User login
Neoadjuvant immunotherapy for resectable head and neck cancer holds therapeutic benefit
The findings, published Sept. 2 in JAMA Otolaryngology Head & Neck Surgery, are noteworthy because the need for effective treatments in head and neck cancers is critical. It is the sixth most common malignancy in the world largely because of tobacco use and alcohol consumption and long-term outcomes are generally poor.
Currently, the standard care for patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) includes the surgical removal of the tumor followed by chemotherapy and radiotherapy. Despite new treatments, including pembrolizumab and nivolumab for platinum-refractory advanced head and neck squamous cell carcinoma (HNSCC), there are high rates of recurrence.
“The emerging approach of neoadjuvant immunotherapy for solid cancers has set the ground for the integration of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors into the neoadjuvant setting of head and neck squamous cell carcinoma treatment,” wrote the authors of the review which was led by Nidal Muhanna, MD, PhD, Tel Aviv Sourasky Medical Center, Tel Aviv University. “The results [of this analysis] demonstrated favorable outcomes and acceptable tolerance of the administration of neoadjuvant PD-1\PD-L1 inhibitors.”
The analysis included 10 studies
The review included 10 cohort studies and randomized clinical trials of 344 patients who were undergoing treatment for HNSCC between 2015 and 2021. In eight studies, patients received neoadjuvant immunotherapy, and in two studies, patients received combined immunotherapy with neoadjuvant chemotherapy and/or radiotherapy.
The overall pathological response rate was 9.7% (95% confidence interval, 3.1%-18.9%) for primary tumors treated with neoadjuvant immunotherapy or, 2.9% (95% CI, 0%-9.5%) for the pathological complete response rate (with a range of 0%-16.7%).
Treatment with neoadjuvant immunotherapy was ultimately found to be statistically significant (odds ratio, 0.07; 95% CI, 0.03-0.18). Plus, favorable associations for treatment with neoadjuvant immunotherapy were found with nodal pathological complete response. In two studies cited in the analysis, combination treatment with neoadjuvant immunotherapy and chemotherapy and/or radiation before surgery had an overall pathological complete response rate of 53%.
The major pathologic response in which less than 10% of the tumor remained after treatment varied greatly between 2.9% and 31.0% in five studies. The mean major pathologic response in these cases was 9.7%, which suggested a statistically significant association. A major pathologic response for lymph nodes was described in three studies as statistically significant for neoadjuvant immunotherapy.
In terms of adverse events, 8.4% (95% CI, 0.2%-23.2%) of patients were treated for autoimmune colitis, duodenal hemorrhage, mucositis, nausea, vomiting, and syncope.
Combination treatment with neoadjuvant immunotherapy with chemotherapy or radiotherapy continues to be evaluated in clinical trials (NCT03721757, NCT03635164, and NCT03618134). “Whether these combinations have synergistic effects or provide any therapeutic benefit, compared with single-agent therapy is still under investigation. It has been hypothesized that chemotherapy preceding the administration of neoadjuvant immunotherapy may increase antigen presentation by dendritic cells and enhance immune activation against the tumor, which can potentially increase therapeutic efficacy,” the authors wrote.
Other ongoing clinical trials will report survival data in the upcoming years. One of these trials is the IMSTAR-HN, a phase 3 clinical trial assessing neoadjuvant nivolumab with and without ipilimumab as first-line treatment with curative intent for HNSCC. It will report disease-free survival, overall survival, and progression-free survival outcomes.
The authors reported no disclosures.
The findings, published Sept. 2 in JAMA Otolaryngology Head & Neck Surgery, are noteworthy because the need for effective treatments in head and neck cancers is critical. It is the sixth most common malignancy in the world largely because of tobacco use and alcohol consumption and long-term outcomes are generally poor.
Currently, the standard care for patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) includes the surgical removal of the tumor followed by chemotherapy and radiotherapy. Despite new treatments, including pembrolizumab and nivolumab for platinum-refractory advanced head and neck squamous cell carcinoma (HNSCC), there are high rates of recurrence.
“The emerging approach of neoadjuvant immunotherapy for solid cancers has set the ground for the integration of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors into the neoadjuvant setting of head and neck squamous cell carcinoma treatment,” wrote the authors of the review which was led by Nidal Muhanna, MD, PhD, Tel Aviv Sourasky Medical Center, Tel Aviv University. “The results [of this analysis] demonstrated favorable outcomes and acceptable tolerance of the administration of neoadjuvant PD-1\PD-L1 inhibitors.”
The analysis included 10 studies
The review included 10 cohort studies and randomized clinical trials of 344 patients who were undergoing treatment for HNSCC between 2015 and 2021. In eight studies, patients received neoadjuvant immunotherapy, and in two studies, patients received combined immunotherapy with neoadjuvant chemotherapy and/or radiotherapy.
The overall pathological response rate was 9.7% (95% confidence interval, 3.1%-18.9%) for primary tumors treated with neoadjuvant immunotherapy or, 2.9% (95% CI, 0%-9.5%) for the pathological complete response rate (with a range of 0%-16.7%).
Treatment with neoadjuvant immunotherapy was ultimately found to be statistically significant (odds ratio, 0.07; 95% CI, 0.03-0.18). Plus, favorable associations for treatment with neoadjuvant immunotherapy were found with nodal pathological complete response. In two studies cited in the analysis, combination treatment with neoadjuvant immunotherapy and chemotherapy and/or radiation before surgery had an overall pathological complete response rate of 53%.
The major pathologic response in which less than 10% of the tumor remained after treatment varied greatly between 2.9% and 31.0% in five studies. The mean major pathologic response in these cases was 9.7%, which suggested a statistically significant association. A major pathologic response for lymph nodes was described in three studies as statistically significant for neoadjuvant immunotherapy.
In terms of adverse events, 8.4% (95% CI, 0.2%-23.2%) of patients were treated for autoimmune colitis, duodenal hemorrhage, mucositis, nausea, vomiting, and syncope.
Combination treatment with neoadjuvant immunotherapy with chemotherapy or radiotherapy continues to be evaluated in clinical trials (NCT03721757, NCT03635164, and NCT03618134). “Whether these combinations have synergistic effects or provide any therapeutic benefit, compared with single-agent therapy is still under investigation. It has been hypothesized that chemotherapy preceding the administration of neoadjuvant immunotherapy may increase antigen presentation by dendritic cells and enhance immune activation against the tumor, which can potentially increase therapeutic efficacy,” the authors wrote.
Other ongoing clinical trials will report survival data in the upcoming years. One of these trials is the IMSTAR-HN, a phase 3 clinical trial assessing neoadjuvant nivolumab with and without ipilimumab as first-line treatment with curative intent for HNSCC. It will report disease-free survival, overall survival, and progression-free survival outcomes.
The authors reported no disclosures.
The findings, published Sept. 2 in JAMA Otolaryngology Head & Neck Surgery, are noteworthy because the need for effective treatments in head and neck cancers is critical. It is the sixth most common malignancy in the world largely because of tobacco use and alcohol consumption and long-term outcomes are generally poor.
Currently, the standard care for patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) includes the surgical removal of the tumor followed by chemotherapy and radiotherapy. Despite new treatments, including pembrolizumab and nivolumab for platinum-refractory advanced head and neck squamous cell carcinoma (HNSCC), there are high rates of recurrence.
“The emerging approach of neoadjuvant immunotherapy for solid cancers has set the ground for the integration of programmed cell death 1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors into the neoadjuvant setting of head and neck squamous cell carcinoma treatment,” wrote the authors of the review which was led by Nidal Muhanna, MD, PhD, Tel Aviv Sourasky Medical Center, Tel Aviv University. “The results [of this analysis] demonstrated favorable outcomes and acceptable tolerance of the administration of neoadjuvant PD-1\PD-L1 inhibitors.”
The analysis included 10 studies
The review included 10 cohort studies and randomized clinical trials of 344 patients who were undergoing treatment for HNSCC between 2015 and 2021. In eight studies, patients received neoadjuvant immunotherapy, and in two studies, patients received combined immunotherapy with neoadjuvant chemotherapy and/or radiotherapy.
The overall pathological response rate was 9.7% (95% confidence interval, 3.1%-18.9%) for primary tumors treated with neoadjuvant immunotherapy or, 2.9% (95% CI, 0%-9.5%) for the pathological complete response rate (with a range of 0%-16.7%).
Treatment with neoadjuvant immunotherapy was ultimately found to be statistically significant (odds ratio, 0.07; 95% CI, 0.03-0.18). Plus, favorable associations for treatment with neoadjuvant immunotherapy were found with nodal pathological complete response. In two studies cited in the analysis, combination treatment with neoadjuvant immunotherapy and chemotherapy and/or radiation before surgery had an overall pathological complete response rate of 53%.
The major pathologic response in which less than 10% of the tumor remained after treatment varied greatly between 2.9% and 31.0% in five studies. The mean major pathologic response in these cases was 9.7%, which suggested a statistically significant association. A major pathologic response for lymph nodes was described in three studies as statistically significant for neoadjuvant immunotherapy.
In terms of adverse events, 8.4% (95% CI, 0.2%-23.2%) of patients were treated for autoimmune colitis, duodenal hemorrhage, mucositis, nausea, vomiting, and syncope.
Combination treatment with neoadjuvant immunotherapy with chemotherapy or radiotherapy continues to be evaluated in clinical trials (NCT03721757, NCT03635164, and NCT03618134). “Whether these combinations have synergistic effects or provide any therapeutic benefit, compared with single-agent therapy is still under investigation. It has been hypothesized that chemotherapy preceding the administration of neoadjuvant immunotherapy may increase antigen presentation by dendritic cells and enhance immune activation against the tumor, which can potentially increase therapeutic efficacy,” the authors wrote.
Other ongoing clinical trials will report survival data in the upcoming years. One of these trials is the IMSTAR-HN, a phase 3 clinical trial assessing neoadjuvant nivolumab with and without ipilimumab as first-line treatment with curative intent for HNSCC. It will report disease-free survival, overall survival, and progression-free survival outcomes.
The authors reported no disclosures.
FROM THE JOURNALS
Noise in medicine
A 26-year-old woman who reports a history of acyclovir-resistant herpes complains of a recurring, stinging rash around her mouth. Topical tacrolimus made it worse, she said. On exam, she has somewhat grouped pustules on her cutaneous lip. I mentioned her to colleagues, saying: “I’ve a patient with acyclovir-resistant herpes who isn’t improving on high-dose Valtrex.” They proffered a few alternative diagnoses and treatment recommendations. I tried several to no avail.
(it is after all only one condition). Nobel Prize–winning economist Daniel Kahneman, PhD, with two other authors, has written a brilliant book about this cognitive unreliability called “Noise: A Flaw in Human Judgment” (New York: Hachette Book Group, 2021).
Both bias and noise create trouble for us. Although biases get more attention, noise is both more prevalent and insidious. In a 2016 article, Dr. Kahneman and coauthors use a bathroom scale as an analogy to explain the difference. “We would say that the scale is biased if its readings are generally either too high or too low. A scale that consistently underestimates true weight by exactly 4 pounds is seriously biased but free of noise. A scale that gives two different readings when you step on it twice is noisy.” In the case presented, “measurements” by me and my colleagues were returning different “readings.” There is one true diagnosis and best treatment, yet because of noise, we waste time and resources by not getting it right the first time.
There is also evidence of bias in this case. For example, there’s probably some confirmation bias: The patient said she has a history of antiviral-resistant herpes; therefore, her rash might appear to be herpes. Also there might be salience bias: it’s easy to see how prominent pustules might be herpes simplex virus. Noise is an issue in many misdiagnoses, but trickier to see. In most instances, we don’t have the opportunity to get multiple assessments of the same case. When examined though, interrater reliability in medicine is often found to be shockingly low, an indication of how much noise there is in our clinical judgments. This leads to waste, frustration – and can even be dangerous when we’re trying to diagnose cancers such as melanoma, lung, or breast cancer.
Dr. Kahneman and colleagues have excellent recommendations on how to reduce noise, such as tips for good decision hygiene (e.g., using differential diagnoses) and using algorithms (e.g., calculating Apgar or LACE scores). I also liked their strategy of aggregating expert opinions. Fascinatingly, averaging multiple independent assessments is mathematically guaranteed to reduce noise. (God, I love economists). This is true of measurements and opinions: If you use 100 judgments for a case, you reduce noise by 90% (the noise is divided by the square root of the number of judgments averaged). So 20 colleagues’ opinions would reduce noise by almost 80%. However, those 20 opinions must be independent to avoid spurious agreement. (Again, math for the win.)
I showed photos of my patient to a few other dermatologists. They independently returned the same result: perioral dermatitis. This was the correct diagnosis and reminded me why grand rounds and tumor boards are such a great help. Multiple, independent assessments are more likely to get it right than just one opinion because we are canceling out the noise. But remember, grand rounds has to be old-school style – no looking at your coresident answers before giving yours!
Our patient cleared after restarting her topical tacrolimus and a bit of doxycycline. Credit the wisdom of the crowd. Reassuringly though, Dr. Kahneman also shows that expertise does matter in minimizing error. So that fellowship you did was still a great idea.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. He reports having no conflicts of interest. Write to him at [email protected].
A 26-year-old woman who reports a history of acyclovir-resistant herpes complains of a recurring, stinging rash around her mouth. Topical tacrolimus made it worse, she said. On exam, she has somewhat grouped pustules on her cutaneous lip. I mentioned her to colleagues, saying: “I’ve a patient with acyclovir-resistant herpes who isn’t improving on high-dose Valtrex.” They proffered a few alternative diagnoses and treatment recommendations. I tried several to no avail.
(it is after all only one condition). Nobel Prize–winning economist Daniel Kahneman, PhD, with two other authors, has written a brilliant book about this cognitive unreliability called “Noise: A Flaw in Human Judgment” (New York: Hachette Book Group, 2021).
Both bias and noise create trouble for us. Although biases get more attention, noise is both more prevalent and insidious. In a 2016 article, Dr. Kahneman and coauthors use a bathroom scale as an analogy to explain the difference. “We would say that the scale is biased if its readings are generally either too high or too low. A scale that consistently underestimates true weight by exactly 4 pounds is seriously biased but free of noise. A scale that gives two different readings when you step on it twice is noisy.” In the case presented, “measurements” by me and my colleagues were returning different “readings.” There is one true diagnosis and best treatment, yet because of noise, we waste time and resources by not getting it right the first time.
There is also evidence of bias in this case. For example, there’s probably some confirmation bias: The patient said she has a history of antiviral-resistant herpes; therefore, her rash might appear to be herpes. Also there might be salience bias: it’s easy to see how prominent pustules might be herpes simplex virus. Noise is an issue in many misdiagnoses, but trickier to see. In most instances, we don’t have the opportunity to get multiple assessments of the same case. When examined though, interrater reliability in medicine is often found to be shockingly low, an indication of how much noise there is in our clinical judgments. This leads to waste, frustration – and can even be dangerous when we’re trying to diagnose cancers such as melanoma, lung, or breast cancer.
Dr. Kahneman and colleagues have excellent recommendations on how to reduce noise, such as tips for good decision hygiene (e.g., using differential diagnoses) and using algorithms (e.g., calculating Apgar or LACE scores). I also liked their strategy of aggregating expert opinions. Fascinatingly, averaging multiple independent assessments is mathematically guaranteed to reduce noise. (God, I love economists). This is true of measurements and opinions: If you use 100 judgments for a case, you reduce noise by 90% (the noise is divided by the square root of the number of judgments averaged). So 20 colleagues’ opinions would reduce noise by almost 80%. However, those 20 opinions must be independent to avoid spurious agreement. (Again, math for the win.)
I showed photos of my patient to a few other dermatologists. They independently returned the same result: perioral dermatitis. This was the correct diagnosis and reminded me why grand rounds and tumor boards are such a great help. Multiple, independent assessments are more likely to get it right than just one opinion because we are canceling out the noise. But remember, grand rounds has to be old-school style – no looking at your coresident answers before giving yours!
Our patient cleared after restarting her topical tacrolimus and a bit of doxycycline. Credit the wisdom of the crowd. Reassuringly though, Dr. Kahneman also shows that expertise does matter in minimizing error. So that fellowship you did was still a great idea.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. He reports having no conflicts of interest. Write to him at [email protected].
A 26-year-old woman who reports a history of acyclovir-resistant herpes complains of a recurring, stinging rash around her mouth. Topical tacrolimus made it worse, she said. On exam, she has somewhat grouped pustules on her cutaneous lip. I mentioned her to colleagues, saying: “I’ve a patient with acyclovir-resistant herpes who isn’t improving on high-dose Valtrex.” They proffered a few alternative diagnoses and treatment recommendations. I tried several to no avail.
(it is after all only one condition). Nobel Prize–winning economist Daniel Kahneman, PhD, with two other authors, has written a brilliant book about this cognitive unreliability called “Noise: A Flaw in Human Judgment” (New York: Hachette Book Group, 2021).
