [if the law were in place] I would not have been able to offer an abortion to a developmentally delayed, nonverbal patient who was raped by her brother,” she said. “I would not have been able to offer an abortion to the service person who was sexually assaulted by a coworker in the field. I would not have been able to offer an abortion to a person with a pregnancy complicated by a hypoplastic left heart, congenital diaphragmatic hernias with the stomach in the thorax, an unformed lumbar spine, and other anomalies.”

Bhavik Kumar, MD, a family medicine physician and medical director for primary and trans care at Planned Parenthood Gulf Coast in Houston, said the effects of the new law in Texas are already apparent. As he told ABC News last fall, he used to perform 20-30 abortions per day, but the number dwindled immediately the day the law went into effect.

At the ACOG presentation, Dr. Kumar highlighted a March 2022 research brief that reported that abortions in Texas fell by half in the month after the law was implemented compared with the previous year. And the average number of abortions performed on Texans who left the state grew by more than 10-fold from the period of September-December 2019 (514) to September-December 2021 (5,574).

Once the law went into effect, Dr. Kumar said, “we began to see longer waiting times at clinics in nearby states, wait times that started out as short as a day go to an average of 2-3 weeks to get an initial appointment. And some of these states also have mandatory delays of up to 72 hours.”

Dr. Kumar added that he’s “heard from emergency-room physicians and nurses who call and ask me what they can and cannot say when providing care for pregnant people in Texas and how they should be counseling their patients who may need emergency or urgent care after returning to Texas.”

Dr. Brandi cautioned colleagues that even ob.gyns. who don’t perform abortions will still be affected by the overturning of Roe. In some states, they’ll have to understand the rules about treating women with early ruptured membranes when cardiac motion is detected or with atopic pregnancies with cardiac activity at risk of potential tubal rupture.

The speakers urged colleagues to take action at the ballot box and their own clinics to protect patients. “While the recent leak is a truly scary moment for our country and for our practices, I’m hopeful that it will help galvanize our communities,” Dr. Brandi said. Regardless of where you live, regardless of where you practice, this ruling impacts all ob.gyns., everyone in this room. Each of us needs to go home after this conference and figure out what you are going to do to make sure that our patients can still get the care that they need.”

SAN DIEGO – The end of the legal standards set by Roe v. Wade will likely lead to bans in as many as 26 states and send a flood of abortion seekers to the remaining states that still allow the procedure, an obstetrician-gynecologist warned colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

“The blue states neighboring those states will likely see an outpouring of patients among those who can travel,” Kristyn Brandi, MD, of New Jersey Medical School, Newark, said in a presentation about legal threats to abortion rights. “These will likely flood the health care systems and delay care for everyone. Make no mistake: Virtually all ob.gyns. across the country have the potential to be impacted.”

Indeed, research suggests that thousands more Texans than usual are heading out of state for abortions each month in the wake of a new, strict antiabortion law there.

Only three sessions at the 3-day ACOG meeting directly addressed abortion. But the topic was clearly on the minds of attendees in the wake of the release of a leaked draft of a Supreme Court ruling that would eliminate federal protection for abortion rights.

The 57,000-member ACOG organization firmly supports abortion rights and declares on its website that “Abortion Is Healthcare.”

In a workshop on challenges to abortion, ACOG chief of staff Dorothea Calvano Lindquist said “we remain your steadfast partner in advocacy and guidance on all levels.”

Ivana S. Thompson, MD, an ob.gyn. at Vanderbilt University, Nashville, Tenn., explained in a presentation that Roe v. Wade established a framework for regulations around abortion; they may not be regulated during the first trimester, but states may impose rules in the second semester that are related to health. “And then in the third trimester, once the fetus reaches viability, the state may regulate abortions or even prohibit them entirely, so long as there are exceptions for medical emergencies,” she said.

The Supreme Court ruling in the 1992 case of Planned Parenthood v. Casey did away with the trimester framework, Dr. Thompson said, and declared that abortion regulations could not place an “undue burden” on women.

This change allowed laws that “are purposely designed to trap providers and clinics and to restrict their ability to provide abortions, not due to health concerns but really just to prevent pregnant people from accessing care,” she said.

In 2018, Mississippi passed a law – which never went into effect and is now challenged before the Supreme Court – that makes most abortions illegal after 15 weeks. And in September 2021, a Texas law went into effect that outlaws abortions after a fetal heartbeat is detected.

