MDedge Emergency Medicine

Since the start of the pandemic, supply-chain problems have permeated just about every industry sector. While most of the media attention has focused on toilet paper and retail shipment delays, a darker, more sinister supply chain disruption has been unfolding, one that entails a sophisticated criminal enterprise that has been operating at scale to distribute and profit from counterfeit HIV drugs.

Recently, news has emerged – most notably in the Wall Street Journal – with reports of a Justice Department investigation into what appears to be a national drug trafficking network comprising more than 70 distributors and marketers.

The details read like a best-selling crime novel.

Since last year, authorities have seized 85,247 bottles of counterfeit HIV drugs, both Biktarvy (bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg tablets) and Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets). Law enforcement has conducted raids at 17 locations in eight states. Doctored supply chain papers have provided cover for the fake medicines and the individuals behind them.

But unlike the inconvenience of sparse toilet paper, this crime poses life-threatening risks to millions of patients with HIV who rely on Biktarvy to suppress the virus or Descovy to prevent infection from it. Even worse, some patients have been exposed to over-the-counter painkillers or the antipsychotic drug quetiapine fumarate masquerading as HIV drugs in legitimate but repurposed bottles.

Gilead Sciences (Foster City, Calif.), which manufactures both Biktarvy and Descovy, declined to comment when contacted, instead referring this news organization to previous press statements.
 

Falsified HIV medications, illicit purchases over 2 Years

On Aug. 5, 2021, Gilead first warned the public that it had become aware of tampered and counterfeit Biktarvy and Descovy tablets. In coordination with the Food and Drug Administration, it alerted pharmacies to “investigate the potential for counterfeit or tampered Gilead medication sold by [unauthorized] distributors that may be within their recent supply.”

On Jan. 19, 2022, Gilead issued a second statement outlining ongoing actions in coordination with U.S. marshals and local law enforcement to remove these illegal medications from circulation and prevent further distribution.

The timing of the most recent announcement was not accidental. The day before, a federal judge serving the U.S. District Court for the Eastern District of New York unsealed documents detailing the company’s lawsuit against dozens of individuals and entities who they alleged had engaged in a highly coordinated effort to defraud pharmacies and consumers. The suit followed two prior Gilead filings that ultimately resulted in court-issued ex parte seizure orders (orders that allow a court to seize property without the property owner’s consent) and the recovery of more than 1,000 bottles containing questionable Gilead medications.

The lawsuit centered on Cambridge, Mass.–based wholesale pharmaceutical distributor Safe Chain Solutions and its two cofounders. The document is peppered with terms such as “shifting series of fly-by-night corporate entities,” “gray market” distributors, a “dedicated sales force,” and “shell entities,” along with accusations that the defendants were believed to have made purchases of gold bullion, jewelry, and other luxury items for conversion into cash.

In a curious twist of fate, this sinister effort appeared to have been first revealed not by a pharmacist but by a patient who had returned a bottle of Biktarvy with “foreign medication inside” to the California pharmacy that dispensed it.

“Specifically with HIV medications, there’s no point in which the pharmacy is actually opening the bottle, breaking the seal, and counting out pills to put into a smaller prescription bottle,” Emily Heil, PharmD, BCIDP, AAHIVP, associate professor of infectious diseases in the department of pharmacy practice and science at the University of Maryland School of Pharmacy, Baltimore, told this news organization.

“But that’s also why pharmacies work with these centralized groups of distributors that maintain a chain of command and fidelity with drug manufacturers so that we don’t run into these situations,” she said.

This is the link in the chain where that tightly coordinated and highly regulated process was broken.

Although Gilead and Safe Chain Solutions were informed of the incident as early as August 2020, the distributor repeatedly refused to identify the supplier and the pedigree (the record demonstrating the chain of all sales or transfers of a specific drug, going back to the manufacturer, as required by the FDA’s Drug Supply Chain Security Act in 2013).

Later that year, Janssen Pharmaceutical Companies of Johnson & Johnson issued a media statement saying that they had been alerted to the distribution of counterfeit Symtuza (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) to three pharmacies in the United States.

A spokesperson for the FDA declined to comment on the ongoing investigation when contacted by this news organization and instead wrote in an email that the agency “will continue to use all available tools to ensure consumers and patients have access to a safe and effective medical product supply.”
 

Old dog, new tricks

This is not the first time that HIV drugs have been targeted for criminal benefit. An analysis published in September 2014 in JAMA highlighted a federal investigation that year into a $32 million dollar scheme to defraud Medicare’s Part D program for HIV drugs and divert them for resale on the black market.

What’s more, prior research and news reports highlight the attractiveness of HIV drug diversion both for the buyer and the seller – not only because of the cost of the drugs themselves but also because of institutional or systemic deficiencies that exclude certain individuals from obtaining treatment through federal initiatives such as the Ryan White/AIDS Drug Assistance program.

In its most recent statement, Gilead reinforced that this practice remains alive and well.

On the buyer side, the company stated, many of the counterfeits originated from suppliers who purchased Gilead HIV medication from individuals after it was first dispensed to them. Unfortunately, the exploitation of individuals with low incomes who experience homelessness or substance use/abuse echoes a pattern whereby HIV patients sell medications to cover personal needs or are forced to buy them on the black market to keep up with their treatment regimens.

On the supply side, Gilead explained that individuals’ medications “are unlawfully resold ... on the secondary market by way of counterfeit supply chain documentation, concealing and fraudulently misrepresenting its origin. All of these counterfeits were sold as though they were legitimate Gilead products.”

But counterfeit pedigrees make it impossible to verify where the products came from, how they have been handled and stored, and what pills are in the bottles – all of which can have dire consequences for patients who ingest them.

The ramifications can be devastating.

“With HIV meds specifically, the worst case scenario would be if the medication is not actually the medication they’re supposed to be on,” said Dr. Heil, reinforcing that the increased safety net provided with viral suppression and against transmission is lost.

Dr. Heil pointed to another significant risk: resistance.

“In a situation like this, where maybe it’s not the full strength of the medication, maybe it’s expired and lost potency or was not stored correctly or is not even the accurate medication, changing those drug level exposures potentially puts the patient at risk for developing resistance to their regimen without them knowing.”

Yet another risk was posed by the replacement of HIV drugs with other medications, such as quetiapine, which increased the risk for life-threatening and irreversible side effects. The lawsuit included a story of a patient who unknowingly took quetiapine after receiving a counterfeit bottle of Biktarvy and could not speak or walk afterward.

Where this tale will ultimately end is unclear. There’s no telling what other activities or bad actors the Justice Department investigation will uncover as it works to unravel the counterfeit network’s activities and deal with its aftermath.

Regardless, clinicians are encouraged to inform HIV patients about the risks associated with counterfeit medications, how to determine whether the drugs they’ve been dispensed are authentic, and to report any product they believe to be counterfeit or to have been tampered with to their doctors, pharmacies, and to Gilead or other drug manufacturers.

“It’s okay to ask questions of your pharmacy about where they get their medications from,” noted Dr. Heil. “If patients have access to an independent pharmacy, it’s a great way for them to have a relationship with their pharmacist.

“We went into this profession to be able to have those conversations with patients,” Dr. Heil said.

The FDA recommends that patients receiving these medications who believe that their drugs may be counterfeit or who experience any adverse effects report the event to FDA’s MedWatch Safety Information and Adverse Event Reporting Program (1-800-FDA-1088 or www.fda.gov/medwatch).

Dr. Heil reported having no relevant financial relationships.

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

Since the start of the pandemic, supply-chain problems have permeated just about every industry sector. While most of the media attention has focused on toilet paper and retail shipment delays, a darker, more sinister supply chain disruption has been unfolding, one that entails a sophisticated criminal enterprise that has been operating at scale to distribute and profit from counterfeit HIV drugs.

Recently, news has emerged – most notably in the Wall Street Journal – with reports of a Justice Department investigation into what appears to be a national drug trafficking network comprising more than 70 distributors and marketers.

The details read like a best-selling crime novel.

Since last year, authorities have seized 85,247 bottles of counterfeit HIV drugs, both Biktarvy (bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg tablets) and Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets). Law enforcement has conducted raids at 17 locations in eight states. Doctored supply chain papers have provided cover for the fake medicines and the individuals behind them.

But unlike the inconvenience of sparse toilet paper, this crime poses life-threatening risks to millions of patients with HIV who rely on Biktarvy to suppress the virus or Descovy to prevent infection from it. Even worse, some patients have been exposed to over-the-counter painkillers or the antipsychotic drug quetiapine fumarate masquerading as HIV drugs in legitimate but repurposed bottles.

Gilead Sciences (Foster City, Calif.), which manufactures both Biktarvy and Descovy, declined to comment when contacted, instead referring this news organization to previous press statements.
 

Falsified HIV medications, illicit purchases over 2 Years

On Aug. 5, 2021, Gilead first warned the public that it had become aware of tampered and counterfeit Biktarvy and Descovy tablets. In coordination with the Food and Drug Administration, it alerted pharmacies to “investigate the potential for counterfeit or tampered Gilead medication sold by [unauthorized] distributors that may be within their recent supply.”

On Jan. 19, 2022, Gilead issued a second statement outlining ongoing actions in coordination with U.S. marshals and local law enforcement to remove these illegal medications from circulation and prevent further distribution.

The timing of the most recent announcement was not accidental. The day before, a federal judge serving the U.S. District Court for the Eastern District of New York unsealed documents detailing the company’s lawsuit against dozens of individuals and entities who they alleged had engaged in a highly coordinated effort to defraud pharmacies and consumers. The suit followed two prior Gilead filings that ultimately resulted in court-issued ex parte seizure orders (orders that allow a court to seize property without the property owner’s consent) and the recovery of more than 1,000 bottles containing questionable Gilead medications.

The lawsuit centered on Cambridge, Mass.–based wholesale pharmaceutical distributor Safe Chain Solutions and its two cofounders. The document is peppered with terms such as “shifting series of fly-by-night corporate entities,” “gray market” distributors, a “dedicated sales force,” and “shell entities,” along with accusations that the defendants were believed to have made purchases of gold bullion, jewelry, and other luxury items for conversion into cash.

In a curious twist of fate, this sinister effort appeared to have been first revealed not by a pharmacist but by a patient who had returned a bottle of Biktarvy with “foreign medication inside” to the California pharmacy that dispensed it.

“Specifically with HIV medications, there’s no point in which the pharmacy is actually opening the bottle, breaking the seal, and counting out pills to put into a smaller prescription bottle,” Emily Heil, PharmD, BCIDP, AAHIVP, associate professor of infectious diseases in the department of pharmacy practice and science at the University of Maryland School of Pharmacy, Baltimore, told this news organization.

“But that’s also why pharmacies work with these centralized groups of distributors that maintain a chain of command and fidelity with drug manufacturers so that we don’t run into these situations,” she said.

This is the link in the chain where that tightly coordinated and highly regulated process was broken.

Although Gilead and Safe Chain Solutions were informed of the incident as early as August 2020, the distributor repeatedly refused to identify the supplier and the pedigree (the record demonstrating the chain of all sales or transfers of a specific drug, going back to the manufacturer, as required by the FDA’s Drug Supply Chain Security Act in 2013).

Later that year, Janssen Pharmaceutical Companies of Johnson & Johnson issued a media statement saying that they had been alerted to the distribution of counterfeit Symtuza (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) to three pharmacies in the United States.

A spokesperson for the FDA declined to comment on the ongoing investigation when contacted by this news organization and instead wrote in an email that the agency “will continue to use all available tools to ensure consumers and patients have access to a safe and effective medical product supply.”
 

Old dog, new tricks

This is not the first time that HIV drugs have been targeted for criminal benefit. An analysis published in September 2014 in JAMA highlighted a federal investigation that year into a $32 million dollar scheme to defraud Medicare’s Part D program for HIV drugs and divert them for resale on the black market.

What’s more, prior research and news reports highlight the attractiveness of HIV drug diversion both for the buyer and the seller – not only because of the cost of the drugs themselves but also because of institutional or systemic deficiencies that exclude certain individuals from obtaining treatment through federal initiatives such as the Ryan White/AIDS Drug Assistance program.

In its most recent statement, Gilead reinforced that this practice remains alive and well.

On the buyer side, the company stated, many of the counterfeits originated from suppliers who purchased Gilead HIV medication from individuals after it was first dispensed to them. Unfortunately, the exploitation of individuals with low incomes who experience homelessness or substance use/abuse echoes a pattern whereby HIV patients sell medications to cover personal needs or are forced to buy them on the black market to keep up with their treatment regimens.

On the supply side, Gilead explained that individuals’ medications “are unlawfully resold ... on the secondary market by way of counterfeit supply chain documentation, concealing and fraudulently misrepresenting its origin. All of these counterfeits were sold as though they were legitimate Gilead products.”

But counterfeit pedigrees make it impossible to verify where the products came from, how they have been handled and stored, and what pills are in the bottles – all of which can have dire consequences for patients who ingest them.

The ramifications can be devastating.

“With HIV meds specifically, the worst case scenario would be if the medication is not actually the medication they’re supposed to be on,” said Dr. Heil, reinforcing that the increased safety net provided with viral suppression and against transmission is lost.

Dr. Heil pointed to another significant risk: resistance.

“In a situation like this, where maybe it’s not the full strength of the medication, maybe it’s expired and lost potency or was not stored correctly or is not even the accurate medication, changing those drug level exposures potentially puts the patient at risk for developing resistance to their regimen without them knowing.”

Yet another risk was posed by the replacement of HIV drugs with other medications, such as quetiapine, which increased the risk for life-threatening and irreversible side effects. The lawsuit included a story of a patient who unknowingly took quetiapine after receiving a counterfeit bottle of Biktarvy and could not speak or walk afterward.

Where this tale will ultimately end is unclear. There’s no telling what other activities or bad actors the Justice Department investigation will uncover as it works to unravel the counterfeit network’s activities and deal with its aftermath.

Regardless, clinicians are encouraged to inform HIV patients about the risks associated with counterfeit medications, how to determine whether the drugs they’ve been dispensed are authentic, and to report any product they believe to be counterfeit or to have been tampered with to their doctors, pharmacies, and to Gilead or other drug manufacturers.

“It’s okay to ask questions of your pharmacy about where they get their medications from,” noted Dr. Heil. “If patients have access to an independent pharmacy, it’s a great way for them to have a relationship with their pharmacist.

“We went into this profession to be able to have those conversations with patients,” Dr. Heil said.

The FDA recommends that patients receiving these medications who believe that their drugs may be counterfeit or who experience any adverse effects report the event to FDA’s MedWatch Safety Information and Adverse Event Reporting Program (1-800-FDA-1088 or www.fda.gov/medwatch).

Dr. Heil reported having no relevant financial relationships.

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

Since the start of the pandemic, supply-chain problems have permeated just about every industry sector. While most of the media attention has focused on toilet paper and retail shipment delays, a darker, more sinister supply chain disruption has been unfolding, one that entails a sophisticated criminal enterprise that has been operating at scale to distribute and profit from counterfeit HIV drugs.

Recently, news has emerged – most notably in the Wall Street Journal – with reports of a Justice Department investigation into what appears to be a national drug trafficking network comprising more than 70 distributors and marketers.

The details read like a best-selling crime novel.

Since last year, authorities have seized 85,247 bottles of counterfeit HIV drugs, both Biktarvy (bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg tablets) and Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg tablets). Law enforcement has conducted raids at 17 locations in eight states. Doctored supply chain papers have provided cover for the fake medicines and the individuals behind them.

But unlike the inconvenience of sparse toilet paper, this crime poses life-threatening risks to millions of patients with HIV who rely on Biktarvy to suppress the virus or Descovy to prevent infection from it. Even worse, some patients have been exposed to over-the-counter painkillers or the antipsychotic drug quetiapine fumarate masquerading as HIV drugs in legitimate but repurposed bottles.

Gilead Sciences (Foster City, Calif.), which manufactures both Biktarvy and Descovy, declined to comment when contacted, instead referring this news organization to previous press statements.
 

Falsified HIV medications, illicit purchases over 2 Years

On Aug. 5, 2021, Gilead first warned the public that it had become aware of tampered and counterfeit Biktarvy and Descovy tablets. In coordination with the Food and Drug Administration, it alerted pharmacies to “investigate the potential for counterfeit or tampered Gilead medication sold by [unauthorized] distributors that may be within their recent supply.”

On Jan. 19, 2022, Gilead issued a second statement outlining ongoing actions in coordination with U.S. marshals and local law enforcement to remove these illegal medications from circulation and prevent further distribution.

The timing of the most recent announcement was not accidental. The day before, a federal judge serving the U.S. District Court for the Eastern District of New York unsealed documents detailing the company’s lawsuit against dozens of individuals and entities who they alleged had engaged in a highly coordinated effort to defraud pharmacies and consumers. The suit followed two prior Gilead filings that ultimately resulted in court-issued ex parte seizure orders (orders that allow a court to seize property without the property owner’s consent) and the recovery of more than 1,000 bottles containing questionable Gilead medications.

The lawsuit centered on Cambridge, Mass.–based wholesale pharmaceutical distributor Safe Chain Solutions and its two cofounders. The document is peppered with terms such as “shifting series of fly-by-night corporate entities,” “gray market” distributors, a “dedicated sales force,” and “shell entities,” along with accusations that the defendants were believed to have made purchases of gold bullion, jewelry, and other luxury items for conversion into cash.

In a curious twist of fate, this sinister effort appeared to have been first revealed not by a pharmacist but by a patient who had returned a bottle of Biktarvy with “foreign medication inside” to the California pharmacy that dispensed it.

“Specifically with HIV medications, there’s no point in which the pharmacy is actually opening the bottle, breaking the seal, and counting out pills to put into a smaller prescription bottle,” Emily Heil, PharmD, BCIDP, AAHIVP, associate professor of infectious diseases in the department of pharmacy practice and science at the University of Maryland School of Pharmacy, Baltimore, told this news organization.

“But that’s also why pharmacies work with these centralized groups of distributors that maintain a chain of command and fidelity with drug manufacturers so that we don’t run into these situations,” she said.

This is the link in the chain where that tightly coordinated and highly regulated process was broken.

Although Gilead and Safe Chain Solutions were informed of the incident as early as August 2020, the distributor repeatedly refused to identify the supplier and the pedigree (the record demonstrating the chain of all sales or transfers of a specific drug, going back to the manufacturer, as required by the FDA’s Drug Supply Chain Security Act in 2013).

Later that year, Janssen Pharmaceutical Companies of Johnson & Johnson issued a media statement saying that they had been alerted to the distribution of counterfeit Symtuza (darunavir/cobicistat/emtricitabine/tenofovir alafenamide) to three pharmacies in the United States.

A spokesperson for the FDA declined to comment on the ongoing investigation when contacted by this news organization and instead wrote in an email that the agency “will continue to use all available tools to ensure consumers and patients have access to a safe and effective medical product supply.”
 

Old dog, new tricks

This is not the first time that HIV drugs have been targeted for criminal benefit. An analysis published in September 2014 in JAMA highlighted a federal investigation that year into a $32 million dollar scheme to defraud Medicare’s Part D program for HIV drugs and divert them for resale on the black market.

What’s more, prior research and news reports highlight the attractiveness of HIV drug diversion both for the buyer and the seller – not only because of the cost of the drugs themselves but also because of institutional or systemic deficiencies that exclude certain individuals from obtaining treatment through federal initiatives such as the Ryan White/AIDS Drug Assistance program.

In its most recent statement, Gilead reinforced that this practice remains alive and well.

On the buyer side, the company stated, many of the counterfeits originated from suppliers who purchased Gilead HIV medication from individuals after it was first dispensed to them. Unfortunately, the exploitation of individuals with low incomes who experience homelessness or substance use/abuse echoes a pattern whereby HIV patients sell medications to cover personal needs or are forced to buy them on the black market to keep up with their treatment regimens.

On the supply side, Gilead explained that individuals’ medications “are unlawfully resold ... on the secondary market by way of counterfeit supply chain documentation, concealing and fraudulently misrepresenting its origin. All of these counterfeits were sold as though they were legitimate Gilead products.”

But counterfeit pedigrees make it impossible to verify where the products came from, how they have been handled and stored, and what pills are in the bottles – all of which can have dire consequences for patients who ingest them.

The ramifications can be devastating.

“With HIV meds specifically, the worst case scenario would be if the medication is not actually the medication they’re supposed to be on,” said Dr. Heil, reinforcing that the increased safety net provided with viral suppression and against transmission is lost.

Dr. Heil pointed to another significant risk: resistance.

“In a situation like this, where maybe it’s not the full strength of the medication, maybe it’s expired and lost potency or was not stored correctly or is not even the accurate medication, changing those drug level exposures potentially puts the patient at risk for developing resistance to their regimen without them knowing.”

Yet another risk was posed by the replacement of HIV drugs with other medications, such as quetiapine, which increased the risk for life-threatening and irreversible side effects. The lawsuit included a story of a patient who unknowingly took quetiapine after receiving a counterfeit bottle of Biktarvy and could not speak or walk afterward.