Both bias and noise create trouble for us. Although biases get more attention, noise is both more prevalent and insidious. In a 2016 article, Dr. Kahneman and coauthors use a bathroom scale as an analogy to explain the difference. “We would say that the scale is biased if its readings are generally either too high or too low. A scale that consistently underestimates true weight by exactly 4 pounds is seriously biased but free of noise. A scale that gives two different readings when you step on it twice is noisy.” In the case presented, “measurements” by me and my colleagues were returning different “readings.” There is one true diagnosis and best treatment, yet because of noise, we waste time and resources by not getting it right the first time.
There is also evidence of bias in this case. For example, there’s probably some confirmation bias: The patient said she has a history of antiviral-resistant herpes; therefore, her rash might appear to be herpes. Also there might be salience bias: it’s easy to see how prominent pustules might be herpes simplex virus. Noise is an issue in many misdiagnoses, but trickier to see. In most instances, we don’t have the opportunity to get multiple assessments of the same case. When examined though, interrater reliability in medicine is often found to be shockingly low, an indication of how much noise there is in our clinical judgments. This leads to waste, frustration – and can even be dangerous when we’re trying to diagnose cancers such as melanoma, lung, or breast cancer.
Dr. Kahneman and colleagues have excellent recommendations on how to reduce noise, such as tips for good decision hygiene (e.g., using differential diagnoses) and using algorithms (e.g., calculating Apgar or LACE scores). I also liked their strategy of aggregating expert opinions. Fascinatingly, averaging multiple independent assessments is mathematically guaranteed to reduce noise. (God, I love economists). This is true of measurements and opinions: If you use 100 judgments for a case, you reduce noise by 90% (the noise is divided by the square root of the number of judgments averaged). So 20 colleagues’ opinions would reduce noise by almost 80%. However, those 20 opinions must be independent to avoid spurious agreement. (Again, math for the win.)
I showed photos of my patient to a few other dermatologists. They independently returned the same result: perioral dermatitis. This was the correct diagnosis and reminded me why grand rounds and tumor boards are such a great help. Multiple, independent assessments are more likely to get it right than just one opinion because we are canceling out the noise. But remember, grand rounds has to be old-school style – no looking at your coresident answers before giving yours!
Our patient cleared after restarting her topical tacrolimus and a bit of doxycycline. Credit the wisdom of the crowd. Reassuringly though, Dr. Kahneman also shows that expertise does matter in minimizing error. So that fellowship you did was still a great idea.
Dr. Benabio is director of Healthcare Transformation and chief of dermatology at Kaiser Permanente San Diego. The opinions expressed in this column are his own and do not represent those of Kaiser Permanente. Dr. Benabio is @Dermdoc on Twitter. He reports having no conflicts of interest. Write to him at [email protected].
Real-world data generate debate on definition of flare in axial spondyloarthritis
How best to define axial spondyloarthritis (axSpA) flares in practice remains the subject of some debate as evidenced by the discussion that followed an abstract presentation at the 12th International Congress on Spondyloarthritides.
It’s an important topic, said Maxime Breban, MD, PhD, of Ambroise Paré Hospital in Paris, as flares can adversely affect patient outcomes. The absence of flares may also a useful measure of how well a patient is responding to treatment in clinical trials and whether a treatment can be tapered.
“There have been many ways to define flares in the past and there is no consensus,” he observed.
Although the Assessment of Spondyloarthritis International Society (ASAS) devised 12 preliminary definitions of flare in 2016, “these were not that good when we moved to patients,” Dr. Breban suggested.
The ASAS definitions were based on patient vignettes, he explained, and used a combination of variables from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a visual analog scale (VAS) of pain, and the Ankylosing Spondylitis Disease Activity Score based on C-reactive protein (ASDAS-CRP).
The study that Dr. Breban presented looked at the performance of the ASAS preliminary definitions of axSpA flares in a real-life patient population, as well as prospectively determining how variations in BASDAI and VAS pain were associated with patient-perceived flares of disease.
A total of 99 patients took part in the study, recruited through a secure e-health platform called SPONDY+. Once a week, patients completed the BASDAI questionnaire and the pain VAS, and stated whether their disease had flared in the past week.
Receiver operating characteristic (ROC) curves were calculated to see how well the BASDAI and pain VAS identified patients who were experiencing a flare or had a recently resolved flare of axSpA.
Dr. Breban reported that variation in the BASDAI “appears a suitable variable to monitor the occurrence and resolution of patient-reported flare in axial spondylarthritis.”
In predicting a flare, the area under the curve (AUC) was significantly higher for the change in BASDAI than for the change in pain VAS, at a respective 0.81 and 0.77 (P = .01). However, both variables were similarly accurate in predicting the resolution of a flare, with respective AUCs of 0.78 and 0.80 (P = .3).
A 0.22-point increase in BASDAI was reported to be the best balance between sensitivity (70%) and specificity (79%) for a flare. However, this is “outside of what is possible within a test–retest situation,” Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center, said during discussion.
Dr. van der Heijde told Dr. Breban: “I understand that that comes out of your data, that that’s the best combination for sensitivity and specificity, but the next step is to decide if that makes sense.”
The ROC curves that Dr. Breban presented showed the range of sensitivities and specificities that could be achieved. If the specificity was increased to be 90% or higher, the specificity fell to 55%, with the change in BASDAI being an increase of 0.8 points. Conversely, bringing the sensitivity above 90% meant the specificity dropped to 39% and the change in BASDAI was a decrease of 0.1 point.
“So that means you can choose whatever you want as a cutoff,” Dr. Breban said. It depends on what you are aiming to do. “If you want to identify a flare, you can increase sensitivity, or specificity, according to what your purpose is,” he suggested.
“The next step, of course, is what to choose as a flare. Then it depends on how you want to use a flare if you want to use a flare to change the treatment,” agreed Dr. van der Heijde. “That was why, in the ASAS group, it was decided to have a high specificity so that you are not changing treatment all the time.”
In the data that Dr. Breban presented, the ASAS preliminary definitions were highly specific but lacked sensitivity. None of the ASAS definitions yielded sensitivity values higher than 37%, whereas specificity was higher than 95% for all of them.
The study’s design did not allow researchers to test the ASDAS-CRP as a definition of flare in its real-world patient sample. Thus, it is looking only at the patient’s perspective on flare, and there is a “huge discrepancy” between patient and physician-reported disease activity, Dr. van der Heijde noted. “So, I think before using your data to really choose the flare definition, I think we need to take it all into account.”
Maxime Dougados, MD, PhD, of Cochin Hospital in Paris, who has been “deeply involved in the elaboration of the definition of flare” added his thoughts: “Flare means for me, not a status, but a change,” he observed.
But if the aim of treating people with axSpA is to achieve a good or acceptable state of health, he questioned whether work should be continued to define the concept of a flare.
The definition of a flare was conceived for use in clinical trials mainly, Dr. van der Heijde noted. It helped to assess how changes in treatment might affect the outcomes of patients. In clinical practice, especially now with treat-to-target gaining more and more traction in axSpA, she agreed that perhaps the goal should be to focus more on the health status of patients.
Dr. Breban acknowledged that the SPONDY+ platform has been developed by bepatient with support from Merck Sharp & Dohme. No other disclosures were made.
How best to define axial spondyloarthritis (axSpA) flares in practice remains the subject of some debate as evidenced by the discussion that followed an abstract presentation at the 12th International Congress on Spondyloarthritides.
It’s an important topic, said Maxime Breban, MD, PhD, of Ambroise Paré Hospital in Paris, as flares can adversely affect patient outcomes. The absence of flares may also a useful measure of how well a patient is responding to treatment in clinical trials and whether a treatment can be tapered.
“There have been many ways to define flares in the past and there is no consensus,” he observed.
Although the Assessment of Spondyloarthritis International Society (ASAS) devised 12 preliminary definitions of flare in 2016, “these were not that good when we moved to patients,” Dr. Breban suggested.
The ASAS definitions were based on patient vignettes, he explained, and used a combination of variables from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a visual analog scale (VAS) of pain, and the Ankylosing Spondylitis Disease Activity Score based on C-reactive protein (ASDAS-CRP).
The study that Dr. Breban presented looked at the performance of the ASAS preliminary definitions of axSpA flares in a real-life patient population, as well as prospectively determining how variations in BASDAI and VAS pain were associated with patient-perceived flares of disease.
A total of 99 patients took part in the study, recruited through a secure e-health platform called SPONDY+. Once a week, patients completed the BASDAI questionnaire and the pain VAS, and stated whether their disease had flared in the past week.
Receiver operating characteristic (ROC) curves were calculated to see how well the BASDAI and pain VAS identified patients who were experiencing a flare or had a recently resolved flare of axSpA.
Dr. Breban reported that variation in the BASDAI “appears a suitable variable to monitor the occurrence and resolution of patient-reported flare in axial spondylarthritis.”
In predicting a flare, the area under the curve (AUC) was significantly higher for the change in BASDAI than for the change in pain VAS, at a respective 0.81 and 0.77 (P = .01). However, both variables were similarly accurate in predicting the resolution of a flare, with respective AUCs of 0.78 and 0.80 (P = .3).
A 0.22-point increase in BASDAI was reported to be the best balance between sensitivity (70%) and specificity (79%) for a flare. However, this is “outside of what is possible within a test–retest situation,” Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center, said during discussion.
Dr. van der Heijde told Dr. Breban: “I understand that that comes out of your data, that that’s the best combination for sensitivity and specificity, but the next step is to decide if that makes sense.”
The ROC curves that Dr. Breban presented showed the range of sensitivities and specificities that could be achieved. If the specificity was increased to be 90% or higher, the specificity fell to 55%, with the change in BASDAI being an increase of 0.8 points. Conversely, bringing the sensitivity above 90% meant the specificity dropped to 39% and the change in BASDAI was a decrease of 0.1 point.
“So that means you can choose whatever you want as a cutoff,” Dr. Breban said. It depends on what you are aiming to do. “If you want to identify a flare, you can increase sensitivity, or specificity, according to what your purpose is,” he suggested.
“The next step, of course, is what to choose as a flare. Then it depends on how you want to use a flare if you want to use a flare to change the treatment,” agreed Dr. van der Heijde. “That was why, in the ASAS group, it was decided to have a high specificity so that you are not changing treatment all the time.”
In the data that Dr. Breban presented, the ASAS preliminary definitions were highly specific but lacked sensitivity. None of the ASAS definitions yielded sensitivity values higher than 37%, whereas specificity was higher than 95% for all of them.
The study’s design did not allow researchers to test the ASDAS-CRP as a definition of flare in its real-world patient sample. Thus, it is looking only at the patient’s perspective on flare, and there is a “huge discrepancy” between patient and physician-reported disease activity, Dr. van der Heijde noted. “So, I think before using your data to really choose the flare definition, I think we need to take it all into account.”
Maxime Dougados, MD, PhD, of Cochin Hospital in Paris, who has been “deeply involved in the elaboration of the definition of flare” added his thoughts: “Flare means for me, not a status, but a change,” he observed.
But if the aim of treating people with axSpA is to achieve a good or acceptable state of health, he questioned whether work should be continued to define the concept of a flare.
The definition of a flare was conceived for use in clinical trials mainly, Dr. van der Heijde noted. It helped to assess how changes in treatment might affect the outcomes of patients. In clinical practice, especially now with treat-to-target gaining more and more traction in axSpA, she agreed that perhaps the goal should be to focus more on the health status of patients.
Dr. Breban acknowledged that the SPONDY+ platform has been developed by bepatient with support from Merck Sharp & Dohme. No other disclosures were made.
How best to define axial spondyloarthritis (axSpA) flares in practice remains the subject of some debate as evidenced by the discussion that followed an abstract presentation at the 12th International Congress on Spondyloarthritides.
It’s an important topic, said Maxime Breban, MD, PhD, of Ambroise Paré Hospital in Paris, as flares can adversely affect patient outcomes. The absence of flares may also a useful measure of how well a patient is responding to treatment in clinical trials and whether a treatment can be tapered.
“There have been many ways to define flares in the past and there is no consensus,” he observed.
Although the Assessment of Spondyloarthritis International Society (ASAS) devised 12 preliminary definitions of flare in 2016, “these were not that good when we moved to patients,” Dr. Breban suggested.
The ASAS definitions were based on patient vignettes, he explained, and used a combination of variables from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), a visual analog scale (VAS) of pain, and the Ankylosing Spondylitis Disease Activity Score based on C-reactive protein (ASDAS-CRP).
The study that Dr. Breban presented looked at the performance of the ASAS preliminary definitions of axSpA flares in a real-life patient population, as well as prospectively determining how variations in BASDAI and VAS pain were associated with patient-perceived flares of disease.
A total of 99 patients took part in the study, recruited through a secure e-health platform called SPONDY+. Once a week, patients completed the BASDAI questionnaire and the pain VAS, and stated whether their disease had flared in the past week.
Receiver operating characteristic (ROC) curves were calculated to see how well the BASDAI and pain VAS identified patients who were experiencing a flare or had a recently resolved flare of axSpA.
Dr. Breban reported that variation in the BASDAI “appears a suitable variable to monitor the occurrence and resolution of patient-reported flare in axial spondylarthritis.”
In predicting a flare, the area under the curve (AUC) was significantly higher for the change in BASDAI than for the change in pain VAS, at a respective 0.81 and 0.77 (P = .01). However, both variables were similarly accurate in predicting the resolution of a flare, with respective AUCs of 0.78 and 0.80 (P = .3).
A 0.22-point increase in BASDAI was reported to be the best balance between sensitivity (70%) and specificity (79%) for a flare. However, this is “outside of what is possible within a test–retest situation,” Désirée van der Heijde, MD, PhD, of Leiden (the Netherlands) University Medical Center, said during discussion.
Dr. van der Heijde told Dr. Breban: “I understand that that comes out of your data, that that’s the best combination for sensitivity and specificity, but the next step is to decide if that makes sense.”
The ROC curves that Dr. Breban presented showed the range of sensitivities and specificities that could be achieved. If the specificity was increased to be 90% or higher, the specificity fell to 55%, with the change in BASDAI being an increase of 0.8 points. Conversely, bringing the sensitivity above 90% meant the specificity dropped to 39% and the change in BASDAI was a decrease of 0.1 point.
“So that means you can choose whatever you want as a cutoff,” Dr. Breban said. It depends on what you are aiming to do. “If you want to identify a flare, you can increase sensitivity, or specificity, according to what your purpose is,” he suggested.
“The next step, of course, is what to choose as a flare. Then it depends on how you want to use a flare if you want to use a flare to change the treatment,” agreed Dr. van der Heijde. “That was why, in the ASAS group, it was decided to have a high specificity so that you are not changing treatment all the time.”
In the data that Dr. Breban presented, the ASAS preliminary definitions were highly specific but lacked sensitivity. None of the ASAS definitions yielded sensitivity values higher than 37%, whereas specificity was higher than 95% for all of them.
The study’s design did not allow researchers to test the ASDAS-CRP as a definition of flare in its real-world patient sample. Thus, it is looking only at the patient’s perspective on flare, and there is a “huge discrepancy” between patient and physician-reported disease activity, Dr. van der Heijde noted. “So, I think before using your data to really choose the flare definition, I think we need to take it all into account.”
Maxime Dougados, MD, PhD, of Cochin Hospital in Paris, who has been “deeply involved in the elaboration of the definition of flare” added his thoughts: “Flare means for me, not a status, but a change,” he observed.
But if the aim of treating people with axSpA is to achieve a good or acceptable state of health, he questioned whether work should be continued to define the concept of a flare.
The definition of a flare was conceived for use in clinical trials mainly, Dr. van der Heijde noted. It helped to assess how changes in treatment might affect the outcomes of patients. In clinical practice, especially now with treat-to-target gaining more and more traction in axSpA, she agreed that perhaps the goal should be to focus more on the health status of patients.
Dr. Breban acknowledged that the SPONDY+ platform has been developed by bepatient with support from Merck Sharp & Dohme. No other disclosures were made.
FROM THE 2021 SPA CONGRESS
Flagellate Shiitake Mushroom Reaction With Histologic Features of Acute Generalized Exanthematous Pustulosis
To the Editor:
A 59-year-old man presented with a severely pruritic rash on the legs, arms, abdomen, groin, and buttocks of 3 days’ duration. He reported subjective fever and chills. Prior to the appearance of the rash, the patient and his family had eaten shiitake mushrooms daily for 3 days. He denied any new medications in the last several months or any recent upper respiratory or gastrointestinal tract illnesses. His medical history included type 2 diabetes mellitus and diabetes-induced end-stage renal disease requiring home peritoneal dialysis. His long-term medications for diabetes mellitus, hypertension, benign prostatic hyperplasia, hyperlipidemia, and insomnia included amlodipine, atorvastatin, finasteride, gabapentin, insulin glargine, linagliptin, metoprolol, and mirtazapine.
Physical examination revealed an afebrile man with medium brown skin tone and diffuse, bright red, erythematous patches on the lower legs, axillae, medial forearms, lateral trunk, lower abdomen, and groin. There were distinct flagellate, linear, red patches on the lower legs (Figure 1). In addition, small clusters of 1- to 2-mm superficial pustules were present on the right upper medial thigh and left forearm with micropapules grouped in the skin folds.