What happens if Roe is overturned and laws that ban or severely limit abortion go into effect in states across the country? In Nashville, Dr. Thompson said, patients will have to travel to Illinois – more than 300 miles away – to reach the nearest abortion clinic.

“When I think about my own clinical practice over the last year, [if the law were in place] I would not have been able to offer an abortion to a developmentally delayed, nonverbal patient who was raped by her brother,” she said. “I would not have been able to offer an abortion to the service person who was sexually assaulted by a coworker in the field. I would not have been able to offer an abortion to a person with a pregnancy complicated by a hypoplastic left heart, congenital diaphragmatic hernias with the stomach in the thorax, an unformed lumbar spine, and other anomalies.”

Bhavik Kumar, MD, a family medicine physician and medical director for primary and trans care at Planned Parenthood Gulf Coast in Houston, said the effects of the new law in Texas are already apparent. As he told ABC News last fall, he used to perform 20-30 abortions per day, but the number dwindled immediately the day the law went into effect.

At the ACOG presentation, Dr. Kumar highlighted a March 2022 research brief that reported that abortions in Texas fell by half in the month after the law was implemented compared with the previous year. And the average number of abortions performed on Texans who left the state grew by more than 10-fold from the period of September-December 2019 (514) to September-December 2021 (5,574).

Once the law went into effect, Dr. Kumar said, “we began to see longer waiting times at clinics in nearby states, wait times that started out as short as a day go to an average of 2-3 weeks to get an initial appointment. And some of these states also have mandatory delays of up to 72 hours.”

Dr. Kumar added that he’s “heard from emergency-room physicians and nurses who call and ask me what they can and cannot say when providing care for pregnant people in Texas and how they should be counseling their patients who may need emergency or urgent care after returning to Texas.”

Dr. Brandi cautioned colleagues that even ob.gyns. who don’t perform abortions will still be affected by the overturning of Roe. In some states, they’ll have to understand the rules about treating women with early ruptured membranes when cardiac motion is detected or with atopic pregnancies with cardiac activity at risk of potential tubal rupture.

The speakers urged colleagues to take action at the ballot box and their own clinics to protect patients. “While the recent leak is a truly scary moment for our country and for our practices, I’m hopeful that it will help galvanize our communities,” Dr. Brandi said. Regardless of where you live, regardless of where you practice, this ruling impacts all ob.gyns., everyone in this room. Each of us needs to go home after this conference and figure out what you are going to do to make sure that our patients can still get the care that they need.”

SAN DIEGO – The end of the legal standards set by Roe v. Wade will likely lead to bans in as many as 26 states and send a flood of abortion seekers to the remaining states that still allow the procedure, an obstetrician-gynecologist warned colleagues at the annual clinical and scientific meeting of the American College of Obstetricians and Gynecologists.

“The blue states neighboring those states will likely see an outpouring of patients among those who can travel,” Kristyn Brandi, MD, of New Jersey Medical School, Newark, said in a presentation about legal threats to abortion rights. “These will likely flood the health care systems and delay care for everyone. Make no mistake: Virtually all ob.gyns. across the country have the potential to be impacted.”

Indeed, research suggests that thousands more Texans than usual are heading out of state for abortions each month in the wake of a new, strict antiabortion law there.

Only three sessions at the 3-day ACOG meeting directly addressed abortion. But the topic was clearly on the minds of attendees in the wake of the release of a leaked draft of a Supreme Court ruling that would eliminate federal protection for abortion rights.

The 57,000-member ACOG organization firmly supports abortion rights and declares on its website that “Abortion Is Healthcare.”

In a workshop on challenges to abortion, ACOG chief of staff Dorothea Calvano Lindquist said “we remain your steadfast partner in advocacy and guidance on all levels.”

Ivana S. Thompson, MD, an ob.gyn. at Vanderbilt University, Nashville, Tenn., explained in a presentation that Roe v. Wade established a framework for regulations around abortion; they may not be regulated during the first trimester, but states may impose rules in the second semester that are related to health. “And then in the third trimester, once the fetus reaches viability, the state may regulate abortions or even prohibit them entirely, so long as there are exceptions for medical emergencies,” she said.

The Supreme Court ruling in the 1992 case of Planned Parenthood v. Casey did away with the trimester framework, Dr. Thompson said, and declared that abortion regulations could not place an “undue burden” on women.

