Hematology News

Belatedly, the disproportionate impact of COVID-19 on patients of color is getting attention. By now, we’ve read the headlines. Black people in the United States make up about 13% of the population but account for almost three times (34%) as many deaths. This story repeats – in other countries and in other minority communities.

Early detection is critical both to initiate supportive care and to isolate affected individuals and limit spread. Skin manifestations of COVID-19, especially those that occur early in the disease (eg, vesicular eruptions) or have prognostic significance (livedo, retiform purpura, necrosis), are critical to this goal of early recognition.

In this context, a recent systematic literature review looked at all articles describing skin manifestations associated with COVID-19. The investigators identified 46 articles published between March and May 2020 which included a total of 130 clinical images.

The following findings from this study are striking:

• 92% of the published images of COVID-associated skin manifestations were in I-III.
• Only 6% of COVID skin lesions included in the articles were in patients with skin type IV.
• None showed COVID skin lesions in skin types V or VI.
• Only six of the articles reported race and ethnicity demographics. In those, 91% of the patients were White and 9% were Hispanic.

These results reveal a critical lack of representative clinical images of COVID-associated skin manifestations in patients of color. This deficiency is made all the more egregious given the fact that patients of color, including those who are Black, Latinx, and Native American, have been especially hard hit by the COVID-19 pandemic and suffer disproportionate disease-related morbidity and mortality.
 

As the study authors point out, skin manifestations in people of color often differ significantly from findings in White skin (for example, look at the figure depicting the rash typical of Kawasaki disease in a dark-skinned child compared with a light-skinned child). It is not a stretch to suggest that skin manifestations associated with COVID-19 may look very different in darker skin.

These investigators have identified a damning lack of images of COVID-19–associated skin manifestations in patients with darker skin. This isn’t a new phenomenon. Almost half of dermatologists feel that they’ve had insufficient exposure to skin disease in darker skin types. Skin of color remains underrepresented in medical journals.

Like other forms of passive, institutional racism, this deficiency will only be improved if dermatologists and dermatology publications actively seek out COVID-associated skin manifestations in patients of color and prioritize sharing these images. A medical student in the United Kingdom has gotten the ball rolling, compiling a handbook of clinical signs in darker skin types as part of a student-staff partnership at St. George’s Hospital and the University of London. At this time, Mind the Gap is looking for a publisher.

Dr. Lipper is an assistant clinical professor at the University of Vermont, Burlington, and a staff physician in the department of dermatology at Danbury (Conn.) Hospital. He has disclosed no relevant financial relationships.
 

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

Belatedly, the disproportionate impact of COVID-19 on patients of color is getting attention. By now, we’ve read the headlines. Black people in the United States make up about 13% of the population but account for almost three times (34%) as many deaths. This story repeats – in other countries and in other minority communities.

Early detection is critical both to initiate supportive care and to isolate affected individuals and limit spread. Skin manifestations of COVID-19, especially those that occur early in the disease (eg, vesicular eruptions) or have prognostic significance (livedo, retiform purpura, necrosis), are critical to this goal of early recognition.

In this context, a recent systematic literature review looked at all articles describing skin manifestations associated with COVID-19. The investigators identified 46 articles published between March and May 2020 which included a total of 130 clinical images.

The following findings from this study are striking:

• 92% of the published images of COVID-associated skin manifestations were in I-III.
• Only 6% of COVID skin lesions included in the articles were in patients with skin type IV.
• None showed COVID skin lesions in skin types V or VI.
• Only six of the articles reported race and ethnicity demographics. In those, 91% of the patients were White and 9% were Hispanic.

These results reveal a critical lack of representative clinical images of COVID-associated skin manifestations in patients of color. This deficiency is made all the more egregious given the fact that patients of color, including those who are Black, Latinx, and Native American, have been especially hard hit by the COVID-19 pandemic and suffer disproportionate disease-related morbidity and mortality.
 

As the study authors point out, skin manifestations in people of color often differ significantly from findings in White skin (for example, look at the figure depicting the rash typical of Kawasaki disease in a dark-skinned child compared with a light-skinned child). It is not a stretch to suggest that skin manifestations associated with COVID-19 may look very different in darker skin.

These investigators have identified a damning lack of images of COVID-19–associated skin manifestations in patients with darker skin. This isn’t a new phenomenon. Almost half of dermatologists feel that they’ve had insufficient exposure to skin disease in darker skin types. Skin of color remains underrepresented in medical journals.

Like other forms of passive, institutional racism, this deficiency will only be improved if dermatologists and dermatology publications actively seek out COVID-associated skin manifestations in patients of color and prioritize sharing these images. A medical student in the United Kingdom has gotten the ball rolling, compiling a handbook of clinical signs in darker skin types as part of a student-staff partnership at St. George’s Hospital and the University of London. At this time, Mind the Gap is looking for a publisher.

Dr. Lipper is an assistant clinical professor at the University of Vermont, Burlington, and a staff physician in the department of dermatology at Danbury (Conn.) Hospital. He has disclosed no relevant financial relationships.
 

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

Belatedly, the disproportionate impact of COVID-19 on patients of color is getting attention. By now, we’ve read the headlines. Black people in the United States make up about 13% of the population but account for almost three times (34%) as many deaths. This story repeats – in other countries and in other minority communities.

Early detection is critical both to initiate supportive care and to isolate affected individuals and limit spread. Skin manifestations of COVID-19, especially those that occur early in the disease (eg, vesicular eruptions) or have prognostic significance (livedo, retiform purpura, necrosis), are critical to this goal of early recognition.

In this context, a recent systematic literature review looked at all articles describing skin manifestations associated with COVID-19. The investigators identified 46 articles published between March and May 2020 which included a total of 130 clinical images.

The following findings from this study are striking:

• 92% of the published images of COVID-associated skin manifestations were in I-III.
• Only 6% of COVID skin lesions included in the articles were in patients with skin type IV.
• None showed COVID skin lesions in skin types V or VI.
• Only six of the articles reported race and ethnicity demographics. In those, 91% of the patients were White and 9% were Hispanic.

These results reveal a critical lack of representative clinical images of COVID-associated skin manifestations in patients of color. This deficiency is made all the more egregious given the fact that patients of color, including those who are Black, Latinx, and Native American, have been especially hard hit by the COVID-19 pandemic and suffer disproportionate disease-related morbidity and mortality.
 

As the study authors point out, skin manifestations in people of color often differ significantly from findings in White skin (for example, look at the figure depicting the rash typical of Kawasaki disease in a dark-skinned child compared with a light-skinned child). It is not a stretch to suggest that skin manifestations associated with COVID-19 may look very different in darker skin.

These investigators have identified a damning lack of images of COVID-19–associated skin manifestations in patients with darker skin. This isn’t a new phenomenon. Almost half of dermatologists feel that they’ve had insufficient exposure to skin disease in darker skin types. Skin of color remains underrepresented in medical journals.

Like other forms of passive, institutional racism, this deficiency will only be improved if dermatologists and dermatology publications actively seek out COVID-associated skin manifestations in patients of color and prioritize sharing these images. A medical student in the United Kingdom has gotten the ball rolling, compiling a handbook of clinical signs in darker skin types as part of a student-staff partnership at St. George’s Hospital and the University of London. At this time, Mind the Gap is looking for a publisher.

Dr. Lipper is an assistant clinical professor at the University of Vermont, Burlington, and a staff physician in the department of dermatology at Danbury (Conn.) Hospital. He has disclosed no relevant financial relationships.
 

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

In the era of COVID-19, cancer treatment should not be discontinued or delayed if it can affect overall survival, according to new recommendations from an international team of experts.

Another important recommendation is to stop labeling all patients with cancer as being vulnerable to infection with the virus as it can lead to inappropriate care with potential negative outcomes.

“Although it was reasonable to adopt over-protective measures for our patients at the outbreak of a novel infective disease which was not previously observed in humans, we now need to step away from the assumption that all cancer patients are vulnerable to COVID-19,” said first author of the consensus article Giuseppe Curigliano, MD, PhD, of the European Institute of Oncology, Milan, Italy, in a statement. “The implications have been important because for some patients treatment was delayed or interrupted over the last few months, and I believe that we will see the impact of this over-precautionary approach in the...future.”

The recommendations were issued by the European Society of Medical Oncology (ESMO) to help guide physicians in “optimizing the pathway to cancer care” as well as to improve outcomes during the pandemic. The recommendations were published online July 31 in Annals of Oncology.

Studies have found that patients with cancer face a higher risk of serious complications and death if they develop COVID-19. Data from the COVID-19 and Cancer Consortium registry, for example, showed that patients with progressing cancer and COVID-19 infection had a fivefold increase in the risk of 30-day mortality compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer.

But while this may be true for some patients, Curigliano and colleagues emphasize that individuals with cancer are not a heterogeneous group and that the term “cancer” itself represents myriad different diseases. The European experts note that current evidence suggests many patients with solid tumors are not more vulnerable to serious complications than the general population.

Thus, cancer prognoses vary considerably, and addressing all patients with cancer as being “COVID-19-vulnerable is probably neither reasonable nor informative,” say the authors.