A shave biopsy specimen from a pustule on the right upper medial thigh revealed spongiotic dermatitis with neutrophilic subcorneal pustule formation and frequent eosinophils (Figure 2). The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (Figure 3). These histologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). No biopsy was performed on the flagellate patches due to its clinically distinct presentation and well-established association with shiitake mushroom ingestion.
The patient was treated with triamcinolone ointment and systemic corticosteroids to reduce pruritus and quickly clear the lesions due to his comorbidities. He recovered completely within 1 week and had no evidence of postinflammatory hyperpigmentation from the flagellate dermatitis.
Flagellate dermatitis is an intensely pruritic dermatitis characterized by 1-mm, disseminated, erythematous papules in a linear grouped arrangement secondary to koebnerization due to the patient scratching. It was first described in 1977 by Nakamura.1 Although it rarely is seen outside of China and Japan, there are well-established associations of flagellate dermatitis with bleomycin and shiitake mushroom (Lentinula edodes) ingestion. One key clinical difference between the two causes is that postinflammatory hyperpigmentation changes usually are seen with bleomycin-induced flagellate dermatitis and typically are not present with shiitake mushroom–induced flagellate dermatitis.2 Following ingestion of shiitake mushrooms, the median time of onset of presentation typically is 24 hours but ranges from 12 hours to 5 days. Most patients completely recover by 3 weeks, with or without treatment.3 Although the pathogenesis of shiitake mushroom–induced flagellate dermatitis is not clear, the most common theory is a toxic reaction to lentinan, a polysaccharide isolated from shiitake mushrooms. However, type I and IV allergic hypersensitivities also have been supported by the time of onset, clearance, severe pruritus, benefit from steroids and antihistamines, and lack of grouped outbreaks in people exposed to shared meals containing shiitake mushrooms.3,4 Furthermore, there is a case of patch test–confirmed allergic contact dermatitis to shiitake mushrooms, demonstrating a 1+ reaction at 96 hours to the cap of a shiitake mushroom but a negative pin-prick test at 20 minutes, suggesting type IV hypersensitivity.5 An additional case revealed a positive skin-prick test with formation of a 4-mm wheal and subsequent pruritic papules and vesicles appearing 48 to 72 hours later at the prick site.6 Subsequent cases have been reported in association with consumption of raw shiitake mushrooms, but cases have been reported after consumption of fully cooked mushrooms, which does not support a toxin-mediated theory, as cooking the mushroom before consumption likely would denature or change the structure of the suspected toxin.2
Acute generalized exanthematous pustulosis is a rare eruption that occurs due to ingestion of a causative agent, usually an antibiotic, and is characterized by the presence of fever and disseminated, erythematous, pinpoint, sterile pustules on the skin and mucous membranes. It affects 1 to 5 persons per million per year, with more than 90% of cases attributed to drug ingestion.7 Spontaneous resolution can be expected within 15 days of its onset; however, there is a mortality rate of up to 5% that occurs most often in those with severe comorbidities or in older patients, for whom systemic corticosteroid therapy may be justified.7,8 A multinational case-control study conducted to evaluate the risk of AGEP associated with certain drugs revealed macrolides (namely pristinamycin); β-lactam antibiotics including penicillin, aminopenicillin, and cephalosporin; quinolones; hydroxychloroquine; anti-infective sulfonamides; terbinafine; and diltiazem as the most strongly associated culprits.9 Our patient’s flagellate dermatitis was unique in that it also showed histologic features of AGEP. The pathogenesis of drug-induced AGEP has been partially elucidated and involves activation of drug-specific CD4+ and CD8+ T cells that migrate to the skin and participate in apoptotic signaling of keratinocytes and recruitment of neutrophils and eosinophils, which form subcorneal sterile pustules.7 In a study of severe cutaneous adverse drug reactions, 50% (7/14) of patients with AGEP had positive patch tests to the causative agent.10 This T cell–dependent response explains why the condition responds to systemic corticosteroids. Additionally, our case report of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP suggests that the pathogenesis of flagellate dermatitis may be a T cell–mediated type IV hypersensitivity reaction. The time of onset, lack of grouped outbreaks in those sharing shiitake mushroom–containing meals, severe pruritus, lack of cases demonstrating an anaphylactic or wheal and flare response, benefit of steroids, and a case with histologic features of AGEP all lend support to this theory.
We report a case of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP. The time course, histologic features of AGEP, absence of new medications, and resolution with discontinuation of shiitake mushrooms lends support of the hypothesis that the pathogenesis of shiitake mushroom–induced flagellate dermatitis is similar to AGEP’s type IV hypersensitivity reaction. To further elucidate its pathogenesis, skin prick testing and patch testing with shiitake mushrooms in patients exhibiting shiitake mushroom–induced flagellate dermatitis may prove to be beneficial.
- Nakamura T. Toxicoderma caused by shiitake (Lentinus edodes)[in Japanese]. Jpn J Clin Dermatol. 1977;31:65-68.
- Chu EY, Anand D, Dawn A, et al. Shiitake dermatitis: a report of 3 cases and review of the literature. Cutis. 2013;91:287-290.
- Boels D, Landreau A, Bruneau C, et al. Shiitake dermatitis recorded by French Poison Control Centers—new case series with clinical observations. Clin Toxicol (Phila). 2014;52:625-628.
- Nakamura T. Shiitake (Lentinus edodes) dermatitis. Contact Dermatitis. 1992;27:65-70.
- Curnow P, Tam M. Contact dermatitis to shiitake mushroom. Australas J Dermatol. 2003;44:155-157.
- Lippert U, Martin V, Schwertfeger C, et al. Shiitake dermatitis. Br J Dermatol. 2003;148:178-179.
- Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol. 2012;53:87-92.
- Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28:113-119.
- Sidoroff A, Dunant A, Viboud C, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case-control study (EuroSCAR). Br J Dermatol. 2007;157:989-996.
- Wolkenstein P, Chosidow O, Flechet ML, et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis. 1996;35:234-236.
To the Editor:
A 59-year-old man presented with a severely pruritic rash on the legs, arms, abdomen, groin, and buttocks of 3 days’ duration. He reported subjective fever and chills. Prior to the appearance of the rash, the patient and his family had eaten shiitake mushrooms daily for 3 days. He denied any new medications in the last several months or any recent upper respiratory or gastrointestinal tract illnesses. His medical history included type 2 diabetes mellitus and diabetes-induced end-stage renal disease requiring home peritoneal dialysis. His long-term medications for diabetes mellitus, hypertension, benign prostatic hyperplasia, hyperlipidemia, and insomnia included amlodipine, atorvastatin, finasteride, gabapentin, insulin glargine, linagliptin, metoprolol, and mirtazapine.
Physical examination revealed an afebrile man with medium brown skin tone and diffuse, bright red, erythematous patches on the lower legs, axillae, medial forearms, lateral trunk, lower abdomen, and groin. There were distinct flagellate, linear, red patches on the lower legs (Figure 1). In addition, small clusters of 1- to 2-mm superficial pustules were present on the right upper medial thigh and left forearm with micropapules grouped in the skin folds.
A shave biopsy specimen from a pustule on the right upper medial thigh revealed spongiotic dermatitis with neutrophilic subcorneal pustule formation and frequent eosinophils (Figure 2). The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (Figure 3). These histologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). No biopsy was performed on the flagellate patches due to its clinically distinct presentation and well-established association with shiitake mushroom ingestion.
The patient was treated with triamcinolone ointment and systemic corticosteroids to reduce pruritus and quickly clear the lesions due to his comorbidities. He recovered completely within 1 week and had no evidence of postinflammatory hyperpigmentation from the flagellate dermatitis.
Flagellate dermatitis is an intensely pruritic dermatitis characterized by 1-mm, disseminated, erythematous papules in a linear grouped arrangement secondary to koebnerization due to the patient scratching. It was first described in 1977 by Nakamura.1 Although it rarely is seen outside of China and Japan, there are well-established associations of flagellate dermatitis with bleomycin and shiitake mushroom (Lentinula edodes) ingestion. One key clinical difference between the two causes is that postinflammatory hyperpigmentation changes usually are seen with bleomycin-induced flagellate dermatitis and typically are not present with shiitake mushroom–induced flagellate dermatitis.2 Following ingestion of shiitake mushrooms, the median time of onset of presentation typically is 24 hours but ranges from 12 hours to 5 days. Most patients completely recover by 3 weeks, with or without treatment.3 Although the pathogenesis of shiitake mushroom–induced flagellate dermatitis is not clear, the most common theory is a toxic reaction to lentinan, a polysaccharide isolated from shiitake mushrooms. However, type I and IV allergic hypersensitivities also have been supported by the time of onset, clearance, severe pruritus, benefit from steroids and antihistamines, and lack of grouped outbreaks in people exposed to shared meals containing shiitake mushrooms.3,4 Furthermore, there is a case of patch test–confirmed allergic contact dermatitis to shiitake mushrooms, demonstrating a 1+ reaction at 96 hours to the cap of a shiitake mushroom but a negative pin-prick test at 20 minutes, suggesting type IV hypersensitivity.5 An additional case revealed a positive skin-prick test with formation of a 4-mm wheal and subsequent pruritic papules and vesicles appearing 48 to 72 hours later at the prick site.6 Subsequent cases have been reported in association with consumption of raw shiitake mushrooms, but cases have been reported after consumption of fully cooked mushrooms, which does not support a toxin-mediated theory, as cooking the mushroom before consumption likely would denature or change the structure of the suspected toxin.2
Acute generalized exanthematous pustulosis is a rare eruption that occurs due to ingestion of a causative agent, usually an antibiotic, and is characterized by the presence of fever and disseminated, erythematous, pinpoint, sterile pustules on the skin and mucous membranes. It affects 1 to 5 persons per million per year, with more than 90% of cases attributed to drug ingestion.7 Spontaneous resolution can be expected within 15 days of its onset; however, there is a mortality rate of up to 5% that occurs most often in those with severe comorbidities or in older patients, for whom systemic corticosteroid therapy may be justified.7,8 A multinational case-control study conducted to evaluate the risk of AGEP associated with certain drugs revealed macrolides (namely pristinamycin); β-lactam antibiotics including penicillin, aminopenicillin, and cephalosporin; quinolones; hydroxychloroquine; anti-infective sulfonamides; terbinafine; and diltiazem as the most strongly associated culprits.9 Our patient’s flagellate dermatitis was unique in that it also showed histologic features of AGEP. The pathogenesis of drug-induced AGEP has been partially elucidated and involves activation of drug-specific CD4+ and CD8+ T cells that migrate to the skin and participate in apoptotic signaling of keratinocytes and recruitment of neutrophils and eosinophils, which form subcorneal sterile pustules.7 In a study of severe cutaneous adverse drug reactions, 50% (7/14) of patients with AGEP had positive patch tests to the causative agent.10 This T cell–dependent response explains why the condition responds to systemic corticosteroids. Additionally, our case report of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP suggests that the pathogenesis of flagellate dermatitis may be a T cell–mediated type IV hypersensitivity reaction. The time of onset, lack of grouped outbreaks in those sharing shiitake mushroom–containing meals, severe pruritus, lack of cases demonstrating an anaphylactic or wheal and flare response, benefit of steroids, and a case with histologic features of AGEP all lend support to this theory.
We report a case of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP. The time course, histologic features of AGEP, absence of new medications, and resolution with discontinuation of shiitake mushrooms lends support of the hypothesis that the pathogenesis of shiitake mushroom–induced flagellate dermatitis is similar to AGEP’s type IV hypersensitivity reaction. To further elucidate its pathogenesis, skin prick testing and patch testing with shiitake mushrooms in patients exhibiting shiitake mushroom–induced flagellate dermatitis may prove to be beneficial.
To the Editor:
A 59-year-old man presented with a severely pruritic rash on the legs, arms, abdomen, groin, and buttocks of 3 days’ duration. He reported subjective fever and chills. Prior to the appearance of the rash, the patient and his family had eaten shiitake mushrooms daily for 3 days. He denied any new medications in the last several months or any recent upper respiratory or gastrointestinal tract illnesses. His medical history included type 2 diabetes mellitus and diabetes-induced end-stage renal disease requiring home peritoneal dialysis. His long-term medications for diabetes mellitus, hypertension, benign prostatic hyperplasia, hyperlipidemia, and insomnia included amlodipine, atorvastatin, finasteride, gabapentin, insulin glargine, linagliptin, metoprolol, and mirtazapine.
Physical examination revealed an afebrile man with medium brown skin tone and diffuse, bright red, erythematous patches on the lower legs, axillae, medial forearms, lateral trunk, lower abdomen, and groin. There were distinct flagellate, linear, red patches on the lower legs (Figure 1). In addition, small clusters of 1- to 2-mm superficial pustules were present on the right upper medial thigh and left forearm with micropapules grouped in the skin folds.
A shave biopsy specimen from a pustule on the right upper medial thigh revealed spongiotic dermatitis with neutrophilic subcorneal pustule formation and frequent eosinophils (Figure 2). The dermis contained scattered mixed inflammatory cells including neutrophils, eosinophils, lymphocytes, and histiocytes (Figure 3). These histologic findings were consistent with acute generalized exanthematous pustulosis (AGEP). No biopsy was performed on the flagellate patches due to its clinically distinct presentation and well-established association with shiitake mushroom ingestion.
The patient was treated with triamcinolone ointment and systemic corticosteroids to reduce pruritus and quickly clear the lesions due to his comorbidities. He recovered completely within 1 week and had no evidence of postinflammatory hyperpigmentation from the flagellate dermatitis.
Flagellate dermatitis is an intensely pruritic dermatitis characterized by 1-mm, disseminated, erythematous papules in a linear grouped arrangement secondary to koebnerization due to the patient scratching. It was first described in 1977 by Nakamura.1 Although it rarely is seen outside of China and Japan, there are well-established associations of flagellate dermatitis with bleomycin and shiitake mushroom (Lentinula edodes) ingestion. One key clinical difference between the two causes is that postinflammatory hyperpigmentation changes usually are seen with bleomycin-induced flagellate dermatitis and typically are not present with shiitake mushroom–induced flagellate dermatitis.2 Following ingestion of shiitake mushrooms, the median time of onset of presentation typically is 24 hours but ranges from 12 hours to 5 days. Most patients completely recover by 3 weeks, with or without treatment.3 Although the pathogenesis of shiitake mushroom–induced flagellate dermatitis is not clear, the most common theory is a toxic reaction to lentinan, a polysaccharide isolated from shiitake mushrooms. However, type I and IV allergic hypersensitivities also have been supported by the time of onset, clearance, severe pruritus, benefit from steroids and antihistamines, and lack of grouped outbreaks in people exposed to shared meals containing shiitake mushrooms.3,4 Furthermore, there is a case of patch test–confirmed allergic contact dermatitis to shiitake mushrooms, demonstrating a 1+ reaction at 96 hours to the cap of a shiitake mushroom but a negative pin-prick test at 20 minutes, suggesting type IV hypersensitivity.5 An additional case revealed a positive skin-prick test with formation of a 4-mm wheal and subsequent pruritic papules and vesicles appearing 48 to 72 hours later at the prick site.6 Subsequent cases have been reported in association with consumption of raw shiitake mushrooms, but cases have been reported after consumption of fully cooked mushrooms, which does not support a toxin-mediated theory, as cooking the mushroom before consumption likely would denature or change the structure of the suspected toxin.2
Acute generalized exanthematous pustulosis is a rare eruption that occurs due to ingestion of a causative agent, usually an antibiotic, and is characterized by the presence of fever and disseminated, erythematous, pinpoint, sterile pustules on the skin and mucous membranes. It affects 1 to 5 persons per million per year, with more than 90% of cases attributed to drug ingestion.7 Spontaneous resolution can be expected within 15 days of its onset; however, there is a mortality rate of up to 5% that occurs most often in those with severe comorbidities or in older patients, for whom systemic corticosteroid therapy may be justified.7,8 A multinational case-control study conducted to evaluate the risk of AGEP associated with certain drugs revealed macrolides (namely pristinamycin); β-lactam antibiotics including penicillin, aminopenicillin, and cephalosporin; quinolones; hydroxychloroquine; anti-infective sulfonamides; terbinafine; and diltiazem as the most strongly associated culprits.9 Our patient’s flagellate dermatitis was unique in that it also showed histologic features of AGEP. The pathogenesis of drug-induced AGEP has been partially elucidated and involves activation of drug-specific CD4+ and CD8+ T cells that migrate to the skin and participate in apoptotic signaling of keratinocytes and recruitment of neutrophils and eosinophils, which form subcorneal sterile pustules.7 In a study of severe cutaneous adverse drug reactions, 50% (7/14) of patients with AGEP had positive patch tests to the causative agent.10 This T cell–dependent response explains why the condition responds to systemic corticosteroids. Additionally, our case report of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP suggests that the pathogenesis of flagellate dermatitis may be a T cell–mediated type IV hypersensitivity reaction. The time of onset, lack of grouped outbreaks in those sharing shiitake mushroom–containing meals, severe pruritus, lack of cases demonstrating an anaphylactic or wheal and flare response, benefit of steroids, and a case with histologic features of AGEP all lend support to this theory.