Where this tale will ultimately end is unclear. There’s no telling what other activities or bad actors the Justice Department investigation will uncover as it works to unravel the counterfeit network’s activities and deal with its aftermath.

Regardless, clinicians are encouraged to inform HIV patients about the risks associated with counterfeit medications, how to determine whether the drugs they’ve been dispensed are authentic, and to report any product they believe to be counterfeit or to have been tampered with to their doctors, pharmacies, and to Gilead or other drug manufacturers.

“It’s okay to ask questions of your pharmacy about where they get their medications from,” noted Dr. Heil. “If patients have access to an independent pharmacy, it’s a great way for them to have a relationship with their pharmacist.

“We went into this profession to be able to have those conversations with patients,” Dr. Heil said.

The FDA recommends that patients receiving these medications who believe that their drugs may be counterfeit or who experience any adverse effects report the event to FDA’s MedWatch Safety Information and Adverse Event Reporting Program (1-800-FDA-1088 or www.fda.gov/medwatch).

Dr. Heil reported having no relevant financial relationships.

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

The number of overdose deaths in adolescents nearly doubled in 2020 from the year before and increased substantially again in 2021 after nearly a decade of fairly stable rates, according to data published in a JAMA research letter.

Most of the deaths involved fentanyl, the researchers found.

Joseph Friedman, MPH, of the Center for Social Medicine and Humanities at the University of California, Los Angeles, led the study, which analyzed adolescent (14-18 years old) overdose deaths in the United States from 2010 to June 2021 in light of increasing contamination in the supply of illicit drugs.

The researchers found there were 518 deaths among adolescents (2.40 per 100,000 population) in 2010, and the rates remained stable through 2019 with 492 deaths (2.36 per 100,000).

In 2020, however, deaths spiked to 954 (4.57 per 100 000), increasing by 94.3%, compared with 2019. In 2021, they increased another 20%.

The rise in fentanyl-involved deaths was particularly striking. Fentanyl-involved deaths increased from 253 (1.21 per 100,000) in 2019 to 680 (3.26 per 100,000) in 2020. The numbers through June 2021 were annualized for 2021 and calculations predicted 884 deaths (4.23 per 100,000) for the year.
 

Numbers point to fentanyl potency

In 2021, more than three-fourths (77.14%) of adolescent overdose deaths involved fentanyl, compared with 13.26% for benzodiazepines, 9.77% for methamphetamine, 7.33% for cocaine, 5.76% for prescription opioids, and 2.27% for heroin.

American Indian and Alaska Native adolescents had the highest overdose rate in 2021 (n = 24; 11.79 per 100,000), followed by Latinx adolescents (n = 354; 6.98 per 100,000).

“These adolescent trends fit a wider pattern of increasing racial and ethnic inequalities in overdose that deserve further investigation and intervention efforts,” the authors wrote.
 

Pandemic’s role unclear

The spikes in adolescent overdoses overlap the COVID-19 pandemic, but Dr. Friedman said in an interview the pandemic “may or may not have been a big factor. “

The authors wrote that drug use had generally been stable among adolescents between 2010 and 2020. The number of 10th graders reporting any illicit drug use was 30.2% in 2010 and 30.4% in 2020.

“So it’s not that more teens are using drugs. It’s just that drug use is becoming more dangerous due to the spread of counterfeit pills containing fentanyls,” Dr. Friedman said.

The authors noted that “the illicit drug supply has increasingly become contaminated with illicitly manufactured fentanyls and other synthetic opioid and benzodiazepine analogues.”

Mr. Friedman said the pandemic may have accelerated the spread of more dangerous forms of drugs as supply chains were disrupted.

Benjamin Brady, DrPH, an assistant professor at the University of Arizona, Tucson, who also has an appointment in the university’s Comprehensive Pain and Addiction Center, said in an interview the numbers that Dr. Friedman and colleagues present represent “worst fears coming true.”

He said he and his colleagues in the field “were anticipating a rise in overdose deaths for the next 5-10 years because of the way the supply-and-demand environment exists in the U.S.”

Dr. Brady explained that restricting access to prescription opioids has had an unfortunate side effect in decreasing access to a safer supply of drugs.

“Without having solutions that would reduce demand at the same rate, supply of the safer form of the drug has been reduced; that has pushed people toward heroin and street drugs and from 2016 on those have been adulterated with fentanyl,” he said.

He said the United States, compared with other developed nations, has been slower to embrace longer-term harm-reduction strategies and to improve access to treatment and care.

COVID likely also has exacerbated the problem in terms of isolation and reduction in quality of life that has adolescents seeking to fill that void with drugs, Dr. Brady said. They may be completely unaware that the drugs they are seeking are commonly cut with counterfeit fentanyl.

“Fentanyl can be up to 50 times stronger than heroin,” he noted. “Even just a little bit of fentanyl dramatically changes the risk profile on an overdose.”

Increasing rates of mental health concerns among adolescents over decades also contribute to drug-seeking trends, Dr. Brady noted.
 

Overdose increases in the overall population were smaller

In the overall population, the percentage increases were not nearly as large in 2020 and 2021 as they were for adolescents.

Rates of overdose deaths in the overall population increased steadily from 2010 and reached 70,630 in 2019. In 2020, the deaths increased to 91,799 (an increase of 29.48% from 2019) and increased 11.48% in 2021.

The researchers analyzed numbers from the Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiologic Research) database, which has records of all U.S. deaths for which drug overdose was listed as the underlying cause.

The authors and Dr. Brady report no relevant financial relationships.

The number of overdose deaths in adolescents nearly doubled in 2020 from the year before and increased substantially again in 2021 after nearly a decade of fairly stable rates, according to data published in a JAMA research letter.

Most of the deaths involved fentanyl, the researchers found.

Joseph Friedman, MPH, of the Center for Social Medicine and Humanities at the University of California, Los Angeles, led the study, which analyzed adolescent (14-18 years old) overdose deaths in the United States from 2010 to June 2021 in light of increasing contamination in the supply of illicit drugs.

The researchers found there were 518 deaths among adolescents (2.40 per 100,000 population) in 2010, and the rates remained stable through 2019 with 492 deaths (2.36 per 100,000).

In 2020, however, deaths spiked to 954 (4.57 per 100 000), increasing by 94.3%, compared with 2019. In 2021, they increased another 20%.

The rise in fentanyl-involved deaths was particularly striking. Fentanyl-involved deaths increased from 253 (1.21 per 100,000) in 2019 to 680 (3.26 per 100,000) in 2020. The numbers through June 2021 were annualized for 2021 and calculations predicted 884 deaths (4.23 per 100,000) for the year.
 

Numbers point to fentanyl potency

In 2021, more than three-fourths (77.14%) of adolescent overdose deaths involved fentanyl, compared with 13.26% for benzodiazepines, 9.77% for methamphetamine, 7.33% for cocaine, 5.76% for prescription opioids, and 2.27% for heroin.

American Indian and Alaska Native adolescents had the highest overdose rate in 2021 (n = 24; 11.79 per 100,000), followed by Latinx adolescents (n = 354; 6.98 per 100,000).

“These adolescent trends fit a wider pattern of increasing racial and ethnic inequalities in overdose that deserve further investigation and intervention efforts,” the authors wrote.
 

Pandemic’s role unclear

The spikes in adolescent overdoses overlap the COVID-19 pandemic, but Dr. Friedman said in an interview the pandemic “may or may not have been a big factor. “

The authors wrote that drug use had generally been stable among adolescents between 2010 and 2020. The number of 10th graders reporting any illicit drug use was 30.2% in 2010 and 30.4% in 2020.

“So it’s not that more teens are using drugs. It’s just that drug use is becoming more dangerous due to the spread of counterfeit pills containing fentanyls,” Dr. Friedman said.

The authors noted that “the illicit drug supply has increasingly become contaminated with illicitly manufactured fentanyls and other synthetic opioid and benzodiazepine analogues.”

Mr. Friedman said the pandemic may have accelerated the spread of more dangerous forms of drugs as supply chains were disrupted.

Benjamin Brady, DrPH, an assistant professor at the University of Arizona, Tucson, who also has an appointment in the university’s Comprehensive Pain and Addiction Center, said in an interview the numbers that Dr. Friedman and colleagues present represent “worst fears coming true.”

He said he and his colleagues in the field “were anticipating a rise in overdose deaths for the next 5-10 years because of the way the supply-and-demand environment exists in the U.S.”

Dr. Brady explained that restricting access to prescription opioids has had an unfortunate side effect in decreasing access to a safer supply of drugs.

“Without having solutions that would reduce demand at the same rate, supply of the safer form of the drug has been reduced; that has pushed people toward heroin and street drugs and from 2016 on those have been adulterated with fentanyl,” he said.

He said the United States, compared with other developed nations, has been slower to embrace longer-term harm-reduction strategies and to improve access to treatment and care.

COVID likely also has exacerbated the problem in terms of isolation and reduction in quality of life that has adolescents seeking to fill that void with drugs, Dr. Brady said. They may be completely unaware that the drugs they are seeking are commonly cut with counterfeit fentanyl.

“Fentanyl can be up to 50 times stronger than heroin,” he noted. “Even just a little bit of fentanyl dramatically changes the risk profile on an overdose.”

Increasing rates of mental health concerns among adolescents over decades also contribute to drug-seeking trends, Dr. Brady noted.
 

Overdose increases in the overall population were smaller

In the overall population, the percentage increases were not nearly as large in 2020 and 2021 as they were for adolescents.

Rates of overdose deaths in the overall population increased steadily from 2010 and reached 70,630 in 2019. In 2020, the deaths increased to 91,799 (an increase of 29.48% from 2019) and increased 11.48% in 2021.

The researchers analyzed numbers from the Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiologic Research) database, which has records of all U.S. deaths for which drug overdose was listed as the underlying cause.

The authors and Dr. Brady report no relevant financial relationships.

The number of overdose deaths in adolescents nearly doubled in 2020 from the year before and increased substantially again in 2021 after nearly a decade of fairly stable rates, according to data published in a JAMA research letter.

Most of the deaths involved fentanyl, the researchers found.

Joseph Friedman, MPH, of the Center for Social Medicine and Humanities at the University of California, Los Angeles, led the study, which analyzed adolescent (14-18 years old) overdose deaths in the United States from 2010 to June 2021 in light of increasing contamination in the supply of illicit drugs.

The researchers found there were 518 deaths among adolescents (2.40 per 100,000 population) in 2010, and the rates remained stable through 2019 with 492 deaths (2.36 per 100,000).

In 2020, however, deaths spiked to 954 (4.57 per 100 000), increasing by 94.3%, compared with 2019. In 2021, they increased another 20%.

The rise in fentanyl-involved deaths was particularly striking. Fentanyl-involved deaths increased from 253 (1.21 per 100,000) in 2019 to 680 (3.26 per 100,000) in 2020. The numbers through June 2021 were annualized for 2021 and calculations predicted 884 deaths (4.23 per 100,000) for the year.
 

Numbers point to fentanyl potency

In 2021, more than three-fourths (77.14%) of adolescent overdose deaths involved fentanyl, compared with 13.26% for benzodiazepines, 9.77% for methamphetamine, 7.33% for cocaine, 5.76% for prescription opioids, and 2.27% for heroin.

American Indian and Alaska Native adolescents had the highest overdose rate in 2021 (n = 24; 11.79 per 100,000), followed by Latinx adolescents (n = 354; 6.98 per 100,000).

“These adolescent trends fit a wider pattern of increasing racial and ethnic inequalities in overdose that deserve further investigation and intervention efforts,” the authors wrote.
 

Pandemic’s role unclear

The spikes in adolescent overdoses overlap the COVID-19 pandemic, but Dr. Friedman said in an interview the pandemic “may or may not have been a big factor. “

The authors wrote that drug use had generally been stable among adolescents between 2010 and 2020. The number of 10th graders reporting any illicit drug use was 30.2% in 2010 and 30.4% in 2020.

“So it’s not that more teens are using drugs. It’s just that drug use is becoming more dangerous due to the spread of counterfeit pills containing fentanyls,” Dr. Friedman said.

The authors noted that “the illicit drug supply has increasingly become contaminated with illicitly manufactured fentanyls and other synthetic opioid and benzodiazepine analogues.”

Mr. Friedman said the pandemic may have accelerated the spread of more dangerous forms of drugs as supply chains were disrupted.

Benjamin Brady, DrPH, an assistant professor at the University of Arizona, Tucson, who also has an appointment in the university’s Comprehensive Pain and Addiction Center, said in an interview the numbers that Dr. Friedman and colleagues present represent “worst fears coming true.”

He said he and his colleagues in the field “were anticipating a rise in overdose deaths for the next 5-10 years because of the way the supply-and-demand environment exists in the U.S.”

Dr. Brady explained that restricting access to prescription opioids has had an unfortunate side effect in decreasing access to a safer supply of drugs.

“Without having solutions that would reduce demand at the same rate, supply of the safer form of the drug has been reduced; that has pushed people toward heroin and street drugs and from 2016 on those have been adulterated with fentanyl,” he said.

He said the United States, compared with other developed nations, has been slower to embrace longer-term harm-reduction strategies and to improve access to treatment and care.

COVID likely also has exacerbated the problem in terms of isolation and reduction in quality of life that has adolescents seeking to fill that void with drugs, Dr. Brady said. They may be completely unaware that the drugs they are seeking are commonly cut with counterfeit fentanyl.

“Fentanyl can be up to 50 times stronger than heroin,” he noted. “Even just a little bit of fentanyl dramatically changes the risk profile on an overdose.”

Increasing rates of mental health concerns among adolescents over decades also contribute to drug-seeking trends, Dr. Brady noted.
 

Overdose increases in the overall population were smaller

In the overall population, the percentage increases were not nearly as large in 2020 and 2021 as they were for adolescents.

Rates of overdose deaths in the overall population increased steadily from 2010 and reached 70,630 in 2019. In 2020, the deaths increased to 91,799 (an increase of 29.48% from 2019) and increased 11.48% in 2021.

The researchers analyzed numbers from the Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiologic Research) database, which has records of all U.S. deaths for which drug overdose was listed as the underlying cause.

The authors and Dr. Brady report no relevant financial relationships.

An analysis at a large academic health system suggests that universal screening might help to reduce problematic disparities in depression treatment.  

The study began soon after the U.S. Preventive Services Task Force recommended depression screening for all adults in 2016. The task force based this recommendation on evidence that people who are screened and treated experience fewer debilitating symptoms.

In the new research, the investigators analyzed electronic health record data following a rollout of a universal depression screening program at the University of California, San Francisco. The researchers found that the overall rate of depression screening doubled at six primary care practices over a little more than 2 years, reaching nearly 90%. The investigators presented the data April 9 at the Society of General Internal Medicine 2022 Annual Meeting in Orlando.

Meanwhile, screening disparities diminished for men, older individuals, racial and ethnic minorities, and people with language barriers – all groups that are undertreated for depression.

“It shows that if a health system is really invested, it can achieve really high depression screening,” primary investigator Maria Garcia, MD, MPH, co-director of UCSF’s Multiethnic Health Equity Research Center, told this news organization.
 

Methods for identifying depression

The health system assigned medical assistants to administer annual screening using a validated tool, the Patient Health Questionnaire-2 (PHQ-2). A “yes” response to either of its two questions triggered a longer questionnaire, the PHQ-9, used to diagnose and guide treatment.

Screening forms were available in multiple languages. Medical assistants received training on the importance of identifying depression in undertreated groups, and a banner was inserted in the electronic health record to indicate a screening was due, Dr. Garcia said.

During the rollout, a committee was assigned to monitor screening rates and adjust strategies to target disparities.

Dr. Garcia and fellow researchers calculated the likelihood of a patient being screened starting in September 2017 – when a field for depression screening status was added to the system’s electronic health record – until the rollout was completed on Dec. 31, 2019.
 

Screening disparities narrowed for all groups studied

The screening rate for patients who had a primary care visit increased from 40.5% to 88.8%. Early on, patients with language barriers were less likely to be screened than English-speaking White individuals (odds ratios, 0.55-0.59). Men were less likely to be screened than women (OR, 0.82; 95% confidence interval, 0.78-0.86), and the likelihood of being screened decreased as people got older. By 2019, screening disparities had narrowed for all groups and were only statistically significant for men (OR, 0.87; 95% CI, 0.81-0.93).

Ian Kronish, MD, MPH, a general internist and associate professor of medicine at Columbia University, New York, called the increases “impressive,” adding that the data show universal depression screening is possible in a system that serves a diverse population.

Dr. Kronish, who was not involved in this study, noted that other research indicates screening does not result in a significant reduction in depressive symptoms in the overall population. He found this to be the case in a trial he led, which focused on patients with recent cardiac events, for example.

“Given all the effort that is going into depression screening and the inclusion of depression screening as a quality metric, we need definitive randomized clinical trials testing whether depression screening leads to increased treatment uptake and, importantly, improved depressive symptoms and quality of life,” he said.

Dr. Garcia acknowledged that more work needs to be done to address treatment barriers, such as language and lack of insurance, and assess whether greater recognition of depressive symptoms in underserved groups can lead to effective treatment. “But this is an important step to know that universal depression screening narrowed disparities in screening over time,” she added.

Dr. Garcia and Dr. Kronish have disclosed no relevant financial relationships.

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

An analysis at a large academic health system suggests that universal screening might help to reduce problematic disparities in depression treatment.  

The study began soon after the U.S. Preventive Services Task Force recommended depression screening for all adults in 2016. The task force based this recommendation on evidence that people who are screened and treated experience fewer debilitating symptoms.

In the new research, the investigators analyzed electronic health record data following a rollout of a universal depression screening program at the University of California, San Francisco. The researchers found that the overall rate of depression screening doubled at six primary care practices over a little more than 2 years, reaching nearly 90%. The investigators presented the data April 9 at the Society of General Internal Medicine 2022 Annual Meeting in Orlando.

Meanwhile, screening disparities diminished for men, older individuals, racial and ethnic minorities, and people with language barriers – all groups that are undertreated for depression.

“It shows that if a health system is really invested, it can achieve really high depression screening,” primary investigator Maria Garcia, MD, MPH, co-director of UCSF’s Multiethnic Health Equity Research Center, told this news organization.
 

Methods for identifying depression

The health system assigned medical assistants to administer annual screening using a validated tool, the Patient Health Questionnaire-2 (PHQ-2). A “yes” response to either of its two questions triggered a longer questionnaire, the PHQ-9, used to diagnose and guide treatment.

Screening forms were available in multiple languages. Medical assistants received training on the importance of identifying depression in undertreated groups, and a banner was inserted in the electronic health record to indicate a screening was due, Dr. Garcia said.

During the rollout, a committee was assigned to monitor screening rates and adjust strategies to target disparities.

Dr. Garcia and fellow researchers calculated the likelihood of a patient being screened starting in September 2017 – when a field for depression screening status was added to the system’s electronic health record – until the rollout was completed on Dec. 31, 2019.
 

Screening disparities narrowed for all groups studied

The screening rate for patients who had a primary care visit increased from 40.5% to 88.8%. Early on, patients with language barriers were less likely to be screened than English-speaking White individuals (odds ratios, 0.55-0.59). Men were less likely to be screened than women (OR, 0.82; 95% confidence interval, 0.78-0.86), and the likelihood of being screened decreased as people got older. By 2019, screening disparities had narrowed for all groups and were only statistically significant for men (OR, 0.87; 95% CI, 0.81-0.93).

Ian Kronish, MD, MPH, a general internist and associate professor of medicine at Columbia University, New York, called the increases “impressive,” adding that the data show universal depression screening is possible in a system that serves a diverse population.

Dr. Kronish, who was not involved in this study, noted that other research indicates screening does not result in a significant reduction in depressive symptoms in the overall population. He found this to be the case in a trial he led, which focused on patients with recent cardiac events, for example.

“Given all the effort that is going into depression screening and the inclusion of depression screening as a quality metric, we need definitive randomized clinical trials testing whether depression screening leads to increased treatment uptake and, importantly, improved depressive symptoms and quality of life,” he said.

Dr. Garcia acknowledged that more work needs to be done to address treatment barriers, such as language and lack of insurance, and assess whether greater recognition of depressive symptoms in underserved groups can lead to effective treatment. “But this is an important step to know that universal depression screening narrowed disparities in screening over time,” she added.

Dr. Garcia and Dr. Kronish have disclosed no relevant financial relationships.

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

An analysis at a large academic health system suggests that universal screening might help to reduce problematic disparities in depression treatment.  

The study began soon after the U.S. Preventive Services Task Force recommended depression screening for all adults in 2016. The task force based this recommendation on evidence that people who are screened and treated experience fewer debilitating symptoms.

In the new research, the investigators analyzed electronic health record data following a rollout of a universal depression screening program at the University of California, San Francisco. The researchers found that the overall rate of depression screening doubled at six primary care practices over a little more than 2 years, reaching nearly 90%. The investigators presented the data April 9 at the Society of General Internal Medicine 2022 Annual Meeting in Orlando.