Dramatic changes were initiated in cancer management for all cancer types, nevertheless, and although these changes seemed reasonable in an acute pandemic situation, note the authors, they were made in the absence of strong supportive evidence. Attempts to define the individualized risk for a given patient, taking into account their primary tumor subtype, stage, age, and gender, have been limited.

“Based on current evidence, only patients who are elderly, with multiple comorbidities, and receiving chemotherapy are vulnerable to the infection,” explained Curigliano.

However, on a positive note, a recently published prospective cohort study looked at approximately 800 patients with cancer – who had symptomatic COVID-19 – in the United Kingdom. The analysis showed no association at all between the risk for death and receiving chemotherapy or immunotherapy, points out Medscape commentator David Kerr, MD, of the University of Oxford, UK, in a recent commentary.

Key recommendations

An international consortium was established by ESMO, and the interdisciplinary expert panel consisted of 64 experts and one voting patient advocate. They agreed on 28 statements that can be used to help with many of the current clinical and technical areas of uncertainty that range from diagnosis to treatment decisions.

The following are several of the key recommendations:

• Patients with cancer who face the highest risk of severe COVID-19 are characterized by active and progressive cancer, advanced age, poor performance status, smoking status, comorbidities, and possibly type of cancer.
• Telehealth and digital health can be excellent tools for some types of care such as primary care triage and counseling, but meeting in person may be more effective for situations that include delivery of key cancer-related information and for patients with complex cancer needs.
• Prior to hospital admission, patients with cancer should be tested for COVID-19, if feasible, and if they are considered at high risk, regardless of symptoms or chest radiological findings.
• Patients with cancer and COVID-19 have a higher risk of thromboembolic events, and prophylaxis using low molecular weight  or novel oral anticoagulants is recommended.
• Immune checkpoint inhibitors should not be withheld or delayed when there is a significant survival benefit, but use should be postponed in patients who test positive for COVID-19 until they recover.
• Use of high-dose steroids in patients with cancer infected with COVID-19 could potentially increase the risk of mortality, and a switch should be made to another immunosuppressant, if possible.
• The decision to use tyrosine kinase inhibitors (TKIs) of the PI3K/AKT/mTOR or RAS/RAF/MEK axis is complex, as they interfere with critical pathways involved in innate or adaptive immune responses. Stopping or withholding therapy depends on the risk-benefit balance, and the magnitude of benefit from the TKI needs to be considered.

The authors conclude that “ultimately, this set of statements will serve as a dynamic knowledge repository that will be better informed by accumulating data on SARS-CoV-2 biology, COVID-19 pandemic characteristics, on the risk of cancer patients for COVID-19 and its modulating factors, and finally, on optimal cancer care in the presence of the virus.”

No funding was reported for the current study. Several authors have disclosed relationships with industry, which are listed in the article.
 

This article first appeared on Medscape.com.

In the era of COVID-19, cancer treatment should not be discontinued or delayed if it can affect overall survival, according to new recommendations from an international team of experts.

Another important recommendation is to stop labeling all patients with cancer as being vulnerable to infection with the virus as it can lead to inappropriate care with potential negative outcomes.

“Although it was reasonable to adopt over-protective measures for our patients at the outbreak of a novel infective disease which was not previously observed in humans, we now need to step away from the assumption that all cancer patients are vulnerable to COVID-19,” said first author of the consensus article Giuseppe Curigliano, MD, PhD, of the European Institute of Oncology, Milan, Italy, in a statement. “The implications have been important because for some patients treatment was delayed or interrupted over the last few months, and I believe that we will see the impact of this over-precautionary approach in the...future.”

The recommendations were issued by the European Society of Medical Oncology (ESMO) to help guide physicians in “optimizing the pathway to cancer care” as well as to improve outcomes during the pandemic. The recommendations were published online July 31 in Annals of Oncology.

Studies have found that patients with cancer face a higher risk of serious complications and death if they develop COVID-19. Data from the COVID-19 and Cancer Consortium registry, for example, showed that patients with progressing cancer and COVID-19 infection had a fivefold increase in the risk of 30-day mortality compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer.

But while this may be true for some patients, Curigliano and colleagues emphasize that individuals with cancer are not a heterogeneous group and that the term “cancer” itself represents myriad different diseases. The European experts note that current evidence suggests many patients with solid tumors are not more vulnerable to serious complications than the general population.

Thus, cancer prognoses vary considerably, and addressing all patients with cancer as being “COVID-19-vulnerable is probably neither reasonable nor informative,” say the authors.

Dramatic changes were initiated in cancer management for all cancer types, nevertheless, and although these changes seemed reasonable in an acute pandemic situation, note the authors, they were made in the absence of strong supportive evidence. Attempts to define the individualized risk for a given patient, taking into account their primary tumor subtype, stage, age, and gender, have been limited.

“Based on current evidence, only patients who are elderly, with multiple comorbidities, and receiving chemotherapy are vulnerable to the infection,” explained Curigliano.

However, on a positive note, a recently published prospective cohort study looked at approximately 800 patients with cancer – who had symptomatic COVID-19 – in the United Kingdom. The analysis showed no association at all between the risk for death and receiving chemotherapy or immunotherapy, points out Medscape commentator David Kerr, MD, of the University of Oxford, UK, in a recent commentary.

Key recommendations

An international consortium was established by ESMO, and the interdisciplinary expert panel consisted of 64 experts and one voting patient advocate. They agreed on 28 statements that can be used to help with many of the current clinical and technical areas of uncertainty that range from diagnosis to treatment decisions.

The following are several of the key recommendations:

• Patients with cancer who face the highest risk of severe COVID-19 are characterized by active and progressive cancer, advanced age, poor performance status, smoking status, comorbidities, and possibly type of cancer.
• Telehealth and digital health can be excellent tools for some types of care such as primary care triage and counseling, but meeting in person may be more effective for situations that include delivery of key cancer-related information and for patients with complex cancer needs.
• Prior to hospital admission, patients with cancer should be tested for COVID-19, if feasible, and if they are considered at high risk, regardless of symptoms or chest radiological findings.
• Patients with cancer and COVID-19 have a higher risk of thromboembolic events, and prophylaxis using low molecular weight  or novel oral anticoagulants is recommended.
• Immune checkpoint inhibitors should not be withheld or delayed when there is a significant survival benefit, but use should be postponed in patients who test positive for COVID-19 until they recover.
• Use of high-dose steroids in patients with cancer infected with COVID-19 could potentially increase the risk of mortality, and a switch should be made to another immunosuppressant, if possible.
• The decision to use tyrosine kinase inhibitors (TKIs) of the PI3K/AKT/mTOR or RAS/RAF/MEK axis is complex, as they interfere with critical pathways involved in innate or adaptive immune responses. Stopping or withholding therapy depends on the risk-benefit balance, and the magnitude of benefit from the TKI needs to be considered.

The authors conclude that “ultimately, this set of statements will serve as a dynamic knowledge repository that will be better informed by accumulating data on SARS-CoV-2 biology, COVID-19 pandemic characteristics, on the risk of cancer patients for COVID-19 and its modulating factors, and finally, on optimal cancer care in the presence of the virus.”

No funding was reported for the current study. Several authors have disclosed relationships with industry, which are listed in the article.
 

This article first appeared on Medscape.com.

In the era of COVID-19, cancer treatment should not be discontinued or delayed if it can affect overall survival, according to new recommendations from an international team of experts.

Another important recommendation is to stop labeling all patients with cancer as being vulnerable to infection with the virus as it can lead to inappropriate care with potential negative outcomes.

“Although it was reasonable to adopt over-protective measures for our patients at the outbreak of a novel infective disease which was not previously observed in humans, we now need to step away from the assumption that all cancer patients are vulnerable to COVID-19,” said first author of the consensus article Giuseppe Curigliano, MD, PhD, of the European Institute of Oncology, Milan, Italy, in a statement. “The implications have been important because for some patients treatment was delayed or interrupted over the last few months, and I believe that we will see the impact of this over-precautionary approach in the...future.”

The recommendations were issued by the European Society of Medical Oncology (ESMO) to help guide physicians in “optimizing the pathway to cancer care” as well as to improve outcomes during the pandemic. The recommendations were published online July 31 in Annals of Oncology.

Studies have found that patients with cancer face a higher risk of serious complications and death if they develop COVID-19. Data from the COVID-19 and Cancer Consortium registry, for example, showed that patients with progressing cancer and COVID-19 infection had a fivefold increase in the risk of 30-day mortality compared with COVID-19–positive cancer patients who were in remission or had no evidence of cancer.

But while this may be true for some patients, Curigliano and colleagues emphasize that individuals with cancer are not a heterogeneous group and that the term “cancer” itself represents myriad different diseases. The European experts note that current evidence suggests many patients with solid tumors are not more vulnerable to serious complications than the general population.

Thus, cancer prognoses vary considerably, and addressing all patients with cancer as being “COVID-19-vulnerable is probably neither reasonable nor informative,” say the authors.