We report a case of shiitake mushroom–induced flagellate dermatitis with histologic features of AGEP. The time course, histologic features of AGEP, absence of new medications, and resolution with discontinuation of shiitake mushrooms lends support of the hypothesis that the pathogenesis of shiitake mushroom–induced flagellate dermatitis is similar to AGEP’s type IV hypersensitivity reaction. To further elucidate its pathogenesis, skin prick testing and patch testing with shiitake mushrooms in patients exhibiting shiitake mushroom–induced flagellate dermatitis may prove to be beneficial.
- Nakamura T. Toxicoderma caused by shiitake (Lentinus edodes)[in Japanese]. Jpn J Clin Dermatol. 1977;31:65-68.
- Chu EY, Anand D, Dawn A, et al. Shiitake dermatitis: a report of 3 cases and review of the literature. Cutis. 2013;91:287-290.
- Boels D, Landreau A, Bruneau C, et al. Shiitake dermatitis recorded by French Poison Control Centers—new case series with clinical observations. Clin Toxicol (Phila). 2014;52:625-628.
- Nakamura T. Shiitake (Lentinus edodes) dermatitis. Contact Dermatitis. 1992;27:65-70.
- Curnow P, Tam M. Contact dermatitis to shiitake mushroom. Australas J Dermatol. 2003;44:155-157.
- Lippert U, Martin V, Schwertfeger C, et al. Shiitake dermatitis. Br J Dermatol. 2003;148:178-179.
- Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol. 2012;53:87-92.
- Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28:113-119.
- Sidoroff A, Dunant A, Viboud C, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case-control study (EuroSCAR). Br J Dermatol. 2007;157:989-996.
- Wolkenstein P, Chosidow O, Flechet ML, et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis. 1996;35:234-236.
- Nakamura T. Toxicoderma caused by shiitake (Lentinus edodes)[in Japanese]. Jpn J Clin Dermatol. 1977;31:65-68.
- Chu EY, Anand D, Dawn A, et al. Shiitake dermatitis: a report of 3 cases and review of the literature. Cutis. 2013;91:287-290.
- Boels D, Landreau A, Bruneau C, et al. Shiitake dermatitis recorded by French Poison Control Centers—new case series with clinical observations. Clin Toxicol (Phila). 2014;52:625-628.
- Nakamura T. Shiitake (Lentinus edodes) dermatitis. Contact Dermatitis. 1992;27:65-70.
- Curnow P, Tam M. Contact dermatitis to shiitake mushroom. Australas J Dermatol. 2003;44:155-157.
- Lippert U, Martin V, Schwertfeger C, et al. Shiitake dermatitis. Br J Dermatol. 2003;148:178-179.
- Fernando SL. Acute generalised exanthematous pustulosis. Australas J Dermatol. 2012;53:87-92.
- Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28:113-119.
- Sidoroff A, Dunant A, Viboud C, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case-control study (EuroSCAR). Br J Dermatol. 2007;157:989-996.
- Wolkenstein P, Chosidow O, Flechet ML, et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis. 1996;35:234-236.
Practice Points
- Ingestion of shiitake mushrooms and bleomycin is associated with flagellate dermatitis.
- Acute generalized exanthematous pustulosis (AGEP) is a rare condition associated with certain drug ingestion.
When children and teens with cancer get COVID-19
Although most children and adolescents with cancer have mild illness from COVID-19 infection, some do experience severe disease and a small percentage even die, according to a recent analysis.
The findings, published online in Lancet Oncology, represent the first global registry data spanning different income groups to report COVID-19 outcomes in pediatric oncology patients.
“We wanted to create a global pool of evidence to answer the question: Do we see severe [COVID-19] infection [in children with cancer]?” corresponding author Sheena Mukkada, MD, St. Jude Children’s Research Hospital, Memphis, said in an interview.
In a cohort of 1,319 pediatric patients followed for 30 days, Dr. Mukkada and colleagues reported that 80% of these patients had asymptomatic to moderate disease from COVID-19, while 1 in 5 experienced severe or critical illness and almost 4% died – four times the mortality rate observed in published cohorts of general pediatric patients.
The results highlight that “children and adolescents with cancer generally recover without incident from COVID-19, but can have a severe course of infection,” the authors concluded.
And knowing that some children can get very sick, investigators wanted “to identify who these patients are so that we can prioritize and protect that group,” she added.
Echoing that sentiment, Kathy Pritchard-Jones, MD, president of the International Society of Paediatric Oncology and coauthor on the study, noted in a press release that, “by working together to create this global registry, we have enabled hospitals around the world to rapidly share and learn how COVID-19 is affecting children with cancer.”
Dr. Pritchard-Jones commented that overall these results provide reassurance that “many children can continue their cancer treatment safely, but they also highlight important clinical features that may predict a more severe clinical course and the need for greater vigilance for some patients.”
Inside the Global Registry data
The Global Registry of COVID-19 in Childhood Cancer, created jointly by St. Jude Children’s Research Hospital and SIOP, included data from 131 institutions in 45 countries. Children recruited into the registry between April 2020 and February 2021 ranged in age from infancy to 18 years old.
Most patients remained asymptomatic (35%) or experienced mild to moderate illness (45%), though 20% did develop severe or critical illness.
The investigators highlighted several factors associated with a greater risk of developing more severe illness from COVID-19, which included cancer type, intensity of therapy, age, absolute lymphocyte count, and presence of comorbidities or COVID-19 symptoms.
Notably, more than 80% of either severe or critical infections occurred in patients with hematologic malignancies – with 56% of cases in patients with acute lymphoblastic lymphoma or acute lymphoblastic leukemia – followed by extracranial solid tumors (15.8%), and central nervous system tumors (2.7%).
In patients with acute lymphoblastic leukemia or acute lymphoblastic lymphoma, severe or critical disease was most common in those receiving induction therapy (30%), relapse or refractory therapy (30%), and those in the maintenance or continuation phase of therapy (19%).
Older age was associated with a higher likelihood of having severe disease – with the lowest risk in infants (9.7%) and the highest in the 15- to 18-year-old cohort (27.3%).
Patients with lymphopenia who had an absolute lymphocyte count of 300 cells per mm3 or less and an absolute neutrophil count of 500 cells per mm3 or more also had an elevated risk of severe illness from COVID-19.
Regarding whether the presence of lymphopenia or neutropenia should change the treatment approach, Dr. Mukkada noted that, when possible, these patients should receive antiviral treatment, such as remdesivir, if the center has antivirals, or be prioritized for hospital admission.
Modifying cancer treatment might be recommended if patients are highly lymphopenic or have very low neutrophil counts, but a more effective strategy is simply to ensure that age-eligible children and adolescents with cancer or who have had a hematopoietic stem-cell transplantation have been fully vaccinated against COVID-19. For children who are not yet age-eligible, everyone around them should be vaccinated.
Pediatric patients in low- and middle-income countries were also more likely to have severe or critical outcomes from COVID-19 (41.7%), compared with patients in other income groups (23.9%).
The impact of COVID-19 “has been felt in every corner of the world, but particularly in low- and middle-income countries, compared to high-income countries,” senior author Carlos Rodriguez-Galindo, MD, global director at St. Jude, said in a statement.
In terms of the intersection of cancer treatment and COVID diagnosis, almost 83% of pediatric patients were receiving treatment for their cancer. Chemotherapy was withheld in about 45% of these patients and some modification to the treatment regimen occurred in almost 56% of participants on active therapy.
“Treatment modifications were least common in patients from upper-middle–income countries, compared with other income groups,” the authors wrote.
Although an interesting observation, Dr. Mukkada noted that the registry data could not explain why treatment modifications occurred less frequently in upper-middle income countries as opposed to high-income and lower-income countries.
U.K. Monitoring Project
Not all studies, however, have found that COVID-19 infection is significantly more severe in children with cancer. In a 2020 report from the U.K. Paediatric Coronavirus Cancer Monitoring Project, researchers evaluated all children in the United Kingdom under the age of 16 diagnosed with COVID and cancer.
“[Given that] we had complete coverage of every center in the U.K. that cares for children with cancer, we are confident that we picked up at least all the severe or critical cases,” lead author Gerard Millen, MD, honorary clinical research fellow, University of Birmingham (England), said in an interview.
Between March 2020 and July 2020, Dr. Millen and colleagues identified 54 positive cases of COVID-19, 15 (28%) of which were asymptomatic, 34 (63%) mild, and 4 (7.4%) severe or critical – more in line with the incidence of severe illness reported in the general pediatric population.
“Thankfully, we had no children with cancer in the U.K. who died from COVID-19,” Dr. Millen noted. “Overall, in the U.K., we have taken the approach that the majority of children with cancer in this country are at very low risk from COVID-19 and that we do not have good evidence to modify their treatment.”
Dr. Millen pointed out that the data in the U.K. study were “remarkably similar” to those from the high-income countries in the global St. Jude/SIOP cohort, where 7.4% of patients in that cohort had severe or critical disease, compared with 7.4% of patients from their own U.K. cohort.
“I think many of the key differences between the two cohorts reflect the fact that access to treatment in many low- to middle-income countries is more challenging with many factors contributing to overall poorer outcomes for both cancer and noncancer metrics,” Dr. Millen said.
Both the U.K. and registry studies were performed prior to vaccinations becoming available to older children, and before the emergence of certain variants, including the Delta variant, which is responsible for the most recent surge of COVID-19 infections around the world.
Data on COVID-19 vaccination in children with cancer are limited but promising so far.
As for whether the Delta variant might affect outcomes for children with cancer and COVID-19, Dr. Mukkada could only speculate, but she noted that “what we are hearing anecdotally about the [Delta] disease being more severe, even in patients who don’t have cancer, is leading us to say that we can’t close the registry yet. We are still actively enrolling children.”
The study was funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute. The study authors and Dr. Millen disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Although most children and adolescents with cancer have mild illness from COVID-19 infection, some do experience severe disease and a small percentage even die, according to a recent analysis.
The findings, published online in Lancet Oncology, represent the first global registry data spanning different income groups to report COVID-19 outcomes in pediatric oncology patients.
“We wanted to create a global pool of evidence to answer the question: Do we see severe [COVID-19] infection [in children with cancer]?” corresponding author Sheena Mukkada, MD, St. Jude Children’s Research Hospital, Memphis, said in an interview.
In a cohort of 1,319 pediatric patients followed for 30 days, Dr. Mukkada and colleagues reported that 80% of these patients had asymptomatic to moderate disease from COVID-19, while 1 in 5 experienced severe or critical illness and almost 4% died – four times the mortality rate observed in published cohorts of general pediatric patients.
The results highlight that “children and adolescents with cancer generally recover without incident from COVID-19, but can have a severe course of infection,” the authors concluded.
And knowing that some children can get very sick, investigators wanted “to identify who these patients are so that we can prioritize and protect that group,” she added.
Echoing that sentiment, Kathy Pritchard-Jones, MD, president of the International Society of Paediatric Oncology and coauthor on the study, noted in a press release that, “by working together to create this global registry, we have enabled hospitals around the world to rapidly share and learn how COVID-19 is affecting children with cancer.”
Dr. Pritchard-Jones commented that overall these results provide reassurance that “many children can continue their cancer treatment safely, but they also highlight important clinical features that may predict a more severe clinical course and the need for greater vigilance for some patients.”
Inside the Global Registry data
The Global Registry of COVID-19 in Childhood Cancer, created jointly by St. Jude Children’s Research Hospital and SIOP, included data from 131 institutions in 45 countries. Children recruited into the registry between April 2020 and February 2021 ranged in age from infancy to 18 years old.
Most patients remained asymptomatic (35%) or experienced mild to moderate illness (45%), though 20% did develop severe or critical illness.
The investigators highlighted several factors associated with a greater risk of developing more severe illness from COVID-19, which included cancer type, intensity of therapy, age, absolute lymphocyte count, and presence of comorbidities or COVID-19 symptoms.
Notably, more than 80% of either severe or critical infections occurred in patients with hematologic malignancies – with 56% of cases in patients with acute lymphoblastic lymphoma or acute lymphoblastic leukemia – followed by extracranial solid tumors (15.8%), and central nervous system tumors (2.7%).
In patients with acute lymphoblastic leukemia or acute lymphoblastic lymphoma, severe or critical disease was most common in those receiving induction therapy (30%), relapse or refractory therapy (30%), and those in the maintenance or continuation phase of therapy (19%).
Older age was associated with a higher likelihood of having severe disease – with the lowest risk in infants (9.7%) and the highest in the 15- to 18-year-old cohort (27.3%).
Patients with lymphopenia who had an absolute lymphocyte count of 300 cells per mm3 or less and an absolute neutrophil count of 500 cells per mm3 or more also had an elevated risk of severe illness from COVID-19.
Regarding whether the presence of lymphopenia or neutropenia should change the treatment approach, Dr. Mukkada noted that, when possible, these patients should receive antiviral treatment, such as remdesivir, if the center has antivirals, or be prioritized for hospital admission.
Modifying cancer treatment might be recommended if patients are highly lymphopenic or have very low neutrophil counts, but a more effective strategy is simply to ensure that age-eligible children and adolescents with cancer or who have had a hematopoietic stem-cell transplantation have been fully vaccinated against COVID-19. For children who are not yet age-eligible, everyone around them should be vaccinated.
Pediatric patients in low- and middle-income countries were also more likely to have severe or critical outcomes from COVID-19 (41.7%), compared with patients in other income groups (23.9%).
The impact of COVID-19 “has been felt in every corner of the world, but particularly in low- and middle-income countries, compared to high-income countries,” senior author Carlos Rodriguez-Galindo, MD, global director at St. Jude, said in a statement.
In terms of the intersection of cancer treatment and COVID diagnosis, almost 83% of pediatric patients were receiving treatment for their cancer. Chemotherapy was withheld in about 45% of these patients and some modification to the treatment regimen occurred in almost 56% of participants on active therapy.
“Treatment modifications were least common in patients from upper-middle–income countries, compared with other income groups,” the authors wrote.
Although an interesting observation, Dr. Mukkada noted that the registry data could not explain why treatment modifications occurred less frequently in upper-middle income countries as opposed to high-income and lower-income countries.
U.K. Monitoring Project
Not all studies, however, have found that COVID-19 infection is significantly more severe in children with cancer. In a 2020 report from the U.K. Paediatric Coronavirus Cancer Monitoring Project, researchers evaluated all children in the United Kingdom under the age of 16 diagnosed with COVID and cancer.
“[Given that] we had complete coverage of every center in the U.K. that cares for children with cancer, we are confident that we picked up at least all the severe or critical cases,” lead author Gerard Millen, MD, honorary clinical research fellow, University of Birmingham (England), said in an interview.
Between March 2020 and July 2020, Dr. Millen and colleagues identified 54 positive cases of COVID-19, 15 (28%) of which were asymptomatic, 34 (63%) mild, and 4 (7.4%) severe or critical – more in line with the incidence of severe illness reported in the general pediatric population.
“Thankfully, we had no children with cancer in the U.K. who died from COVID-19,” Dr. Millen noted. “Overall, in the U.K., we have taken the approach that the majority of children with cancer in this country are at very low risk from COVID-19 and that we do not have good evidence to modify their treatment.”
Dr. Millen pointed out that the data in the U.K. study were “remarkably similar” to those from the high-income countries in the global St. Jude/SIOP cohort, where 7.4% of patients in that cohort had severe or critical disease, compared with 7.4% of patients from their own U.K. cohort.
“I think many of the key differences between the two cohorts reflect the fact that access to treatment in many low- to middle-income countries is more challenging with many factors contributing to overall poorer outcomes for both cancer and noncancer metrics,” Dr. Millen said.
Both the U.K. and registry studies were performed prior to vaccinations becoming available to older children, and before the emergence of certain variants, including the Delta variant, which is responsible for the most recent surge of COVID-19 infections around the world.
Data on COVID-19 vaccination in children with cancer are limited but promising so far.
As for whether the Delta variant might affect outcomes for children with cancer and COVID-19, Dr. Mukkada could only speculate, but she noted that “what we are hearing anecdotally about the [Delta] disease being more severe, even in patients who don’t have cancer, is leading us to say that we can’t close the registry yet. We are still actively enrolling children.”
The study was funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute. The study authors and Dr. Millen disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Although most children and adolescents with cancer have mild illness from COVID-19 infection, some do experience severe disease and a small percentage even die, according to a recent analysis.
The findings, published online in Lancet Oncology, represent the first global registry data spanning different income groups to report COVID-19 outcomes in pediatric oncology patients.
“We wanted to create a global pool of evidence to answer the question: Do we see severe [COVID-19] infection [in children with cancer]?” corresponding author Sheena Mukkada, MD, St. Jude Children’s Research Hospital, Memphis, said in an interview.