This change allowed laws that “are purposely designed to trap providers and clinics and to restrict their ability to provide abortions, not due to health concerns but really just to prevent pregnant people from accessing care,” she said.

In 2018, Mississippi passed a law – which never went into effect and is now challenged before the Supreme Court – that makes most abortions illegal after 15 weeks. And in September 2021, a Texas law went into effect that outlaws abortions after a fetal heartbeat is detected.

What happens if Roe is overturned and laws that ban or severely limit abortion go into effect in states across the country? In Nashville, Dr. Thompson said, patients will have to travel to Illinois – more than 300 miles away – to reach the nearest abortion clinic.

“When I think about my own clinical practice over the last year, [if the law were in place] I would not have been able to offer an abortion to a developmentally delayed, nonverbal patient who was raped by her brother,” she said. “I would not have been able to offer an abortion to the service person who was sexually assaulted by a coworker in the field. I would not have been able to offer an abortion to a person with a pregnancy complicated by a hypoplastic left heart, congenital diaphragmatic hernias with the stomach in the thorax, an unformed lumbar spine, and other anomalies.”

Bhavik Kumar, MD, a family medicine physician and medical director for primary and trans care at Planned Parenthood Gulf Coast in Houston, said the effects of the new law in Texas are already apparent. As he told ABC News last fall, he used to perform 20-30 abortions per day, but the number dwindled immediately the day the law went into effect.

At the ACOG presentation, Dr. Kumar highlighted a March 2022 research brief that reported that abortions in Texas fell by half in the month after the law was implemented compared with the previous year. And the average number of abortions performed on Texans who left the state grew by more than 10-fold from the period of September-December 2019 (514) to September-December 2021 (5,574).

Once the law went into effect, Dr. Kumar said, “we began to see longer waiting times at clinics in nearby states, wait times that started out as short as a day go to an average of 2-3 weeks to get an initial appointment. And some of these states also have mandatory delays of up to 72 hours.”

Dr. Kumar added that he’s “heard from emergency-room physicians and nurses who call and ask me what they can and cannot say when providing care for pregnant people in Texas and how they should be counseling their patients who may need emergency or urgent care after returning to Texas.”

Dr. Brandi cautioned colleagues that even ob.gyns. who don’t perform abortions will still be affected by the overturning of Roe. In some states, they’ll have to understand the rules about treating women with early ruptured membranes when cardiac motion is detected or with atopic pregnancies with cardiac activity at risk of potential tubal rupture.

The speakers urged colleagues to take action at the ballot box and their own clinics to protect patients. “While the recent leak is a truly scary moment for our country and for our practices, I’m hopeful that it will help galvanize our communities,” Dr. Brandi said. Regardless of where you live, regardless of where you practice, this ruling impacts all ob.gyns., everyone in this room. Each of us needs to go home after this conference and figure out what you are going to do to make sure that our patients can still get the care that they need.”

A recent article on Medscape entitled “Online Reviews Most Important Factor in Choosing a Doctor: Survey” really got me thinking about my online presence. According to the results of a new Press Ganey survey, online reviews and star ratings are the most important factor for consumers when choosing a new health care provider, even more so than the recommendation of another doctor. Almost 85% of the survey respondents said they wouldn’t make an appointment with a referred provider if they had a rating of less than 4 stars.

To be honest, I’ve rarely thought about my ratings or online reviews, and I almost never enter my own name into a web browser to see what might emerge. I don’t use most popular social media apps, I don’t have a professional website, and I was completely late in joining LinkedIn. After considering the Press Ganey survey results, though, I’m wondering how many patients (or potential patients) have found me online. And what exactly did they see?

So, I just searched online for my ratings and reviews. There weren’t many direct hits (although I’m not sure if that is a good thing or not). One of the results listed me as a “Fibromyalgia Doctor” at www.lymeforums.org. To be clear, I’m a locum tenens infectious diseases provider with a focus on inpatient consultations and teaching. I couldn’t find any reviews for myself on WebMD, but I had one rating on the Healthgrades website – I was pleased to see someone gave me 5 stars (though there weren’t any comments) until I realized the site listed my address at an ob.gyn. office; I’m not even sure if that rating was meant for me.

Use of the Internet to assess my qualities as a physician is clearly limited, and much of the online information about my specialty and practice sites is completely inaccurate. Yet, according to the Press Ganey survey, the average consumer uses three different websites and reads more than five online reviews before making a provider decision. Once they’ve seen a provider, though, patients rank practice customer service and communication as more important than “bedside manner” when considering a 5-star review. So, it appears that many physician reviews and ratings probably reflect the performance of the office staff, not the provider.