Dramatic changes were initiated in cancer management for all cancer types, nevertheless, and although these changes seemed reasonable in an acute pandemic situation, note the authors, they were made in the absence of strong supportive evidence. Attempts to define the individualized risk for a given patient, taking into account their primary tumor subtype, stage, age, and gender, have been limited.

“Based on current evidence, only patients who are elderly, with multiple comorbidities, and receiving chemotherapy are vulnerable to the infection,” explained Curigliano.

However, on a positive note, a recently published prospective cohort study looked at approximately 800 patients with cancer – who had symptomatic COVID-19 – in the United Kingdom. The analysis showed no association at all between the risk for death and receiving chemotherapy or immunotherapy, points out Medscape commentator David Kerr, MD, of the University of Oxford, UK, in a recent commentary.

Key recommendations

An international consortium was established by ESMO, and the interdisciplinary expert panel consisted of 64 experts and one voting patient advocate. They agreed on 28 statements that can be used to help with many of the current clinical and technical areas of uncertainty that range from diagnosis to treatment decisions.

The following are several of the key recommendations:

• Patients with cancer who face the highest risk of severe COVID-19 are characterized by active and progressive cancer, advanced age, poor performance status, smoking status, comorbidities, and possibly type of cancer.
• Telehealth and digital health can be excellent tools for some types of care such as primary care triage and counseling, but meeting in person may be more effective for situations that include delivery of key cancer-related information and for patients with complex cancer needs.
• Prior to hospital admission, patients with cancer should be tested for COVID-19, if feasible, and if they are considered at high risk, regardless of symptoms or chest radiological findings.
• Patients with cancer and COVID-19 have a higher risk of thromboembolic events, and prophylaxis using low molecular weight  or novel oral anticoagulants is recommended.
• Immune checkpoint inhibitors should not be withheld or delayed when there is a significant survival benefit, but use should be postponed in patients who test positive for COVID-19 until they recover.
• Use of high-dose steroids in patients with cancer infected with COVID-19 could potentially increase the risk of mortality, and a switch should be made to another immunosuppressant, if possible.
• The decision to use tyrosine kinase inhibitors (TKIs) of the PI3K/AKT/mTOR or RAS/RAF/MEK axis is complex, as they interfere with critical pathways involved in innate or adaptive immune responses. Stopping or withholding therapy depends on the risk-benefit balance, and the magnitude of benefit from the TKI needs to be considered.

The authors conclude that “ultimately, this set of statements will serve as a dynamic knowledge repository that will be better informed by accumulating data on SARS-CoV-2 biology, COVID-19 pandemic characteristics, on the risk of cancer patients for COVID-19 and its modulating factors, and finally, on optimal cancer care in the presence of the virus.”

No funding was reported for the current study. Several authors have disclosed relationships with industry, which are listed in the article.
 

This article first appeared on Medscape.com.

Evidence that the heart can take a major hit in patients hospitalized with COVID-19, especially those already with cardiovascular disease (CV) or its risk factors, has been sadly apparent from the pandemic’s earliest days.

Less clear from case studies and small series to date has been whether SARS-CoV-2 directly attacks the heart and whether acute cardiac effects of the illness may lead to some kind of lingering cardiomyopathy.

The field’s grasp of those issues advanced a bit in two new reports published July 27 in JAMA Cardiology that seem to validate concerns the virus can infect the myocardium, without necessarily causing myocarditis and the possibility that some “recovered” patients may be left with persisting myocardial injury and inflammation that potentially could later manifest as heart failure.

Persisting inflammation by cardiac magnetic resonance

A prospective cohort study with 100 patients recovered from a recent bout of the disease showed evidence of ventricular dysfunction, greater ventricular mass, and in 78% of the cohort, signs of myocardial inflammation by cardiac magnetic resonance (CMR) imaging. The CMR findings correlated with elevations in troponin T by high-sensitivity assay (hs-TnT).

Two-thirds of the cohort, whose acute COVID-19 severity had “ranged from asymptomatic to minor-to-moderate symptoms,” had recovered at home, whereas the remaining “severely unwell patients” had been hospitalized, wrote the authors, led by Valentina O. Püntmann, MD, PhD, University Hospital Frankfurt (Germany).

None of the patients had a history of heart failure or cardiomyopathy, although some had hypertension, diabetes, or evidence of coronary disease.

“Our findings demonstrate that participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup with regards to severity and extent,” the group noted.

“There is a considerable ongoing myocardial inflammation in the heart muscle weeks after recovery from COVID-19 illness. This finding is important because it may herald a considerable burden of heart failure in a few years down the line,” Dr. Püntmann said in an interview.

Early diagnosis would offer “a good chance that early treatment could reduce the relentless course of inflammatory damage or even halt it,” she said.

“The relatively clear onset of COVID-19 illness provides an opportunity, which we often do not have with other conditions, to take a proactive action and to look for heart involvement early, within a few weeks of recovery.”

The study’s CMR evidence of inflammation edema, scarring, and pericardial effusion are among “the major diagnostic criteria for inflammatory and viral myocarditis,” observed Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, Houston, who wasn’t part of either new study.

The findings suggest – consistent with previous evidence – that some patients with recent COVID-19 may be left with ongoing myocardial inflammation, and this study further adds that it could potentially become subacute or even chronic and in some may not be totally reversible, she said in an interview. How long the effects are likely to persist “remains to be determined. We need longer-term outcomes data.”

Viral presence without myocarditis

The accompanying report featured a postmortem analysis of hearts from 39 patients with mostly severe COVID-19 that pointed to a significant SARS-CoV-2 presence and signs that the virus vigorously replicated in the myocardium.

But there was no evidence that the infection led to fulminant myocarditis. Rather, the virus had apparently infiltrated the heart by localizing in interstitial cells or in macrophages that took up in the myocardium without actually entering myocytes, concluded the report’s authors, led by Diana Lindner, PhD, from the University Heart and Vascular Centre, Hamburg (Germany).

The findings suggest “that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis,” the group wrote.

Previously in the literature, in “cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology,” they concluded.

No evidence of the virus was seen in 15 cases, about 61% of the group. In 16 of the remaining 24 hearts, the viral load exceeded 1,000 copies per mcg of RNA, a substantial presence. Those 16 showed increased expression of inflammatory cytokines but no inflammatory cell infiltrates or changes in leukocyte counts, the researchers noted.

“Findings of suggested viral replication in the cases with a very high viral load are showing that we need to do more studies to find out long-term consequences, which we do not know right now,” senior author Dirk Westermann, MD, also from the University Heart and Vascular Centre, Hamburg, said.

Implications for heart failure

The postmortem findings from Dr. Lindner and associates “provide intriguing evidence that COVID-19 is associated with at least some component of myocardial injury, perhaps as the result of direct viral infection of the heart,” wrote Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, and Gregg C. Fonarow, MD, from the University of California, Los Angeles, in an editorial accompanying both reports.

The CMR study from Dr. Püntmann and colleagues – on the backdrop of earlier COVID-19 observations – suggests the potential for “residual left ventricular dysfunction and ongoing inflammation” in the months following a COVID-19 diagnosis. Both developments may be “of sufficient concern to represent a nidus for new-onset heart failure and other cardiovascular complications,” contend Dr. Yancy and Dr. Fonarow.

“When added to the postmortem pathological findings from Lindner et al, we see the plot thickening and we are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to COVID-19 may potentially evolve as the natural history of this infection becomes clearer,” they wrote.

Some patients, having recovered from the acute illness, may be left with a chronic inflammatory state that probably puts them at increased risk for future heart failure, agreed Dr. Bozkurt when interviewed. “They could show further decline in cardiac function, and their recovery might take longer than with the usual viral illnesses that we see,” she said.

“There could also be a risk of sudden death. Inflammation sometimes gives rise to sudden death and ventricular arrhythmia, which I would be very worried about, especially if the myocardium is stressed,” Dr. Bozkurt said. “So competitive sports in those patients potentially could be risky.”

COVID-19 cohort vs. matched control subjects

The CMR study from Dr. Püntmann and colleagues prospectively entered 100 patients recently recovered from an acute bout of COVID-19, either at home or at a hospital, who were followed in a registry based at University Hospital Frankfurt. Their median age was 49 years; 47% were female. They were compared with 50 age- and sex-matched control patients and 50 apparently healthy volunteers matched for risk factors, the group noted.

On the same day as the CMR assessment, the recently recovered patients, compared with the healthy control subjects and risk-factor matched control subjects, respectively, showed (P ≤ .001 in each case):

• A reduced left ventricular (LV) ejection fraction: 56% vs. 60% and 61%.
• A higher LV end-diastolic volume index: 86 mL/m² vs. 80 mL/m² and 75 mL/m^2.
• A greater LV mass index: 51 g/m² vs. 47 g/m² and 53 g/m^2.
• A higher hs-TnT level: 5.6 pg/mL vs. 3.2 pg/mL and 3.9 pg/mL.
• A greater prevalence of hs-TnT levels 3 pg/mL or more: 71% vs. 11% and 31%.