Meanwhile, screening disparities diminished for men, older individuals, racial and ethnic minorities, and people with language barriers – all groups that are undertreated for depression.

“It shows that if a health system is really invested, it can achieve really high depression screening,” primary investigator Maria Garcia, MD, MPH, co-director of UCSF’s Multiethnic Health Equity Research Center, told this news organization.
 

Methods for identifying depression

The health system assigned medical assistants to administer annual screening using a validated tool, the Patient Health Questionnaire-2 (PHQ-2). A “yes” response to either of its two questions triggered a longer questionnaire, the PHQ-9, used to diagnose and guide treatment.

Screening forms were available in multiple languages. Medical assistants received training on the importance of identifying depression in undertreated groups, and a banner was inserted in the electronic health record to indicate a screening was due, Dr. Garcia said.

During the rollout, a committee was assigned to monitor screening rates and adjust strategies to target disparities.

Dr. Garcia and fellow researchers calculated the likelihood of a patient being screened starting in September 2017 – when a field for depression screening status was added to the system’s electronic health record – until the rollout was completed on Dec. 31, 2019.
 

Screening disparities narrowed for all groups studied

The screening rate for patients who had a primary care visit increased from 40.5% to 88.8%. Early on, patients with language barriers were less likely to be screened than English-speaking White individuals (odds ratios, 0.55-0.59). Men were less likely to be screened than women (OR, 0.82; 95% confidence interval, 0.78-0.86), and the likelihood of being screened decreased as people got older. By 2019, screening disparities had narrowed for all groups and were only statistically significant for men (OR, 0.87; 95% CI, 0.81-0.93).

Ian Kronish, MD, MPH, a general internist and associate professor of medicine at Columbia University, New York, called the increases “impressive,” adding that the data show universal depression screening is possible in a system that serves a diverse population.

Dr. Kronish, who was not involved in this study, noted that other research indicates screening does not result in a significant reduction in depressive symptoms in the overall population. He found this to be the case in a trial he led, which focused on patients with recent cardiac events, for example.

“Given all the effort that is going into depression screening and the inclusion of depression screening as a quality metric, we need definitive randomized clinical trials testing whether depression screening leads to increased treatment uptake and, importantly, improved depressive symptoms and quality of life,” he said.

Dr. Garcia acknowledged that more work needs to be done to address treatment barriers, such as language and lack of insurance, and assess whether greater recognition of depressive symptoms in underserved groups can lead to effective treatment. “But this is an important step to know that universal depression screening narrowed disparities in screening over time,” she added.

Dr. Garcia and Dr. Kronish have disclosed no relevant financial relationships.

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

Medical errors in all settings contributed to as many as 250,000 deaths per year in the United States between 2000 and 2008, according to a 2016 study.¹ Diagnostic error, in particular, remains a leading cause of morbidity and mortality in the United States and worldwide. In 2017, 12 million patients (roughly 5% of all US adults) who sought outpatient care experienced missed, delayed, or incorrect diagnosis at least once.²

In his classic work, How Doctors Think, Jerome Groopman, MD, explored the diagnostic process with a focus on the role of cognitive bias in clinical decision-making. Groopman examined how physicians can become sidetracked in their thinking and “blinded” to potential alternative diagnoses.³ Medical error is not necessarily because of a deficiency in medical knowledge; rather, physicians become susceptible to medical error when defective and faulty reasoning distort their diagnostic ability.⁴

Cognitive bias in the diagnostic process has been extensively studied, and a full review is beyond the scope of this article.⁵ However, here we will examine pathways leading to diagnostic errors in the primary care setting, specifically the role of cognitive bias in the work-up of polymyalgia rheumatica (PMR), ovarian cancer (OC), Lewy body dementia (LBD), and fibromyalgia (FM). As these 4 disease states are seen with low-to-moderate frequency in primary care, cognitive bias can complicate accurate diagnosis. But first, a word about how to understand clinical reasoning.

There are 2 types of reasoning (and 1 is more prone to error)

Physician clinical reasoning can be divided into 2 different cognitive approaches.

Type 1 reasoning employs intuition and heuristics; this type is automatic, reflexive, and quick.⁵ While the use of mental shortcuts in type 1 increases the speed with which decisions are made, it also makes this form of reasoning more prone to error.

Type 2 reasoning requires conscious effort. It is goal directed and rigorous and therefore slower than type 1 reasoning. Extrapolated to the clinical context, clinicians transition from type 2 to type 1 reasoning as they gain experience and training throughout their careers and develop their own conscious and subconscious heuristics. Deviations from accurate decision-making occur in a systematic manner due to cognitive biases and result in medical error.⁶table 1⁷ lists common types of cognitive bias.

An important question to ask. Physicians tend to fall into a pattern of quick, type 1 reasoning. However, it’s important to strive to maintain a broad differential diagnosis and avoid premature closure of the diagnostic process. It’s critical that we consider alternative diagnoses (ie, consciously move from type 1 to type 2 thinking) and continue to ask ourselves, “What else?” while working through differential diagnoses. This can be a powerful debiasing technique.

Continue to: The discussion...

The discussion of the following 4 disease states demonstrates how cognitive bias can lead to diagnostic error.

Case 1

An 82-year-old woman with a history of hypertension; wide-angle glaucoma; stage 2 chronic kidney disease; osteopenia; severe osteoarthritis (OA) affecting the hips, shoulders, and knees; insomnia; and depression is transferred to a new family medicine practice for evaluation. She has been taking nonsteroidal anti-­inflammatory drugs (NSAIDs) for chronic pain secondary to OA for 6 months, with no improvement in symptoms.

The patient is barely able to ambulate and appears to be in considerable pain. She is relying heavily on her walker and is assisted by her granddaughter. The primary care physician (PCP) obtains a detailed history that includes chronic shoulder and hip pain. Given that the patient has not responded to NSAID treatment over the previous 6 months, the PCP takes a moment to reconsider the diagnosis of OA and considers other options.

It’s critical that we consider alternative diagnoses and continue to ask ourselves, “What else?” while working through differential diagnoses.

In light of the high prevalence of PMR in older women, the physician pursues a more specific physical examination tailored to ferret out PMR. He had learned this diagnostic shortcut as a resident, remembered it, and adeptly applied it whenever circumstances warranted. He asks the patient to raise her arms above her head (goalpost sign). She is unable to perform this task and experiences severe bilateral shoulder pain on trial. The PCP then places the patient on the examining table and attempts to assist her in rolling toward him. The patient is also unable to perform this maneuver and experiences significant bilateral hip pain on trial.

Based primarily on the patient’s history and physical exam findings, the PCP makes a presumptive diagnosis of PMR vs OA vs combined PMR with OA, orders an erythrocyte sedimentation rate (ESR) and basic rheumatologic marker panel, and starts the patient on prednisone 10 mg/d. Lab work comes back and reveals mildly elevated ESR with all other findings within normal limits. Two weeks later, the patient returns for her follow-up visit, walking without a walker for the first time in years.

PMR can be mistaken for OA

PMR is the most common inflammatory rheumatic disease in older patients.⁸ It is a debilitating illness with simple, effective treatment but has devastating consequences if missed or left untreated.⁹ PMR typically manifests in patients older than age 50, with a peak incidence at 80 years of age. It is also far more common in women.¹⁰

Approximately 80% of patients with PMR initially present to their PCP, often posing a diagnostic challenge to many clinicians.¹¹ Due to overlap in symptoms, the condition is often misdiagnosed as OA, a more common condition seen by PCPs. Also, there are no specific diagnostic tests for PMR. An elevated ESR can help confirm the diagnosis, but one-third of patients with PMR have a normal ESR.¹² Therefore, the diagnostic conundrum the physician faces is OA vs rheumatoid arthritis (RA), PMR, or another condition.

Continue to: The consequences...

The consequences of a missed and delayed PMR diagnosis range from seriously impaired quality of life to significantly increased risk of vascular events (eg, blindness, stroke) due to temporal arteritis.¹³ Early diagnosis is even more critical as the risk of a vascular event and death is highest during initial phases of the disease course.¹⁴

FPs often miss this Dx. A timely diagnosis relies almost exclusively on an accurate, thorough history and physical exam. However, PCPs often struggle to correctly diagnose PMR. According to a study by Bahlas and colleagues,¹⁵ the accuracy rate for correctly diagnosing PMR was 24% among a cohort of family physicians.

The differential diagnosis for PMR is broad and includes seronegative spondyloarthropathies, malignancy, Lyme disease, hypothyroidism, and both RA and OA.¹⁶ 

PCPs are extremely adept at correctly diagnosing RA, but not PMR. A study by Blaauw and colleagues¹⁷ comparing PCPs and rheumatologists found PCPs correctly identified 92% of RA cases but only 55% of PMR cases. When rheumatologists reviewed these same cases, they correctly identified PMR and RA almost 100% of the time.¹⁷ The difference in diagnostic accuracy between rheumatologists and PCPs suggests limited experience and gaps in fund of knowledge. 

Making the diagnosis. The diagnosis of PMR is often made on empiric response to corticosteroid treatment, but doing so based solely on a patient’s response is controversial.¹⁸ There are rare instances in which patients with PMR fail to respond to treatment. On the other hand, some inflammatory conditions that mimic or share symptoms with PMR also respond to corticosteroids, potentially resulting in erroneous confirmation bias.

Some classification criteria use rapid response to low-dose prednisone/­prednisolone (≤ 20 mg) to confirm the diagnosis,¹⁹ while other more recent guidelines no longer include this approach.²⁰ If PMR continues to be suspected after a trial of steroids is unsuccessful, the PCP can try another course of higher dose steroids or consult with Rheumatology.

Case 2 

A woman in her mid-40s presented to a PCP’s office with a chief complaint of dyspepsia and bloating.^a The patient was attending a meeting in New York City, and this was her first visit to this physician. The patient previously had been treated for these symptoms by her hometown PCP and gastroenterologist.

Continue to: A full history...

A full history and physical exam revealed a myriad of gastrointestinal (GI) complaints, such as diarrhea. But the PCP recalled a recent roundtable discussion on debiasing techniques specifically related to gynecologic disorders, including OC. Therefore, he decided to include OC in the differential diagnosis—something he would not routinely have done given the preponderance of GI symptoms. Despite the patient’s reluctance and time constraints, the PCP ordered a transvaginal ultrasound. Findings from the ultrasound study revealed stage II OC, which carries a good prognosis. The patient is currently undergoing treatment and was last reported as doing well.

Early signs of ovarian cancer can be chalked up to a “GI issue”

OC is the second most common gynecologic cancer²¹ and the fifth leading cause of cancer-related death²² in US women. Compared to other cancers, the prognosis for localized ­early-stage OC is surprisingly good, with a 5-year survival rate approaching 93%.²³ However, most disease is detected in later stages, and the 5-year survival rate drops to a low of 29%.²⁴

There remains no established screening protocol for OC. Fewer than a quarter of all cases are diagnosed in stage I, and detection of OC relies heavily on the physician’s ability to decipher vague symptomatology that overlaps with other, more common maladies. This poses an obvious diagnostic challenge and, not surprisingly, a high level of susceptibility to cognitive bias. 

Most PCPs correctly identified bloating as a key symptom of ovarian cancer; however, they weren’t as good at identifying less common symptoms, such as inability to finish a meal.

More than 90% of patients with OC present with some combination of the following symptoms prior to diagnosis: abdominal (77%), GI (70%), pain (58%), constitutional (50%), urinary (34%), and pelvic (26%).²⁵ The 3 most common isolated symptoms in patients with OC are abdominal bloating, decrease in appetite, and frank abdominal pain.²⁶ Patients with biopsy-confirmed OC experience these symptoms an average of 6 months prior to actual diagnosis.²⁷

Knowledge gaps play a role. Studies assessing the ability of health care providers to identify presenting symptoms of OC reveal specific knowledge gaps. For instance, in a survey by Gajjar and colleagues,²⁸ most PCPs correctly identified bloating as a key symptom of OC; however, they weren’t as good at identifying less common symptoms, such as inability to finish a meal and early satiety. Moreover, survey participants misinterpreted or missed GI symptoms as an important manifestation of early OC disease.²⁸ These specific knowledge gaps combine with physician errors in thinking, further obscuring and extending the diagnostic process. The point prevalence for OC is relatively low, and many PCPs only encounter a few cases during their entire career.²⁹ This low pre-test probability may also fuel the delay in diagnosis.

Watch for these forms of bias. Since nonspecific symptoms of early-stage OC resemble those of other more benign conditions, a form of anchoring error known as multiple alternatives bias can arise. In this scenario, clinicians investigate only 1 potential plausible diagnosis and remain focused on that single, often faulty, conclusion. This persists despite other equally plausible alternatives that arise as the investigation proceeds.²⁸

Affective error may also play a role in missed or delayed diagnosis. For example, a physician would prefer to diagnose and treat a common GI illness than consider OC. Another distortion involves outcome bias wherein the physician gives more significance to benign conditions such as irritable bowel syndrome because they have a more favorable outcome and clear treatment path. Physicians also favor these benign conditions because they encounter them more frequently than OC in the clinic setting. (This is known as availability bias.) Outcome bias and multiple alternatives bias can result in noninvestigation of symptoms and inefficient or improper management, leading to a delay in arriving at the correct diagnosis or anchoring on a plausible but incorrect diagnosis.

Continue to: An incorrect initial diagnostic...

An incorrect initial diagnostic path often triggers a cascade of subsequent errors. The physician orders additional unhelpful and expensive tests in an effort to characterize the suspected GI pathology. This then leads the physician to prematurely terminate the work-up and accept the most favored diagnosis. Lastly, sunk-cost fallacy comes into play: The physician has “invested” time and energy investigating a particular diagnosis and rather than abandon the presumed diagnosis, continues to put more time and effort in going down an incorrect diagnostic path. 

A series of failures. These biases and miscues have been observed in several studies. For example, a survey of 1725 women by Goff and colleagues³⁰ sought to identify factors related to delayed OC diagnosis. The authors found that the following factors were significantly associated with a delayed diagnosis: omission of a pelvic exam at initial presentation, a separate exploration of a multitude of collateral symptoms, a failure to order ultrasound/computed tomography/CA-125 test, and a failure to consider age as a factor (especially if the patient was outside the norm). 

Responses from the survey also revealed that physicians initially ordered work-ups related to GI etiology and only later considered a pelvic work-up. This suggests that well-known presenting signs and symptoms or a constellation of typical and atypical symptoms of OC often failed to trigger physician recognition. Understandably, patients presenting with menorrhagia or gynecologic complaints are more likely to have OC detected at an earlier stage than patients who present with GI or abdominal signs alone.³¹ table 2⁷ summarizes some of the cognitive biases seen in the diagnostic path of OC.

Case 3

A 56-year-old man is brought to the ED by his wife and children for evaluation of odd behavior and episodes of confusion. The patient recently had a negative neurologic work-up for transient ischemic attack and cerebrovascular accident and is admitted for further work-up. He reports visual hallucinations to nursing staff. Screening for memory problems shows no significant deficits. The patient in fact scored a 27 on the Mini–Mental State Examination, well within the normal range. The family notes that the patient has had difficulty with planning over the previous year and has not seemed like his “old self.” The patient has no history of psychosis, schizophrenia, bipolar disorder, or any other psychiatric illness.

While in the hospital, he becomes acutely upset by the hallucinations and is given haloperidol and lorazepam by house staff. In the morning, the patient exhibits severe signs of Parkinson disease that include rigidity and masked facies.

Given the patient’s poor response to haloperidol and continued confusion, the team consulted Neurology and Psychiatry. Gathering a more detailed history from the patient and family, the patient is given a diagnosis of classic LBD. The antipsychotic medications are stopped. The patient and his family receive education about LBD treatment and management, and the patient is discharged to outpatient care.

Psychiatric symptoms can be an early “misdirect” in cases of Lewy body disease

LBD, the second leading neurodegenerative dementia after Alzheimer disease (AD), affects 1.5 million Americans,³² representing about 10% of all dementia cases. LBD and AD overlap in 25% of dementia cases.³³ In patients older than 85 years, the prevalence jumps to 5% of the general population and 22% of all cases of dementia.³³ Despite its prevalence, a recent study showed that only 6% of PCPs correctly identified LBD as the primary diagnosis when presented with typical case examples.³² 

Continue to: 3 stages of presentation

3 stages of presentation. Unlike other forms of dementia, LBD typically presents first with psychiatric symptoms, then with cognitive impairment, and last with parkinsonian symptoms. Additionally, rapid eye movement sleep behavior disorder and often subtle elements of nonmemory cognitive impairment distinguish LBD from both AD and vascular dementia.³² The primary cognitive deficit in LBD is not in memory but in attention, executive functioning, and visuospatial ability.³⁴ Only in the later stages of the disease do patients exhibit gradual and progressive memory loss. 

Mistaken for many things. When evaluating patients exhibiting signs of dementia, it’s important to include LBD in the differential, with increased suspicion for patients experiencing episodes of psychosis or delirium. The uniqueness of LBD lies in its psychotic symptomatology, particularly during earlier stages of the disease. This feature helps distinguish LBD from both AD and vascular dementia. As seen in the case, LBD can also be confused with acute delirium.

The uniqueness of Lewy body dementia lies in its psychotic symptomatology, particularly during earlier stages of the disease.

Older adult patients presenting to the ED or clinic with visual hallucinations, delirium, and mental confusion may receive a false diagnosis of schizophrenia, medication- or substance-induced psychosis, Parkinson disease, or delirium of unknown etiology.³⁵ Unfortunately, LBD is often overlooked and not considered in the differential diagnosis. Due to underrecognition, patients may receive treatment with typical antipsychotics. The addition of a neuroleptic to help control the psychotic symptoms causes patients with LBD to develop severe extrapyramidal symptoms and worsening mental status,³⁶ leading to severe parkinsonian signs, which further muddies the diagnostic process. In addition, treatment for suspected Parkinson disease, including carbidopa-levodopa, has no benefit for patients with LBD and may increase psychotic symptoms.³⁷

First-line treatment for LBD includes psychoeducation for the patient and family, cholinesterase inhibitors (eg, rivastigmine), and avoidance of high-potency antipsychotics, such as haloperidol. Although persistent hallucinations and psychosis remain difficult to treat in LBD, low-dose quetiapine is 1 option. Incorrectly diagnosing and prescribing treatment for another condition exacerbates symptoms in this patient population.

Case 4

A 36-year-old Hispanic woman presents to the PCP for her annual physical exam. The patient’s medical record shows 2 previous office visits over the past 2 years—an annual physical exam and an office visit for the flu vaccine. The patient is highly accomplished in her profession, working as a certified public accountant for a major corporation. She is a nonsmoker and reports only casual social drinking and no recreational drug use. The patient is slightly overweight for her height but is otherwise healthy. Previous lab studies are within normal limits.

The patient has been experiencing chronic pain for the past few years after a motor vehicle accident. She has seen a physiatrist and another provider, both of whom found no “objective” causes of her chronic pain. They started the patient on sertraline for depression and an analgesic, both of which were ineffective.

The patient likes to exercise at a gym twice a week by doing light cardio (treadmill) exercise and light weightlifting. Lately, however, she has been unable to exercise due to the pain. At this visit, she mentions having low energy, poor sleep, frequent fatigue, and generalized soreness and pain in multiple areas of her body. The PCP recognizes the patient’s presenting symptoms as significant for FM and starts her on pregabalin and hydrotherapy, with positive results.

Continue to: Fibromyalgia skepticism may lead to a Dx of depression

FM, the second most common disorder seen in rheumatologic practice after OA, is estimated to affect approximately 1 in 20 patients (approximately 5 million Americans) in the primary care setting.^38,39 The condition has a high female-to-male preponderance (3.4% vs 0.5%).⁴⁰ While the primary symptom of FM is chronic pain, patients commonly present with fatigue and sleep disturbance.⁴¹ Comorbid conditions include headaches, irritable bowel syndrome, and mood disturbances (most commonly anxiety and depression). 

Patients with fibromyalgia, who are often otherwise healthy, often present multiple times to the same PCP with a chief complaint of chronic pain.

Several studies have explored reasons for the misdiagnosis and underdiagnosis of FM. One important factor is ongoing skepticism among some physicians and the public, in general, as to whether FM is a real disease. This issue was addressed by a study by White and colleagues,⁴² who estimated and compared the point prevalence of FM and related disorders in Amish vs non-Amish adults. The authors hypothesized that if litigation and/or compensation availability have a major impact on FM prevalence, then there would be a near zero prevalence of FM in the Amish community. And yet, researchers found an overall age- and sex-adjusted FM prevalence of 7.3% (95% CI; 5.3%-9.7%); this was both statistically greater than zero (P < .0001) and greater than 2 control populations of non-Amish adults (both P < .05).

Many physicians consider FM fundamentally an emotional disturbance, and the high preponderance of FM in female patients may contribute to this misconception as reports of pain and emotional distress by women are often dismissed as hysteria.⁴³ Physicians often explore the emotional aspects of FM, incorrectly diagnosing patients with depression and subsequently treating them with a psychotropic drug.³⁹ Alternatively, they may focus on the musculoskeletal presentations of FM and prescribe analgesics or physical therapy, both of which do little to alleviate FM. 