Given the few hits that I encountered when searching my own name, I’m not convinced I need to do anything differently about my online presence; essentially, I don’t really have one. However, there were certainly a lot of other physicians with the same last name as mine who did have impressive numbers of reviews and ratings. One doctor of cosmetic surgery had more than 200 reviews on multiple sites; almost all were positive, but a few patients rated him at 1 or 2 (out of 5) stars, suggesting that patients should find a new surgeon. What does one do about those outliers?

Medicine is indeed a business and patients behave as consumers when searching the web for a health care provider. Another survey has suggested that just one negative review may cause a business to risk losing 22% of its customers, and that multiple bad ratings are even worse – nearly 60% of customers will avoid a business with three or more negative online reviews.

A few years ago, The Washington Post published an article about doctors who were fighting back against bad reviews. Unfortunately, while trying to directly combat inaccuracies, some providers divulged sensitive patient information and suffered the consequences of HIPAA violations. Many legal experts suggest that, in most cases, physicians should restrain from responding publicly to negative online reviews, however tempting it may be to react.

If a negative review is attributed to a specific patient, some lawyers recommend contacting them privately by phone to address their concerns; this may clear the air enough to result in a withdrawal of the negative review or rating. Flagging and reporting fake or unsubstantiated negative reviews (or reviews that violate the Terms of Service of a specific platform) can be done. Consultation with an Internet defamation attorney might be helpful in some circumstances, though hopefully, legal action such as a lawsuit or a cease-and-desist letter can be avoided.

For physicians who do maintain an online presence, engaging with an online reputation management service can help suppress fake or negative reviews while offering strategies for building a better reputation. As for me, I think that I’m grateful my name hasn’t attracted a lot of attention at physician ranking and review sites. I guess we’ll see if it stays that way.

Dr. Devlin is president of Locum Infectious Disease Services, and an independent contractor for Weatherby Healthcare. She has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

A recent article on Medscape entitled “Online Reviews Most Important Factor in Choosing a Doctor: Survey” really got me thinking about my online presence. According to the results of a new Press Ganey survey, online reviews and star ratings are the most important factor for consumers when choosing a new health care provider, even more so than the recommendation of another doctor. Almost 85% of the survey respondents said they wouldn’t make an appointment with a referred provider if they had a rating of less than 4 stars.

To be honest, I’ve rarely thought about my ratings or online reviews, and I almost never enter my own name into a web browser to see what might emerge. I don’t use most popular social media apps, I don’t have a professional website, and I was completely late in joining LinkedIn. After considering the Press Ganey survey results, though, I’m wondering how many patients (or potential patients) have found me online. And what exactly did they see?

So, I just searched online for my ratings and reviews. There weren’t many direct hits (although I’m not sure if that is a good thing or not). One of the results listed me as a “Fibromyalgia Doctor” at www.lymeforums.org. To be clear, I’m a locum tenens infectious diseases provider with a focus on inpatient consultations and teaching. I couldn’t find any reviews for myself on WebMD, but I had one rating on the Healthgrades website – I was pleased to see someone gave me 5 stars (though there weren’t any comments) until I realized the site listed my address at an ob.gyn. office; I’m not even sure if that rating was meant for me.

Use of the Internet to assess my qualities as a physician is clearly limited, and much of the online information about my specialty and practice sites is completely inaccurate. Yet, according to the Press Ganey survey, the average consumer uses three different websites and reads more than five online reviews before making a provider decision. Once they’ve seen a provider, though, patients rank practice customer service and communication as more important than “bedside manner” when considering a 5-star review. So, it appears that many physician reviews and ratings probably reflect the performance of the office staff, not the provider.

Given the few hits that I encountered when searching my own name, I’m not convinced I need to do anything differently about my online presence; essentially, I don’t really have one. However, there were certainly a lot of other physicians with the same last name as mine who did have impressive numbers of reviews and ratings. One doctor of cosmetic surgery had more than 200 reviews on multiple sites; almost all were positive, but a few patients rated him at 1 or 2 (out of 5) stars, suggesting that patients should find a new surgeon. What does one do about those outliers?