At CMR, 78% of the recovered COVID-19 patients showed abnormalities that included raised myocardial native T1 and T2 mapping, which is suggestive of fibrosis and edema from inflammation, compared with the two control groups (P < .001 for all differences), “independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis,” the group wrote. Native T1 and T2 mapping correlated significantly with hs-TnT.

“We now have the diagnostic means to detect cardiac inflammation early, and we need make every effort to apply them in every day practice,”Dr. Püntmann said in the interview.

“Using cardiac MRI will allow us to raise our game against COVID-19 and proactively develop efficient cardioprotective treatments,” she said. “Until we have effective means of protecting from the infection, that is vaccination, we must act swiftly and within the means at hand.”

The analysis evokes several other ways patients with COVID-19 might be screened for significant myocardial involvement.

“Strategies could include checking troponins, not only at admission but maybe at discharge and perhaps even those individuals who are at home and are not necessarily requiring care,” Dr. Bozkurt said.

“Biomarker profiling and screening for ongoing inflammation probably are going to be important components of COVID-19, especially for those with subclinical risk and disease.”

Dr. Westermann proposed that troponin elevations at discharge “might be a good starting point” for selecting COVID-19 patients for functional testing or imaging to screen for cardiac sequelae. Performing such tests routinely now “would be overwhelming given the massive increase in patients we still see today.”

Dr. Püntmann had no disclosures; statements of potential conflict for the other authors are in the report. Dr. Bozkurt has previously disclosed receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, and Respicardia; serving on a data safety monitoring board for LivaNova USA ; and having unspecified relationships with Abbott Laboratories. Dr. Lindner had no disclosures; Dr. Westermann reported receiving personal fees from AstraZeneca, Bayer, Novartis, and Medtronic. Dr. Yancy is a deputy editor and Dr. Fonarow a section editor for JAMA Cardiology. Dr. Yancy had no other disclosures. Dr. Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis.

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

Evidence that the heart can take a major hit in patients hospitalized with COVID-19, especially those already with cardiovascular disease (CV) or its risk factors, has been sadly apparent from the pandemic’s earliest days.

Less clear from case studies and small series to date has been whether SARS-CoV-2 directly attacks the heart and whether acute cardiac effects of the illness may lead to some kind of lingering cardiomyopathy.

The field’s grasp of those issues advanced a bit in two new reports published July 27 in JAMA Cardiology that seem to validate concerns the virus can infect the myocardium, without necessarily causing myocarditis and the possibility that some “recovered” patients may be left with persisting myocardial injury and inflammation that potentially could later manifest as heart failure.

Persisting inflammation by cardiac magnetic resonance

A prospective cohort study with 100 patients recovered from a recent bout of the disease showed evidence of ventricular dysfunction, greater ventricular mass, and in 78% of the cohort, signs of myocardial inflammation by cardiac magnetic resonance (CMR) imaging. The CMR findings correlated with elevations in troponin T by high-sensitivity assay (hs-TnT).

Two-thirds of the cohort, whose acute COVID-19 severity had “ranged from asymptomatic to minor-to-moderate symptoms,” had recovered at home, whereas the remaining “severely unwell patients” had been hospitalized, wrote the authors, led by Valentina O. Püntmann, MD, PhD, University Hospital Frankfurt (Germany).

None of the patients had a history of heart failure or cardiomyopathy, although some had hypertension, diabetes, or evidence of coronary disease.

“Our findings demonstrate that participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup with regards to severity and extent,” the group noted.

“There is a considerable ongoing myocardial inflammation in the heart muscle weeks after recovery from COVID-19 illness. This finding is important because it may herald a considerable burden of heart failure in a few years down the line,” Dr. Püntmann said in an interview.

Early diagnosis would offer “a good chance that early treatment could reduce the relentless course of inflammatory damage or even halt it,” she said.

“The relatively clear onset of COVID-19 illness provides an opportunity, which we often do not have with other conditions, to take a proactive action and to look for heart involvement early, within a few weeks of recovery.”

The study’s CMR evidence of inflammation edema, scarring, and pericardial effusion are among “the major diagnostic criteria for inflammatory and viral myocarditis,” observed Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, Houston, who wasn’t part of either new study.

The findings suggest – consistent with previous evidence – that some patients with recent COVID-19 may be left with ongoing myocardial inflammation, and this study further adds that it could potentially become subacute or even chronic and in some may not be totally reversible, she said in an interview. How long the effects are likely to persist “remains to be determined. We need longer-term outcomes data.”

Viral presence without myocarditis

The accompanying report featured a postmortem analysis of hearts from 39 patients with mostly severe COVID-19 that pointed to a significant SARS-CoV-2 presence and signs that the virus vigorously replicated in the myocardium.

But there was no evidence that the infection led to fulminant myocarditis. Rather, the virus had apparently infiltrated the heart by localizing in interstitial cells or in macrophages that took up in the myocardium without actually entering myocytes, concluded the report’s authors, led by Diana Lindner, PhD, from the University Heart and Vascular Centre, Hamburg (Germany).

The findings suggest “that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis,” the group wrote.

Previously in the literature, in “cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology,” they concluded.

No evidence of the virus was seen in 15 cases, about 61% of the group. In 16 of the remaining 24 hearts, the viral load exceeded 1,000 copies per mcg of RNA, a substantial presence. Those 16 showed increased expression of inflammatory cytokines but no inflammatory cell infiltrates or changes in leukocyte counts, the researchers noted.

“Findings of suggested viral replication in the cases with a very high viral load are showing that we need to do more studies to find out long-term consequences, which we do not know right now,” senior author Dirk Westermann, MD, also from the University Heart and Vascular Centre, Hamburg, said.

Implications for heart failure

The postmortem findings from Dr. Lindner and associates “provide intriguing evidence that COVID-19 is associated with at least some component of myocardial injury, perhaps as the result of direct viral infection of the heart,” wrote Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, and Gregg C. Fonarow, MD, from the University of California, Los Angeles, in an editorial accompanying both reports.

The CMR study from Dr. Püntmann and colleagues – on the backdrop of earlier COVID-19 observations – suggests the potential for “residual left ventricular dysfunction and ongoing inflammation” in the months following a COVID-19 diagnosis. Both developments may be “of sufficient concern to represent a nidus for new-onset heart failure and other cardiovascular complications,” contend Dr. Yancy and Dr. Fonarow.

“When added to the postmortem pathological findings from Lindner et al, we see the plot thickening and we are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to COVID-19 may potentially evolve as the natural history of this infection becomes clearer,” they wrote.

Some patients, having recovered from the acute illness, may be left with a chronic inflammatory state that probably puts them at increased risk for future heart failure, agreed Dr. Bozkurt when interviewed. “They could show further decline in cardiac function, and their recovery might take longer than with the usual viral illnesses that we see,” she said.

“There could also be a risk of sudden death. Inflammation sometimes gives rise to sudden death and ventricular arrhythmia, which I would be very worried about, especially if the myocardium is stressed,” Dr. Bozkurt said. “So competitive sports in those patients potentially could be risky.”

COVID-19 cohort vs. matched control subjects

The CMR study from Dr. Püntmann and colleagues prospectively entered 100 patients recently recovered from an acute bout of COVID-19, either at home or at a hospital, who were followed in a registry based at University Hospital Frankfurt. Their median age was 49 years; 47% were female. They were compared with 50 age- and sex-matched control patients and 50 apparently healthy volunteers matched for risk factors, the group noted.

On the same day as the CMR assessment, the recently recovered patients, compared with the healthy control subjects and risk-factor matched control subjects, respectively, showed (P ≤ .001 in each case):

• A reduced left ventricular (LV) ejection fraction: 56% vs. 60% and 61%.
• A higher LV end-diastolic volume index: 86 mL/m² vs. 80 mL/m² and 75 mL/m^2.
• A greater LV mass index: 51 g/m² vs. 47 g/m² and 53 g/m^2.
• A higher hs-TnT level: 5.6 pg/mL vs. 3.2 pg/mL and 3.9 pg/mL.
• A greater prevalence of hs-TnT levels 3 pg/mL or more: 71% vs. 11% and 31%.

At CMR, 78% of the recovered COVID-19 patients showed abnormalities that included raised myocardial native T1 and T2 mapping, which is suggestive of fibrosis and edema from inflammation, compared with the two control groups (P < .001 for all differences), “independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis,” the group wrote. Native T1 and T2 mapping correlated significantly with hs-TnT.

“We now have the diagnostic means to detect cardiac inflammation early, and we need make every effort to apply them in every day practice,”Dr. Püntmann said in the interview.

“Using cardiac MRI will allow us to raise our game against COVID-19 and proactively develop efficient cardioprotective treatments,” she said. “Until we have effective means of protecting from the infection, that is vaccination, we must act swiftly and within the means at hand.”

The analysis evokes several other ways patients with COVID-19 might be screened for significant myocardial involvement.

“Strategies could include checking troponins, not only at admission but maybe at discharge and perhaps even those individuals who are at home and are not necessarily requiring care,” Dr. Bozkurt said.

“Biomarker profiling and screening for ongoing inflammation probably are going to be important components of COVID-19, especially for those with subclinical risk and disease.”