To make the correct diagnosis of FM, the American College of Rheumatology created a specific set of criteria in 1990, which was updated in 2010.⁴⁴ For a diagnosis of FM, a patient must have at least a 3-month history of bilateral pain above and below the waist and along the axial skeletal spine. Although not included in the updated 2010 criteria, many clinicians continue to check for tender points, following the 1990 criteria requiring the presence of 11 of 18 points to make the diagnosis.

At least 3 cognitive biases relating to FM apply: anchoring, availability, and fundamental attribution error (see table 3).⁷ Anchoring occurs when the PCP settles on a psychiatric diagnosis of exaggerated pain syndrome, muscle overuse, or OA and fails to explore alternative etiology. Availability bias may obscure the true diagnosis of FM. Since PCPs see many patients with RA or OA, they may overlook or dismiss the possibility of FM. Attribution error happens when physicians dismiss the complaints of patients with FM as merely due to psychological distress, hysteria, or acting out.⁴³

Patients with FM, who are often otherwise healthy, often present multiple times to the same PCP with a chief complaint of chronic pain. These repeat presentations can result in compassion fatigue and impact care. As Aloush and colleagues⁴⁰ noted in their study, “FM patients were perceived as more difficult than RA patients, with a high level of concern and emotional response. A high proportion of physicians were reluctant to accept them because they feel emotional/psychological difficulties meeting and coping with these patients.”In response, patients with undiagnosed FM or inadequately treated FM may visit other PCPs, which may or may not result in a correct diagnosis and treatment.

We can do better

Primary care physicians face the daunting task of diagnosing and treating a wide range of common conditions while also trying to recognize less-common conditions with atypical presentations—all during a busy clinic workday. Nonetheless, we should strive to overcome internal (eg, cognitive bias and fund-of-knowledge deficits) and external (eg, time constraints, limited resources) pressures to improve diagnostic accuracy and care.

Each of the 4 disease states we’ve discussed have high rates of missed and/or delayed diagnosis. Each presents a unique set of confounders: PMR with its overlapping symptoms of many other rheumatologic diseases; OC with its often vague and misleading GI symptomatology; LBD with overlapping features of AD and Parkinson disease; and FM with skepticism. As gatekeepers to health care, it falls on PCPs to sort out these diagnostic dilemmas to avoid medical errors. Fundamental knowledge of each disease, its unique pathophysiology and symptoms, and varying presentations can be learned, internalized, and subsequently put into clinical practice to improve patient outcomes.

CORRESPONDENCE
Paul D. Rosen MD, Brooklyn Hospital Center, Department of Family Medicine, 121 Dekalb Avenue, Brooklyn, New York 11201; [email protected]

Medical errors in all settings contributed to as many as 250,000 deaths per year in the United States between 2000 and 2008, according to a 2016 study.¹ Diagnostic error, in particular, remains a leading cause of morbidity and mortality in the United States and worldwide. In 2017, 12 million patients (roughly 5% of all US adults) who sought outpatient care experienced missed, delayed, or incorrect diagnosis at least once.²

In his classic work, How Doctors Think, Jerome Groopman, MD, explored the diagnostic process with a focus on the role of cognitive bias in clinical decision-making. Groopman examined how physicians can become sidetracked in their thinking and “blinded” to potential alternative diagnoses.³ Medical error is not necessarily because of a deficiency in medical knowledge; rather, physicians become susceptible to medical error when defective and faulty reasoning distort their diagnostic ability.⁴

Cognitive bias in the diagnostic process has been extensively studied, and a full review is beyond the scope of this article.⁵ However, here we will examine pathways leading to diagnostic errors in the primary care setting, specifically the role of cognitive bias in the work-up of polymyalgia rheumatica (PMR), ovarian cancer (OC), Lewy body dementia (LBD), and fibromyalgia (FM). As these 4 disease states are seen with low-to-moderate frequency in primary care, cognitive bias can complicate accurate diagnosis. But first, a word about how to understand clinical reasoning.

There are 2 types of reasoning (and 1 is more prone to error)

Physician clinical reasoning can be divided into 2 different cognitive approaches.

Type 1 reasoning employs intuition and heuristics; this type is automatic, reflexive, and quick.⁵ While the use of mental shortcuts in type 1 increases the speed with which decisions are made, it also makes this form of reasoning more prone to error.

Type 2 reasoning requires conscious effort. It is goal directed and rigorous and therefore slower than type 1 reasoning. Extrapolated to the clinical context, clinicians transition from type 2 to type 1 reasoning as they gain experience and training throughout their careers and develop their own conscious and subconscious heuristics. Deviations from accurate decision-making occur in a systematic manner due to cognitive biases and result in medical error.⁶table 1⁷ lists common types of cognitive bias.

An important question to ask. Physicians tend to fall into a pattern of quick, type 1 reasoning. However, it’s important to strive to maintain a broad differential diagnosis and avoid premature closure of the diagnostic process. It’s critical that we consider alternative diagnoses (ie, consciously move from type 1 to type 2 thinking) and continue to ask ourselves, “What else?” while working through differential diagnoses. This can be a powerful debiasing technique.

Continue to: The discussion...

The discussion of the following 4 disease states demonstrates how cognitive bias can lead to diagnostic error.

Case 1

An 82-year-old woman with a history of hypertension; wide-angle glaucoma; stage 2 chronic kidney disease; osteopenia; severe osteoarthritis (OA) affecting the hips, shoulders, and knees; insomnia; and depression is transferred to a new family medicine practice for evaluation. She has been taking nonsteroidal anti-­inflammatory drugs (NSAIDs) for chronic pain secondary to OA for 6 months, with no improvement in symptoms.

The patient is barely able to ambulate and appears to be in considerable pain. She is relying heavily on her walker and is assisted by her granddaughter. The primary care physician (PCP) obtains a detailed history that includes chronic shoulder and hip pain. Given that the patient has not responded to NSAID treatment over the previous 6 months, the PCP takes a moment to reconsider the diagnosis of OA and considers other options.

It’s critical that we consider alternative diagnoses and continue to ask ourselves, “What else?” while working through differential diagnoses.

In light of the high prevalence of PMR in older women, the physician pursues a more specific physical examination tailored to ferret out PMR. He had learned this diagnostic shortcut as a resident, remembered it, and adeptly applied it whenever circumstances warranted. He asks the patient to raise her arms above her head (goalpost sign). She is unable to perform this task and experiences severe bilateral shoulder pain on trial. The PCP then places the patient on the examining table and attempts to assist her in rolling toward him. The patient is also unable to perform this maneuver and experiences significant bilateral hip pain on trial.

Based primarily on the patient’s history and physical exam findings, the PCP makes a presumptive diagnosis of PMR vs OA vs combined PMR with OA, orders an erythrocyte sedimentation rate (ESR) and basic rheumatologic marker panel, and starts the patient on prednisone 10 mg/d. Lab work comes back and reveals mildly elevated ESR with all other findings within normal limits. Two weeks later, the patient returns for her follow-up visit, walking without a walker for the first time in years.

PMR can be mistaken for OA

PMR is the most common inflammatory rheumatic disease in older patients.⁸ It is a debilitating illness with simple, effective treatment but has devastating consequences if missed or left untreated.⁹ PMR typically manifests in patients older than age 50, with a peak incidence at 80 years of age. It is also far more common in women.¹⁰

Approximately 80% of patients with PMR initially present to their PCP, often posing a diagnostic challenge to many clinicians.¹¹ Due to overlap in symptoms, the condition is often misdiagnosed as OA, a more common condition seen by PCPs. Also, there are no specific diagnostic tests for PMR. An elevated ESR can help confirm the diagnosis, but one-third of patients with PMR have a normal ESR.¹² Therefore, the diagnostic conundrum the physician faces is OA vs rheumatoid arthritis (RA), PMR, or another condition.

Continue to: The consequences...

The consequences of a missed and delayed PMR diagnosis range from seriously impaired quality of life to significantly increased risk of vascular events (eg, blindness, stroke) due to temporal arteritis.¹³ Early diagnosis is even more critical as the risk of a vascular event and death is highest during initial phases of the disease course.¹⁴

FPs often miss this Dx. A timely diagnosis relies almost exclusively on an accurate, thorough history and physical exam. However, PCPs often struggle to correctly diagnose PMR. According to a study by Bahlas and colleagues,¹⁵ the accuracy rate for correctly diagnosing PMR was 24% among a cohort of family physicians.

The differential diagnosis for PMR is broad and includes seronegative spondyloarthropathies, malignancy, Lyme disease, hypothyroidism, and both RA and OA.¹⁶ 

PCPs are extremely adept at correctly diagnosing RA, but not PMR. A study by Blaauw and colleagues¹⁷ comparing PCPs and rheumatologists found PCPs correctly identified 92% of RA cases but only 55% of PMR cases. When rheumatologists reviewed these same cases, they correctly identified PMR and RA almost 100% of the time.¹⁷ The difference in diagnostic accuracy between rheumatologists and PCPs suggests limited experience and gaps in fund of knowledge. 

Making the diagnosis. The diagnosis of PMR is often made on empiric response to corticosteroid treatment, but doing so based solely on a patient’s response is controversial.¹⁸ There are rare instances in which patients with PMR fail to respond to treatment. On the other hand, some inflammatory conditions that mimic or share symptoms with PMR also respond to corticosteroids, potentially resulting in erroneous confirmation bias.

Some classification criteria use rapid response to low-dose prednisone/­prednisolone (≤ 20 mg) to confirm the diagnosis,¹⁹ while other more recent guidelines no longer include this approach.²⁰ If PMR continues to be suspected after a trial of steroids is unsuccessful, the PCP can try another course of higher dose steroids or consult with Rheumatology.

Case 2 

A woman in her mid-40s presented to a PCP’s office with a chief complaint of dyspepsia and bloating.^a The patient was attending a meeting in New York City, and this was her first visit to this physician. The patient previously had been treated for these symptoms by her hometown PCP and gastroenterologist.

Continue to: A full history...

A full history and physical exam revealed a myriad of gastrointestinal (GI) complaints, such as diarrhea. But the PCP recalled a recent roundtable discussion on debiasing techniques specifically related to gynecologic disorders, including OC. Therefore, he decided to include OC in the differential diagnosis—something he would not routinely have done given the preponderance of GI symptoms. Despite the patient’s reluctance and time constraints, the PCP ordered a transvaginal ultrasound. Findings from the ultrasound study revealed stage II OC, which carries a good prognosis. The patient is currently undergoing treatment and was last reported as doing well.

Early signs of ovarian cancer can be chalked up to a “GI issue”

OC is the second most common gynecologic cancer²¹ and the fifth leading cause of cancer-related death²² in US women. Compared to other cancers, the prognosis for localized ­early-stage OC is surprisingly good, with a 5-year survival rate approaching 93%.²³ However, most disease is detected in later stages, and the 5-year survival rate drops to a low of 29%.²⁴

There remains no established screening protocol for OC. Fewer than a quarter of all cases are diagnosed in stage I, and detection of OC relies heavily on the physician’s ability to decipher vague symptomatology that overlaps with other, more common maladies. This poses an obvious diagnostic challenge and, not surprisingly, a high level of susceptibility to cognitive bias. 

Most PCPs correctly identified bloating as a key symptom of ovarian cancer; however, they weren’t as good at identifying less common symptoms, such as inability to finish a meal.

More than 90% of patients with OC present with some combination of the following symptoms prior to diagnosis: abdominal (77%), GI (70%), pain (58%), constitutional (50%), urinary (34%), and pelvic (26%).²⁵ The 3 most common isolated symptoms in patients with OC are abdominal bloating, decrease in appetite, and frank abdominal pain.²⁶ Patients with biopsy-confirmed OC experience these symptoms an average of 6 months prior to actual diagnosis.²⁷

Knowledge gaps play a role. Studies assessing the ability of health care providers to identify presenting symptoms of OC reveal specific knowledge gaps. For instance, in a survey by Gajjar and colleagues,²⁸ most PCPs correctly identified bloating as a key symptom of OC; however, they weren’t as good at identifying less common symptoms, such as inability to finish a meal and early satiety. Moreover, survey participants misinterpreted or missed GI symptoms as an important manifestation of early OC disease.²⁸ These specific knowledge gaps combine with physician errors in thinking, further obscuring and extending the diagnostic process. The point prevalence for OC is relatively low, and many PCPs only encounter a few cases during their entire career.²⁹ This low pre-test probability may also fuel the delay in diagnosis.

Watch for these forms of bias. Since nonspecific symptoms of early-stage OC resemble those of other more benign conditions, a form of anchoring error known as multiple alternatives bias can arise. In this scenario, clinicians investigate only 1 potential plausible diagnosis and remain focused on that single, often faulty, conclusion. This persists despite other equally plausible alternatives that arise as the investigation proceeds.²⁸

Affective error may also play a role in missed or delayed diagnosis. For example, a physician would prefer to diagnose and treat a common GI illness than consider OC. Another distortion involves outcome bias wherein the physician gives more significance to benign conditions such as irritable bowel syndrome because they have a more favorable outcome and clear treatment path. Physicians also favor these benign conditions because they encounter them more frequently than OC in the clinic setting. (This is known as availability bias.) Outcome bias and multiple alternatives bias can result in noninvestigation of symptoms and inefficient or improper management, leading to a delay in arriving at the correct diagnosis or anchoring on a plausible but incorrect diagnosis.

Continue to: An incorrect initial diagnostic...

An incorrect initial diagnostic path often triggers a cascade of subsequent errors. The physician orders additional unhelpful and expensive tests in an effort to characterize the suspected GI pathology. This then leads the physician to prematurely terminate the work-up and accept the most favored diagnosis. Lastly, sunk-cost fallacy comes into play: The physician has “invested” time and energy investigating a particular diagnosis and rather than abandon the presumed diagnosis, continues to put more time and effort in going down an incorrect diagnostic path. 

A series of failures. These biases and miscues have been observed in several studies. For example, a survey of 1725 women by Goff and colleagues³⁰ sought to identify factors related to delayed OC diagnosis. The authors found that the following factors were significantly associated with a delayed diagnosis: omission of a pelvic exam at initial presentation, a separate exploration of a multitude of collateral symptoms, a failure to order ultrasound/computed tomography/CA-125 test, and a failure to consider age as a factor (especially if the patient was outside the norm). 

Responses from the survey also revealed that physicians initially ordered work-ups related to GI etiology and only later considered a pelvic work-up. This suggests that well-known presenting signs and symptoms or a constellation of typical and atypical symptoms of OC often failed to trigger physician recognition. Understandably, patients presenting with menorrhagia or gynecologic complaints are more likely to have OC detected at an earlier stage than patients who present with GI or abdominal signs alone.³¹ table 2⁷ summarizes some of the cognitive biases seen in the diagnostic path of OC.

Case 3

A 56-year-old man is brought to the ED by his wife and children for evaluation of odd behavior and episodes of confusion. The patient recently had a negative neurologic work-up for transient ischemic attack and cerebrovascular accident and is admitted for further work-up. He reports visual hallucinations to nursing staff. Screening for memory problems shows no significant deficits. The patient in fact scored a 27 on the Mini–Mental State Examination, well within the normal range. The family notes that the patient has had difficulty with planning over the previous year and has not seemed like his “old self.” The patient has no history of psychosis, schizophrenia, bipolar disorder, or any other psychiatric illness.

While in the hospital, he becomes acutely upset by the hallucinations and is given haloperidol and lorazepam by house staff. In the morning, the patient exhibits severe signs of Parkinson disease that include rigidity and masked facies.

Given the patient’s poor response to haloperidol and continued confusion, the team consulted Neurology and Psychiatry. Gathering a more detailed history from the patient and family, the patient is given a diagnosis of classic LBD. The antipsychotic medications are stopped. The patient and his family receive education about LBD treatment and management, and the patient is discharged to outpatient care.

Psychiatric symptoms can be an early “misdirect” in cases of Lewy body disease

LBD, the second leading neurodegenerative dementia after Alzheimer disease (AD), affects 1.5 million Americans,³² representing about 10% of all dementia cases. LBD and AD overlap in 25% of dementia cases.³³ In patients older than 85 years, the prevalence jumps to 5% of the general population and 22% of all cases of dementia.³³ Despite its prevalence, a recent study showed that only 6% of PCPs correctly identified LBD as the primary diagnosis when presented with typical case examples.³² 

Continue to: 3 stages of presentation

3 stages of presentation. Unlike other forms of dementia, LBD typically presents first with psychiatric symptoms, then with cognitive impairment, and last with parkinsonian symptoms. Additionally, rapid eye movement sleep behavior disorder and often subtle elements of nonmemory cognitive impairment distinguish LBD from both AD and vascular dementia.³² The primary cognitive deficit in LBD is not in memory but in attention, executive functioning, and visuospatial ability.³⁴ Only in the later stages of the disease do patients exhibit gradual and progressive memory loss. 

Mistaken for many things. When evaluating patients exhibiting signs of dementia, it’s important to include LBD in the differential, with increased suspicion for patients experiencing episodes of psychosis or delirium. The uniqueness of LBD lies in its psychotic symptomatology, particularly during earlier stages of the disease. This feature helps distinguish LBD from both AD and vascular dementia. As seen in the case, LBD can also be confused with acute delirium.

The uniqueness of Lewy body dementia lies in its psychotic symptomatology, particularly during earlier stages of the disease.

Older adult patients presenting to the ED or clinic with visual hallucinations, delirium, and mental confusion may receive a false diagnosis of schizophrenia, medication- or substance-induced psychosis, Parkinson disease, or delirium of unknown etiology.³⁵ Unfortunately, LBD is often overlooked and not considered in the differential diagnosis. Due to underrecognition, patients may receive treatment with typical antipsychotics. The addition of a neuroleptic to help control the psychotic symptoms causes patients with LBD to develop severe extrapyramidal symptoms and worsening mental status,³⁶ leading to severe parkinsonian signs, which further muddies the diagnostic process. In addition, treatment for suspected Parkinson disease, including carbidopa-levodopa, has no benefit for patients with LBD and may increase psychotic symptoms.³⁷

First-line treatment for LBD includes psychoeducation for the patient and family, cholinesterase inhibitors (eg, rivastigmine), and avoidance of high-potency antipsychotics, such as haloperidol. Although persistent hallucinations and psychosis remain difficult to treat in LBD, low-dose quetiapine is 1 option. Incorrectly diagnosing and prescribing treatment for another condition exacerbates symptoms in this patient population.

Case 4

A 36-year-old Hispanic woman presents to the PCP for her annual physical exam. The patient’s medical record shows 2 previous office visits over the past 2 years—an annual physical exam and an office visit for the flu vaccine. The patient is highly accomplished in her profession, working as a certified public accountant for a major corporation. She is a nonsmoker and reports only casual social drinking and no recreational drug use. The patient is slightly overweight for her height but is otherwise healthy. Previous lab studies are within normal limits.

The patient has been experiencing chronic pain for the past few years after a motor vehicle accident. She has seen a physiatrist and another provider, both of whom found no “objective” causes of her chronic pain. They started the patient on sertraline for depression and an analgesic, both of which were ineffective.

The patient likes to exercise at a gym twice a week by doing light cardio (treadmill) exercise and light weightlifting. Lately, however, she has been unable to exercise due to the pain. At this visit, she mentions having low energy, poor sleep, frequent fatigue, and generalized soreness and pain in multiple areas of her body. The PCP recognizes the patient’s presenting symptoms as significant for FM and starts her on pregabalin and hydrotherapy, with positive results.

Continue to: Fibromyalgia skepticism may lead to a Dx of depression

FM, the second most common disorder seen in rheumatologic practice after OA, is estimated to affect approximately 1 in 20 patients (approximately 5 million Americans) in the primary care setting.^38,39 The condition has a high female-to-male preponderance (3.4% vs 0.5%).⁴⁰ While the primary symptom of FM is chronic pain, patients commonly present with fatigue and sleep disturbance.⁴¹ Comorbid conditions include headaches, irritable bowel syndrome, and mood disturbances (most commonly anxiety and depression). 

Patients with fibromyalgia, who are often otherwise healthy, often present multiple times to the same PCP with a chief complaint of chronic pain.

Several studies have explored reasons for the misdiagnosis and underdiagnosis of FM. One important factor is ongoing skepticism among some physicians and the public, in general, as to whether FM is a real disease. This issue was addressed by a study by White and colleagues,⁴² who estimated and compared the point prevalence of FM and related disorders in Amish vs non-Amish adults. The authors hypothesized that if litigation and/or compensation availability have a major impact on FM prevalence, then there would be a near zero prevalence of FM in the Amish community. And yet, researchers found an overall age- and sex-adjusted FM prevalence of 7.3% (95% CI; 5.3%-9.7%); this was both statistically greater than zero (P < .0001) and greater than 2 control populations of non-Amish adults (both P < .05).