Medicine is indeed a business and patients behave as consumers when searching the web for a health care provider. Another survey has suggested that just one negative review may cause a business to risk losing 22% of its customers, and that multiple bad ratings are even worse – nearly 60% of customers will avoid a business with three or more negative online reviews.

A few years ago, The Washington Post published an article about doctors who were fighting back against bad reviews. Unfortunately, while trying to directly combat inaccuracies, some providers divulged sensitive patient information and suffered the consequences of HIPAA violations. Many legal experts suggest that, in most cases, physicians should restrain from responding publicly to negative online reviews, however tempting it may be to react.

If a negative review is attributed to a specific patient, some lawyers recommend contacting them privately by phone to address their concerns; this may clear the air enough to result in a withdrawal of the negative review or rating. Flagging and reporting fake or unsubstantiated negative reviews (or reviews that violate the Terms of Service of a specific platform) can be done. Consultation with an Internet defamation attorney might be helpful in some circumstances, though hopefully, legal action such as a lawsuit or a cease-and-desist letter can be avoided.

For physicians who do maintain an online presence, engaging with an online reputation management service can help suppress fake or negative reviews while offering strategies for building a better reputation. As for me, I think that I’m grateful my name hasn’t attracted a lot of attention at physician ranking and review sites. I guess we’ll see if it stays that way.

Dr. Devlin is president of Locum Infectious Disease Services, and an independent contractor for Weatherby Healthcare. She has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

A recent article on Medscape entitled “Online Reviews Most Important Factor in Choosing a Doctor: Survey” really got me thinking about my online presence. According to the results of a new Press Ganey survey, online reviews and star ratings are the most important factor for consumers when choosing a new health care provider, even more so than the recommendation of another doctor. Almost 85% of the survey respondents said they wouldn’t make an appointment with a referred provider if they had a rating of less than 4 stars.

To be honest, I’ve rarely thought about my ratings or online reviews, and I almost never enter my own name into a web browser to see what might emerge. I don’t use most popular social media apps, I don’t have a professional website, and I was completely late in joining LinkedIn. After considering the Press Ganey survey results, though, I’m wondering how many patients (or potential patients) have found me online. And what exactly did they see?

So, I just searched online for my ratings and reviews. There weren’t many direct hits (although I’m not sure if that is a good thing or not). One of the results listed me as a “Fibromyalgia Doctor” at www.lymeforums.org. To be clear, I’m a locum tenens infectious diseases provider with a focus on inpatient consultations and teaching. I couldn’t find any reviews for myself on WebMD, but I had one rating on the Healthgrades website – I was pleased to see someone gave me 5 stars (though there weren’t any comments) until I realized the site listed my address at an ob.gyn. office; I’m not even sure if that rating was meant for me.

Use of the Internet to assess my qualities as a physician is clearly limited, and much of the online information about my specialty and practice sites is completely inaccurate. Yet, according to the Press Ganey survey, the average consumer uses three different websites and reads more than five online reviews before making a provider decision. Once they’ve seen a provider, though, patients rank practice customer service and communication as more important than “bedside manner” when considering a 5-star review. So, it appears that many physician reviews and ratings probably reflect the performance of the office staff, not the provider.

Given the few hits that I encountered when searching my own name, I’m not convinced I need to do anything differently about my online presence; essentially, I don’t really have one. However, there were certainly a lot of other physicians with the same last name as mine who did have impressive numbers of reviews and ratings. One doctor of cosmetic surgery had more than 200 reviews on multiple sites; almost all were positive, but a few patients rated him at 1 or 2 (out of 5) stars, suggesting that patients should find a new surgeon. What does one do about those outliers?

Medicine is indeed a business and patients behave as consumers when searching the web for a health care provider. Another survey has suggested that just one negative review may cause a business to risk losing 22% of its customers, and that multiple bad ratings are even worse – nearly 60% of customers will avoid a business with three or more negative online reviews.

A few years ago, The Washington Post published an article about doctors who were fighting back against bad reviews. Unfortunately, while trying to directly combat inaccuracies, some providers divulged sensitive patient information and suffered the consequences of HIPAA violations. Many legal experts suggest that, in most cases, physicians should restrain from responding publicly to negative online reviews, however tempting it may be to react.

If a negative review is attributed to a specific patient, some lawyers recommend contacting them privately by phone to address their concerns; this may clear the air enough to result in a withdrawal of the negative review or rating. Flagging and reporting fake or unsubstantiated negative reviews (or reviews that violate the Terms of Service of a specific platform) can be done. Consultation with an Internet defamation attorney might be helpful in some circumstances, though hopefully, legal action such as a lawsuit or a cease-and-desist letter can be avoided.