Dr. Westermann proposed that troponin elevations at discharge “might be a good starting point” for selecting COVID-19 patients for functional testing or imaging to screen for cardiac sequelae. Performing such tests routinely now “would be overwhelming given the massive increase in patients we still see today.”

Dr. Püntmann had no disclosures; statements of potential conflict for the other authors are in the report. Dr. Bozkurt has previously disclosed receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, and Respicardia; serving on a data safety monitoring board for LivaNova USA ; and having unspecified relationships with Abbott Laboratories. Dr. Lindner had no disclosures; Dr. Westermann reported receiving personal fees from AstraZeneca, Bayer, Novartis, and Medtronic. Dr. Yancy is a deputy editor and Dr. Fonarow a section editor for JAMA Cardiology. Dr. Yancy had no other disclosures. Dr. Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis.

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

Evidence that the heart can take a major hit in patients hospitalized with COVID-19, especially those already with cardiovascular disease (CV) or its risk factors, has been sadly apparent from the pandemic’s earliest days.

Less clear from case studies and small series to date has been whether SARS-CoV-2 directly attacks the heart and whether acute cardiac effects of the illness may lead to some kind of lingering cardiomyopathy.

The field’s grasp of those issues advanced a bit in two new reports published July 27 in JAMA Cardiology that seem to validate concerns the virus can infect the myocardium, without necessarily causing myocarditis and the possibility that some “recovered” patients may be left with persisting myocardial injury and inflammation that potentially could later manifest as heart failure.

Persisting inflammation by cardiac magnetic resonance

A prospective cohort study with 100 patients recovered from a recent bout of the disease showed evidence of ventricular dysfunction, greater ventricular mass, and in 78% of the cohort, signs of myocardial inflammation by cardiac magnetic resonance (CMR) imaging. The CMR findings correlated with elevations in troponin T by high-sensitivity assay (hs-TnT).

Two-thirds of the cohort, whose acute COVID-19 severity had “ranged from asymptomatic to minor-to-moderate symptoms,” had recovered at home, whereas the remaining “severely unwell patients” had been hospitalized, wrote the authors, led by Valentina O. Püntmann, MD, PhD, University Hospital Frankfurt (Germany).

None of the patients had a history of heart failure or cardiomyopathy, although some had hypertension, diabetes, or evidence of coronary disease.

“Our findings demonstrate that participants with a relative paucity of preexisting cardiovascular condition and with mostly home-based recovery had frequent cardiac inflammatory involvement, which was similar to the hospitalized subgroup with regards to severity and extent,” the group noted.

“There is a considerable ongoing myocardial inflammation in the heart muscle weeks after recovery from COVID-19 illness. This finding is important because it may herald a considerable burden of heart failure in a few years down the line,” Dr. Püntmann said in an interview.

Early diagnosis would offer “a good chance that early treatment could reduce the relentless course of inflammatory damage or even halt it,” she said.

“The relatively clear onset of COVID-19 illness provides an opportunity, which we often do not have with other conditions, to take a proactive action and to look for heart involvement early, within a few weeks of recovery.”

The study’s CMR evidence of inflammation edema, scarring, and pericardial effusion are among “the major diagnostic criteria for inflammatory and viral myocarditis,” observed Biykem Bozkurt, MD, PhD, from Baylor College of Medicine, Houston, who wasn’t part of either new study.

The findings suggest – consistent with previous evidence – that some patients with recent COVID-19 may be left with ongoing myocardial inflammation, and this study further adds that it could potentially become subacute or even chronic and in some may not be totally reversible, she said in an interview. How long the effects are likely to persist “remains to be determined. We need longer-term outcomes data.”

Viral presence without myocarditis

The accompanying report featured a postmortem analysis of hearts from 39 patients with mostly severe COVID-19 that pointed to a significant SARS-CoV-2 presence and signs that the virus vigorously replicated in the myocardium.

But there was no evidence that the infection led to fulminant myocarditis. Rather, the virus had apparently infiltrated the heart by localizing in interstitial cells or in macrophages that took up in the myocardium without actually entering myocytes, concluded the report’s authors, led by Diana Lindner, PhD, from the University Heart and Vascular Centre, Hamburg (Germany).

The findings suggest “that the presence of SARS-CoV-2 in cardiac tissue does not necessarily cause an inflammatory reaction consistent with clinical myocarditis,” the group wrote.

Previously in the literature, in “cases in which myocardial inflammation was present, there was also evidence of clinical myocarditis, and therefore the current cases underlie a different pathophysiology,” they concluded.

No evidence of the virus was seen in 15 cases, about 61% of the group. In 16 of the remaining 24 hearts, the viral load exceeded 1,000 copies per mcg of RNA, a substantial presence. Those 16 showed increased expression of inflammatory cytokines but no inflammatory cell infiltrates or changes in leukocyte counts, the researchers noted.

“Findings of suggested viral replication in the cases with a very high viral load are showing that we need to do more studies to find out long-term consequences, which we do not know right now,” senior author Dirk Westermann, MD, also from the University Heart and Vascular Centre, Hamburg, said.

Implications for heart failure

The postmortem findings from Dr. Lindner and associates “provide intriguing evidence that COVID-19 is associated with at least some component of myocardial injury, perhaps as the result of direct viral infection of the heart,” wrote Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, and Gregg C. Fonarow, MD, from the University of California, Los Angeles, in an editorial accompanying both reports.

The CMR study from Dr. Püntmann and colleagues – on the backdrop of earlier COVID-19 observations – suggests the potential for “residual left ventricular dysfunction and ongoing inflammation” in the months following a COVID-19 diagnosis. Both developments may be “of sufficient concern to represent a nidus for new-onset heart failure and other cardiovascular complications,” contend Dr. Yancy and Dr. Fonarow.

“When added to the postmortem pathological findings from Lindner et al, we see the plot thickening and we are inclined to raise a new and very evident concern that cardiomyopathy and heart failure related to COVID-19 may potentially evolve as the natural history of this infection becomes clearer,” they wrote.

Some patients, having recovered from the acute illness, may be left with a chronic inflammatory state that probably puts them at increased risk for future heart failure, agreed Dr. Bozkurt when interviewed. “They could show further decline in cardiac function, and their recovery might take longer than with the usual viral illnesses that we see,” she said.

“There could also be a risk of sudden death. Inflammation sometimes gives rise to sudden death and ventricular arrhythmia, which I would be very worried about, especially if the myocardium is stressed,” Dr. Bozkurt said. “So competitive sports in those patients potentially could be risky.”

COVID-19 cohort vs. matched control subjects

The CMR study from Dr. Püntmann and colleagues prospectively entered 100 patients recently recovered from an acute bout of COVID-19, either at home or at a hospital, who were followed in a registry based at University Hospital Frankfurt. Their median age was 49 years; 47% were female. They were compared with 50 age- and sex-matched control patients and 50 apparently healthy volunteers matched for risk factors, the group noted.

On the same day as the CMR assessment, the recently recovered patients, compared with the healthy control subjects and risk-factor matched control subjects, respectively, showed (P ≤ .001 in each case):

• A reduced left ventricular (LV) ejection fraction: 56% vs. 60% and 61%.
• A higher LV end-diastolic volume index: 86 mL/m² vs. 80 mL/m² and 75 mL/m^2.
• A greater LV mass index: 51 g/m² vs. 47 g/m² and 53 g/m^2.
• A higher hs-TnT level: 5.6 pg/mL vs. 3.2 pg/mL and 3.9 pg/mL.
• A greater prevalence of hs-TnT levels 3 pg/mL or more: 71% vs. 11% and 31%.

At CMR, 78% of the recovered COVID-19 patients showed abnormalities that included raised myocardial native T1 and T2 mapping, which is suggestive of fibrosis and edema from inflammation, compared with the two control groups (P < .001 for all differences), “independent of preexisting conditions, severity and overall course of the acute illness, and the time from the original diagnosis,” the group wrote. Native T1 and T2 mapping correlated significantly with hs-TnT.

“We now have the diagnostic means to detect cardiac inflammation early, and we need make every effort to apply them in every day practice,”Dr. Püntmann said in the interview.

“Using cardiac MRI will allow us to raise our game against COVID-19 and proactively develop efficient cardioprotective treatments,” she said. “Until we have effective means of protecting from the infection, that is vaccination, we must act swiftly and within the means at hand.”

The analysis evokes several other ways patients with COVID-19 might be screened for significant myocardial involvement.

“Strategies could include checking troponins, not only at admission but maybe at discharge and perhaps even those individuals who are at home and are not necessarily requiring care,” Dr. Bozkurt said.

“Biomarker profiling and screening for ongoing inflammation probably are going to be important components of COVID-19, especially for those with subclinical risk and disease.”

Dr. Westermann proposed that troponin elevations at discharge “might be a good starting point” for selecting COVID-19 patients for functional testing or imaging to screen for cardiac sequelae. Performing such tests routinely now “would be overwhelming given the massive increase in patients we still see today.”