In a cohort of 1,319 pediatric patients followed for 30 days, Dr. Mukkada and colleagues reported that 80% of these patients had asymptomatic to moderate disease from COVID-19, while 1 in 5 experienced severe or critical illness and almost 4% died – four times the mortality rate observed in published cohorts of general pediatric patients.
The results highlight that “children and adolescents with cancer generally recover without incident from COVID-19, but can have a severe course of infection,” the authors concluded.
And knowing that some children can get very sick, investigators wanted “to identify who these patients are so that we can prioritize and protect that group,” she added.
Echoing that sentiment, Kathy Pritchard-Jones, MD, president of the International Society of Paediatric Oncology and coauthor on the study, noted in a press release that, “by working together to create this global registry, we have enabled hospitals around the world to rapidly share and learn how COVID-19 is affecting children with cancer.”
Dr. Pritchard-Jones commented that overall these results provide reassurance that “many children can continue their cancer treatment safely, but they also highlight important clinical features that may predict a more severe clinical course and the need for greater vigilance for some patients.”
Inside the Global Registry data
The Global Registry of COVID-19 in Childhood Cancer, created jointly by St. Jude Children’s Research Hospital and SIOP, included data from 131 institutions in 45 countries. Children recruited into the registry between April 2020 and February 2021 ranged in age from infancy to 18 years old.
Most patients remained asymptomatic (35%) or experienced mild to moderate illness (45%), though 20% did develop severe or critical illness.
The investigators highlighted several factors associated with a greater risk of developing more severe illness from COVID-19, which included cancer type, intensity of therapy, age, absolute lymphocyte count, and presence of comorbidities or COVID-19 symptoms.
Notably, more than 80% of either severe or critical infections occurred in patients with hematologic malignancies – with 56% of cases in patients with acute lymphoblastic lymphoma or acute lymphoblastic leukemia – followed by extracranial solid tumors (15.8%), and central nervous system tumors (2.7%).
In patients with acute lymphoblastic leukemia or acute lymphoblastic lymphoma, severe or critical disease was most common in those receiving induction therapy (30%), relapse or refractory therapy (30%), and those in the maintenance or continuation phase of therapy (19%).
Older age was associated with a higher likelihood of having severe disease – with the lowest risk in infants (9.7%) and the highest in the 15- to 18-year-old cohort (27.3%).
Patients with lymphopenia who had an absolute lymphocyte count of 300 cells per mm3 or less and an absolute neutrophil count of 500 cells per mm3 or more also had an elevated risk of severe illness from COVID-19.
Regarding whether the presence of lymphopenia or neutropenia should change the treatment approach, Dr. Mukkada noted that, when possible, these patients should receive antiviral treatment, such as remdesivir, if the center has antivirals, or be prioritized for hospital admission.
Modifying cancer treatment might be recommended if patients are highly lymphopenic or have very low neutrophil counts, but a more effective strategy is simply to ensure that age-eligible children and adolescents with cancer or who have had a hematopoietic stem-cell transplantation have been fully vaccinated against COVID-19. For children who are not yet age-eligible, everyone around them should be vaccinated.
Pediatric patients in low- and middle-income countries were also more likely to have severe or critical outcomes from COVID-19 (41.7%), compared with patients in other income groups (23.9%).
The impact of COVID-19 “has been felt in every corner of the world, but particularly in low- and middle-income countries, compared to high-income countries,” senior author Carlos Rodriguez-Galindo, MD, global director at St. Jude, said in a statement.
In terms of the intersection of cancer treatment and COVID diagnosis, almost 83% of pediatric patients were receiving treatment for their cancer. Chemotherapy was withheld in about 45% of these patients and some modification to the treatment regimen occurred in almost 56% of participants on active therapy.
“Treatment modifications were least common in patients from upper-middle–income countries, compared with other income groups,” the authors wrote.
Although an interesting observation, Dr. Mukkada noted that the registry data could not explain why treatment modifications occurred less frequently in upper-middle income countries as opposed to high-income and lower-income countries.
U.K. Monitoring Project
Not all studies, however, have found that COVID-19 infection is significantly more severe in children with cancer. In a 2020 report from the U.K. Paediatric Coronavirus Cancer Monitoring Project, researchers evaluated all children in the United Kingdom under the age of 16 diagnosed with COVID and cancer.
“[Given that] we had complete coverage of every center in the U.K. that cares for children with cancer, we are confident that we picked up at least all the severe or critical cases,” lead author Gerard Millen, MD, honorary clinical research fellow, University of Birmingham (England), said in an interview.
Between March 2020 and July 2020, Dr. Millen and colleagues identified 54 positive cases of COVID-19, 15 (28%) of which were asymptomatic, 34 (63%) mild, and 4 (7.4%) severe or critical – more in line with the incidence of severe illness reported in the general pediatric population.
“Thankfully, we had no children with cancer in the U.K. who died from COVID-19,” Dr. Millen noted. “Overall, in the U.K., we have taken the approach that the majority of children with cancer in this country are at very low risk from COVID-19 and that we do not have good evidence to modify their treatment.”
Dr. Millen pointed out that the data in the U.K. study were “remarkably similar” to those from the high-income countries in the global St. Jude/SIOP cohort, where 7.4% of patients in that cohort had severe or critical disease, compared with 7.4% of patients from their own U.K. cohort.
“I think many of the key differences between the two cohorts reflect the fact that access to treatment in many low- to middle-income countries is more challenging with many factors contributing to overall poorer outcomes for both cancer and noncancer metrics,” Dr. Millen said.
Both the U.K. and registry studies were performed prior to vaccinations becoming available to older children, and before the emergence of certain variants, including the Delta variant, which is responsible for the most recent surge of COVID-19 infections around the world.
Data on COVID-19 vaccination in children with cancer are limited but promising so far.
As for whether the Delta variant might affect outcomes for children with cancer and COVID-19, Dr. Mukkada could only speculate, but she noted that “what we are hearing anecdotally about the [Delta] disease being more severe, even in patients who don’t have cancer, is leading us to say that we can’t close the registry yet. We are still actively enrolling children.”
The study was funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute. The study authors and Dr. Millen disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
COVID-19 causes major interruption in global HIV progress
“We’ve been set back by COVID but we’ve seen remarkable resilience, a lot of innovation and creativity,” Siobhan Crowley MD, head of HIV at the Global Fund, said in an interview.
“If you consider that 21.9 million people are getting antiretrovirals at this point through the Global Fund, I think that needs to be appreciated. Ten years ago, that wouldn’t have been the case; all of those people would have disappeared into the ethers,” she said.
Through close partnerships with the U.S. Agency for International Development, the U.S. President’s Emergency Plan for AIDS Relief, and other Western countries and organizations, the Global Fund has invested $22.7 billion in programs to prevent and treat HIV and AIDS, and $3.8 billion in tuberculosis (TB)/HIV programs, according to the organization’s 2021 Results Report.
But the report also underscores the significant effect that the COVID-19 pandemic has had on funded countries’ progress toward achieving renewed 90-90-90 targets for HIV testing/diagnosis, treatment, and viral suppression by 2030.
The setbacks have been challenging and have touched nearly every service from prevention to treatment. According to the report, between 2019 and 2020:
- Voluntary male circumcision declined by 27%.
- Numbers reached by HIV prevention programs fell by 11%.
- 4.5% fewer mothers received medications to prevent HIV transmission to their babies.
- HIV testing services, including initiation, decreased by 22%.
The numbers tell only a part of the story, according to Dr. Crowley.
“We put in place an emergency mechanism to make funds available for countries to do everything except vaccines in support of COVID,” Dr. Crowley explained. (As of August 2021, these funds had been allocated to 107 countries and 16 multicountry programs.)
Countries were advised that they could use the emergency funds three different ways: 1) for COVID-specific purposes (e.g., diagnostics, oxygen, personal protective equipment; 2) to support mitigation strategies geared toward protecting existing HIV, tuberculosis, and malaria programs and getting them back on track; and 3) for so-called “health system fixes,” such as investing in data systems to track COVID, HIV, and other core diseases, as well as the community workforce.
With regard to HIV, each country supported by the Global Fund was asked to ensure that multimonth (3-6 months) dispensing was implemented and/or accelerated so that patients could avoid congested facilities, and, wherever possible, that drugs were delivered or accessed outside the facility. One example of the success of this effort was found in South Africa, where the number of people on antiretrovirals increased almost threefold, from 1.2 million to 4.2 million people.
Countries also were asked to adapt HIV testing procedures by, for example, moving organized testing out of the facilities and into neighborhoods to meet people where they are. Rapid diagnostic testing and triage care linkage using technologies such as WhatsApp were the result, as were opportunities for home testing which, Dr. Crowley noted, remains a critical component of the overall strategy.
“The self-test is important for two reasons, not just because you are trying to find people with HIV, but also, when people know that they’re negative, they know what they can or should do to stay negative,” she said. “It’s quite a powerful motivator.”
Self-testing might also help countries motivate the 6 million people who know that they have HIV but are not on treatment. But there are still 4.1 million residing in these countries who aren’t aware that they are infected, according to the report. This figure is especially troubling, considering that some may also be harboring TB coinfections, including multidrug-resistant TB (MDR-TB).
The imperfect storm globally and in the U.S.
“One of the things that was striking in the report was the decline in the number of people reached with testing and prevention services,” Chris Beyrer, MD, MPH, the Desmond M. Tutu Professor of Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in an interview. Dr. Beyrer was not involved in the report’s development.
“You know, a 10% decline in 1 year to reach people in need is substantial,” he said. “Let’s say it continues; many people are predicting that we won’t have reasonable coverage for low-income countries with COVID until 2023. That adds up to a substantial decline in people reached with these services.”
Dr. Beyrer also expressed concern about the convergence of HIV and TB in already overburdened, fragile health care systems. “Globally, the No. 1 cause of death for people living with HIV is TB, and of course, it’s highly transmissible. So, in many high-burden countries, children are exposed, typically from household members early on, and so the number of people with latent TB infection is just enormous.
“If you look at the report, the worst outcomes are MDR-TB. Those multidrug-resistant and extensively-drug-resistant strains are really a threat to everybody,” Dr. Beyrer said.
But it’s not time for U.S. providers to rest on their laurels either. Dr. Beyrer noted that the 22% decline in HIV testing reported by the Global Fund is similar to what has been happening in the United States with elective procedures such as HIV testing and even preventive procedures like medical male circumcision.
“It’s very clear here in the Global Fund data that the majority of new infections worldwide are in key populations [that] include gay and bisexual men, men who have sex with men, transgender women who have sex with men, people who inject drugs, and sex workers of all genders. Those are people who already faced barriers to health care access and were made worse by COVID.”
Dr. Beyrer noted that, according to the Centers for Disease Control and Prevention, in 2019 in the United States, 68% of new HIV infections occurred in gay and bisexual men, and the effect that COVID-19 will have is still unknown. He also noted the similarity between the most marginalized populations in the Global Fund report and African American men, who have not realized the same increase in the use of preexposure prophylaxis or the same decline in new infections as have their White counterparts.
“It’s also where we are seeing the worst of COVID, low immunization coverage, and high rates of hospitalization and death. ... It’s a dark, dark time for many,” Dr. Crowley said. “And there has also been some amazing resilience and adaptation. The weird thing is, the HIV platform is a natural platform; I mean, if we can keep 21.9 million people on treatment, we can probably deliver them a COVID test and a vaccine.”
Dr. Crowley and Dr. Beyrer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“We’ve been set back by COVID but we’ve seen remarkable resilience, a lot of innovation and creativity,” Siobhan Crowley MD, head of HIV at the Global Fund, said in an interview.
“If you consider that 21.9 million people are getting antiretrovirals at this point through the Global Fund, I think that needs to be appreciated. Ten years ago, that wouldn’t have been the case; all of those people would have disappeared into the ethers,” she said.
Through close partnerships with the U.S. Agency for International Development, the U.S. President’s Emergency Plan for AIDS Relief, and other Western countries and organizations, the Global Fund has invested $22.7 billion in programs to prevent and treat HIV and AIDS, and $3.8 billion in tuberculosis (TB)/HIV programs, according to the organization’s 2021 Results Report.
But the report also underscores the significant effect that the COVID-19 pandemic has had on funded countries’ progress toward achieving renewed 90-90-90 targets for HIV testing/diagnosis, treatment, and viral suppression by 2030.
The setbacks have been challenging and have touched nearly every service from prevention to treatment. According to the report, between 2019 and 2020:
- Voluntary male circumcision declined by 27%.
- Numbers reached by HIV prevention programs fell by 11%.
- 4.5% fewer mothers received medications to prevent HIV transmission to their babies.
- HIV testing services, including initiation, decreased by 22%.
The numbers tell only a part of the story, according to Dr. Crowley.
“We put in place an emergency mechanism to make funds available for countries to do everything except vaccines in support of COVID,” Dr. Crowley explained. (As of August 2021, these funds had been allocated to 107 countries and 16 multicountry programs.)
Countries were advised that they could use the emergency funds three different ways: 1) for COVID-specific purposes (e.g., diagnostics, oxygen, personal protective equipment; 2) to support mitigation strategies geared toward protecting existing HIV, tuberculosis, and malaria programs and getting them back on track; and 3) for so-called “health system fixes,” such as investing in data systems to track COVID, HIV, and other core diseases, as well as the community workforce.
With regard to HIV, each country supported by the Global Fund was asked to ensure that multimonth (3-6 months) dispensing was implemented and/or accelerated so that patients could avoid congested facilities, and, wherever possible, that drugs were delivered or accessed outside the facility. One example of the success of this effort was found in South Africa, where the number of people on antiretrovirals increased almost threefold, from 1.2 million to 4.2 million people.
Countries also were asked to adapt HIV testing procedures by, for example, moving organized testing out of the facilities and into neighborhoods to meet people where they are. Rapid diagnostic testing and triage care linkage using technologies such as WhatsApp were the result, as were opportunities for home testing which, Dr. Crowley noted, remains a critical component of the overall strategy.
“The self-test is important for two reasons, not just because you are trying to find people with HIV, but also, when people know that they’re negative, they know what they can or should do to stay negative,” she said. “It’s quite a powerful motivator.”
Self-testing might also help countries motivate the 6 million people who know that they have HIV but are not on treatment. But there are still 4.1 million residing in these countries who aren’t aware that they are infected, according to the report. This figure is especially troubling, considering that some may also be harboring TB coinfections, including multidrug-resistant TB (MDR-TB).
The imperfect storm globally and in the U.S.
“One of the things that was striking in the report was the decline in the number of people reached with testing and prevention services,” Chris Beyrer, MD, MPH, the Desmond M. Tutu Professor of Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in an interview. Dr. Beyrer was not involved in the report’s development.
“You know, a 10% decline in 1 year to reach people in need is substantial,” he said. “Let’s say it continues; many people are predicting that we won’t have reasonable coverage for low-income countries with COVID until 2023. That adds up to a substantial decline in people reached with these services.”
Dr. Beyrer also expressed concern about the convergence of HIV and TB in already overburdened, fragile health care systems. “Globally, the No. 1 cause of death for people living with HIV is TB, and of course, it’s highly transmissible. So, in many high-burden countries, children are exposed, typically from household members early on, and so the number of people with latent TB infection is just enormous.
“If you look at the report, the worst outcomes are MDR-TB. Those multidrug-resistant and extensively-drug-resistant strains are really a threat to everybody,” Dr. Beyrer said.
But it’s not time for U.S. providers to rest on their laurels either. Dr. Beyrer noted that the 22% decline in HIV testing reported by the Global Fund is similar to what has been happening in the United States with elective procedures such as HIV testing and even preventive procedures like medical male circumcision.
“It’s very clear here in the Global Fund data that the majority of new infections worldwide are in key populations [that] include gay and bisexual men, men who have sex with men, transgender women who have sex with men, people who inject drugs, and sex workers of all genders. Those are people who already faced barriers to health care access and were made worse by COVID.”
Dr. Beyrer noted that, according to the Centers for Disease Control and Prevention, in 2019 in the United States, 68% of new HIV infections occurred in gay and bisexual men, and the effect that COVID-19 will have is still unknown. He also noted the similarity between the most marginalized populations in the Global Fund report and African American men, who have not realized the same increase in the use of preexposure prophylaxis or the same decline in new infections as have their White counterparts.
“It’s also where we are seeing the worst of COVID, low immunization coverage, and high rates of hospitalization and death. ... It’s a dark, dark time for many,” Dr. Crowley said. “And there has also been some amazing resilience and adaptation. The weird thing is, the HIV platform is a natural platform; I mean, if we can keep 21.9 million people on treatment, we can probably deliver them a COVID test and a vaccine.”
Dr. Crowley and Dr. Beyrer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“We’ve been set back by COVID but we’ve seen remarkable resilience, a lot of innovation and creativity,” Siobhan Crowley MD, head of HIV at the Global Fund, said in an interview.
“If you consider that 21.9 million people are getting antiretrovirals at this point through the Global Fund, I think that needs to be appreciated. Ten years ago, that wouldn’t have been the case; all of those people would have disappeared into the ethers,” she said.