For physicians who do maintain an online presence, engaging with an online reputation management service can help suppress fake or negative reviews while offering strategies for building a better reputation. As for me, I think that I’m grateful my name hasn’t attracted a lot of attention at physician ranking and review sites. I guess we’ll see if it stays that way.

Dr. Devlin is president of Locum Infectious Disease Services, and an independent contractor for Weatherby Healthcare. She has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

New data present further evidence that SARS-CoV-2 infection can settle in the gastrointestinal tract and that it can persist long after the infection has cleared the lungs.

Infection of the GI tract may figure prominently in long COVID, the study authors suggested.

Led by Aravind Natarajan, PhD, with the departments of genetics and medicine at Stanford (Calif.) University, they analyzed fecal RNA shedding up to 10 months after a COVID-19 diagnosis in 673 stool samples from 113 patients with mild to moderate disease.

They found that, in the week after diagnosis, COVID RNA remnants were present in the stool of approximately half (49.2%) of the patients. Seven months later, about 4% of them shed fecal viral RNA.

The authors noted that there was no ongoing SARS-CoV-2 RNA shedding in respiratory samples of patients at the 4-month mark.

Using self-reported symptoms regularly collected by questionnaire, they also found a correlation of long-term fecal shedding of SARS-CoV-2 RNA with abdominal pain, nausea, and vomiting.

The findings were published online in Med.
 

Implications of long-term viral shedding

Previous studies have found SARS-CoV-2 RNA in respiratory and fecal samples and have documented viral replication in lung and intestinal tissue. But before the current study, little had been known about long-term shedding, especially in those who have mild COVID. Most studies of viral shedding have been with severe COVID cases.

The authors noted that most studies of this kind are cross-sectional. The few other longitudinal studies have focused on early time points just after diagnosis.

Senior author Ami S. Bhatt, MD, associate professor in the departments of medicine and hematology at Stanford University, said in an interview that, though the viral genetic material in the feces lingers, on the basis of available evidence, it is highly unlikely to be contagious in most cases.

She said that understanding the dynamics of fecal shedding of SARS-CoV-2 genetic material will help interpret wastewater-based studies that are trying to determine population prevalence of the virus.

“While we don’t know the exact clinical importance of the longer-term shedding of SARS-CoV-2 in individuals with COVID-19, some have speculated that those who have long-term shedding of SARS-CoV-2 may have ongoing infections that might benefit from treatment,” she said.

“Our data support the idea that the long-term GI-related symptoms in some people might be the consequence of an ongoing infection in the GI tract, even after the respiratory infection has cleared,” Dr. Bhatt said.

“Alternatively, the presence of ongoing viral genetic material in the gut might be a trigger for the immune system to continually be active against the virus, and our immune system reaction may be the reason for long COVID–type symptoms,” she added. “This area is ripe for additional studies.”

Dr. Bhatt and colleagues will continue studying viral shedding in fecal samples as part of the nationwide RECOVER Initiative.

When reached for comment, David A. Johnson, MD, professor of medicine and chief of gastroenterology, Eastern Virginia Medical School, Norfolk, said in an interview that previous studies have indicated that the virus may be detected in the stool for a month or more and for about 2 weeks on average. Whether the virus is infectious has been in question.

But it’s not so much that the virus is infectious in the GI tract and causing symptoms, he said. Rather, there are biomic changes related to COVID, including a loss of diversity in the gut bacteria, which disrupts the balance.

“This may actually in some way predispose some patients to impaired clearance of their symptoms,” Dr. Johnson explained. “There seems to be a growing recognition that this entity called long-haul COVID may be related to specific bacterial disruptions, and the more rapidly you can resolve these disruptions, the less likely you are to continue with long-haul symptoms.”

He said that, among people who have mild COVID, the virus typically clears and gut bacteria return to normal. With severe or persistent illness, gut dysbiosis persists, he said.

“People need to be aware that the GI tract is involved in a sizable percent of patients with COVID,” Dr. Johnson said. “The GI-tract testing may reflect that the virus is there, but persistence of the detectable test positivity is very unlikely to reflect active virus.”

The authors noted that they collected only six samples from the participants over the 10-month study period.