Many physicians consider FM fundamentally an emotional disturbance, and the high preponderance of FM in female patients may contribute to this misconception as reports of pain and emotional distress by women are often dismissed as hysteria.⁴³ Physicians often explore the emotional aspects of FM, incorrectly diagnosing patients with depression and subsequently treating them with a psychotropic drug.³⁹ Alternatively, they may focus on the musculoskeletal presentations of FM and prescribe analgesics or physical therapy, both of which do little to alleviate FM. 

To make the correct diagnosis of FM, the American College of Rheumatology created a specific set of criteria in 1990, which was updated in 2010.⁴⁴ For a diagnosis of FM, a patient must have at least a 3-month history of bilateral pain above and below the waist and along the axial skeletal spine. Although not included in the updated 2010 criteria, many clinicians continue to check for tender points, following the 1990 criteria requiring the presence of 11 of 18 points to make the diagnosis.

At least 3 cognitive biases relating to FM apply: anchoring, availability, and fundamental attribution error (see table 3).⁷ Anchoring occurs when the PCP settles on a psychiatric diagnosis of exaggerated pain syndrome, muscle overuse, or OA and fails to explore alternative etiology. Availability bias may obscure the true diagnosis of FM. Since PCPs see many patients with RA or OA, they may overlook or dismiss the possibility of FM. Attribution error happens when physicians dismiss the complaints of patients with FM as merely due to psychological distress, hysteria, or acting out.⁴³

Patients with FM, who are often otherwise healthy, often present multiple times to the same PCP with a chief complaint of chronic pain. These repeat presentations can result in compassion fatigue and impact care. As Aloush and colleagues⁴⁰ noted in their study, “FM patients were perceived as more difficult than RA patients, with a high level of concern and emotional response. A high proportion of physicians were reluctant to accept them because they feel emotional/psychological difficulties meeting and coping with these patients.”In response, patients with undiagnosed FM or inadequately treated FM may visit other PCPs, which may or may not result in a correct diagnosis and treatment.

We can do better

Primary care physicians face the daunting task of diagnosing and treating a wide range of common conditions while also trying to recognize less-common conditions with atypical presentations—all during a busy clinic workday. Nonetheless, we should strive to overcome internal (eg, cognitive bias and fund-of-knowledge deficits) and external (eg, time constraints, limited resources) pressures to improve diagnostic accuracy and care.

Each of the 4 disease states we’ve discussed have high rates of missed and/or delayed diagnosis. Each presents a unique set of confounders: PMR with its overlapping symptoms of many other rheumatologic diseases; OC with its often vague and misleading GI symptomatology; LBD with overlapping features of AD and Parkinson disease; and FM with skepticism. As gatekeepers to health care, it falls on PCPs to sort out these diagnostic dilemmas to avoid medical errors. Fundamental knowledge of each disease, its unique pathophysiology and symptoms, and varying presentations can be learned, internalized, and subsequently put into clinical practice to improve patient outcomes.

CORRESPONDENCE
Paul D. Rosen MD, Brooklyn Hospital Center, Department of Family Medicine, 121 Dekalb Avenue, Brooklyn, New York 11201; [email protected]

Medical errors in all settings contributed to as many as 250,000 deaths per year in the United States between 2000 and 2008, according to a 2016 study.¹ Diagnostic error, in particular, remains a leading cause of morbidity and mortality in the United States and worldwide. In 2017, 12 million patients (roughly 5% of all US adults) who sought outpatient care experienced missed, delayed, or incorrect diagnosis at least once.²

In his classic work, How Doctors Think, Jerome Groopman, MD, explored the diagnostic process with a focus on the role of cognitive bias in clinical decision-making. Groopman examined how physicians can become sidetracked in their thinking and “blinded” to potential alternative diagnoses.³ Medical error is not necessarily because of a deficiency in medical knowledge; rather, physicians become susceptible to medical error when defective and faulty reasoning distort their diagnostic ability.⁴

Cognitive bias in the diagnostic process has been extensively studied, and a full review is beyond the scope of this article.⁵ However, here we will examine pathways leading to diagnostic errors in the primary care setting, specifically the role of cognitive bias in the work-up of polymyalgia rheumatica (PMR), ovarian cancer (OC), Lewy body dementia (LBD), and fibromyalgia (FM). As these 4 disease states are seen with low-to-moderate frequency in primary care, cognitive bias can complicate accurate diagnosis. But first, a word about how to understand clinical reasoning.

There are 2 types of reasoning (and 1 is more prone to error)

Physician clinical reasoning can be divided into 2 different cognitive approaches.

Type 1 reasoning employs intuition and heuristics; this type is automatic, reflexive, and quick.⁵ While the use of mental shortcuts in type 1 increases the speed with which decisions are made, it also makes this form of reasoning more prone to error.

Type 2 reasoning requires conscious effort. It is goal directed and rigorous and therefore slower than type 1 reasoning. Extrapolated to the clinical context, clinicians transition from type 2 to type 1 reasoning as they gain experience and training throughout their careers and develop their own conscious and subconscious heuristics. Deviations from accurate decision-making occur in a systematic manner due to cognitive biases and result in medical error.⁶table 1⁷ lists common types of cognitive bias.

An important question to ask. Physicians tend to fall into a pattern of quick, type 1 reasoning. However, it’s important to strive to maintain a broad differential diagnosis and avoid premature closure of the diagnostic process. It’s critical that we consider alternative diagnoses (ie, consciously move from type 1 to type 2 thinking) and continue to ask ourselves, “What else?” while working through differential diagnoses. This can be a powerful debiasing technique.

Continue to: The discussion...

The discussion of the following 4 disease states demonstrates how cognitive bias can lead to diagnostic error.

Case 1

An 82-year-old woman with a history of hypertension; wide-angle glaucoma; stage 2 chronic kidney disease; osteopenia; severe osteoarthritis (OA) affecting the hips, shoulders, and knees; insomnia; and depression is transferred to a new family medicine practice for evaluation. She has been taking nonsteroidal anti-­inflammatory drugs (NSAIDs) for chronic pain secondary to OA for 6 months, with no improvement in symptoms.

The patient is barely able to ambulate and appears to be in considerable pain. She is relying heavily on her walker and is assisted by her granddaughter. The primary care physician (PCP) obtains a detailed history that includes chronic shoulder and hip pain. Given that the patient has not responded to NSAID treatment over the previous 6 months, the PCP takes a moment to reconsider the diagnosis of OA and considers other options.

It’s critical that we consider alternative diagnoses and continue to ask ourselves, “What else?” while working through differential diagnoses.

In light of the high prevalence of PMR in older women, the physician pursues a more specific physical examination tailored to ferret out PMR. He had learned this diagnostic shortcut as a resident, remembered it, and adeptly applied it whenever circumstances warranted. He asks the patient to raise her arms above her head (goalpost sign). She is unable to perform this task and experiences severe bilateral shoulder pain on trial. The PCP then places the patient on the examining table and attempts to assist her in rolling toward him. The patient is also unable to perform this maneuver and experiences significant bilateral hip pain on trial.

Based primarily on the patient’s history and physical exam findings, the PCP makes a presumptive diagnosis of PMR vs OA vs combined PMR with OA, orders an erythrocyte sedimentation rate (ESR) and basic rheumatologic marker panel, and starts the patient on prednisone 10 mg/d. Lab work comes back and reveals mildly elevated ESR with all other findings within normal limits. Two weeks later, the patient returns for her follow-up visit, walking without a walker for the first time in years.

PMR can be mistaken for OA

PMR is the most common inflammatory rheumatic disease in older patients.⁸ It is a debilitating illness with simple, effective treatment but has devastating consequences if missed or left untreated.⁹ PMR typically manifests in patients older than age 50, with a peak incidence at 80 years of age. It is also far more common in women.¹⁰

Approximately 80% of patients with PMR initially present to their PCP, often posing a diagnostic challenge to many clinicians.¹¹ Due to overlap in symptoms, the condition is often misdiagnosed as OA, a more common condition seen by PCPs. Also, there are no specific diagnostic tests for PMR. An elevated ESR can help confirm the diagnosis, but one-third of patients with PMR have a normal ESR.¹² Therefore, the diagnostic conundrum the physician faces is OA vs rheumatoid arthritis (RA), PMR, or another condition.

Continue to: The consequences...

The consequences of a missed and delayed PMR diagnosis range from seriously impaired quality of life to significantly increased risk of vascular events (eg, blindness, stroke) due to temporal arteritis.¹³ Early diagnosis is even more critical as the risk of a vascular event and death is highest during initial phases of the disease course.¹⁴

FPs often miss this Dx. A timely diagnosis relies almost exclusively on an accurate, thorough history and physical exam. However, PCPs often struggle to correctly diagnose PMR. According to a study by Bahlas and colleagues,¹⁵ the accuracy rate for correctly diagnosing PMR was 24% among a cohort of family physicians.

The differential diagnosis for PMR is broad and includes seronegative spondyloarthropathies, malignancy, Lyme disease, hypothyroidism, and both RA and OA.¹⁶ 

PCPs are extremely adept at correctly diagnosing RA, but not PMR. A study by Blaauw and colleagues¹⁷ comparing PCPs and rheumatologists found PCPs correctly identified 92% of RA cases but only 55% of PMR cases. When rheumatologists reviewed these same cases, they correctly identified PMR and RA almost 100% of the time.¹⁷ The difference in diagnostic accuracy between rheumatologists and PCPs suggests limited experience and gaps in fund of knowledge. 

Making the diagnosis. The diagnosis of PMR is often made on empiric response to corticosteroid treatment, but doing so based solely on a patient’s response is controversial.¹⁸ There are rare instances in which patients with PMR fail to respond to treatment. On the other hand, some inflammatory conditions that mimic or share symptoms with PMR also respond to corticosteroids, potentially resulting in erroneous confirmation bias.

Some classification criteria use rapid response to low-dose prednisone/­prednisolone (≤ 20 mg) to confirm the diagnosis,¹⁹ while other more recent guidelines no longer include this approach.²⁰ If PMR continues to be suspected after a trial of steroids is unsuccessful, the PCP can try another course of higher dose steroids or consult with Rheumatology.

Case 2 

A woman in her mid-40s presented to a PCP’s office with a chief complaint of dyspepsia and bloating.^a The patient was attending a meeting in New York City, and this was her first visit to this physician. The patient previously had been treated for these symptoms by her hometown PCP and gastroenterologist.

Continue to: A full history...

A full history and physical exam revealed a myriad of gastrointestinal (GI) complaints, such as diarrhea. But the PCP recalled a recent roundtable discussion on debiasing techniques specifically related to gynecologic disorders, including OC. Therefore, he decided to include OC in the differential diagnosis—something he would not routinely have done given the preponderance of GI symptoms. Despite the patient’s reluctance and time constraints, the PCP ordered a transvaginal ultrasound. Findings from the ultrasound study revealed stage II OC, which carries a good prognosis. The patient is currently undergoing treatment and was last reported as doing well.

Early signs of ovarian cancer can be chalked up to a “GI issue”

OC is the second most common gynecologic cancer²¹ and the fifth leading cause of cancer-related death²² in US women. Compared to other cancers, the prognosis for localized ­early-stage OC is surprisingly good, with a 5-year survival rate approaching 93%.²³ However, most disease is detected in later stages, and the 5-year survival rate drops to a low of 29%.²⁴

There remains no established screening protocol for OC. Fewer than a quarter of all cases are diagnosed in stage I, and detection of OC relies heavily on the physician’s ability to decipher vague symptomatology that overlaps with other, more common maladies. This poses an obvious diagnostic challenge and, not surprisingly, a high level of susceptibility to cognitive bias. 

Most PCPs correctly identified bloating as a key symptom of ovarian cancer; however, they weren’t as good at identifying less common symptoms, such as inability to finish a meal.

More than 90% of patients with OC present with some combination of the following symptoms prior to diagnosis: abdominal (77%), GI (70%), pain (58%), constitutional (50%), urinary (34%), and pelvic (26%).²⁵ The 3 most common isolated symptoms in patients with OC are abdominal bloating, decrease in appetite, and frank abdominal pain.²⁶ Patients with biopsy-confirmed OC experience these symptoms an average of 6 months prior to actual diagnosis.²⁷

Knowledge gaps play a role. Studies assessing the ability of health care providers to identify presenting symptoms of OC reveal specific knowledge gaps. For instance, in a survey by Gajjar and colleagues,²⁸ most PCPs correctly identified bloating as a key symptom of OC; however, they weren’t as good at identifying less common symptoms, such as inability to finish a meal and early satiety. Moreover, survey participants misinterpreted or missed GI symptoms as an important manifestation of early OC disease.²⁸ These specific knowledge gaps combine with physician errors in thinking, further obscuring and extending the diagnostic process. The point prevalence for OC is relatively low, and many PCPs only encounter a few cases during their entire career.²⁹ This low pre-test probability may also fuel the delay in diagnosis.

Watch for these forms of bias. Since nonspecific symptoms of early-stage OC resemble those of other more benign conditions, a form of anchoring error known as multiple alternatives bias can arise. In this scenario, clinicians investigate only 1 potential plausible diagnosis and remain focused on that single, often faulty, conclusion. This persists despite other equally plausible alternatives that arise as the investigation proceeds.²⁸

Affective error may also play a role in missed or delayed diagnosis. For example, a physician would prefer to diagnose and treat a common GI illness than consider OC. Another distortion involves outcome bias wherein the physician gives more significance to benign conditions such as irritable bowel syndrome because they have a more favorable outcome and clear treatment path. Physicians also favor these benign conditions because they encounter them more frequently than OC in the clinic setting. (This is known as availability bias.) Outcome bias and multiple alternatives bias can result in noninvestigation of symptoms and inefficient or improper management, leading to a delay in arriving at the correct diagnosis or anchoring on a plausible but incorrect diagnosis.

Continue to: An incorrect initial diagnostic...

An incorrect initial diagnostic path often triggers a cascade of subsequent errors. The physician orders additional unhelpful and expensive tests in an effort to characterize the suspected GI pathology. This then leads the physician to prematurely terminate the work-up and accept the most favored diagnosis. Lastly, sunk-cost fallacy comes into play: The physician has “invested” time and energy investigating a particular diagnosis and rather than abandon the presumed diagnosis, continues to put more time and effort in going down an incorrect diagnostic path. 

A series of failures. These biases and miscues have been observed in several studies. For example, a survey of 1725 women by Goff and colleagues³⁰ sought to identify factors related to delayed OC diagnosis. The authors found that the following factors were significantly associated with a delayed diagnosis: omission of a pelvic exam at initial presentation, a separate exploration of a multitude of collateral symptoms, a failure to order ultrasound/computed tomography/CA-125 test, and a failure to consider age as a factor (especially if the patient was outside the norm). 

Responses from the survey also revealed that physicians initially ordered work-ups related to GI etiology and only later considered a pelvic work-up. This suggests that well-known presenting signs and symptoms or a constellation of typical and atypical symptoms of OC often failed to trigger physician recognition. Understandably, patients presenting with menorrhagia or gynecologic complaints are more likely to have OC detected at an earlier stage than patients who present with GI or abdominal signs alone.³¹ table 2⁷ summarizes some of the cognitive biases seen in the diagnostic path of OC.

Case 3

A 56-year-old man is brought to the ED by his wife and children for evaluation of odd behavior and episodes of confusion. The patient recently had a negative neurologic work-up for transient ischemic attack and cerebrovascular accident and is admitted for further work-up. He reports visual hallucinations to nursing staff. Screening for memory problems shows no significant deficits. The patient in fact scored a 27 on the Mini–Mental State Examination, well within the normal range. The family notes that the patient has had difficulty with planning over the previous year and has not seemed like his “old self.” The patient has no history of psychosis, schizophrenia, bipolar disorder, or any other psychiatric illness.

While in the hospital, he becomes acutely upset by the hallucinations and is given haloperidol and lorazepam by house staff. In the morning, the patient exhibits severe signs of Parkinson disease that include rigidity and masked facies.

Given the patient’s poor response to haloperidol and continued confusion, the team consulted Neurology and Psychiatry. Gathering a more detailed history from the patient and family, the patient is given a diagnosis of classic LBD. The antipsychotic medications are stopped. The patient and his family receive education about LBD treatment and management, and the patient is discharged to outpatient care.

Psychiatric symptoms can be an early “misdirect” in cases of Lewy body disease

LBD, the second leading neurodegenerative dementia after Alzheimer disease (AD), affects 1.5 million Americans,³² representing about 10% of all dementia cases. LBD and AD overlap in 25% of dementia cases.³³ In patients older than 85 years, the prevalence jumps to 5% of the general population and 22% of all cases of dementia.³³ Despite its prevalence, a recent study showed that only 6% of PCPs correctly identified LBD as the primary diagnosis when presented with typical case examples.³² 

Continue to: 3 stages of presentation

3 stages of presentation. Unlike other forms of dementia, LBD typically presents first with psychiatric symptoms, then with cognitive impairment, and last with parkinsonian symptoms. Additionally, rapid eye movement sleep behavior disorder and often subtle elements of nonmemory cognitive impairment distinguish LBD from both AD and vascular dementia.³² The primary cognitive deficit in LBD is not in memory but in attention, executive functioning, and visuospatial ability.³⁴ Only in the later stages of the disease do patients exhibit gradual and progressive memory loss. 

Mistaken for many things. When evaluating patients exhibiting signs of dementia, it’s important to include LBD in the differential, with increased suspicion for patients experiencing episodes of psychosis or delirium. The uniqueness of LBD lies in its psychotic symptomatology, particularly during earlier stages of the disease. This feature helps distinguish LBD from both AD and vascular dementia. As seen in the case, LBD can also be confused with acute delirium.

The uniqueness of Lewy body dementia lies in its psychotic symptomatology, particularly during earlier stages of the disease.

Older adult patients presenting to the ED or clinic with visual hallucinations, delirium, and mental confusion may receive a false diagnosis of schizophrenia, medication- or substance-induced psychosis, Parkinson disease, or delirium of unknown etiology.³⁵ Unfortunately, LBD is often overlooked and not considered in the differential diagnosis. Due to underrecognition, patients may receive treatment with typical antipsychotics. The addition of a neuroleptic to help control the psychotic symptoms causes patients with LBD to develop severe extrapyramidal symptoms and worsening mental status,³⁶ leading to severe parkinsonian signs, which further muddies the diagnostic process. In addition, treatment for suspected Parkinson disease, including carbidopa-levodopa, has no benefit for patients with LBD and may increase psychotic symptoms.³⁷

First-line treatment for LBD includes psychoeducation for the patient and family, cholinesterase inhibitors (eg, rivastigmine), and avoidance of high-potency antipsychotics, such as haloperidol. Although persistent hallucinations and psychosis remain difficult to treat in LBD, low-dose quetiapine is 1 option. Incorrectly diagnosing and prescribing treatment for another condition exacerbates symptoms in this patient population.

Case 4

A 36-year-old Hispanic woman presents to the PCP for her annual physical exam. The patient’s medical record shows 2 previous office visits over the past 2 years—an annual physical exam and an office visit for the flu vaccine. The patient is highly accomplished in her profession, working as a certified public accountant for a major corporation. She is a nonsmoker and reports only casual social drinking and no recreational drug use. The patient is slightly overweight for her height but is otherwise healthy. Previous lab studies are within normal limits.

The patient has been experiencing chronic pain for the past few years after a motor vehicle accident. She has seen a physiatrist and another provider, both of whom found no “objective” causes of her chronic pain. They started the patient on sertraline for depression and an analgesic, both of which were ineffective.

The patient likes to exercise at a gym twice a week by doing light cardio (treadmill) exercise and light weightlifting. Lately, however, she has been unable to exercise due to the pain. At this visit, she mentions having low energy, poor sleep, frequent fatigue, and generalized soreness and pain in multiple areas of her body. The PCP recognizes the patient’s presenting symptoms as significant for FM and starts her on pregabalin and hydrotherapy, with positive results.

Continue to: Fibromyalgia skepticism may lead to a Dx of depression

FM, the second most common disorder seen in rheumatologic practice after OA, is estimated to affect approximately 1 in 20 patients (approximately 5 million Americans) in the primary care setting.^38,39 The condition has a high female-to-male preponderance (3.4% vs 0.5%).⁴⁰ While the primary symptom of FM is chronic pain, patients commonly present with fatigue and sleep disturbance.⁴¹ Comorbid conditions include headaches, irritable bowel syndrome, and mood disturbances (most commonly anxiety and depression). 

Patients with fibromyalgia, who are often otherwise healthy, often present multiple times to the same PCP with a chief complaint of chronic pain.

Several studies have explored reasons for the misdiagnosis and underdiagnosis of FM. One important factor is ongoing skepticism among some physicians and the public, in general, as to whether FM is a real disease. This issue was addressed by a study by White and colleagues,⁴² who estimated and compared the point prevalence of FM and related disorders in Amish vs non-Amish adults. The authors hypothesized that if litigation and/or compensation availability have a major impact on FM prevalence, then there would be a near zero prevalence of FM in the Amish community. And yet, researchers found an overall age- and sex-adjusted FM prevalence of 7.3% (95% CI; 5.3%-9.7%); this was both statistically greater than zero (P < .0001) and greater than 2 control populations of non-Amish adults (both P < .05).