Through close partnerships with the U.S. Agency for International Development, the U.S. President’s Emergency Plan for AIDS Relief, and other Western countries and organizations, the Global Fund has invested $22.7 billion in programs to prevent and treat HIV and AIDS, and $3.8 billion in tuberculosis (TB)/HIV programs, according to the organization’s 2021 Results Report.
But the report also underscores the significant effect that the COVID-19 pandemic has had on funded countries’ progress toward achieving renewed 90-90-90 targets for HIV testing/diagnosis, treatment, and viral suppression by 2030.
The setbacks have been challenging and have touched nearly every service from prevention to treatment. According to the report, between 2019 and 2020:
- Voluntary male circumcision declined by 27%.
- Numbers reached by HIV prevention programs fell by 11%.
- 4.5% fewer mothers received medications to prevent HIV transmission to their babies.
- HIV testing services, including initiation, decreased by 22%.
The numbers tell only a part of the story, according to Dr. Crowley.
“We put in place an emergency mechanism to make funds available for countries to do everything except vaccines in support of COVID,” Dr. Crowley explained. (As of August 2021, these funds had been allocated to 107 countries and 16 multicountry programs.)
Countries were advised that they could use the emergency funds three different ways: 1) for COVID-specific purposes (e.g., diagnostics, oxygen, personal protective equipment; 2) to support mitigation strategies geared toward protecting existing HIV, tuberculosis, and malaria programs and getting them back on track; and 3) for so-called “health system fixes,” such as investing in data systems to track COVID, HIV, and other core diseases, as well as the community workforce.
With regard to HIV, each country supported by the Global Fund was asked to ensure that multimonth (3-6 months) dispensing was implemented and/or accelerated so that patients could avoid congested facilities, and, wherever possible, that drugs were delivered or accessed outside the facility. One example of the success of this effort was found in South Africa, where the number of people on antiretrovirals increased almost threefold, from 1.2 million to 4.2 million people.
Countries also were asked to adapt HIV testing procedures by, for example, moving organized testing out of the facilities and into neighborhoods to meet people where they are. Rapid diagnostic testing and triage care linkage using technologies such as WhatsApp were the result, as were opportunities for home testing which, Dr. Crowley noted, remains a critical component of the overall strategy.
“The self-test is important for two reasons, not just because you are trying to find people with HIV, but also, when people know that they’re negative, they know what they can or should do to stay negative,” she said. “It’s quite a powerful motivator.”
Self-testing might also help countries motivate the 6 million people who know that they have HIV but are not on treatment. But there are still 4.1 million residing in these countries who aren’t aware that they are infected, according to the report. This figure is especially troubling, considering that some may also be harboring TB coinfections, including multidrug-resistant TB (MDR-TB).
The imperfect storm globally and in the U.S.
“One of the things that was striking in the report was the decline in the number of people reached with testing and prevention services,” Chris Beyrer, MD, MPH, the Desmond M. Tutu Professor of Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health in Baltimore, said in an interview. Dr. Beyrer was not involved in the report’s development.
“You know, a 10% decline in 1 year to reach people in need is substantial,” he said. “Let’s say it continues; many people are predicting that we won’t have reasonable coverage for low-income countries with COVID until 2023. That adds up to a substantial decline in people reached with these services.”
Dr. Beyrer also expressed concern about the convergence of HIV and TB in already overburdened, fragile health care systems. “Globally, the No. 1 cause of death for people living with HIV is TB, and of course, it’s highly transmissible. So, in many high-burden countries, children are exposed, typically from household members early on, and so the number of people with latent TB infection is just enormous.
“If you look at the report, the worst outcomes are MDR-TB. Those multidrug-resistant and extensively-drug-resistant strains are really a threat to everybody,” Dr. Beyrer said.
But it’s not time for U.S. providers to rest on their laurels either. Dr. Beyrer noted that the 22% decline in HIV testing reported by the Global Fund is similar to what has been happening in the United States with elective procedures such as HIV testing and even preventive procedures like medical male circumcision.
“It’s very clear here in the Global Fund data that the majority of new infections worldwide are in key populations [that] include gay and bisexual men, men who have sex with men, transgender women who have sex with men, people who inject drugs, and sex workers of all genders. Those are people who already faced barriers to health care access and were made worse by COVID.”
Dr. Beyrer noted that, according to the Centers for Disease Control and Prevention, in 2019 in the United States, 68% of new HIV infections occurred in gay and bisexual men, and the effect that COVID-19 will have is still unknown. He also noted the similarity between the most marginalized populations in the Global Fund report and African American men, who have not realized the same increase in the use of preexposure prophylaxis or the same decline in new infections as have their White counterparts.
“It’s also where we are seeing the worst of COVID, low immunization coverage, and high rates of hospitalization and death. ... It’s a dark, dark time for many,” Dr. Crowley said. “And there has also been some amazing resilience and adaptation. The weird thing is, the HIV platform is a natural platform; I mean, if we can keep 21.9 million people on treatment, we can probably deliver them a COVID test and a vaccine.”
Dr. Crowley and Dr. Beyrer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New AHA guidance targets obesity-related hypertension
Whereas previous scientific statements from the American Heart Association have addressed how diet, physical activity, and weight control can help prevent and manage hypertension, a new AHA statement focuses on obesity-related hypertension.
The document, which was published online Sept. 20, 2021, in Hypertension, also identifies knowledge gaps and suggests future research directions.
“Given [that] obesity is a major risk factor for hypertension, and hypertension is one of the greatest (if not the greatest) attributable risk factors for most cardiovascular diseases, we thought it was important to focus on weight loss strategies and update what we know about the treatment options that are available to treat obesity hypertension,” writing group chair Michael E. Hall, MD, told this news organization.
“Medical and surgical strategies may help with long-term weight and blood pressure improvement, in addition to a heart-healthy diet and physical activity,” he noted in a press release from the AHA. “We often don’t consider medications or metabolic surgery until after there has been target organ damage, such as heart injury or having a stroke.”
However, by acting earlier, “we may be able to prevent these complications,” added Dr. Hall, associate division director for cardiovascular diseases at the University of Mississippi Medical Center in Jackson.
“This is not a call for greater use of one specific therapy,” he clarified. “However, we do know that more aggressive treatments including antiobesity medications or metabolic surgery are underutilized.”
According to Dr. Hall, “we treat the secondary problem [i.e., the hypertension or diabetes], but we are not treating the root cause [obesity] as aggressively.”
“Hopefully this statement will increase awareness that there are several [treatment] options [and] bring attention to this major health issue,” he said.
He added that the most important question, in his mind, is how best to tackle obesity among children and adolescents to lower their risk of hypertension and other associated complications.
The statement is aimed at both primary care providers and specialists.
Diet, physical activity help, but weight regain common
Losing 5%-10% of body weight can lead to a more than 5–mm Hg reduction in systolic blood pressure and a 4–mm Hg reduction in diastolic blood pressure, the statement notes. Losing 10 kg may lower systolic blood pressure by 5-20 mm Hg.
To manage weight, control hypertension, and reduce the risk of cardiovascular disease, guidelines recommend the Mediterranean diet or the Dietary Approaches to Stop Hypertension (DASH) diet, which both emphasize fruits, vegetables, legumes, nuts, and seeds, with moderate intake of fish, seafood, poultry, and dairy, and low intake of red and processed meats and sweets. The Mediterranean diet also includes olive oil and moderate consumption of (mainly red) wine.
The effect of intermittent fasting on blood pressure control is not clear, the statement noted.
It added that typically 150-225 minutes and 225-420 minutes of physical activity per week can produce weight loss of 2-3 kg or 5-7.5 kg respectively, and 200-300 minutes of physical activity per week is needed to maintain this weight loss.
“Successful weight-loss maintenance over years therefore typically requires high levels of [physical activity] and limited sedentary time, frequent weight monitoring, and high levels of dietary restraint,” and weight regain is common, the authors summarize.
Other options to address obesity, hypertension
Weight-loss pharmacotherapies and metabolic surgery are other options to treat obesity and lower hypertension.
The statement reports that four drugs are approved by the Food and Drug Administration for long-term weight loss: Orlistat (Xenical, Alli), phentermine/topiramate extended release (Qsymia), naltrexone/bupropion (Contrave), and liraglutide 3.0 mg (Saxenda). On June 4, the FDA approved a fifth drug, semaglutide (Wegovy).
The long-term effects of antiobesity medications on blood pressure are mixed.
However, “prescription rates for these drugs remain low, likely because of limited insurance coverage and low levels of clinical proficiency with treating obesity,” Dr. Hall and colleagues write.
Metabolic surgery could be a weight loss option for certain patients, and it is associated with blood pressure lowering.
In the 100-patient Gastric Bypass to Treat Obese Patients With Steady Hypertension (GATEWAY) trial, published in Circulation in 2018, more patients in the Roux-en-Y gastric-bypass group than the control group (84% vs. 13%) met the primary outcome of a 30% or greater reduction in the number of blood pressure-lowering medications at 12 months while maintaining an office blood pressure less than 140/90 mm Hg.
Unanswered questions, future research directions
In 2015-2016, an estimated 18.5% of U.S. children and adolescents aged 2-19 years had obesity, the statement notes. Children with obesity have a twofold increased risk of incident hypertension, and those with severe obesity have an over fourfold increased risk of this outcome, compared with children who have a healthy weight.
Dr. Hall and colleagues emphasized that, “as the prevalence of obesity continues to increase, hypertension and associated cardiorenal diseases will also increase unless more effective strategies to prevent and treat obesity are developed.”
They identified 17 unanswered questions (knowledge gaps) that can guide the direction of future research. These include:
- What new strategies and science-based guidelines are needed to curb the growing evidence of childhood obesity?
- Does intentional weight loss with pharmacotherapy or metabolic surgery in childhood and early adulthood prevent hypertension and subsequent target organ damage in later life?
- What is the optimal amount of time that clinicians should allow before recommending more aggressive weight management strategies (that is, antiobesity medications or metabolic surgery) or hypertension strategies beyond lifestyle changes?
“To me,” Dr. Hall said, “addressing childhood obesity hypertension and determining optimal timing of antiobesity therapies are the most important [issues]. Certainly, these therapies (i.e., diets, medications, surgeries) have some risks, but we don’t have a clear understanding if their benefits outweigh these risks in younger obese people or whether initiating these therapies before the onset of target organ damage such as heart failure” outweigh the risks.
Dr. Hall has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
A version of this article first appeared on Medscape.com.
Whereas previous scientific statements from the American Heart Association have addressed how diet, physical activity, and weight control can help prevent and manage hypertension, a new AHA statement focuses on obesity-related hypertension.
The document, which was published online Sept. 20, 2021, in Hypertension, also identifies knowledge gaps and suggests future research directions.
“Given [that] obesity is a major risk factor for hypertension, and hypertension is one of the greatest (if not the greatest) attributable risk factors for most cardiovascular diseases, we thought it was important to focus on weight loss strategies and update what we know about the treatment options that are available to treat obesity hypertension,” writing group chair Michael E. Hall, MD, told this news organization.
“Medical and surgical strategies may help with long-term weight and blood pressure improvement, in addition to a heart-healthy diet and physical activity,” he noted in a press release from the AHA. “We often don’t consider medications or metabolic surgery until after there has been target organ damage, such as heart injury or having a stroke.”
However, by acting earlier, “we may be able to prevent these complications,” added Dr. Hall, associate division director for cardiovascular diseases at the University of Mississippi Medical Center in Jackson.
“This is not a call for greater use of one specific therapy,” he clarified. “However, we do know that more aggressive treatments including antiobesity medications or metabolic surgery are underutilized.”
According to Dr. Hall, “we treat the secondary problem [i.e., the hypertension or diabetes], but we are not treating the root cause [obesity] as aggressively.”
“Hopefully this statement will increase awareness that there are several [treatment] options [and] bring attention to this major health issue,” he said.
He added that the most important question, in his mind, is how best to tackle obesity among children and adolescents to lower their risk of hypertension and other associated complications.
The statement is aimed at both primary care providers and specialists.
Diet, physical activity help, but weight regain common
Losing 5%-10% of body weight can lead to a more than 5–mm Hg reduction in systolic blood pressure and a 4–mm Hg reduction in diastolic blood pressure, the statement notes. Losing 10 kg may lower systolic blood pressure by 5-20 mm Hg.
To manage weight, control hypertension, and reduce the risk of cardiovascular disease, guidelines recommend the Mediterranean diet or the Dietary Approaches to Stop Hypertension (DASH) diet, which both emphasize fruits, vegetables, legumes, nuts, and seeds, with moderate intake of fish, seafood, poultry, and dairy, and low intake of red and processed meats and sweets. The Mediterranean diet also includes olive oil and moderate consumption of (mainly red) wine.
The effect of intermittent fasting on blood pressure control is not clear, the statement noted.
It added that typically 150-225 minutes and 225-420 minutes of physical activity per week can produce weight loss of 2-3 kg or 5-7.5 kg respectively, and 200-300 minutes of physical activity per week is needed to maintain this weight loss.
“Successful weight-loss maintenance over years therefore typically requires high levels of [physical activity] and limited sedentary time, frequent weight monitoring, and high levels of dietary restraint,” and weight regain is common, the authors summarize.
Other options to address obesity, hypertension
Weight-loss pharmacotherapies and metabolic surgery are other options to treat obesity and lower hypertension.
The statement reports that four drugs are approved by the Food and Drug Administration for long-term weight loss: Orlistat (Xenical, Alli), phentermine/topiramate extended release (Qsymia), naltrexone/bupropion (Contrave), and liraglutide 3.0 mg (Saxenda). On June 4, the FDA approved a fifth drug, semaglutide (Wegovy).
The long-term effects of antiobesity medications on blood pressure are mixed.
However, “prescription rates for these drugs remain low, likely because of limited insurance coverage and low levels of clinical proficiency with treating obesity,” Dr. Hall and colleagues write.
Metabolic surgery could be a weight loss option for certain patients, and it is associated with blood pressure lowering.
In the 100-patient Gastric Bypass to Treat Obese Patients With Steady Hypertension (GATEWAY) trial, published in Circulation in 2018, more patients in the Roux-en-Y gastric-bypass group than the control group (84% vs. 13%) met the primary outcome of a 30% or greater reduction in the number of blood pressure-lowering medications at 12 months while maintaining an office blood pressure less than 140/90 mm Hg.
Unanswered questions, future research directions
In 2015-2016, an estimated 18.5% of U.S. children and adolescents aged 2-19 years had obesity, the statement notes. Children with obesity have a twofold increased risk of incident hypertension, and those with severe obesity have an over fourfold increased risk of this outcome, compared with children who have a healthy weight.
Dr. Hall and colleagues emphasized that, “as the prevalence of obesity continues to increase, hypertension and associated cardiorenal diseases will also increase unless more effective strategies to prevent and treat obesity are developed.”
They identified 17 unanswered questions (knowledge gaps) that can guide the direction of future research. These include:
- What new strategies and science-based guidelines are needed to curb the growing evidence of childhood obesity?
- Does intentional weight loss with pharmacotherapy or metabolic surgery in childhood and early adulthood prevent hypertension and subsequent target organ damage in later life?
- What is the optimal amount of time that clinicians should allow before recommending more aggressive weight management strategies (that is, antiobesity medications or metabolic surgery) or hypertension strategies beyond lifestyle changes?
“To me,” Dr. Hall said, “addressing childhood obesity hypertension and determining optimal timing of antiobesity therapies are the most important [issues]. Certainly, these therapies (i.e., diets, medications, surgeries) have some risks, but we don’t have a clear understanding if their benefits outweigh these risks in younger obese people or whether initiating these therapies before the onset of target organ damage such as heart failure” outweigh the risks.
Dr. Hall has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
A version of this article first appeared on Medscape.com.
Whereas previous scientific statements from the American Heart Association have addressed how diet, physical activity, and weight control can help prevent and manage hypertension, a new AHA statement focuses on obesity-related hypertension.
The document, which was published online Sept. 20, 2021, in Hypertension, also identifies knowledge gaps and suggests future research directions.
“Given [that] obesity is a major risk factor for hypertension, and hypertension is one of the greatest (if not the greatest) attributable risk factors for most cardiovascular diseases, we thought it was important to focus on weight loss strategies and update what we know about the treatment options that are available to treat obesity hypertension,” writing group chair Michael E. Hall, MD, told this news organization.
“Medical and surgical strategies may help with long-term weight and blood pressure improvement, in addition to a heart-healthy diet and physical activity,” he noted in a press release from the AHA. “We often don’t consider medications or metabolic surgery until after there has been target organ damage, such as heart injury or having a stroke.”
However, by acting earlier, “we may be able to prevent these complications,” added Dr. Hall, associate division director for cardiovascular diseases at the University of Mississippi Medical Center in Jackson.
“This is not a call for greater use of one specific therapy,” he clarified. “However, we do know that more aggressive treatments including antiobesity medications or metabolic surgery are underutilized.”
According to Dr. Hall, “we treat the secondary problem [i.e., the hypertension or diabetes], but we are not treating the root cause [obesity] as aggressively.”