“Follow-up studies with more frequent sampling, especially in the first 2 months after diagnosis, may help build a more nuanced model of decline of fecal viral RNA concentration over time,” they wrote.

The study was supported by a Stanford ChemH-IMA grant, fellowships from the AACR and the National Science Foundation, and the National Institutes of Health. The authors and Dr. Johnson reported no relevant financial relationships. Dr. Johnson is a regular contributor to this news organization.

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

New data present further evidence that SARS-CoV-2 infection can settle in the gastrointestinal tract and that it can persist long after the infection has cleared the lungs.

Infection of the GI tract may figure prominently in long COVID, the study authors suggested.

Led by Aravind Natarajan, PhD, with the departments of genetics and medicine at Stanford (Calif.) University, they analyzed fecal RNA shedding up to 10 months after a COVID-19 diagnosis in 673 stool samples from 113 patients with mild to moderate disease.

They found that, in the week after diagnosis, COVID RNA remnants were present in the stool of approximately half (49.2%) of the patients. Seven months later, about 4% of them shed fecal viral RNA.

The authors noted that there was no ongoing SARS-CoV-2 RNA shedding in respiratory samples of patients at the 4-month mark.

Using self-reported symptoms regularly collected by questionnaire, they also found a correlation of long-term fecal shedding of SARS-CoV-2 RNA with abdominal pain, nausea, and vomiting.

The findings were published online in Med.
 

Implications of long-term viral shedding

Previous studies have found SARS-CoV-2 RNA in respiratory and fecal samples and have documented viral replication in lung and intestinal tissue. But before the current study, little had been known about long-term shedding, especially in those who have mild COVID. Most studies of viral shedding have been with severe COVID cases.

The authors noted that most studies of this kind are cross-sectional. The few other longitudinal studies have focused on early time points just after diagnosis.

Senior author Ami S. Bhatt, MD, associate professor in the departments of medicine and hematology at Stanford University, said in an interview that, though the viral genetic material in the feces lingers, on the basis of available evidence, it is highly unlikely to be contagious in most cases.

She said that understanding the dynamics of fecal shedding of SARS-CoV-2 genetic material will help interpret wastewater-based studies that are trying to determine population prevalence of the virus.

“While we don’t know the exact clinical importance of the longer-term shedding of SARS-CoV-2 in individuals with COVID-19, some have speculated that those who have long-term shedding of SARS-CoV-2 may have ongoing infections that might benefit from treatment,” she said.

“Our data support the idea that the long-term GI-related symptoms in some people might be the consequence of an ongoing infection in the GI tract, even after the respiratory infection has cleared,” Dr. Bhatt said.

“Alternatively, the presence of ongoing viral genetic material in the gut might be a trigger for the immune system to continually be active against the virus, and our immune system reaction may be the reason for long COVID–type symptoms,” she added. “This area is ripe for additional studies.”

Dr. Bhatt and colleagues will continue studying viral shedding in fecal samples as part of the nationwide RECOVER Initiative.

When reached for comment, David A. Johnson, MD, professor of medicine and chief of gastroenterology, Eastern Virginia Medical School, Norfolk, said in an interview that previous studies have indicated that the virus may be detected in the stool for a month or more and for about 2 weeks on average. Whether the virus is infectious has been in question.

But it’s not so much that the virus is infectious in the GI tract and causing symptoms, he said. Rather, there are biomic changes related to COVID, including a loss of diversity in the gut bacteria, which disrupts the balance.

“This may actually in some way predispose some patients to impaired clearance of their symptoms,” Dr. Johnson explained. “There seems to be a growing recognition that this entity called long-haul COVID may be related to specific bacterial disruptions, and the more rapidly you can resolve these disruptions, the less likely you are to continue with long-haul symptoms.”

He said that, among people who have mild COVID, the virus typically clears and gut bacteria return to normal. With severe or persistent illness, gut dysbiosis persists, he said.

“People need to be aware that the GI tract is involved in a sizable percent of patients with COVID,” Dr. Johnson said. “The GI-tract testing may reflect that the virus is there, but persistence of the detectable test positivity is very unlikely to reflect active virus.”

The authors noted that they collected only six samples from the participants over the 10-month study period.

“Follow-up studies with more frequent sampling, especially in the first 2 months after diagnosis, may help build a more nuanced model of decline of fecal viral RNA concentration over time,” they wrote.