Dr. Püntmann had no disclosures; statements of potential conflict for the other authors are in the report. Dr. Bozkurt has previously disclosed receiving consultant fees or honoraria from Bayer Healthcare, Bristol-Myers Squibb, Lantheus Medical Imaging, and Respicardia; serving on a data safety monitoring board for LivaNova USA ; and having unspecified relationships with Abbott Laboratories. Dr. Lindner had no disclosures; Dr. Westermann reported receiving personal fees from AstraZeneca, Bayer, Novartis, and Medtronic. Dr. Yancy is a deputy editor and Dr. Fonarow a section editor for JAMA Cardiology. Dr. Yancy had no other disclosures. Dr. Fonarow reported receiving personal fees from Abbott Laboratories, Amgen, AstraZeneca, Bayer, CHF Solutions, Edwards Lifesciences, Janssen, Medtronic, Merck, and Novartis.

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

An erythematous rash was the most common cutaneous manifestation in patients with COVID-19, followed by chilblain-like lesions and urticaria-like lesions in a systematic review of mostly European studies.

Qing Zhao, MD, Xiaokai Fang, MD, and their colleagues at the Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, in Jinan, China, reported the results of a literature review of 44 articles published through May 2020 that included 507 patients with cutaneous manifestations of COVID-19. The review was published in the Journal of The European Academy of Dermatology and Venereology.

Nearly all of the patients (96%) were from Europe, and more than half were women (60%), with an average age of 49 years. Most patients had multiple skin symptoms, with the most common being erythema (44%), chilblain-like lesions (20%), urticaria-like lesions (16%), vesicular manifestations (13%), livedo/necrosis (6%), and petechiae (almost 2%). The authors described erythema as being present in specific sites, such as the trunk, extremities, flexural regions, face, and mucous membranes. Slightly less than half of all patients had significant pruritus.

Data on systemic COVID-19 symptoms were available for 431 patients and included fever in about two-thirds of patients and cough in almost 70%, with dyspnea in almost half of patients. Almost 60% had fatigue, and almost 60% had asthenia. Information about the onset of skin symptoms was available in 88 patients; of these patients, lesions were seen an average of almost 10 days after systemic symptoms appeared and, in almost 15%, were the first symptoms noted.

Histopathologic exams were done for only 23 patients and, in all cases, showed “inflammatory features without specific pathological changes, such as lymphocyte infiltration.” In one study, reverse transcription polymerase chain reaction testing of skin biopsy specimens tested negative for SARS-CoV-2.

Expression of ACE2, the receptor of SARS-CoV-2, in the skin was evaluated in six of the studies. “Higher ACE2 expression was identified in keratinocytes, mainly in differentiating keratinocytes and basal cells compared to the other cells of skin tissues,” the authors wrote. These results were confirmed with immunohistochemistry, which, they said, found “ACE2-positive keratinocytes in the stratum basal, the stratum spinosum, and the stratum granulosum of epiderma.” They added that this provides evidence “for percutaneous infection or the entry of virus into patients through skin tissues,” but cautioned that more research is needed.

The authors acknowledged that there are still many unanswered questions about COVID-19, and that more clinical data and research are needed, to improve the understanding of the cutaneous manifestations associated with COVID-19.

Pathogenesis of different cutaneous manifestations may be different, Dr. Femia said. For example, urticaria and morbilliform eruption were described by the authors of the review as more benign eruptions, but pathogenesis may differ from that of so-called COVID toes and from the pathogenesis of purpura and ulcerations seen in patients with more severe disease, she noted. It is plausible, she added, that purpura and ulcerations may be a “direct invasion of SARS-CoV-2 into endothelial cells,” which creates secondary processes “that ultimately destroy the skin.”

Urticaria and morbilliform eruptions, on the other hand, “are more simply that the immune system is recognizing COVID, and in doing so, is also recognizing some antigens in the skin and creating a hypersensitive response to the skin” and has “nothing to do with the SARS-CoV-2 virus actually being in that location,” she said.

It is important to differentiate between patients who have skin manifestations attributed to COVID-19 and those with manifestations independent of COVID-19, which is difficult, Dr. Femia noted. A patient with COVID-19 and a cutaneous manifestation may be having a reaction to a medication. “It’s important to have a critical eye and to remember that, when we see these manifestations, we should always be investigating whether there was an alternative cause so that we can better learn what exactly we should be attributing to this infection,” she said

Adam Friedman, MD, professor and interim chair of dermatology at George Washington University, Washington, said the authors of the review had presented interesting work, but made some “assumptions that need to be proven.” Dr. Friedman also was not involved in the research, but agreed in an interview with the assessment that it is unlikely SARS-CoV-2 would penetrate the skin. While some viruses – such as the poxvirus that causes molluscum contagiosum and the herpes simplex virus – invade keratinocytes specifically, there is a particular clinical phenotype that results that is associated with changes in the epidermis. However, “the skin manifestations of COVID-19 do not fit with direct skin invasion, [but] rather the immune response to systemic disease,” he said.

“[I]n terms of systemic invasion through the skin, it is possible, but this study certainly doesn’t show that. The presence/expression of ACE2 in the epidermis doesn’t translate to route of infection,” Dr. Friedman said..

The study received financial support from Shandong First Medical University, the Innovation Project of Shandong Academy of Medical Sciences and the Shandong Province Taishan Scholar Project. The authors report no relevant financial disclosures. Dr. Femia and Dr. Friedman had no relevant financial disclosures.

SOURCE: Zhao Q et al. J Eur Acad Dermatol Venereol. 2020 Jun 28. doi: 10.1111/jdv.16778.

An erythematous rash was the most common cutaneous manifestation in patients with COVID-19, followed by chilblain-like lesions and urticaria-like lesions in a systematic review of mostly European studies.

Qing Zhao, MD, Xiaokai Fang, MD, and their colleagues at the Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, in Jinan, China, reported the results of a literature review of 44 articles published through May 2020 that included 507 patients with cutaneous manifestations of COVID-19. The review was published in the Journal of The European Academy of Dermatology and Venereology.

Nearly all of the patients (96%) were from Europe, and more than half were women (60%), with an average age of 49 years. Most patients had multiple skin symptoms, with the most common being erythema (44%), chilblain-like lesions (20%), urticaria-like lesions (16%), vesicular manifestations (13%), livedo/necrosis (6%), and petechiae (almost 2%). The authors described erythema as being present in specific sites, such as the trunk, extremities, flexural regions, face, and mucous membranes. Slightly less than half of all patients had significant pruritus.

Data on systemic COVID-19 symptoms were available for 431 patients and included fever in about two-thirds of patients and cough in almost 70%, with dyspnea in almost half of patients. Almost 60% had fatigue, and almost 60% had asthenia. Information about the onset of skin symptoms was available in 88 patients; of these patients, lesions were seen an average of almost 10 days after systemic symptoms appeared and, in almost 15%, were the first symptoms noted.

Histopathologic exams were done for only 23 patients and, in all cases, showed “inflammatory features without specific pathological changes, such as lymphocyte infiltration.” In one study, reverse transcription polymerase chain reaction testing of skin biopsy specimens tested negative for SARS-CoV-2.

Expression of ACE2, the receptor of SARS-CoV-2, in the skin was evaluated in six of the studies. “Higher ACE2 expression was identified in keratinocytes, mainly in differentiating keratinocytes and basal cells compared to the other cells of skin tissues,” the authors wrote. These results were confirmed with immunohistochemistry, which, they said, found “ACE2-positive keratinocytes in the stratum basal, the stratum spinosum, and the stratum granulosum of epiderma.” They added that this provides evidence “for percutaneous infection or the entry of virus into patients through skin tissues,” but cautioned that more research is needed.

The authors acknowledged that there are still many unanswered questions about COVID-19, and that more clinical data and research are needed, to improve the understanding of the cutaneous manifestations associated with COVID-19.

Pathogenesis of different cutaneous manifestations may be different, Dr. Femia said. For example, urticaria and morbilliform eruption were described by the authors of the review as more benign eruptions, but pathogenesis may differ from that of so-called COVID toes and from the pathogenesis of purpura and ulcerations seen in patients with more severe disease, she noted. It is plausible, she added, that purpura and ulcerations may be a “direct invasion of SARS-CoV-2 into endothelial cells,” which creates secondary processes “that ultimately destroy the skin.”

Urticaria and morbilliform eruptions, on the other hand, “are more simply that the immune system is recognizing COVID, and in doing so, is also recognizing some antigens in the skin and creating a hypersensitive response to the skin” and has “nothing to do with the SARS-CoV-2 virus actually being in that location,” she said.

It is important to differentiate between patients who have skin manifestations attributed to COVID-19 and those with manifestations independent of COVID-19, which is difficult, Dr. Femia noted. A patient with COVID-19 and a cutaneous manifestation may be having a reaction to a medication. “It’s important to have a critical eye and to remember that, when we see these manifestations, we should always be investigating whether there was an alternative cause so that we can better learn what exactly we should be attributing to this infection,” she said

Adam Friedman, MD, professor and interim chair of dermatology at George Washington University, Washington, said the authors of the review had presented interesting work, but made some “assumptions that need to be proven.” Dr. Friedman also was not involved in the research, but agreed in an interview with the assessment that it is unlikely SARS-CoV-2 would penetrate the skin. While some viruses – such as the poxvirus that causes molluscum contagiosum and the herpes simplex virus – invade keratinocytes specifically, there is a particular clinical phenotype that results that is associated with changes in the epidermis. However, “the skin manifestations of COVID-19 do not fit with direct skin invasion, [but] rather the immune response to systemic disease,” he said.