Many physicians consider FM fundamentally an emotional disturbance, and the high preponderance of FM in female patients may contribute to this misconception as reports of pain and emotional distress by women are often dismissed as hysteria.⁴³ Physicians often explore the emotional aspects of FM, incorrectly diagnosing patients with depression and subsequently treating them with a psychotropic drug.³⁹ Alternatively, they may focus on the musculoskeletal presentations of FM and prescribe analgesics or physical therapy, both of which do little to alleviate FM. 

To make the correct diagnosis of FM, the American College of Rheumatology created a specific set of criteria in 1990, which was updated in 2010.⁴⁴ For a diagnosis of FM, a patient must have at least a 3-month history of bilateral pain above and below the waist and along the axial skeletal spine. Although not included in the updated 2010 criteria, many clinicians continue to check for tender points, following the 1990 criteria requiring the presence of 11 of 18 points to make the diagnosis.

At least 3 cognitive biases relating to FM apply: anchoring, availability, and fundamental attribution error (see table 3).⁷ Anchoring occurs when the PCP settles on a psychiatric diagnosis of exaggerated pain syndrome, muscle overuse, or OA and fails to explore alternative etiology. Availability bias may obscure the true diagnosis of FM. Since PCPs see many patients with RA or OA, they may overlook or dismiss the possibility of FM. Attribution error happens when physicians dismiss the complaints of patients with FM as merely due to psychological distress, hysteria, or acting out.⁴³

Patients with FM, who are often otherwise healthy, often present multiple times to the same PCP with a chief complaint of chronic pain. These repeat presentations can result in compassion fatigue and impact care. As Aloush and colleagues⁴⁰ noted in their study, “FM patients were perceived as more difficult than RA patients, with a high level of concern and emotional response. A high proportion of physicians were reluctant to accept them because they feel emotional/psychological difficulties meeting and coping with these patients.”In response, patients with undiagnosed FM or inadequately treated FM may visit other PCPs, which may or may not result in a correct diagnosis and treatment.

We can do better

Primary care physicians face the daunting task of diagnosing and treating a wide range of common conditions while also trying to recognize less-common conditions with atypical presentations—all during a busy clinic workday. Nonetheless, we should strive to overcome internal (eg, cognitive bias and fund-of-knowledge deficits) and external (eg, time constraints, limited resources) pressures to improve diagnostic accuracy and care.

Each of the 4 disease states we’ve discussed have high rates of missed and/or delayed diagnosis. Each presents a unique set of confounders: PMR with its overlapping symptoms of many other rheumatologic diseases; OC with its often vague and misleading GI symptomatology; LBD with overlapping features of AD and Parkinson disease; and FM with skepticism. As gatekeepers to health care, it falls on PCPs to sort out these diagnostic dilemmas to avoid medical errors. Fundamental knowledge of each disease, its unique pathophysiology and symptoms, and varying presentations can be learned, internalized, and subsequently put into clinical practice to improve patient outcomes.

CORRESPONDENCE
Paul D. Rosen MD, Brooklyn Hospital Center, Department of Family Medicine, 121 Dekalb Avenue, Brooklyn, New York 11201; [email protected]

The Food and Drug Administration has approved dexmedetomidine (Igalmi, BioXcel Therapeutics) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

This is the first FDA-approved, orally dissolving, self-administered sublingual treatment for this indication. With a demonstrated onset of action as early as 20 minutes, it shows a high response rate in patients at both 120-mcg and 180-mcg doses.

Olivier Le Moal/Getty Images

An estimated 7.3 million individuals in the United States are diagnosed with schizophrenia or bipolar disorders, and up to one-quarter of them experience episodes of agitation that can occur 10-17 times annually. These episodes represent a significant burden for patients, caregivers, and the health care system.

“There are large numbers of patients who experience agitation associated with schizophrenia and bipolar disorders, and this condition has been a long-standing challenge for health care professionals to treat,” said John Krystal, MD, the Robert L. McNeil Jr. Professor of Translational Research and chair of the department of psychiatry at Yale University, New Haven, Conn.

“The approval of Igalmi, a self-administered film with a desirable onset of action, represents a milestone moment. It provides health care teams with an innovative tool to help control agitation. As clinicians, we welcome this much-needed new oral treatment option,” he added.

“Igalmi is the first new acute treatment for schizophrenia or bipolar disorder–associated agitation in nearly a decade and represents a differentiated approach to helping patients manage this difficult and debilitating symptom,” said Vimal Mehta, PhD, CEO of BioXcel Therapeutics.

The FDA approval of Igalmi is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trials that evaluated Igalmi for the acute treatment of agitation associated with schizophrenia (SERENITY I) or bipolar I or II disorder (SERENITY II).

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were somnolence, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. All adverse drug reactions were mild to moderate in severity. While Igalmi was not associated with any treatment-related serious adverse effects in phase 3 studies, it may cause notable side effects, including hypotension, orthostatic hypotension, bradycardia, QT interval prolongation, and somnolence.

As previously reported by this news organization, data from the phase 3 SERENITY II trial that evaluated Igalmi in bipolar disorders were published in JAMA.

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

The Food and Drug Administration has approved dexmedetomidine (Igalmi, BioXcel Therapeutics) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

This is the first FDA-approved, orally dissolving, self-administered sublingual treatment for this indication. With a demonstrated onset of action as early as 20 minutes, it shows a high response rate in patients at both 120-mcg and 180-mcg doses.

Olivier Le Moal/Getty Images

An estimated 7.3 million individuals in the United States are diagnosed with schizophrenia or bipolar disorders, and up to one-quarter of them experience episodes of agitation that can occur 10-17 times annually. These episodes represent a significant burden for patients, caregivers, and the health care system.

“There are large numbers of patients who experience agitation associated with schizophrenia and bipolar disorders, and this condition has been a long-standing challenge for health care professionals to treat,” said John Krystal, MD, the Robert L. McNeil Jr. Professor of Translational Research and chair of the department of psychiatry at Yale University, New Haven, Conn.

“The approval of Igalmi, a self-administered film with a desirable onset of action, represents a milestone moment. It provides health care teams with an innovative tool to help control agitation. As clinicians, we welcome this much-needed new oral treatment option,” he added.

“Igalmi is the first new acute treatment for schizophrenia or bipolar disorder–associated agitation in nearly a decade and represents a differentiated approach to helping patients manage this difficult and debilitating symptom,” said Vimal Mehta, PhD, CEO of BioXcel Therapeutics.

The FDA approval of Igalmi is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trials that evaluated Igalmi for the acute treatment of agitation associated with schizophrenia (SERENITY I) or bipolar I or II disorder (SERENITY II).

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were somnolence, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. All adverse drug reactions were mild to moderate in severity. While Igalmi was not associated with any treatment-related serious adverse effects in phase 3 studies, it may cause notable side effects, including hypotension, orthostatic hypotension, bradycardia, QT interval prolongation, and somnolence.

As previously reported by this news organization, data from the phase 3 SERENITY II trial that evaluated Igalmi in bipolar disorders were published in JAMA.

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

The Food and Drug Administration has approved dexmedetomidine (Igalmi, BioXcel Therapeutics) sublingual film for the acute treatment of agitation associated with schizophrenia or bipolar I or II disorder in adults.

This is the first FDA-approved, orally dissolving, self-administered sublingual treatment for this indication. With a demonstrated onset of action as early as 20 minutes, it shows a high response rate in patients at both 120-mcg and 180-mcg doses.

Olivier Le Moal/Getty Images

An estimated 7.3 million individuals in the United States are diagnosed with schizophrenia or bipolar disorders, and up to one-quarter of them experience episodes of agitation that can occur 10-17 times annually. These episodes represent a significant burden for patients, caregivers, and the health care system.

“There are large numbers of patients who experience agitation associated with schizophrenia and bipolar disorders, and this condition has been a long-standing challenge for health care professionals to treat,” said John Krystal, MD, the Robert L. McNeil Jr. Professor of Translational Research and chair of the department of psychiatry at Yale University, New Haven, Conn.

“The approval of Igalmi, a self-administered film with a desirable onset of action, represents a milestone moment. It provides health care teams with an innovative tool to help control agitation. As clinicians, we welcome this much-needed new oral treatment option,” he added.

“Igalmi is the first new acute treatment for schizophrenia or bipolar disorder–associated agitation in nearly a decade and represents a differentiated approach to helping patients manage this difficult and debilitating symptom,” said Vimal Mehta, PhD, CEO of BioXcel Therapeutics.

The FDA approval of Igalmi is based on data from two pivotal randomized, double-blinded, placebo-controlled, parallel-group, phase 3 trials that evaluated Igalmi for the acute treatment of agitation associated with schizophrenia (SERENITY I) or bipolar I or II disorder (SERENITY II).

The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) were somnolence, paresthesia or oral hypoesthesia, dizziness, dry mouth, hypotension, and orthostatic hypotension. All adverse drug reactions were mild to moderate in severity. While Igalmi was not associated with any treatment-related serious adverse effects in phase 3 studies, it may cause notable side effects, including hypotension, orthostatic hypotension, bradycardia, QT interval prolongation, and somnolence.

As previously reported by this news organization, data from the phase 3 SERENITY II trial that evaluated Igalmi in bipolar disorders were published in JAMA.

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

There’s a strong likelihood that the antidepressant fluvoxamine (Luvox) may moderately lower rates of hospitalization caused by COVID-19 in unvaccinated patients, a new systematic review and meta-analysis has found. But outside experts differ over whether the evidence from just three studies is strong enough to warrant adding the drug to the COVID-19 armamentarium.

The report, published online in JAMA Network Open, looked at three studies and estimated that the drug could reduce the relative risk of hospitalization by around 25% (likelihood of moderate effect, 81.6%-91.8%), depending on the type of analysis used.

“This research might be valuable, but the jury remains out until several other adequately powered and designed trials are completed,” said infectious disease specialist Carl J. Fichtenbaum, MD, of the University of Cincinnati, who’s familiar with the findings. “I’m not sure how useful this is given we have several antiviral agents available. Why would we choose this over Paxlovid, remdesivir, or molnupiravir?”

According to Dr. Fichtenbaum, researchers began focusing on fluvoxamine after case reports about patients improving while on the medication. This led to further interest, he said, boosted by the drug’s known ability to dampen the immune system.

A Silicon Valley investor and antivaccine activist named Steve Kirsch has been pushing the drug along with the debunked treatment hydroxychloroquine. He’s accused the government of a cover-up of fluvoxamine’s worth, according to MIT Technology Review, and he wrote a commentary that referred to the drug as “the fast, easy, safe, simple, low-cost solution to COVID that works 100% of the time that nobody wants to talk about.”

For the new analysis, researchers examined three randomized clinical trials with a total of 2,196 participants. The most extensive trial, the TOGETHER study in Brazil (n = 1,497), focused on an unusual outcome: It linked the drug to a 32% reduction in relative risk of patients with COVID-19 being hospitalized in an ED for fewer than 6 hours or transferred to a tertiary hospital because of the disease.

Another study, the STOP COVID 2 trial in the United States and Canada (n = 547), was stopped because too few patients could be recruited to provide useful results. The initial phase of this trial, STOP COVID 1 (n = 152), was also included in the analysis.

All participants in the three studies were unvaccinated. Their median age was 46-50 years, 55%-72% were women, and 44%-56% were obese. Most were multiracial due to the high number of participants from Brazil.

“In the Bayesian analyses, the pooled risk ratio in favor of fluvoxamine was 0.78 (95% confidence interval, 0.58-1.08) for the weakly neutral prior and 0.73 (95% CI, 0.53-1.01) for the moderately optimistic prior,” the researchers reported, referring to a reduction in risk of hospitalization. “In the frequentist meta-analysis, the pooled risk ratio in favor of fluvoxamine was 0.75 (95% CI, 0.58-0.97; I², 0.2%).”

Two of the authors of the new analysis were also coauthors of the TOGETHER trial and both STOP COVID trials.

Corresponding author Emily G. McDonald, MD, division of experimental medicine at McGill University, Montreal, said in an interview that the findings show fluvoxamine “very likely reduces hospitalization in high-risk outpatient adults with COVID-19. This effect varies depending on your baseline risk of developing complications in the first place.”

Dr. McDonald added that “fluvoxamine is an option to reduce hospitalizations in high-risk adults. It is likely effective, is inexpensive, and has a long safety track record.” She also noted that “not all countries have access to Paxlovid, and some people have drug interactions that preclude its use. Existing monoclonals are not effective with newer variants.”

The drug’s apparent anti-inflammatory properties seem to be key, she said. According to her, the next steps should be “testing lower doses to see if they remain effective, following patients long term to see what impact there is on long COVID symptoms, testing related medications in the drug class to see if they also show an effect, and testing in vaccinated people and with newer variants.”

In an interview, biostatistician James Watson, PhD, of the Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand, and Nuffield department of medicine, University of Oxford, England, said the findings of the analysis are “not overwhelming data.”

He noted the TOGETHER study’s unusual focus on ED visits that latest fewer than 6 hours, which he described as “not a very objective endpoint.” The new meta-analysis focused instead on “outcome data on emergency department visits lasting more than 24 hours and used this as a more representative proxy for hospital admission than an ED visit alone.”

Dr. Fichtenbaum also highlighted the odd endpoint. “Most of us would have chosen something like use of oxygen, requirement for ventilation, or death,” he said. “There are many reasons why people go to the ED. This endpoint is not very strong.”

He also noted that the three studies “are very different in design and endpoints.”

Jeffrey S. Morris, PhD, a biostatistician at the University of Pennsylvania, Philadelphia, offered a different perspective about the findings in an interview. “There’s good evidence that it helps some,” he said, and may reduce hospitalizations by 10%. “If the pill is super cheap and toxicity is very acceptable, it’s not adding additional risk. Most clinicians would say that: ‘If I’m reducing risk by 10%, it’s worthwhile.’ ”

No funding was reported. Two authors report having a patent application filed by Washington University for methods of treating COVID-19 during the conduct of the study. Dr. Watson is an investigator for studies analyzing antiviral drugs and Prozac as COVID-19 treatments. Dr. Fichtenbaum and Dr. Morris disclosed no relevant financial relationships.

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

There’s a strong likelihood that the antidepressant fluvoxamine (Luvox) may moderately lower rates of hospitalization caused by COVID-19 in unvaccinated patients, a new systematic review and meta-analysis has found. But outside experts differ over whether the evidence from just three studies is strong enough to warrant adding the drug to the COVID-19 armamentarium.

The report, published online in JAMA Network Open, looked at three studies and estimated that the drug could reduce the relative risk of hospitalization by around 25% (likelihood of moderate effect, 81.6%-91.8%), depending on the type of analysis used.

“This research might be valuable, but the jury remains out until several other adequately powered and designed trials are completed,” said infectious disease specialist Carl J. Fichtenbaum, MD, of the University of Cincinnati, who’s familiar with the findings. “I’m not sure how useful this is given we have several antiviral agents available. Why would we choose this over Paxlovid, remdesivir, or molnupiravir?”

According to Dr. Fichtenbaum, researchers began focusing on fluvoxamine after case reports about patients improving while on the medication. This led to further interest, he said, boosted by the drug’s known ability to dampen the immune system.

A Silicon Valley investor and antivaccine activist named Steve Kirsch has been pushing the drug along with the debunked treatment hydroxychloroquine. He’s accused the government of a cover-up of fluvoxamine’s worth, according to MIT Technology Review, and he wrote a commentary that referred to the drug as “the fast, easy, safe, simple, low-cost solution to COVID that works 100% of the time that nobody wants to talk about.”

For the new analysis, researchers examined three randomized clinical trials with a total of 2,196 participants. The most extensive trial, the TOGETHER study in Brazil (n = 1,497), focused on an unusual outcome: It linked the drug to a 32% reduction in relative risk of patients with COVID-19 being hospitalized in an ED for fewer than 6 hours or transferred to a tertiary hospital because of the disease.

Another study, the STOP COVID 2 trial in the United States and Canada (n = 547), was stopped because too few patients could be recruited to provide useful results. The initial phase of this trial, STOP COVID 1 (n = 152), was also included in the analysis.

All participants in the three studies were unvaccinated. Their median age was 46-50 years, 55%-72% were women, and 44%-56% were obese. Most were multiracial due to the high number of participants from Brazil.

“In the Bayesian analyses, the pooled risk ratio in favor of fluvoxamine was 0.78 (95% confidence interval, 0.58-1.08) for the weakly neutral prior and 0.73 (95% CI, 0.53-1.01) for the moderately optimistic prior,” the researchers reported, referring to a reduction in risk of hospitalization. “In the frequentist meta-analysis, the pooled risk ratio in favor of fluvoxamine was 0.75 (95% CI, 0.58-0.97; I², 0.2%).”

Two of the authors of the new analysis were also coauthors of the TOGETHER trial and both STOP COVID trials.

Corresponding author Emily G. McDonald, MD, division of experimental medicine at McGill University, Montreal, said in an interview that the findings show fluvoxamine “very likely reduces hospitalization in high-risk outpatient adults with COVID-19. This effect varies depending on your baseline risk of developing complications in the first place.”

Dr. McDonald added that “fluvoxamine is an option to reduce hospitalizations in high-risk adults. It is likely effective, is inexpensive, and has a long safety track record.” She also noted that “not all countries have access to Paxlovid, and some people have drug interactions that preclude its use. Existing monoclonals are not effective with newer variants.”

The drug’s apparent anti-inflammatory properties seem to be key, she said. According to her, the next steps should be “testing lower doses to see if they remain effective, following patients long term to see what impact there is on long COVID symptoms, testing related medications in the drug class to see if they also show an effect, and testing in vaccinated people and with newer variants.”

In an interview, biostatistician James Watson, PhD, of the Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand, and Nuffield department of medicine, University of Oxford, England, said the findings of the analysis are “not overwhelming data.”

He noted the TOGETHER study’s unusual focus on ED visits that latest fewer than 6 hours, which he described as “not a very objective endpoint.” The new meta-analysis focused instead on “outcome data on emergency department visits lasting more than 24 hours and used this as a more representative proxy for hospital admission than an ED visit alone.”

Dr. Fichtenbaum also highlighted the odd endpoint. “Most of us would have chosen something like use of oxygen, requirement for ventilation, or death,” he said. “There are many reasons why people go to the ED. This endpoint is not very strong.”

He also noted that the three studies “are very different in design and endpoints.”

Jeffrey S. Morris, PhD, a biostatistician at the University of Pennsylvania, Philadelphia, offered a different perspective about the findings in an interview. “There’s good evidence that it helps some,” he said, and may reduce hospitalizations by 10%. “If the pill is super cheap and toxicity is very acceptable, it’s not adding additional risk. Most clinicians would say that: ‘If I’m reducing risk by 10%, it’s worthwhile.’ ”

No funding was reported. Two authors report having a patent application filed by Washington University for methods of treating COVID-19 during the conduct of the study. Dr. Watson is an investigator for studies analyzing antiviral drugs and Prozac as COVID-19 treatments. Dr. Fichtenbaum and Dr. Morris disclosed no relevant financial relationships.

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

There’s a strong likelihood that the antidepressant fluvoxamine (Luvox) may moderately lower rates of hospitalization caused by COVID-19 in unvaccinated patients, a new systematic review and meta-analysis has found. But outside experts differ over whether the evidence from just three studies is strong enough to warrant adding the drug to the COVID-19 armamentarium.

The report, published online in JAMA Network Open, looked at three studies and estimated that the drug could reduce the relative risk of hospitalization by around 25% (likelihood of moderate effect, 81.6%-91.8%), depending on the type of analysis used.

“This research might be valuable, but the jury remains out until several other adequately powered and designed trials are completed,” said infectious disease specialist Carl J. Fichtenbaum, MD, of the University of Cincinnati, who’s familiar with the findings. “I’m not sure how useful this is given we have several antiviral agents available. Why would we choose this over Paxlovid, remdesivir, or molnupiravir?”

According to Dr. Fichtenbaum, researchers began focusing on fluvoxamine after case reports about patients improving while on the medication. This led to further interest, he said, boosted by the drug’s known ability to dampen the immune system.

A Silicon Valley investor and antivaccine activist named Steve Kirsch has been pushing the drug along with the debunked treatment hydroxychloroquine. He’s accused the government of a cover-up of fluvoxamine’s worth, according to MIT Technology Review, and he wrote a commentary that referred to the drug as “the fast, easy, safe, simple, low-cost solution to COVID that works 100% of the time that nobody wants to talk about.”

For the new analysis, researchers examined three randomized clinical trials with a total of 2,196 participants. The most extensive trial, the TOGETHER study in Brazil (n = 1,497), focused on an unusual outcome: It linked the drug to a 32% reduction in relative risk of patients with COVID-19 being hospitalized in an ED for fewer than 6 hours or transferred to a tertiary hospital because of the disease.