The study was supported by a Stanford ChemH-IMA grant, fellowships from the AACR and the National Science Foundation, and the National Institutes of Health. The authors and Dr. Johnson reported no relevant financial relationships. Dr. Johnson is a regular contributor to this news organization.

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

New data present further evidence that SARS-CoV-2 infection can settle in the gastrointestinal tract and that it can persist long after the infection has cleared the lungs.

Infection of the GI tract may figure prominently in long COVID, the study authors suggested.

Led by Aravind Natarajan, PhD, with the departments of genetics and medicine at Stanford (Calif.) University, they analyzed fecal RNA shedding up to 10 months after a COVID-19 diagnosis in 673 stool samples from 113 patients with mild to moderate disease.

They found that, in the week after diagnosis, COVID RNA remnants were present in the stool of approximately half (49.2%) of the patients. Seven months later, about 4% of them shed fecal viral RNA.

The authors noted that there was no ongoing SARS-CoV-2 RNA shedding in respiratory samples of patients at the 4-month mark.

Using self-reported symptoms regularly collected by questionnaire, they also found a correlation of long-term fecal shedding of SARS-CoV-2 RNA with abdominal pain, nausea, and vomiting.

The findings were published online in Med.
 

Implications of long-term viral shedding

Previous studies have found SARS-CoV-2 RNA in respiratory and fecal samples and have documented viral replication in lung and intestinal tissue. But before the current study, little had been known about long-term shedding, especially in those who have mild COVID. Most studies of viral shedding have been with severe COVID cases.

The authors noted that most studies of this kind are cross-sectional. The few other longitudinal studies have focused on early time points just after diagnosis.

Senior author Ami S. Bhatt, MD, associate professor in the departments of medicine and hematology at Stanford University, said in an interview that, though the viral genetic material in the feces lingers, on the basis of available evidence, it is highly unlikely to be contagious in most cases.

She said that understanding the dynamics of fecal shedding of SARS-CoV-2 genetic material will help interpret wastewater-based studies that are trying to determine population prevalence of the virus.

“While we don’t know the exact clinical importance of the longer-term shedding of SARS-CoV-2 in individuals with COVID-19, some have speculated that those who have long-term shedding of SARS-CoV-2 may have ongoing infections that might benefit from treatment,” she said.

“Our data support the idea that the long-term GI-related symptoms in some people might be the consequence of an ongoing infection in the GI tract, even after the respiratory infection has cleared,” Dr. Bhatt said.

“Alternatively, the presence of ongoing viral genetic material in the gut might be a trigger for the immune system to continually be active against the virus, and our immune system reaction may be the reason for long COVID–type symptoms,” she added. “This area is ripe for additional studies.”

Dr. Bhatt and colleagues will continue studying viral shedding in fecal samples as part of the nationwide RECOVER Initiative.

When reached for comment, David A. Johnson, MD, professor of medicine and chief of gastroenterology, Eastern Virginia Medical School, Norfolk, said in an interview that previous studies have indicated that the virus may be detected in the stool for a month or more and for about 2 weeks on average. Whether the virus is infectious has been in question.

But it’s not so much that the virus is infectious in the GI tract and causing symptoms, he said. Rather, there are biomic changes related to COVID, including a loss of diversity in the gut bacteria, which disrupts the balance.

“This may actually in some way predispose some patients to impaired clearance of their symptoms,” Dr. Johnson explained. “There seems to be a growing recognition that this entity called long-haul COVID may be related to specific bacterial disruptions, and the more rapidly you can resolve these disruptions, the less likely you are to continue with long-haul symptoms.”

He said that, among people who have mild COVID, the virus typically clears and gut bacteria return to normal. With severe or persistent illness, gut dysbiosis persists, he said.

“People need to be aware that the GI tract is involved in a sizable percent of patients with COVID,” Dr. Johnson said. “The GI-tract testing may reflect that the virus is there, but persistence of the detectable test positivity is very unlikely to reflect active virus.”

The authors noted that they collected only six samples from the participants over the 10-month study period.

“Follow-up studies with more frequent sampling, especially in the first 2 months after diagnosis, may help build a more nuanced model of decline of fecal viral RNA concentration over time,” they wrote.

The study was supported by a Stanford ChemH-IMA grant, fellowships from the AACR and the National Science Foundation, and the National Institutes of Health. The authors and Dr. Johnson reported no relevant financial relationships. Dr. Johnson is a regular contributor to this news organization.

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