“[I]n terms of systemic invasion through the skin, it is possible, but this study certainly doesn’t show that. The presence/expression of ACE2 in the epidermis doesn’t translate to route of infection,” Dr. Friedman said..

The study received financial support from Shandong First Medical University, the Innovation Project of Shandong Academy of Medical Sciences and the Shandong Province Taishan Scholar Project. The authors report no relevant financial disclosures. Dr. Femia and Dr. Friedman had no relevant financial disclosures.

SOURCE: Zhao Q et al. J Eur Acad Dermatol Venereol. 2020 Jun 28. doi: 10.1111/jdv.16778.

An erythematous rash was the most common cutaneous manifestation in patients with COVID-19, followed by chilblain-like lesions and urticaria-like lesions in a systematic review of mostly European studies.

Qing Zhao, MD, Xiaokai Fang, MD, and their colleagues at the Shandong Provincial Hospital for Skin Diseases & Shandong Provincial Institute of Dermatology and Venereology, in Jinan, China, reported the results of a literature review of 44 articles published through May 2020 that included 507 patients with cutaneous manifestations of COVID-19. The review was published in the Journal of The European Academy of Dermatology and Venereology.

Nearly all of the patients (96%) were from Europe, and more than half were women (60%), with an average age of 49 years. Most patients had multiple skin symptoms, with the most common being erythema (44%), chilblain-like lesions (20%), urticaria-like lesions (16%), vesicular manifestations (13%), livedo/necrosis (6%), and petechiae (almost 2%). The authors described erythema as being present in specific sites, such as the trunk, extremities, flexural regions, face, and mucous membranes. Slightly less than half of all patients had significant pruritus.

Data on systemic COVID-19 symptoms were available for 431 patients and included fever in about two-thirds of patients and cough in almost 70%, with dyspnea in almost half of patients. Almost 60% had fatigue, and almost 60% had asthenia. Information about the onset of skin symptoms was available in 88 patients; of these patients, lesions were seen an average of almost 10 days after systemic symptoms appeared and, in almost 15%, were the first symptoms noted.

Histopathologic exams were done for only 23 patients and, in all cases, showed “inflammatory features without specific pathological changes, such as lymphocyte infiltration.” In one study, reverse transcription polymerase chain reaction testing of skin biopsy specimens tested negative for SARS-CoV-2.

Expression of ACE2, the receptor of SARS-CoV-2, in the skin was evaluated in six of the studies. “Higher ACE2 expression was identified in keratinocytes, mainly in differentiating keratinocytes and basal cells compared to the other cells of skin tissues,” the authors wrote. These results were confirmed with immunohistochemistry, which, they said, found “ACE2-positive keratinocytes in the stratum basal, the stratum spinosum, and the stratum granulosum of epiderma.” They added that this provides evidence “for percutaneous infection or the entry of virus into patients through skin tissues,” but cautioned that more research is needed.

The authors acknowledged that there are still many unanswered questions about COVID-19, and that more clinical data and research are needed, to improve the understanding of the cutaneous manifestations associated with COVID-19.

Pathogenesis of different cutaneous manifestations may be different, Dr. Femia said. For example, urticaria and morbilliform eruption were described by the authors of the review as more benign eruptions, but pathogenesis may differ from that of so-called COVID toes and from the pathogenesis of purpura and ulcerations seen in patients with more severe disease, she noted. It is plausible, she added, that purpura and ulcerations may be a “direct invasion of SARS-CoV-2 into endothelial cells,” which creates secondary processes “that ultimately destroy the skin.”

Urticaria and morbilliform eruptions, on the other hand, “are more simply that the immune system is recognizing COVID, and in doing so, is also recognizing some antigens in the skin and creating a hypersensitive response to the skin” and has “nothing to do with the SARS-CoV-2 virus actually being in that location,” she said.

It is important to differentiate between patients who have skin manifestations attributed to COVID-19 and those with manifestations independent of COVID-19, which is difficult, Dr. Femia noted. A patient with COVID-19 and a cutaneous manifestation may be having a reaction to a medication. “It’s important to have a critical eye and to remember that, when we see these manifestations, we should always be investigating whether there was an alternative cause so that we can better learn what exactly we should be attributing to this infection,” she said

Adam Friedman, MD, professor and interim chair of dermatology at George Washington University, Washington, said the authors of the review had presented interesting work, but made some “assumptions that need to be proven.” Dr. Friedman also was not involved in the research, but agreed in an interview with the assessment that it is unlikely SARS-CoV-2 would penetrate the skin. While some viruses – such as the poxvirus that causes molluscum contagiosum and the herpes simplex virus – invade keratinocytes specifically, there is a particular clinical phenotype that results that is associated with changes in the epidermis. However, “the skin manifestations of COVID-19 do not fit with direct skin invasion, [but] rather the immune response to systemic disease,” he said.

“[I]n terms of systemic invasion through the skin, it is possible, but this study certainly doesn’t show that. The presence/expression of ACE2 in the epidermis doesn’t translate to route of infection,” Dr. Friedman said..

The study received financial support from Shandong First Medical University, the Innovation Project of Shandong Academy of Medical Sciences and the Shandong Province Taishan Scholar Project. The authors report no relevant financial disclosures. Dr. Femia and Dr. Friedman had no relevant financial disclosures.

SOURCE: Zhao Q et al. J Eur Acad Dermatol Venereol. 2020 Jun 28. doi: 10.1111/jdv.16778.

When the pandemic was just emerging from its infancy and we were just beginning to think about social distancing, I was sitting around enjoying an adult beverage and some gluten free (not my choice) snacks with some friends. A retired nurse who had just celebrated her 80th birthday said, “I can’t wait until they’ve developed a vaccine.” A former electrical engineer sitting just short of 2 meters to her left responded, “Don’t save me a place near the front of the line for something that is being developed in a program called Warp Speed.”

Micah Young/istockphoto.com

How do you feel about the potential SARS-CoV-2 vaccine? Are you going to roll up your sleeve as soon as the vaccine becomes available in your community? What are you going to suggest to your patients, your children? I suspect many of you will answer, “It depends.” What factors will you be considering when you try to decide between what is likely to be several competing SARS-CoV-2 vaccines?

Will it make any difference to you which biochemical-immune-bending strategy is being used to make the vaccine? All of them will probably be the result of a clever sounding but novel technique, all of them with a track record that is measured in months and not years. Will you be swayed by how large the trials were? Or how long the follow-up lasted? How effective must the vaccine be to convince you that it is worth receiving or recommending? Do you have the tools and experience to make a decision like that? I know I don’t. And should you and I even be put in a position to make that decision?

In the past, you and I may have relied on the Centers for Disease Control and Prevention for advice. But given the somewhat murky and stormy relationship between the CDC and the president, the vaccine recommendation may be issued by the White House and not the CDC.

For those of us who were practicing medicine during the Swine Flu fiasco of 1976, the pace and the politics surrounding the development of a SARS-CoV-2 vaccine has a discomforting déjà vu quality about it. The fact that like this year 1976 was an election year that infused the development process with a sense of urgency above and beyond any of the concerns about the pandemic that never happened. Although causality was never proven, there was a surge in Guillain-Barré syndrome cases that had been linked temporally to the vaccine.

Of course, our pandemic is real, and it would be imprudent to wait a year or more to watch for long-term vaccine sequelae. However, I am more than a little concerned that fast tracking the development process may result in unfortunate consequences in the short term that could have been avoided with a more measured approach to trialing the vaccines.

The sad reality is that as a nation we tend to be impatient. We are drawn to quick fixes that come in a vial or a capsule. We are learning that simple measures like mask wearing and social distancing can make a difference in slowing the spread of the virus. It would be tragic to rush a vaccine into production that at best turns out to simply be an expensive alternative to the measures that we know work or at worst injures more of us than it saves.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

When the pandemic was just emerging from its infancy and we were just beginning to think about social distancing, I was sitting around enjoying an adult beverage and some gluten free (not my choice) snacks with some friends. A retired nurse who had just celebrated her 80th birthday said, “I can’t wait until they’ve developed a vaccine.” A former electrical engineer sitting just short of 2 meters to her left responded, “Don’t save me a place near the front of the line for something that is being developed in a program called Warp Speed.”

Micah Young/istockphoto.com

How do you feel about the potential SARS-CoV-2 vaccine? Are you going to roll up your sleeve as soon as the vaccine becomes available in your community? What are you going to suggest to your patients, your children? I suspect many of you will answer, “It depends.” What factors will you be considering when you try to decide between what is likely to be several competing SARS-CoV-2 vaccines?