Another study, the STOP COVID 2 trial in the United States and Canada (n = 547), was stopped because too few patients could be recruited to provide useful results. The initial phase of this trial, STOP COVID 1 (n = 152), was also included in the analysis.

All participants in the three studies were unvaccinated. Their median age was 46-50 years, 55%-72% were women, and 44%-56% were obese. Most were multiracial due to the high number of participants from Brazil.

“In the Bayesian analyses, the pooled risk ratio in favor of fluvoxamine was 0.78 (95% confidence interval, 0.58-1.08) for the weakly neutral prior and 0.73 (95% CI, 0.53-1.01) for the moderately optimistic prior,” the researchers reported, referring to a reduction in risk of hospitalization. “In the frequentist meta-analysis, the pooled risk ratio in favor of fluvoxamine was 0.75 (95% CI, 0.58-0.97; I², 0.2%).”

Two of the authors of the new analysis were also coauthors of the TOGETHER trial and both STOP COVID trials.

Corresponding author Emily G. McDonald, MD, division of experimental medicine at McGill University, Montreal, said in an interview that the findings show fluvoxamine “very likely reduces hospitalization in high-risk outpatient adults with COVID-19. This effect varies depending on your baseline risk of developing complications in the first place.”

Dr. McDonald added that “fluvoxamine is an option to reduce hospitalizations in high-risk adults. It is likely effective, is inexpensive, and has a long safety track record.” She also noted that “not all countries have access to Paxlovid, and some people have drug interactions that preclude its use. Existing monoclonals are not effective with newer variants.”

The drug’s apparent anti-inflammatory properties seem to be key, she said. According to her, the next steps should be “testing lower doses to see if they remain effective, following patients long term to see what impact there is on long COVID symptoms, testing related medications in the drug class to see if they also show an effect, and testing in vaccinated people and with newer variants.”

In an interview, biostatistician James Watson, PhD, of the Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand, and Nuffield department of medicine, University of Oxford, England, said the findings of the analysis are “not overwhelming data.”

He noted the TOGETHER study’s unusual focus on ED visits that latest fewer than 6 hours, which he described as “not a very objective endpoint.” The new meta-analysis focused instead on “outcome data on emergency department visits lasting more than 24 hours and used this as a more representative proxy for hospital admission than an ED visit alone.”

Dr. Fichtenbaum also highlighted the odd endpoint. “Most of us would have chosen something like use of oxygen, requirement for ventilation, or death,” he said. “There are many reasons why people go to the ED. This endpoint is not very strong.”

He also noted that the three studies “are very different in design and endpoints.”

Jeffrey S. Morris, PhD, a biostatistician at the University of Pennsylvania, Philadelphia, offered a different perspective about the findings in an interview. “There’s good evidence that it helps some,” he said, and may reduce hospitalizations by 10%. “If the pill is super cheap and toxicity is very acceptable, it’s not adding additional risk. Most clinicians would say that: ‘If I’m reducing risk by 10%, it’s worthwhile.’ ”

No funding was reported. Two authors report having a patent application filed by Washington University for methods of treating COVID-19 during the conduct of the study. Dr. Watson is an investigator for studies analyzing antiviral drugs and Prozac as COVID-19 treatments. Dr. Fichtenbaum and Dr. Morris disclosed no relevant financial relationships.

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

Though overall COVID-19 case counts continue to drop nationally, that’s not the story in every U.S. state.

About half the states have reported increases in COVID cases fueled by the Omicron subvariant, Axios reported. Alaska, Vermont, and Rhode Island had the highest increases, with more than 20 new cases per 100,000 people.

Nationally, the statistics are encouraging, with the 7-day average of daily cases around 26,000 on April 6, down from around 41,000 on March 6, according to the Centers for Disease Control and Prevention. The number of deaths has dropped to an average of around 600 a day, down 34% from 2 weeks ago.

National health officials have said some spots would have a lot of COVID cases.

“Looking across the country, we see that 95% of counties are reporting low COVID-19 community levels, which represent over 97% of the U.S. population,” CDC Director Rochelle Walensky, MD, said April 5 at a White House news briefing.

“If we look more closely at the local level, we find a handful of counties where we are seeing increases in both cases and markers of more severe disease, like hospitalizations and in-patient bed capacity, which have resulted in an increased COVID-19 community level in some areas.”

Meanwhile, the Commonwealth Fund issued a report April 8 saying the U.S. vaccine program had prevented an estimated 2.2 million deaths and 17 million hospitalizations.

If the vaccine program didn’t exist, the United States would have had another 66 million COVID infections and spent about $900 billion more on health care, the foundation said.

The United States has reported about 982,000 COVID-related deaths so far with about 80 million COVID cases, according to the CDC.

“Our findings highlight the profound and ongoing impact of the vaccination program in reducing infections, hospitalizations, and deaths,” the Commonwealth Fund said.

“Investing in vaccination programs also has produced substantial cost savings – approximately the size of one-fifth of annual national health expenditures – by dramatically reducing the amount spent on COVID-19 hospitalizations.”

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

Though overall COVID-19 case counts continue to drop nationally, that’s not the story in every U.S. state.

About half the states have reported increases in COVID cases fueled by the Omicron subvariant, Axios reported. Alaska, Vermont, and Rhode Island had the highest increases, with more than 20 new cases per 100,000 people.

Nationally, the statistics are encouraging, with the 7-day average of daily cases around 26,000 on April 6, down from around 41,000 on March 6, according to the Centers for Disease Control and Prevention. The number of deaths has dropped to an average of around 600 a day, down 34% from 2 weeks ago.

National health officials have said some spots would have a lot of COVID cases.

“Looking across the country, we see that 95% of counties are reporting low COVID-19 community levels, which represent over 97% of the U.S. population,” CDC Director Rochelle Walensky, MD, said April 5 at a White House news briefing.

“If we look more closely at the local level, we find a handful of counties where we are seeing increases in both cases and markers of more severe disease, like hospitalizations and in-patient bed capacity, which have resulted in an increased COVID-19 community level in some areas.”

Meanwhile, the Commonwealth Fund issued a report April 8 saying the U.S. vaccine program had prevented an estimated 2.2 million deaths and 17 million hospitalizations.

If the vaccine program didn’t exist, the United States would have had another 66 million COVID infections and spent about $900 billion more on health care, the foundation said.

The United States has reported about 982,000 COVID-related deaths so far with about 80 million COVID cases, according to the CDC.

“Our findings highlight the profound and ongoing impact of the vaccination program in reducing infections, hospitalizations, and deaths,” the Commonwealth Fund said.

“Investing in vaccination programs also has produced substantial cost savings – approximately the size of one-fifth of annual national health expenditures – by dramatically reducing the amount spent on COVID-19 hospitalizations.”

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

Though overall COVID-19 case counts continue to drop nationally, that’s not the story in every U.S. state.

About half the states have reported increases in COVID cases fueled by the Omicron subvariant, Axios reported. Alaska, Vermont, and Rhode Island had the highest increases, with more than 20 new cases per 100,000 people.

Nationally, the statistics are encouraging, with the 7-day average of daily cases around 26,000 on April 6, down from around 41,000 on March 6, according to the Centers for Disease Control and Prevention. The number of deaths has dropped to an average of around 600 a day, down 34% from 2 weeks ago.

National health officials have said some spots would have a lot of COVID cases.

“Looking across the country, we see that 95% of counties are reporting low COVID-19 community levels, which represent over 97% of the U.S. population,” CDC Director Rochelle Walensky, MD, said April 5 at a White House news briefing.

“If we look more closely at the local level, we find a handful of counties where we are seeing increases in both cases and markers of more severe disease, like hospitalizations and in-patient bed capacity, which have resulted in an increased COVID-19 community level in some areas.”

Meanwhile, the Commonwealth Fund issued a report April 8 saying the U.S. vaccine program had prevented an estimated 2.2 million deaths and 17 million hospitalizations.

If the vaccine program didn’t exist, the United States would have had another 66 million COVID infections and spent about $900 billion more on health care, the foundation said.

The United States has reported about 982,000 COVID-related deaths so far with about 80 million COVID cases, according to the CDC.

“Our findings highlight the profound and ongoing impact of the vaccination program in reducing infections, hospitalizations, and deaths,” the Commonwealth Fund said.

“Investing in vaccination programs also has produced substantial cost savings – approximately the size of one-fifth of annual national health expenditures – by dramatically reducing the amount spent on COVID-19 hospitalizations.”

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

Decades after hospitalists took over inpatient care in the 1990s, hospitalists and primary care physicians (PCPs) still struggle with a communication divide, researchers at one teaching hospital found.

Hospitalists and PCPs want more dialogue while patients are in the hospital in order to coordinate and personalize care, according to data collected at Beth Israel Deaconess Medical Center, Boston. The results were presented at the annual meeting of the Society of General Internal Medicine.

“I think a major takeaway is that both hospitalists and primary care doctors agree that it’s important for primary care doctors to be involved in a patient’s hospitalization. They both identified a value that PCPs can bring to the table,” coresearcher Kristen Flint, MD, a primary care resident, told this news organization.

A majority in both camps reported that communication with the other party occurred in less than 25% of cases, whereas ideally it would happen half of the time. Dr. Flint noted that communication tools differ among hospitals, limiting the applicability of the findings.

The research team surveyed 39 hospitalists and 28 PCPs employed by the medical center during the first half of 2021. They also interviewed six hospitalists as they admitted and discharged patients.

The hospitalist movement, which took hold in response to cost and efficiency demands of managed care, led to the start of inpatient specialists, thereby reducing the need for PCPs to commute between their offices and the hospital to care for patients in both settings. 
 

Primary care involvement is important during hospitalization

In the Beth Israel Deaconess survey, four out of five hospitalists and three-quarters of PCPs agreed that primary care involvement is still important during hospitalization, most critically during discharge and admission. Hospitalists reported that PCPs provide valuable data about a patient’s medical status, social supports, mental health, and goals for care. They also said having such data helps to boost patient trust and improve the quality of inpatient care.

“Most projects around communication between inpatient and outpatient doctors have really focused on the time of discharge,” when clinicians identify what care a patient will need after they leave the hospital, Dr. Flint said. “But we found that both sides felt increased communication at time of admission would also be beneficial.”

The biggest barrier for PCPs, cited by 82% of respondents, was lack of time. Hospitalists’ top impediment was being unable to find contact information for the other party, which was cited by 79% of these survey participants.
 

Hospitalists operate ‘in a very stressful environment’

The Beth Israel Deaconess research “documents what has largely been suspected,” said primary care general internist Allan Goroll, MD.

Dr. Goroll, a professor of medicine at Harvard Medical School, Boston, said in an interview that hospitalists operate “in a very stressful environment.”

“They [hospitalists] appreciate accurate information about a patient’s recent medical history, test results, and responses to treatment as well as a briefing on patient values and preferences, family dynamics, and priorities for the admission. It makes for a safer, more personalized, and more efficient hospital admission,” said Dr. Goroll, who was not involved in the research.

In a 2015 article in the New England Journal of Medicine, Dr. Goroll and Daniel Hunt, MD, director of hospital medicine at Emory University, Atlanta, proposed a collaborative model in which PCPs visit hospitalized patients and serve as consultants to inpatient staff. Dr. Goroll said Massachusetts General Hospital in Boston, where he practices, initiated a study of that approach, but it was interrupted by the pandemic.

“As limited time is the most often cited barrier to communication, future interventions such as asynchronous forms of communication between the two groups should be considered,” the researchers wrote in the NEJM perspective.

To narrow the gap, Beth Israel Deaconess will study converting an admission notification letter sent to PCPs into a two-way communication tool in which PCPs can insert patient information, Dr. Flint said.

Dr. Flint and Dr. Goroll have disclosed no relevant financial relationships.

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

Decades after hospitalists took over inpatient care in the 1990s, hospitalists and primary care physicians (PCPs) still struggle with a communication divide, researchers at one teaching hospital found.

Hospitalists and PCPs want more dialogue while patients are in the hospital in order to coordinate and personalize care, according to data collected at Beth Israel Deaconess Medical Center, Boston. The results were presented at the annual meeting of the Society of General Internal Medicine.

“I think a major takeaway is that both hospitalists and primary care doctors agree that it’s important for primary care doctors to be involved in a patient’s hospitalization. They both identified a value that PCPs can bring to the table,” coresearcher Kristen Flint, MD, a primary care resident, told this news organization.

A majority in both camps reported that communication with the other party occurred in less than 25% of cases, whereas ideally it would happen half of the time. Dr. Flint noted that communication tools differ among hospitals, limiting the applicability of the findings.

The research team surveyed 39 hospitalists and 28 PCPs employed by the medical center during the first half of 2021. They also interviewed six hospitalists as they admitted and discharged patients.

The hospitalist movement, which took hold in response to cost and efficiency demands of managed care, led to the start of inpatient specialists, thereby reducing the need for PCPs to commute between their offices and the hospital to care for patients in both settings. 
 

Primary care involvement is important during hospitalization

In the Beth Israel Deaconess survey, four out of five hospitalists and three-quarters of PCPs agreed that primary care involvement is still important during hospitalization, most critically during discharge and admission. Hospitalists reported that PCPs provide valuable data about a patient’s medical status, social supports, mental health, and goals for care. They also said having such data helps to boost patient trust and improve the quality of inpatient care.

“Most projects around communication between inpatient and outpatient doctors have really focused on the time of discharge,” when clinicians identify what care a patient will need after they leave the hospital, Dr. Flint said. “But we found that both sides felt increased communication at time of admission would also be beneficial.”

The biggest barrier for PCPs, cited by 82% of respondents, was lack of time. Hospitalists’ top impediment was being unable to find contact information for the other party, which was cited by 79% of these survey participants.
 

Hospitalists operate ‘in a very stressful environment’

The Beth Israel Deaconess research “documents what has largely been suspected,” said primary care general internist Allan Goroll, MD.

Dr. Goroll, a professor of medicine at Harvard Medical School, Boston, said in an interview that hospitalists operate “in a very stressful environment.”

“They [hospitalists] appreciate accurate information about a patient’s recent medical history, test results, and responses to treatment as well as a briefing on patient values and preferences, family dynamics, and priorities for the admission. It makes for a safer, more personalized, and more efficient hospital admission,” said Dr. Goroll, who was not involved in the research.

In a 2015 article in the New England Journal of Medicine, Dr. Goroll and Daniel Hunt, MD, director of hospital medicine at Emory University, Atlanta, proposed a collaborative model in which PCPs visit hospitalized patients and serve as consultants to inpatient staff. Dr. Goroll said Massachusetts General Hospital in Boston, where he practices, initiated a study of that approach, but it was interrupted by the pandemic.

“As limited time is the most often cited barrier to communication, future interventions such as asynchronous forms of communication between the two groups should be considered,” the researchers wrote in the NEJM perspective.

To narrow the gap, Beth Israel Deaconess will study converting an admission notification letter sent to PCPs into a two-way communication tool in which PCPs can insert patient information, Dr. Flint said.

Dr. Flint and Dr. Goroll have disclosed no relevant financial relationships.

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

Decades after hospitalists took over inpatient care in the 1990s, hospitalists and primary care physicians (PCPs) still struggle with a communication divide, researchers at one teaching hospital found.

Hospitalists and PCPs want more dialogue while patients are in the hospital in order to coordinate and personalize care, according to data collected at Beth Israel Deaconess Medical Center, Boston. The results were presented at the annual meeting of the Society of General Internal Medicine.

“I think a major takeaway is that both hospitalists and primary care doctors agree that it’s important for primary care doctors to be involved in a patient’s hospitalization. They both identified a value that PCPs can bring to the table,” coresearcher Kristen Flint, MD, a primary care resident, told this news organization.

A majority in both camps reported that communication with the other party occurred in less than 25% of cases, whereas ideally it would happen half of the time. Dr. Flint noted that communication tools differ among hospitals, limiting the applicability of the findings.

The research team surveyed 39 hospitalists and 28 PCPs employed by the medical center during the first half of 2021. They also interviewed six hospitalists as they admitted and discharged patients.

The hospitalist movement, which took hold in response to cost and efficiency demands of managed care, led to the start of inpatient specialists, thereby reducing the need for PCPs to commute between their offices and the hospital to care for patients in both settings. 
 

Primary care involvement is important during hospitalization

In the Beth Israel Deaconess survey, four out of five hospitalists and three-quarters of PCPs agreed that primary care involvement is still important during hospitalization, most critically during discharge and admission. Hospitalists reported that PCPs provide valuable data about a patient’s medical status, social supports, mental health, and goals for care. They also said having such data helps to boost patient trust and improve the quality of inpatient care.

“Most projects around communication between inpatient and outpatient doctors have really focused on the time of discharge,” when clinicians identify what care a patient will need after they leave the hospital, Dr. Flint said. “But we found that both sides felt increased communication at time of admission would also be beneficial.”

The biggest barrier for PCPs, cited by 82% of respondents, was lack of time. Hospitalists’ top impediment was being unable to find contact information for the other party, which was cited by 79% of these survey participants.
 

Hospitalists operate ‘in a very stressful environment’

The Beth Israel Deaconess research “documents what has largely been suspected,” said primary care general internist Allan Goroll, MD.

Dr. Goroll, a professor of medicine at Harvard Medical School, Boston, said in an interview that hospitalists operate “in a very stressful environment.”

“They [hospitalists] appreciate accurate information about a patient’s recent medical history, test results, and responses to treatment as well as a briefing on patient values and preferences, family dynamics, and priorities for the admission. It makes for a safer, more personalized, and more efficient hospital admission,” said Dr. Goroll, who was not involved in the research.

In a 2015 article in the New England Journal of Medicine, Dr. Goroll and Daniel Hunt, MD, director of hospital medicine at Emory University, Atlanta, proposed a collaborative model in which PCPs visit hospitalized patients and serve as consultants to inpatient staff. Dr. Goroll said Massachusetts General Hospital in Boston, where he practices, initiated a study of that approach, but it was interrupted by the pandemic.

“As limited time is the most often cited barrier to communication, future interventions such as asynchronous forms of communication between the two groups should be considered,” the researchers wrote in the NEJM perspective.

To narrow the gap, Beth Israel Deaconess will study converting an admission notification letter sent to PCPs into a two-way communication tool in which PCPs can insert patient information, Dr. Flint said.

Dr. Flint and Dr. Goroll have disclosed no relevant financial relationships.

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

In a deep dive into obscure Chinese language transplant journals, a pair of researchers from Australia and Israel have added a new layer of horror to what’s already known about forced organ harvesting in China.

Searching for documentation that vital organs are being harvested from nonconsenting executed prisoners, a practice that the China Tribunal confirmed “beyond any reasonable doubt” in 2020, Jacob Lavee, MD, an Israeli heart transplant surgeon, and Matthew Roberston, a PhD student at Australian National University, uncovered something even more shocking: that vital organs are being explanted from patients who are still alive.

“We have shown for the first time that the transplant surgeons are the executioners – that the mode of execution is organ procurement. These are self-admissions of executing the patient,” Dr. Lavee told this news organization. “Up until now, there has been what we call circumstantial evidence of this, but our paper is what you’d call the smoking gun, because it’s in the words of the physicians themselves that they are doing it. In the words of these surgeons, intubation was done only after the beginning of surgery, which means the patients were breathing spontaneously up until the moment the operation started ... meaning they were not brain dead.”

The research, published in the American Journal of Transplantation, involved intricate analysis of thousands of Chinese language transplant articles and identified 71 articles in which transplant surgeons describe starting organ procurement surgery before declaring their patients brain dead.

“What we found were improper, illegitimate, nonexistent, or false declarations of brain death,” Mr. Robertson said in an interview. He explained that this violates what’s known as the dead donor rule, which is fundamental in transplant ethics. “The surgeons wrote that the donor was brain dead, but according to everything we know about medical science, they could not possibly have been brain dead because there was no apnea test performed. Brain death is not just something you say, there’s this whole battery of tests, and the key is the apnea test, [in which] the patient is already intubated and ventilated, they turn the machine off, and they’re looking for carbon dioxide in the blood above a certain level.”

Mr. Robertson and Dr. Lavee have painstakingly documented “incriminating sentences” in each of the 71 articles proving that brain death had not occurred before the organ explantation procedure began. “There were two criteria by which we claimed a problematic brain death declaration,” said Mr. Robertson, who translated the Chinese. “One was where the patient was not ventilated and was only intubated after they were declared brain dead; the other was that the intubation took place immediately prior to the surgery beginning.”

“It was mind-boggling,” said Dr. Lavee, from Tel Aviv University. “When I first started reading, my initial reaction is, ‘This can’t be.’ I read it once, and again, and I insisted that Matt get another independent translation of the Chinese just to be sure. I told him, ‘There’s no way a physician, a surgeon could write this – it doesn’t make sense.’ But the more of these papers we read, we saw it was a pattern – and they didn’t come out of a single medical center, they are spread all over China.”