“Hopefully this statement will increase awareness that there are several [treatment] options [and] bring attention to this major health issue,” he said.
He added that the most important question, in his mind, is how best to tackle obesity among children and adolescents to lower their risk of hypertension and other associated complications.
The statement is aimed at both primary care providers and specialists.
Diet, physical activity help, but weight regain common
Losing 5%-10% of body weight can lead to a more than 5–mm Hg reduction in systolic blood pressure and a 4–mm Hg reduction in diastolic blood pressure, the statement notes. Losing 10 kg may lower systolic blood pressure by 5-20 mm Hg.
To manage weight, control hypertension, and reduce the risk of cardiovascular disease, guidelines recommend the Mediterranean diet or the Dietary Approaches to Stop Hypertension (DASH) diet, which both emphasize fruits, vegetables, legumes, nuts, and seeds, with moderate intake of fish, seafood, poultry, and dairy, and low intake of red and processed meats and sweets. The Mediterranean diet also includes olive oil and moderate consumption of (mainly red) wine.
The effect of intermittent fasting on blood pressure control is not clear, the statement noted.
It added that typically 150-225 minutes and 225-420 minutes of physical activity per week can produce weight loss of 2-3 kg or 5-7.5 kg respectively, and 200-300 minutes of physical activity per week is needed to maintain this weight loss.
“Successful weight-loss maintenance over years therefore typically requires high levels of [physical activity] and limited sedentary time, frequent weight monitoring, and high levels of dietary restraint,” and weight regain is common, the authors summarize.
Other options to address obesity, hypertension
Weight-loss pharmacotherapies and metabolic surgery are other options to treat obesity and lower hypertension.
The statement reports that four drugs are approved by the Food and Drug Administration for long-term weight loss: Orlistat (Xenical, Alli), phentermine/topiramate extended release (Qsymia), naltrexone/bupropion (Contrave), and liraglutide 3.0 mg (Saxenda). On June 4, the FDA approved a fifth drug, semaglutide (Wegovy).
The long-term effects of antiobesity medications on blood pressure are mixed.
However, “prescription rates for these drugs remain low, likely because of limited insurance coverage and low levels of clinical proficiency with treating obesity,” Dr. Hall and colleagues write.
Metabolic surgery could be a weight loss option for certain patients, and it is associated with blood pressure lowering.
In the 100-patient Gastric Bypass to Treat Obese Patients With Steady Hypertension (GATEWAY) trial, published in Circulation in 2018, more patients in the Roux-en-Y gastric-bypass group than the control group (84% vs. 13%) met the primary outcome of a 30% or greater reduction in the number of blood pressure-lowering medications at 12 months while maintaining an office blood pressure less than 140/90 mm Hg.
Unanswered questions, future research directions
In 2015-2016, an estimated 18.5% of U.S. children and adolescents aged 2-19 years had obesity, the statement notes. Children with obesity have a twofold increased risk of incident hypertension, and those with severe obesity have an over fourfold increased risk of this outcome, compared with children who have a healthy weight.
Dr. Hall and colleagues emphasized that, “as the prevalence of obesity continues to increase, hypertension and associated cardiorenal diseases will also increase unless more effective strategies to prevent and treat obesity are developed.”
They identified 17 unanswered questions (knowledge gaps) that can guide the direction of future research. These include:
- What new strategies and science-based guidelines are needed to curb the growing evidence of childhood obesity?
- Does intentional weight loss with pharmacotherapy or metabolic surgery in childhood and early adulthood prevent hypertension and subsequent target organ damage in later life?
- What is the optimal amount of time that clinicians should allow before recommending more aggressive weight management strategies (that is, antiobesity medications or metabolic surgery) or hypertension strategies beyond lifestyle changes?
“To me,” Dr. Hall said, “addressing childhood obesity hypertension and determining optimal timing of antiobesity therapies are the most important [issues]. Certainly, these therapies (i.e., diets, medications, surgeries) have some risks, but we don’t have a clear understanding if their benefits outweigh these risks in younger obese people or whether initiating these therapies before the onset of target organ damage such as heart failure” outweigh the risks.
Dr. Hall has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
A version of this article first appeared on Medscape.com.
Should hospitalists use albumin to treat non-SBP infections in patients with cirrhosis?
Caution is advised in patients at risk of pulmonary edema
Case
A 56 year-old male with hypertension, alcohol use disorder, stage II chronic kidney disease, and biopsy-proven cirrhosis presents with fever and chills, pyuria, flank pain, and an acute kidney injury concerning for pyelonephritis. Is there a benefit in treating with albumin in addition to guideline-based antibiotics?
Brief overview of the issue
Albumin is a negatively charged human protein produced by the liver. Albumin comprises 50% of plasma protein and over 75% of plasma oncotic pressure.1 It was first used at Walter Reed Hospital in 1940 and subsequently for burn injuries after the attack on Pearl Harbor in 1941.2
Albumin serves several important physiologic functions including maintaining oncotic pressure, endothelial support, antioxidation, nitrogen oxide scavenging, and buffering and transport of solutes and drugs, including antibiotics. In cirrhosis, albumin is diluted due to sodium and water retention. There is increased redistribution, decreased synthesis by the liver, and impaired albumin molecule binding.3
For patients with liver disease, per the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), albumin should be administered to prevent post paracentesis circulatory dysfunction after large volume paracentesis, to prevent renal failure and mortality in the setting of spontaneous bacterial peritonitis (SBP), and in the diagnosis and treatment of hepatorenal syndrome (HRS) type I to potentially improve mortality.4,5 Beyond these three guideline-based indications, other uses for albumin for patients with liver disease have been proposed, including treatment of hyponatremia, posttransplant fluid resuscitation, diuretic unresponsive ascites, and long-term management of cirrhosis. There has yet to be strong evidence supporting these additional indications. However, given the known benefits of albumin in patients with SBP, there has been recent research into treatment of non-SBP infections, including urinary tract infections.
Overview of the data
There have been three randomized controlled trials (RCTs) regarding albumin administration for the treatment of non-SBP infections for hospitalized patients with cirrhosis. All three trials randomized patients to a treatment arm of albumin and antibiotics versus a control group of antibiotics alone. The treatment protocol prescribed 20% albumin with 1.5 g/kg on day 1 and 1.0 g/kg on day 3. The most common infections studied were pneumonia and urinary tract infection. These RCTs found that albumin administration was associated with improved renal and/or circulatory function, but not with a reduction in mortality.
First, there was a single center RCT by Guevara et al. in 2012 of 110 patients with cirrhosis and infection based on SIRS criteria.6 The primary outcome was 90-day survival with secondary outcomes of renal failure development, renal function at days 3,7 and 14, and circulatory function measured by plasma renin, aldosterone, and norepinephrine. Renal function and circulatory function improved in the albumin group, but not mortality. In a multivariable regression analysis, albumin was statistically predictive of survival (hazard ratio of 0.294).
Second, there was a multicenter RCT by Thévenot et al. in 2015 of 193 patients.7 The primary outcome was 90-day renal failure and the secondary outcome was 90-day survival. Renal failure was chosen as the primary endpoint because of its association with survival in this patient population. The treatment group had delayed onset of renal failure, but no difference in the development of 90-day renal failure or 90-day mortality rate. Notably, eight patients (8.3%) in the albumin group developed pulmonary edema with two deaths. This led the oversight committee to prematurely terminate the study.
Third and most recently, there was a multicenter RCT by Fernández et al. in 2019 of 118 patients.8 The primary outcome was in-hospital mortality, with secondary outcomes of circulatory dysfunction measured by plasma renin concentration, systemic inflammation measured by plasma IL-6 and biomarkers, complications including acute-on-chronic liver failure (ACLF) and nosocomial bacterial infections, and 90-day mortality. Between the albumin and control group, there were no differences in in-hospital mortality (13.1% vs. 10.5%, P > .66), inflammation, circulatory dysfunction, or liver severity. However, a significantly higher proportion of patients in the albumin group had resolution of their ACLF (82.3% vs. 33.3%, P = .003) and a lower proportion developed nosocomial infections (6.6% vs. 24.6%, P = .007). A major weakness of this study was that patients in the albumin group had a higher combined rate of ACLF and kidney dysfunction (44.3% vs. 24.6%, P = .02).
Beyond these three randomized controlled trials, there was a study on the long-term administration of albumin for patients with cirrhosis and ascites. Patients who received twice weekly albumin infusions had a lower 2-year mortality rate and a reduction in the incidence of both SBP and non-SBP infections.9 Another long-term study of albumin administration found similar results with greater 18-month survival and fewer non-SBP infections.10 A trial looking at inflammation in patients without bacterial infections and in biobanked samples from cirrhotic patients with bacterial infections found that treatment with albumin reduced systemic inflammation.11
In summary, the three RCTs looked at comparable patients with cirrhosis and a non-SBP infection and all underwent similar treatment protocols with 20% albumin dosed at 1.5 g/kg on day 1 and 1.0 g/kg on day 3. All studies evaluated mortality in either the primary or secondary outcome, and none found significant differences in mortality between treatment and control groups. Each study also evaluated and found improvement in renal and/or circulatory function. Fernández et al. also found increased resolution of ACLF, fewer nosocomial infections, and reduction in some inflammatory markers. However, all studies had relatively small sample sizes that were underpowered to detect mortality differences. Furthermore, randomization did not lead to well-matched groups, with the treatment group patients in the Fernández study having higher rates of ACLF and kidney dysfunction.
The data suggest that albumin may be beneficial in improving renal and circulatory function. In select patients with ACLF and elevated serum creatinine, albumin treatment may be considered. There has been discussion about the use of albumin preferentially in patients with subdiaphragmatic bacterial infections, most related to increased risk of renal failure such as biliary and urinary tract infections.12 The authors of these studies also note that albumin may be more beneficial in patients with higher baseline creatinine. Caution is warranted for patients with impaired cardiac function or poor respiratory status given the possibility of pulmonary edema. Finally, the high cost of albumin in many medical centers is a major limitation of this treatment approach.
Application of data to our patient
Our patient has cirrhosis and is acutely presenting with pyelonephritis and acute kidney injury. He has no baseline pulmonary disease or oxygen requirement. His recent transthoracic echocardiogram is reviewed and he has no evidence of cardiac disease.
Because he has an elevated creatinine, an infectious process associated with progressive renal failure, and is not at an elevated baseline risk of developing pulmonary edema, albumin would be reasonable to administer at 1.5 g/kg on day 1 and 1.0 g/kg on day 3 of hospitalization.
Bottom line
In certain patients with cirrhosis and a non-SBP infection, the use of albumin to help improve renal and circulatory function is reasonable. There is no evidence that albumin will improve mortality and caution is warranted for patients at risk for pulmonary edema.
Dr. Rambachan is an academic hospital medicine fellow at the University of California, San Francisco.
References
1. Caironi P and Gattinoni L. The clinical use of albumin: the point of view of a specialist in intensive care. Blood Transfus. 2009;7(4):259-67. doi: 10.2450/2009.0002-09.
2. Paine CH et al. Albumin in cirrhosis: More than a colloid. Curr Treat Options Gastroenterol. 2019;17(2):231-43. doi: 10.1007/s11938-019-00227-4.
3. Walayat S et al. Role of albumin in cirrhosis: from a hospitalist’s perspective. J Community Hosp Intern Med Perspect. 2017;7(1):8-14. 2017 Mar 31. doi: 10.1080/20009666.2017.1302704.
4. Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline [for the] management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651-3. doi: 10.1002/hep.26359.
5. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis [published correction appears in J Hepatol. 2018 Nov;69(5):1207]. J Hepatol. 2018 Aug;69(2):406-60. doi: 10.1016/j.jhep.2018.03.024.
6. Guevara M et al. Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. J Hepatol. 2012 Oct;57(4):759-65. doi: 10.1016/j.jhep.2012.06.013.
7. Thévenot T et al. Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial. J Hepatol. 2015 Apr;62(4):822-30. doi: 10.1016/j.jhep.2014.11.017.
8. Fernández J et al. Efficacy of albumin treatment for patients with cirrhosis and infections unrelated to spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol. 2020 Apr;18(4):963-73.e14. doi: 10.1016/j.c gh.2019.07.055.
9. Di Pascoli M et al. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int. 2019 Jan;39(1):98-105. doi: 10.1111/liv.13968.
10. Caraceni P et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial [published correction appears in Lancet. 2018 Aug 4;392(10145):386]. Lancet. 2018 June;391(10138):2417-29. doi: 10.1016/S0140-6736(18)30840-7.
11. Fernández J et al. Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis. Gastroenterology. 2019 July;157(1):149-62. doi: 10.1053/j.gastro.2019.03.021.
12. Fasolato S et al. Renal failure and bacterial infections in patients with cirrhosis: Epidemiology and clinical features. Hepatology. 2007;45(1):223-9. doi: 10.1002/hep.21443.
Key points
- In patients with spontaneous bacterial peritonitis, hepatorenal syndrome, and for large volume paracentesis, albumin improves outcomes and is recommended by guidelines.
- In patients with cirrhosis and a non-SBP infection, there is some evidence that albumin may improve renal and circulatory function.
- Clinicians should be cautious about albumin use in patients at an elevated risk for development of pulmonary edema.
Quiz
Which of the following is not a guideline-recommended use of albumin for patients with cirrhosis?
A. Treatment of type 1 hepatorenal syndrome
B. Treatment of spontaneous bacterial peritonitis
C. To correct plasma albumin < 2.5 g/dL in nontransplant patients
D. Post large-volume paracentesis
The answer is C. Per the EASL and AASLD, A,B, and D are recommended. There is not strong evidence to support administering albumin to correct low plasma albumin.
Additional reading
- Bernardi M et al. Albumin in decompensated cirrhosis: new concepts and perspectives. Gut. 2020 June;69(6):1127-38. doi: 10.1136/gutjnl-2019-318843.
- Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline [for the] management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651-3. doi: 10.1002/hep.26359.
- Paine CH et al. Albumin in cirrhosis: More than a colloid. Curr Treat Options Gastroenterol. 2019 June;17(2):231-43. doi: 10.1007/s11938-019-00227-4.
Caution is advised in patients at risk of pulmonary edema
Caution is advised in patients at risk of pulmonary edema
Case
A 56 year-old male with hypertension, alcohol use disorder, stage II chronic kidney disease, and biopsy-proven cirrhosis presents with fever and chills, pyuria, flank pain, and an acute kidney injury concerning for pyelonephritis. Is there a benefit in treating with albumin in addition to guideline-based antibiotics?
Brief overview of the issue
Albumin is a negatively charged human protein produced by the liver. Albumin comprises 50% of plasma protein and over 75% of plasma oncotic pressure.1 It was first used at Walter Reed Hospital in 1940 and subsequently for burn injuries after the attack on Pearl Harbor in 1941.2
Albumin serves several important physiologic functions including maintaining oncotic pressure, endothelial support, antioxidation, nitrogen oxide scavenging, and buffering and transport of solutes and drugs, including antibiotics. In cirrhosis, albumin is diluted due to sodium and water retention. There is increased redistribution, decreased synthesis by the liver, and impaired albumin molecule binding.3
For patients with liver disease, per the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), albumin should be administered to prevent post paracentesis circulatory dysfunction after large volume paracentesis, to prevent renal failure and mortality in the setting of spontaneous bacterial peritonitis (SBP), and in the diagnosis and treatment of hepatorenal syndrome (HRS) type I to potentially improve mortality.4,5 Beyond these three guideline-based indications, other uses for albumin for patients with liver disease have been proposed, including treatment of hyponatremia, posttransplant fluid resuscitation, diuretic unresponsive ascites, and long-term management of cirrhosis. There has yet to be strong evidence supporting these additional indications. However, given the known benefits of albumin in patients with SBP, there has been recent research into treatment of non-SBP infections, including urinary tract infections.
Overview of the data
There have been three randomized controlled trials (RCTs) regarding albumin administration for the treatment of non-SBP infections for hospitalized patients with cirrhosis. All three trials randomized patients to a treatment arm of albumin and antibiotics versus a control group of antibiotics alone. The treatment protocol prescribed 20% albumin with 1.5 g/kg on day 1 and 1.0 g/kg on day 3. The most common infections studied were pneumonia and urinary tract infection. These RCTs found that albumin administration was associated with improved renal and/or circulatory function, but not with a reduction in mortality.
First, there was a single center RCT by Guevara et al. in 2012 of 110 patients with cirrhosis and infection based on SIRS criteria.6 The primary outcome was 90-day survival with secondary outcomes of renal failure development, renal function at days 3,7 and 14, and circulatory function measured by plasma renin, aldosterone, and norepinephrine. Renal function and circulatory function improved in the albumin group, but not mortality. In a multivariable regression analysis, albumin was statistically predictive of survival (hazard ratio of 0.294).
Second, there was a multicenter RCT by Thévenot et al. in 2015 of 193 patients.7 The primary outcome was 90-day renal failure and the secondary outcome was 90-day survival. Renal failure was chosen as the primary endpoint because of its association with survival in this patient population. The treatment group had delayed onset of renal failure, but no difference in the development of 90-day renal failure or 90-day mortality rate. Notably, eight patients (8.3%) in the albumin group developed pulmonary edema with two deaths. This led the oversight committee to prematurely terminate the study.
Third and most recently, there was a multicenter RCT by Fernández et al. in 2019 of 118 patients.8 The primary outcome was in-hospital mortality, with secondary outcomes of circulatory dysfunction measured by plasma renin concentration, systemic inflammation measured by plasma IL-6 and biomarkers, complications including acute-on-chronic liver failure (ACLF) and nosocomial bacterial infections, and 90-day mortality. Between the albumin and control group, there were no differences in in-hospital mortality (13.1% vs. 10.5%, P > .66), inflammation, circulatory dysfunction, or liver severity. However, a significantly higher proportion of patients in the albumin group had resolution of their ACLF (82.3% vs. 33.3%, P = .003) and a lower proportion developed nosocomial infections (6.6% vs. 24.6%, P = .007). A major weakness of this study was that patients in the albumin group had a higher combined rate of ACLF and kidney dysfunction (44.3% vs. 24.6%, P = .02).
Beyond these three randomized controlled trials, there was a study on the long-term administration of albumin for patients with cirrhosis and ascites. Patients who received twice weekly albumin infusions had a lower 2-year mortality rate and a reduction in the incidence of both SBP and non-SBP infections.9 Another long-term study of albumin administration found similar results with greater 18-month survival and fewer non-SBP infections.10 A trial looking at inflammation in patients without bacterial infections and in biobanked samples from cirrhotic patients with bacterial infections found that treatment with albumin reduced systemic inflammation.11
In summary, the three RCTs looked at comparable patients with cirrhosis and a non-SBP infection and all underwent similar treatment protocols with 20% albumin dosed at 1.5 g/kg on day 1 and 1.0 g/kg on day 3. All studies evaluated mortality in either the primary or secondary outcome, and none found significant differences in mortality between treatment and control groups. Each study also evaluated and found improvement in renal and/or circulatory function. Fernández et al. also found increased resolution of ACLF, fewer nosocomial infections, and reduction in some inflammatory markers. However, all studies had relatively small sample sizes that were underpowered to detect mortality differences. Furthermore, randomization did not lead to well-matched groups, with the treatment group patients in the Fernández study having higher rates of ACLF and kidney dysfunction.
The data suggest that albumin may be beneficial in improving renal and circulatory function. In select patients with ACLF and elevated serum creatinine, albumin treatment may be considered. There has been discussion about the use of albumin preferentially in patients with subdiaphragmatic bacterial infections, most related to increased risk of renal failure such as biliary and urinary tract infections.12 The authors of these studies also note that albumin may be more beneficial in patients with higher baseline creatinine. Caution is warranted for patients with impaired cardiac function or poor respiratory status given the possibility of pulmonary edema. Finally, the high cost of albumin in many medical centers is a major limitation of this treatment approach.
Application of data to our patient
Our patient has cirrhosis and is acutely presenting with pyelonephritis and acute kidney injury. He has no baseline pulmonary disease or oxygen requirement. His recent transthoracic echocardiogram is reviewed and he has no evidence of cardiac disease.
Because he has an elevated creatinine, an infectious process associated with progressive renal failure, and is not at an elevated baseline risk of developing pulmonary edema, albumin would be reasonable to administer at 1.5 g/kg on day 1 and 1.0 g/kg on day 3 of hospitalization.
Bottom line
In certain patients with cirrhosis and a non-SBP infection, the use of albumin to help improve renal and circulatory function is reasonable. There is no evidence that albumin will improve mortality and caution is warranted for patients at risk for pulmonary edema.
Dr. Rambachan is an academic hospital medicine fellow at the University of California, San Francisco.
References
1. Caironi P and Gattinoni L. The clinical use of albumin: the point of view of a specialist in intensive care. Blood Transfus. 2009;7(4):259-67. doi: 10.2450/2009.0002-09.
2. Paine CH et al. Albumin in cirrhosis: More than a colloid. Curr Treat Options Gastroenterol. 2019;17(2):231-43. doi: 10.1007/s11938-019-00227-4.
3. Walayat S et al. Role of albumin in cirrhosis: from a hospitalist’s perspective. J Community Hosp Intern Med Perspect. 2017;7(1):8-14. 2017 Mar 31. doi: 10.1080/20009666.2017.1302704.
4. Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline [for the] management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651-3. doi: 10.1002/hep.26359.
5. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis [published correction appears in J Hepatol. 2018 Nov;69(5):1207]. J Hepatol. 2018 Aug;69(2):406-60. doi: 10.1016/j.jhep.2018.03.024.
6. Guevara M et al. Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. J Hepatol. 2012 Oct;57(4):759-65. doi: 10.1016/j.jhep.2012.06.013.
7. Thévenot T et al. Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial. J Hepatol. 2015 Apr;62(4):822-30. doi: 10.1016/j.jhep.2014.11.017.
8. Fernández J et al. Efficacy of albumin treatment for patients with cirrhosis and infections unrelated to spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol. 2020 Apr;18(4):963-73.e14. doi: 10.1016/j.c gh.2019.07.055.
9. Di Pascoli M et al. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int. 2019 Jan;39(1):98-105. doi: 10.1111/liv.13968.
10. Caraceni P et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial [published correction appears in Lancet. 2018 Aug 4;392(10145):386]. Lancet. 2018 June;391(10138):2417-29. doi: 10.1016/S0140-6736(18)30840-7.
11. Fernández J et al. Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis. Gastroenterology. 2019 July;157(1):149-62. doi: 10.1053/j.gastro.2019.03.021.
12. Fasolato S et al. Renal failure and bacterial infections in patients with cirrhosis: Epidemiology and clinical features. Hepatology. 2007;45(1):223-9. doi: 10.1002/hep.21443.
Key points
- In patients with spontaneous bacterial peritonitis, hepatorenal syndrome, and for large volume paracentesis, albumin improves outcomes and is recommended by guidelines.
- In patients with cirrhosis and a non-SBP infection, there is some evidence that albumin may improve renal and circulatory function.
- Clinicians should be cautious about albumin use in patients at an elevated risk for development of pulmonary edema.
Quiz
Which of the following is not a guideline-recommended use of albumin for patients with cirrhosis?
A. Treatment of type 1 hepatorenal syndrome
B. Treatment of spontaneous bacterial peritonitis
C. To correct plasma albumin < 2.5 g/dL in nontransplant patients
D. Post large-volume paracentesis
The answer is C. Per the EASL and AASLD, A,B, and D are recommended. There is not strong evidence to support administering albumin to correct low plasma albumin.
Additional reading
- Bernardi M et al. Albumin in decompensated cirrhosis: new concepts and perspectives. Gut. 2020 June;69(6):1127-38. doi: 10.1136/gutjnl-2019-318843.
- Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline [for the] management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651-3. doi: 10.1002/hep.26359.
- Paine CH et al. Albumin in cirrhosis: More than a colloid. Curr Treat Options Gastroenterol. 2019 June;17(2):231-43. doi: 10.1007/s11938-019-00227-4.
Case
A 56 year-old male with hypertension, alcohol use disorder, stage II chronic kidney disease, and biopsy-proven cirrhosis presents with fever and chills, pyuria, flank pain, and an acute kidney injury concerning for pyelonephritis. Is there a benefit in treating with albumin in addition to guideline-based antibiotics?
Brief overview of the issue
Albumin is a negatively charged human protein produced by the liver. Albumin comprises 50% of plasma protein and over 75% of plasma oncotic pressure.1 It was first used at Walter Reed Hospital in 1940 and subsequently for burn injuries after the attack on Pearl Harbor in 1941.2
Albumin serves several important physiologic functions including maintaining oncotic pressure, endothelial support, antioxidation, nitrogen oxide scavenging, and buffering and transport of solutes and drugs, including antibiotics. In cirrhosis, albumin is diluted due to sodium and water retention. There is increased redistribution, decreased synthesis by the liver, and impaired albumin molecule binding.3
For patients with liver disease, per the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), albumin should be administered to prevent post paracentesis circulatory dysfunction after large volume paracentesis, to prevent renal failure and mortality in the setting of spontaneous bacterial peritonitis (SBP), and in the diagnosis and treatment of hepatorenal syndrome (HRS) type I to potentially improve mortality.4,5 Beyond these three guideline-based indications, other uses for albumin for patients with liver disease have been proposed, including treatment of hyponatremia, posttransplant fluid resuscitation, diuretic unresponsive ascites, and long-term management of cirrhosis. There has yet to be strong evidence supporting these additional indications. However, given the known benefits of albumin in patients with SBP, there has been recent research into treatment of non-SBP infections, including urinary tract infections.
Overview of the data
There have been three randomized controlled trials (RCTs) regarding albumin administration for the treatment of non-SBP infections for hospitalized patients with cirrhosis. All three trials randomized patients to a treatment arm of albumin and antibiotics versus a control group of antibiotics alone. The treatment protocol prescribed 20% albumin with 1.5 g/kg on day 1 and 1.0 g/kg on day 3. The most common infections studied were pneumonia and urinary tract infection. These RCTs found that albumin administration was associated with improved renal and/or circulatory function, but not with a reduction in mortality.
First, there was a single center RCT by Guevara et al. in 2012 of 110 patients with cirrhosis and infection based on SIRS criteria.6 The primary outcome was 90-day survival with secondary outcomes of renal failure development, renal function at days 3,7 and 14, and circulatory function measured by plasma renin, aldosterone, and norepinephrine. Renal function and circulatory function improved in the albumin group, but not mortality. In a multivariable regression analysis, albumin was statistically predictive of survival (hazard ratio of 0.294).
Second, there was a multicenter RCT by Thévenot et al. in 2015 of 193 patients.7 The primary outcome was 90-day renal failure and the secondary outcome was 90-day survival. Renal failure was chosen as the primary endpoint because of its association with survival in this patient population. The treatment group had delayed onset of renal failure, but no difference in the development of 90-day renal failure or 90-day mortality rate. Notably, eight patients (8.3%) in the albumin group developed pulmonary edema with two deaths. This led the oversight committee to prematurely terminate the study.
Third and most recently, there was a multicenter RCT by Fernández et al. in 2019 of 118 patients.8 The primary outcome was in-hospital mortality, with secondary outcomes of circulatory dysfunction measured by plasma renin concentration, systemic inflammation measured by plasma IL-6 and biomarkers, complications including acute-on-chronic liver failure (ACLF) and nosocomial bacterial infections, and 90-day mortality. Between the albumin and control group, there were no differences in in-hospital mortality (13.1% vs. 10.5%, P > .66), inflammation, circulatory dysfunction, or liver severity. However, a significantly higher proportion of patients in the albumin group had resolution of their ACLF (82.3% vs. 33.3%, P = .003) and a lower proportion developed nosocomial infections (6.6% vs. 24.6%, P = .007). A major weakness of this study was that patients in the albumin group had a higher combined rate of ACLF and kidney dysfunction (44.3% vs. 24.6%, P = .02).
Beyond these three randomized controlled trials, there was a study on the long-term administration of albumin for patients with cirrhosis and ascites. Patients who received twice weekly albumin infusions had a lower 2-year mortality rate and a reduction in the incidence of both SBP and non-SBP infections.9 Another long-term study of albumin administration found similar results with greater 18-month survival and fewer non-SBP infections.10 A trial looking at inflammation in patients without bacterial infections and in biobanked samples from cirrhotic patients with bacterial infections found that treatment with albumin reduced systemic inflammation.11
In summary, the three RCTs looked at comparable patients with cirrhosis and a non-SBP infection and all underwent similar treatment protocols with 20% albumin dosed at 1.5 g/kg on day 1 and 1.0 g/kg on day 3. All studies evaluated mortality in either the primary or secondary outcome, and none found significant differences in mortality between treatment and control groups. Each study also evaluated and found improvement in renal and/or circulatory function. Fernández et al. also found increased resolution of ACLF, fewer nosocomial infections, and reduction in some inflammatory markers. However, all studies had relatively small sample sizes that were underpowered to detect mortality differences. Furthermore, randomization did not lead to well-matched groups, with the treatment group patients in the Fernández study having higher rates of ACLF and kidney dysfunction.
The data suggest that albumin may be beneficial in improving renal and circulatory function. In select patients with ACLF and elevated serum creatinine, albumin treatment may be considered. There has been discussion about the use of albumin preferentially in patients with subdiaphragmatic bacterial infections, most related to increased risk of renal failure such as biliary and urinary tract infections.12 The authors of these studies also note that albumin may be more beneficial in patients with higher baseline creatinine. Caution is warranted for patients with impaired cardiac function or poor respiratory status given the possibility of pulmonary edema. Finally, the high cost of albumin in many medical centers is a major limitation of this treatment approach.
Application of data to our patient
Our patient has cirrhosis and is acutely presenting with pyelonephritis and acute kidney injury. He has no baseline pulmonary disease or oxygen requirement. His recent transthoracic echocardiogram is reviewed and he has no evidence of cardiac disease.
Because he has an elevated creatinine, an infectious process associated with progressive renal failure, and is not at an elevated baseline risk of developing pulmonary edema, albumin would be reasonable to administer at 1.5 g/kg on day 1 and 1.0 g/kg on day 3 of hospitalization.
Bottom line
In certain patients with cirrhosis and a non-SBP infection, the use of albumin to help improve renal and circulatory function is reasonable. There is no evidence that albumin will improve mortality and caution is warranted for patients at risk for pulmonary edema.
Dr. Rambachan is an academic hospital medicine fellow at the University of California, San Francisco.
References
1. Caironi P and Gattinoni L. The clinical use of albumin: the point of view of a specialist in intensive care. Blood Transfus. 2009;7(4):259-67. doi: 10.2450/2009.0002-09.
2. Paine CH et al. Albumin in cirrhosis: More than a colloid. Curr Treat Options Gastroenterol. 2019;17(2):231-43. doi: 10.1007/s11938-019-00227-4.
3. Walayat S et al. Role of albumin in cirrhosis: from a hospitalist’s perspective. J Community Hosp Intern Med Perspect. 2017;7(1):8-14. 2017 Mar 31. doi: 10.1080/20009666.2017.1302704.
4. Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline [for the] management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651-3. doi: 10.1002/hep.26359.
5. European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis [published correction appears in J Hepatol. 2018 Nov;69(5):1207]. J Hepatol. 2018 Aug;69(2):406-60. doi: 10.1016/j.jhep.2018.03.024.
6. Guevara M et al. Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study. J Hepatol. 2012 Oct;57(4):759-65. doi: 10.1016/j.jhep.2012.06.013.
7. Thévenot T et al. Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial. J Hepatol. 2015 Apr;62(4):822-30. doi: 10.1016/j.jhep.2014.11.017.
8. Fernández J et al. Efficacy of albumin treatment for patients with cirrhosis and infections unrelated to spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol. 2020 Apr;18(4):963-73.e14. doi: 10.1016/j.c gh.2019.07.055.
9. Di Pascoli M et al. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int. 2019 Jan;39(1):98-105. doi: 10.1111/liv.13968.
10. Caraceni P et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial [published correction appears in Lancet. 2018 Aug 4;392(10145):386]. Lancet. 2018 June;391(10138):2417-29. doi: 10.1016/S0140-6736(18)30840-7.
11. Fernández J et al. Effects of albumin treatment on systemic and portal hemodynamics and systemic inflammation in patients with decompensated cirrhosis. Gastroenterology. 2019 July;157(1):149-62. doi: 10.1053/j.gastro.2019.03.021.
12. Fasolato S et al. Renal failure and bacterial infections in patients with cirrhosis: Epidemiology and clinical features. Hepatology. 2007;45(1):223-9. doi: 10.1002/hep.21443.
Key points
- In patients with spontaneous bacterial peritonitis, hepatorenal syndrome, and for large volume paracentesis, albumin improves outcomes and is recommended by guidelines.
- In patients with cirrhosis and a non-SBP infection, there is some evidence that albumin may improve renal and circulatory function.
- Clinicians should be cautious about albumin use in patients at an elevated risk for development of pulmonary edema.
Quiz
Which of the following is not a guideline-recommended use of albumin for patients with cirrhosis?
A. Treatment of type 1 hepatorenal syndrome
B. Treatment of spontaneous bacterial peritonitis
C. To correct plasma albumin < 2.5 g/dL in nontransplant patients
D. Post large-volume paracentesis
The answer is C. Per the EASL and AASLD, A,B, and D are recommended. There is not strong evidence to support administering albumin to correct low plasma albumin.
Additional reading
- Bernardi M et al. Albumin in decompensated cirrhosis: new concepts and perspectives. Gut. 2020 June;69(6):1127-38. doi: 10.1136/gutjnl-2019-318843.
- Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases Practice Guideline [for the] management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013 Apr;57(4):1651-3. doi: 10.1002/hep.26359.
- Paine CH et al. Albumin in cirrhosis: More than a colloid. Curr Treat Options Gastroenterol. 2019 June;17(2):231-43. doi: 10.1007/s11938-019-00227-4.