For the analysis, Mr. Robertson wrote code and customized an algorithm to examine 124,770 medical articles from official Chinese databases between 1980 and 2020. The 71 articles revealing cases involving problematic brain death came from 56 hospitals (of which 12 were military) in 33 cities across 15 provinces, they report. In total, 348 surgeons, nurses, anesthesiologists, and other medical workers or researchers were listed as authors of these publications.

Why would these medical personnel write such self-incriminating evidence? The researchers say it’s unclear. “They don’t think anyone’s reading this stuff,” Mr. Robertson suggests. “Sometimes it’s revealed in just five or six characters in a paper of eight pages.” Dr. Lavee wonders if it’s also ignorance. “If this has been a practice for 20 or 30 years in China, I guess nobody at that time was aware they were doing something wrong, although how to declare brain death is something that is known in China. They’ve published a lot about it.”

The article is “evidence that this barbarity continues and is a very valuable contribution that continues to bring attention to an enormous human rights violation,” said Arthur Caplan, PhD, head of the Division of Medical Ethics at New York University’s Grossman School of Medicine. “What they’ve reported has been going on for many, many years, the data are very clear that China’s doing many more transplants than they have cadaver organ donors,” he said, adding that the country’s well-documented and lucrative involvement in transplant tourism “means you have to have a donor ready when the would-be recipient appears; you have to have a matched organ available, and that’s hard to do waiting on a cadaver donor.”

Although the researchers found no incriminating publications after 2015, they speculate that this is likely due to growing awareness among Chinese surgeons that publishing the information would attract international condemnation. “We think these practices are continuing to go on,” said Dr. Lavee. He acknowledged that a voluntary organ donation program is slowly developing in parallel to this. He said, given China’s place as the world’s second largest transplant country behind the U.S., as well as its low rate of voluntary donation, it’s reasonable to conclude that the main source of organs remains prisoners on death row.

Dr. Caplan and the researchers have called for academic institutions and medical journals to resume their previous boycotts of Chinese transplant publications and speakers, but as long as China denies the practices, economic and political leaders will turn a blind eye. “In the past, I don’t think the question of China’s medical professional involvement in the execution of donors has been taken as seriously as it should have,” said Mr. Robertson. “I certainly hope that with the publication of this paper in the leading journal in the field, this will change.”

The study was supported by the Google Cloud Research Credits program, the Australian Government Research Training Program Scholarship, and the Victims of Communism Memorial Foundation. Mr. Robertson, Dr. Lavee, and Dr. Caplan have disclosed no relevant financial relationships.

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

In a deep dive into obscure Chinese language transplant journals, a pair of researchers from Australia and Israel have added a new layer of horror to what’s already known about forced organ harvesting in China.

Searching for documentation that vital organs are being harvested from nonconsenting executed prisoners, a practice that the China Tribunal confirmed “beyond any reasonable doubt” in 2020, Jacob Lavee, MD, an Israeli heart transplant surgeon, and Matthew Roberston, a PhD student at Australian National University, uncovered something even more shocking: that vital organs are being explanted from patients who are still alive.

“We have shown for the first time that the transplant surgeons are the executioners – that the mode of execution is organ procurement. These are self-admissions of executing the patient,” Dr. Lavee told this news organization. “Up until now, there has been what we call circumstantial evidence of this, but our paper is what you’d call the smoking gun, because it’s in the words of the physicians themselves that they are doing it. In the words of these surgeons, intubation was done only after the beginning of surgery, which means the patients were breathing spontaneously up until the moment the operation started ... meaning they were not brain dead.”

The research, published in the American Journal of Transplantation, involved intricate analysis of thousands of Chinese language transplant articles and identified 71 articles in which transplant surgeons describe starting organ procurement surgery before declaring their patients brain dead.

“What we found were improper, illegitimate, nonexistent, or false declarations of brain death,” Mr. Robertson said in an interview. He explained that this violates what’s known as the dead donor rule, which is fundamental in transplant ethics. “The surgeons wrote that the donor was brain dead, but according to everything we know about medical science, they could not possibly have been brain dead because there was no apnea test performed. Brain death is not just something you say, there’s this whole battery of tests, and the key is the apnea test, [in which] the patient is already intubated and ventilated, they turn the machine off, and they’re looking for carbon dioxide in the blood above a certain level.”

Mr. Robertson and Dr. Lavee have painstakingly documented “incriminating sentences” in each of the 71 articles proving that brain death had not occurred before the organ explantation procedure began. “There were two criteria by which we claimed a problematic brain death declaration,” said Mr. Robertson, who translated the Chinese. “One was where the patient was not ventilated and was only intubated after they were declared brain dead; the other was that the intubation took place immediately prior to the surgery beginning.”

“It was mind-boggling,” said Dr. Lavee, from Tel Aviv University. “When I first started reading, my initial reaction is, ‘This can’t be.’ I read it once, and again, and I insisted that Matt get another independent translation of the Chinese just to be sure. I told him, ‘There’s no way a physician, a surgeon could write this – it doesn’t make sense.’ But the more of these papers we read, we saw it was a pattern – and they didn’t come out of a single medical center, they are spread all over China.”

For the analysis, Mr. Robertson wrote code and customized an algorithm to examine 124,770 medical articles from official Chinese databases between 1980 and 2020. The 71 articles revealing cases involving problematic brain death came from 56 hospitals (of which 12 were military) in 33 cities across 15 provinces, they report. In total, 348 surgeons, nurses, anesthesiologists, and other medical workers or researchers were listed as authors of these publications.

Why would these medical personnel write such self-incriminating evidence? The researchers say it’s unclear. “They don’t think anyone’s reading this stuff,” Mr. Robertson suggests. “Sometimes it’s revealed in just five or six characters in a paper of eight pages.” Dr. Lavee wonders if it’s also ignorance. “If this has been a practice for 20 or 30 years in China, I guess nobody at that time was aware they were doing something wrong, although how to declare brain death is something that is known in China. They’ve published a lot about it.”

The article is “evidence that this barbarity continues and is a very valuable contribution that continues to bring attention to an enormous human rights violation,” said Arthur Caplan, PhD, head of the Division of Medical Ethics at New York University’s Grossman School of Medicine. “What they’ve reported has been going on for many, many years, the data are very clear that China’s doing many more transplants than they have cadaver organ donors,” he said, adding that the country’s well-documented and lucrative involvement in transplant tourism “means you have to have a donor ready when the would-be recipient appears; you have to have a matched organ available, and that’s hard to do waiting on a cadaver donor.”

Although the researchers found no incriminating publications after 2015, they speculate that this is likely due to growing awareness among Chinese surgeons that publishing the information would attract international condemnation. “We think these practices are continuing to go on,” said Dr. Lavee. He acknowledged that a voluntary organ donation program is slowly developing in parallel to this. He said, given China’s place as the world’s second largest transplant country behind the U.S., as well as its low rate of voluntary donation, it’s reasonable to conclude that the main source of organs remains prisoners on death row.

Dr. Caplan and the researchers have called for academic institutions and medical journals to resume their previous boycotts of Chinese transplant publications and speakers, but as long as China denies the practices, economic and political leaders will turn a blind eye. “In the past, I don’t think the question of China’s medical professional involvement in the execution of donors has been taken as seriously as it should have,” said Mr. Robertson. “I certainly hope that with the publication of this paper in the leading journal in the field, this will change.”

The study was supported by the Google Cloud Research Credits program, the Australian Government Research Training Program Scholarship, and the Victims of Communism Memorial Foundation. Mr. Robertson, Dr. Lavee, and Dr. Caplan have disclosed no relevant financial relationships.

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

In a deep dive into obscure Chinese language transplant journals, a pair of researchers from Australia and Israel have added a new layer of horror to what’s already known about forced organ harvesting in China.

Searching for documentation that vital organs are being harvested from nonconsenting executed prisoners, a practice that the China Tribunal confirmed “beyond any reasonable doubt” in 2020, Jacob Lavee, MD, an Israeli heart transplant surgeon, and Matthew Roberston, a PhD student at Australian National University, uncovered something even more shocking: that vital organs are being explanted from patients who are still alive.

“We have shown for the first time that the transplant surgeons are the executioners – that the mode of execution is organ procurement. These are self-admissions of executing the patient,” Dr. Lavee told this news organization. “Up until now, there has been what we call circumstantial evidence of this, but our paper is what you’d call the smoking gun, because it’s in the words of the physicians themselves that they are doing it. In the words of these surgeons, intubation was done only after the beginning of surgery, which means the patients were breathing spontaneously up until the moment the operation started ... meaning they were not brain dead.”

The research, published in the American Journal of Transplantation, involved intricate analysis of thousands of Chinese language transplant articles and identified 71 articles in which transplant surgeons describe starting organ procurement surgery before declaring their patients brain dead.

“What we found were improper, illegitimate, nonexistent, or false declarations of brain death,” Mr. Robertson said in an interview. He explained that this violates what’s known as the dead donor rule, which is fundamental in transplant ethics. “The surgeons wrote that the donor was brain dead, but according to everything we know about medical science, they could not possibly have been brain dead because there was no apnea test performed. Brain death is not just something you say, there’s this whole battery of tests, and the key is the apnea test, [in which] the patient is already intubated and ventilated, they turn the machine off, and they’re looking for carbon dioxide in the blood above a certain level.”

Mr. Robertson and Dr. Lavee have painstakingly documented “incriminating sentences” in each of the 71 articles proving that brain death had not occurred before the organ explantation procedure began. “There were two criteria by which we claimed a problematic brain death declaration,” said Mr. Robertson, who translated the Chinese. “One was where the patient was not ventilated and was only intubated after they were declared brain dead; the other was that the intubation took place immediately prior to the surgery beginning.”

“It was mind-boggling,” said Dr. Lavee, from Tel Aviv University. “When I first started reading, my initial reaction is, ‘This can’t be.’ I read it once, and again, and I insisted that Matt get another independent translation of the Chinese just to be sure. I told him, ‘There’s no way a physician, a surgeon could write this – it doesn’t make sense.’ But the more of these papers we read, we saw it was a pattern – and they didn’t come out of a single medical center, they are spread all over China.”

For the analysis, Mr. Robertson wrote code and customized an algorithm to examine 124,770 medical articles from official Chinese databases between 1980 and 2020. The 71 articles revealing cases involving problematic brain death came from 56 hospitals (of which 12 were military) in 33 cities across 15 provinces, they report. In total, 348 surgeons, nurses, anesthesiologists, and other medical workers or researchers were listed as authors of these publications.

Why would these medical personnel write such self-incriminating evidence? The researchers say it’s unclear. “They don’t think anyone’s reading this stuff,” Mr. Robertson suggests. “Sometimes it’s revealed in just five or six characters in a paper of eight pages.” Dr. Lavee wonders if it’s also ignorance. “If this has been a practice for 20 or 30 years in China, I guess nobody at that time was aware they were doing something wrong, although how to declare brain death is something that is known in China. They’ve published a lot about it.”

The article is “evidence that this barbarity continues and is a very valuable contribution that continues to bring attention to an enormous human rights violation,” said Arthur Caplan, PhD, head of the Division of Medical Ethics at New York University’s Grossman School of Medicine. “What they’ve reported has been going on for many, many years, the data are very clear that China’s doing many more transplants than they have cadaver organ donors,” he said, adding that the country’s well-documented and lucrative involvement in transplant tourism “means you have to have a donor ready when the would-be recipient appears; you have to have a matched organ available, and that’s hard to do waiting on a cadaver donor.”

Although the researchers found no incriminating publications after 2015, they speculate that this is likely due to growing awareness among Chinese surgeons that publishing the information would attract international condemnation. “We think these practices are continuing to go on,” said Dr. Lavee. He acknowledged that a voluntary organ donation program is slowly developing in parallel to this. He said, given China’s place as the world’s second largest transplant country behind the U.S., as well as its low rate of voluntary donation, it’s reasonable to conclude that the main source of organs remains prisoners on death row.

Dr. Caplan and the researchers have called for academic institutions and medical journals to resume their previous boycotts of Chinese transplant publications and speakers, but as long as China denies the practices, economic and political leaders will turn a blind eye. “In the past, I don’t think the question of China’s medical professional involvement in the execution of donors has been taken as seriously as it should have,” said Mr. Robertson. “I certainly hope that with the publication of this paper in the leading journal in the field, this will change.”

The study was supported by the Google Cloud Research Credits program, the Australian Government Research Training Program Scholarship, and the Victims of Communism Memorial Foundation. Mr. Robertson, Dr. Lavee, and Dr. Caplan have disclosed no relevant financial relationships.

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

Individuals with a prior diagnosis of pneumonia were significantly more likely to develop chronic otitis media (COM) than were those without a history of pneumonia, based on data from a nationwide cohort study of more than 100,000 patients.

“Recently, middle ear diseases, including COM, have been recognized as respiratory tract diseases beyond the pathophysiological concepts of ventilation dysfunction, with recurrent infection that occurs from anatomically adjacent structures such as the middle ear, mastoid cavity, and eustachian tube,” but the potential link between pneumonia and chronic otitis media and adults in particular has not been examined, wrote Sung Kyun Kim, MD, of Hallym University, Dongtan, South Korea, and colleagues.

In a study recently published in the International Journal of Infectious Diseases, the researchers identified 23,436 adults with COM and 93,744 controls aged 40 years and older from a Korean health insurance database between 2002 and 2015.

The overall incidence of pneumonia in the study population was significantly higher in the COM group compared with controls (9.3% vs. 7.2%, P <.001). The odds ratios of pneumonia were significantly higher in the COM group compared with controls, and a history of pneumonia increased the odds of COM regardless of sex and across all ages.

Pneumonia was defined as when a patient had a diagnosis of pneumonia based on ICD-10 codes and underwent a chest x-ray or chest CT scan. Chronic otitis media was defined as when a patient had a diagnosis based on ICD-10 codes at least two times with one of the following conditions: chronic serous otitis media, chronic mucoid otitis media, other chronic nonsuppurative otitis media, unspecified nonsuppurative otitis media, chronic tubotympanic suppurative otitis media, chronic atticoantral suppurative otitis media, other chronic suppurative otitis media, or unspecified suppurative otitis media.

Age groups were divided into 5-year intervals, and patients were classified into income groups and rural vs. urban residence.

In a further sensitivity analysis, individuals who were diagnosed with pneumonia five or more times before the index date had a significantly higher odds ratio for COM compared with those with less than five diagnoses of pneumonia (adjusted odds ratio, 1.34; P < .001).

Microbiome dysbiosis may explain part of the connection between pneumonia and COM, the researchers wrote in their discussion. Pathogens in the lungs can prompt changes in the microbiome dynamics, as might the use of antibiotics, they said. In addition, “Mucus plugging in the airway caused by pneumonia induces hypoxic conditions and leads to the expression of inflammatory markers in the eustachian tube and middle ear mucosa,” they noted.

The study findings were limited by several factors, including the retrospective design and lack of data on microbiological cultures for antibiotic susceptibility, radiologic findings on the severity of pneumonia, results of pulmonary function tests, and hearing thresholds, the researchers noted. Other limitations were the exclusion of the frequency of upper respiratory infections and antibiotic use due to lack of data, they said.

However, the results show an association between pneumonia diagnoses and increased incidence of COM, which suggests a novel perspective that “infection of the lower respiratory tract may affect the function of the eustachian tube and the middle ear to later cause COM,” they concluded.

The study received no outside funding. The researchers have disclosed no relevant financial relationships.

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

Individuals with a prior diagnosis of pneumonia were significantly more likely to develop chronic otitis media (COM) than were those without a history of pneumonia, based on data from a nationwide cohort study of more than 100,000 patients.

“Recently, middle ear diseases, including COM, have been recognized as respiratory tract diseases beyond the pathophysiological concepts of ventilation dysfunction, with recurrent infection that occurs from anatomically adjacent structures such as the middle ear, mastoid cavity, and eustachian tube,” but the potential link between pneumonia and chronic otitis media and adults in particular has not been examined, wrote Sung Kyun Kim, MD, of Hallym University, Dongtan, South Korea, and colleagues.

In a study recently published in the International Journal of Infectious Diseases, the researchers identified 23,436 adults with COM and 93,744 controls aged 40 years and older from a Korean health insurance database between 2002 and 2015.

The overall incidence of pneumonia in the study population was significantly higher in the COM group compared with controls (9.3% vs. 7.2%, P <.001). The odds ratios of pneumonia were significantly higher in the COM group compared with controls, and a history of pneumonia increased the odds of COM regardless of sex and across all ages.

Pneumonia was defined as when a patient had a diagnosis of pneumonia based on ICD-10 codes and underwent a chest x-ray or chest CT scan. Chronic otitis media was defined as when a patient had a diagnosis based on ICD-10 codes at least two times with one of the following conditions: chronic serous otitis media, chronic mucoid otitis media, other chronic nonsuppurative otitis media, unspecified nonsuppurative otitis media, chronic tubotympanic suppurative otitis media, chronic atticoantral suppurative otitis media, other chronic suppurative otitis media, or unspecified suppurative otitis media.

Age groups were divided into 5-year intervals, and patients were classified into income groups and rural vs. urban residence.

In a further sensitivity analysis, individuals who were diagnosed with pneumonia five or more times before the index date had a significantly higher odds ratio for COM compared with those with less than five diagnoses of pneumonia (adjusted odds ratio, 1.34; P < .001).

Microbiome dysbiosis may explain part of the connection between pneumonia and COM, the researchers wrote in their discussion. Pathogens in the lungs can prompt changes in the microbiome dynamics, as might the use of antibiotics, they said. In addition, “Mucus plugging in the airway caused by pneumonia induces hypoxic conditions and leads to the expression of inflammatory markers in the eustachian tube and middle ear mucosa,” they noted.

The study findings were limited by several factors, including the retrospective design and lack of data on microbiological cultures for antibiotic susceptibility, radiologic findings on the severity of pneumonia, results of pulmonary function tests, and hearing thresholds, the researchers noted. Other limitations were the exclusion of the frequency of upper respiratory infections and antibiotic use due to lack of data, they said.

However, the results show an association between pneumonia diagnoses and increased incidence of COM, which suggests a novel perspective that “infection of the lower respiratory tract may affect the function of the eustachian tube and the middle ear to later cause COM,” they concluded.

The study received no outside funding. The researchers have disclosed no relevant financial relationships.

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

Individuals with a prior diagnosis of pneumonia were significantly more likely to develop chronic otitis media (COM) than were those without a history of pneumonia, based on data from a nationwide cohort study of more than 100,000 patients.

“Recently, middle ear diseases, including COM, have been recognized as respiratory tract diseases beyond the pathophysiological concepts of ventilation dysfunction, with recurrent infection that occurs from anatomically adjacent structures such as the middle ear, mastoid cavity, and eustachian tube,” but the potential link between pneumonia and chronic otitis media and adults in particular has not been examined, wrote Sung Kyun Kim, MD, of Hallym University, Dongtan, South Korea, and colleagues.

In a study recently published in the International Journal of Infectious Diseases, the researchers identified 23,436 adults with COM and 93,744 controls aged 40 years and older from a Korean health insurance database between 2002 and 2015.

The overall incidence of pneumonia in the study population was significantly higher in the COM group compared with controls (9.3% vs. 7.2%, P <.001). The odds ratios of pneumonia were significantly higher in the COM group compared with controls, and a history of pneumonia increased the odds of COM regardless of sex and across all ages.

Pneumonia was defined as when a patient had a diagnosis of pneumonia based on ICD-10 codes and underwent a chest x-ray or chest CT scan. Chronic otitis media was defined as when a patient had a diagnosis based on ICD-10 codes at least two times with one of the following conditions: chronic serous otitis media, chronic mucoid otitis media, other chronic nonsuppurative otitis media, unspecified nonsuppurative otitis media, chronic tubotympanic suppurative otitis media, chronic atticoantral suppurative otitis media, other chronic suppurative otitis media, or unspecified suppurative otitis media.

Age groups were divided into 5-year intervals, and patients were classified into income groups and rural vs. urban residence.

In a further sensitivity analysis, individuals who were diagnosed with pneumonia five or more times before the index date had a significantly higher odds ratio for COM compared with those with less than five diagnoses of pneumonia (adjusted odds ratio, 1.34; P < .001).

Microbiome dysbiosis may explain part of the connection between pneumonia and COM, the researchers wrote in their discussion. Pathogens in the lungs can prompt changes in the microbiome dynamics, as might the use of antibiotics, they said. In addition, “Mucus plugging in the airway caused by pneumonia induces hypoxic conditions and leads to the expression of inflammatory markers in the eustachian tube and middle ear mucosa,” they noted.

The study findings were limited by several factors, including the retrospective design and lack of data on microbiological cultures for antibiotic susceptibility, radiologic findings on the severity of pneumonia, results of pulmonary function tests, and hearing thresholds, the researchers noted. Other limitations were the exclusion of the frequency of upper respiratory infections and antibiotic use due to lack of data, they said.

However, the results show an association between pneumonia diagnoses and increased incidence of COM, which suggests a novel perspective that “infection of the lower respiratory tract may affect the function of the eustachian tube and the middle ear to later cause COM,” they concluded.

The study received no outside funding. The researchers have disclosed no relevant financial relationships.

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