Will it make any difference to you which biochemical-immune-bending strategy is being used to make the vaccine? All of them will probably be the result of a clever sounding but novel technique, all of them with a track record that is measured in months and not years. Will you be swayed by how large the trials were? Or how long the follow-up lasted? How effective must the vaccine be to convince you that it is worth receiving or recommending? Do you have the tools and experience to make a decision like that? I know I don’t. And should you and I even be put in a position to make that decision?

In the past, you and I may have relied on the Centers for Disease Control and Prevention for advice. But given the somewhat murky and stormy relationship between the CDC and the president, the vaccine recommendation may be issued by the White House and not the CDC.

For those of us who were practicing medicine during the Swine Flu fiasco of 1976, the pace and the politics surrounding the development of a SARS-CoV-2 vaccine has a discomforting déjà vu quality about it. The fact that like this year 1976 was an election year that infused the development process with a sense of urgency above and beyond any of the concerns about the pandemic that never happened. Although causality was never proven, there was a surge in Guillain-Barré syndrome cases that had been linked temporally to the vaccine.

Of course, our pandemic is real, and it would be imprudent to wait a year or more to watch for long-term vaccine sequelae. However, I am more than a little concerned that fast tracking the development process may result in unfortunate consequences in the short term that could have been avoided with a more measured approach to trialing the vaccines.

The sad reality is that as a nation we tend to be impatient. We are drawn to quick fixes that come in a vial or a capsule. We are learning that simple measures like mask wearing and social distancing can make a difference in slowing the spread of the virus. It would be tragic to rush a vaccine into production that at best turns out to simply be an expensive alternative to the measures that we know work or at worst injures more of us than it saves.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

When the pandemic was just emerging from its infancy and we were just beginning to think about social distancing, I was sitting around enjoying an adult beverage and some gluten free (not my choice) snacks with some friends. A retired nurse who had just celebrated her 80th birthday said, “I can’t wait until they’ve developed a vaccine.” A former electrical engineer sitting just short of 2 meters to her left responded, “Don’t save me a place near the front of the line for something that is being developed in a program called Warp Speed.”

Micah Young/istockphoto.com

How do you feel about the potential SARS-CoV-2 vaccine? Are you going to roll up your sleeve as soon as the vaccine becomes available in your community? What are you going to suggest to your patients, your children? I suspect many of you will answer, “It depends.” What factors will you be considering when you try to decide between what is likely to be several competing SARS-CoV-2 vaccines?

Will it make any difference to you which biochemical-immune-bending strategy is being used to make the vaccine? All of them will probably be the result of a clever sounding but novel technique, all of them with a track record that is measured in months and not years. Will you be swayed by how large the trials were? Or how long the follow-up lasted? How effective must the vaccine be to convince you that it is worth receiving or recommending? Do you have the tools and experience to make a decision like that? I know I don’t. And should you and I even be put in a position to make that decision?

In the past, you and I may have relied on the Centers for Disease Control and Prevention for advice. But given the somewhat murky and stormy relationship between the CDC and the president, the vaccine recommendation may be issued by the White House and not the CDC.

For those of us who were practicing medicine during the Swine Flu fiasco of 1976, the pace and the politics surrounding the development of a SARS-CoV-2 vaccine has a discomforting déjà vu quality about it. The fact that like this year 1976 was an election year that infused the development process with a sense of urgency above and beyond any of the concerns about the pandemic that never happened. Although causality was never proven, there was a surge in Guillain-Barré syndrome cases that had been linked temporally to the vaccine.

Of course, our pandemic is real, and it would be imprudent to wait a year or more to watch for long-term vaccine sequelae. However, I am more than a little concerned that fast tracking the development process may result in unfortunate consequences in the short term that could have been avoided with a more measured approach to trialing the vaccines.

The sad reality is that as a nation we tend to be impatient. We are drawn to quick fixes that come in a vial or a capsule. We are learning that simple measures like mask wearing and social distancing can make a difference in slowing the spread of the virus. It would be tragic to rush a vaccine into production that at best turns out to simply be an expensive alternative to the measures that we know work or at worst injures more of us than it saves.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

It turns out that a pandemic, at least this COVID-19 version, can be a challenge for folks like me who are seldom at a loss for words. The pandemic has so overwhelmed every corner of our lives that it is hard to think of another topic on which to pontificate and still not tromp on someone’s political toes. One can always write about the pandemic itself, and I’ve tried that, but as the curtain is gradually being pulled back on this crafty little germ one runs the risk of making an observation today that will be disproved in a week or 2. However, I can’t suppress my urge to write, and so I have decided to share a few brief random observations. Of course they are related to the pandemic. And of course I realize that there is a better than fifty percent chance that they will be proved wrong by the time you read my next Letters from Maine.

Under the radar

Phynart Studio/Getty Images

Two of the many mysteries about SARS-CoV-2 involve young children who as a group appear to be less easily infected than adults and even when infected seem to be less likely to spread the disease to other people, particularly adults. One explanation posited by some researchers in France is that young children are less likely to have symptoms such as cough and are less powerful speakers and so might be less likely to spew out a significant number of infected aerosolized droplets (“How to Reopen Schools: What Science and Other Countries Teach Us.” By Pam Belluck, Apoorva Mandavill, and Benedict Carey. New York Times, July 11, 2020). While there are probably several factors to explain this observation, one may be that young children are short, seldom taller than an adult waistline. I suspect the majority of aerosols they emit fall and inactivate harmlessly to the floor several feet below an adult’s nose and mouth. Regardless of the explanation, it appears to be good news for the opening of schools, at least for the early grades.

Forget the deep cleaning

There has been a glut of news stories about reopening schools, and many of these stories are accompanied by images of school custodians with buckets, mops, spray bottles, and sponges scouring desks and walls. The most recent image in our local newspaper was of someone scrubbing the underside of a desk. I know it’s taking the World Health Organization an unconscionable period of time to acknowledge that SARS-CoV-2 is airborne, but the rest of us should have gotten the message long ago and been directing our attention to air handling and ventilation. The urge to scrub and deep clean is a hard habit to break, but this nasty bug is not like influenza or a flesh eating bacteria in which deep cleaning might help. A better image to attach to a story on school reopening would be one of a custodian with a screwdriver struggling to pry open a classroom window that had been painted shut a decade ago.

Managing the inevitable

Middlebury College in Vermont and Bowdoin College here in Brunswick, Maine, are similar in many respects because they are small and situated in relatively isolated small New England towns with good track records for pandemic management. Middlebury has elected to invite all its 2,750 students back to campus, whereas Bowdoin has decided to allow only incoming first years and transfer students (for a total of about 600) to return. Both schools will institute similar testing and social distancing protocols and restrict students from access to their respective towns (“A Tale of 2 Colleges.” By Bill Burger. Inside Higher Ed, June 29,2020). It will be an interesting experiment. I’m voting for Middlebury and not because my son and daughter-in-law are alums, but because I think Middlebury seems to have acknowledged that no matter how diligent one is in creating a SARS-CoV-2–free environment at the outset, these are college kids and there will be some cases on both campuses. It is on how those inevitable realities are managed and contained that an institution should be judged.

Patience

Unfortunately, the pandemic has exposed some of our weaknesses as a nation. We always have been a restless and impatient population eager to get moving and it has driven us to greatness. Hopefully, patience will be a lesson that we will learn, along with many others.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

It turns out that a pandemic, at least this COVID-19 version, can be a challenge for folks like me who are seldom at a loss for words. The pandemic has so overwhelmed every corner of our lives that it is hard to think of another topic on which to pontificate and still not tromp on someone’s political toes. One can always write about the pandemic itself, and I’ve tried that, but as the curtain is gradually being pulled back on this crafty little germ one runs the risk of making an observation today that will be disproved in a week or 2. However, I can’t suppress my urge to write, and so I have decided to share a few brief random observations. Of course they are related to the pandemic. And of course I realize that there is a better than fifty percent chance that they will be proved wrong by the time you read my next Letters from Maine.

Under the radar

Phynart Studio/Getty Images

Two of the many mysteries about SARS-CoV-2 involve young children who as a group appear to be less easily infected than adults and even when infected seem to be less likely to spread the disease to other people, particularly adults. One explanation posited by some researchers in France is that young children are less likely to have symptoms such as cough and are less powerful speakers and so might be less likely to spew out a significant number of infected aerosolized droplets (“How to Reopen Schools: What Science and Other Countries Teach Us.” By Pam Belluck, Apoorva Mandavill, and Benedict Carey. New York Times, July 11, 2020). While there are probably several factors to explain this observation, one may be that young children are short, seldom taller than an adult waistline. I suspect the majority of aerosols they emit fall and inactivate harmlessly to the floor several feet below an adult’s nose and mouth. Regardless of the explanation, it appears to be good news for the opening of schools, at least for the early grades.

Forget the deep cleaning

There has been a glut of news stories about reopening schools, and many of these stories are accompanied by images of school custodians with buckets, mops, spray bottles, and sponges scouring desks and walls. The most recent image in our local newspaper was of someone scrubbing the underside of a desk. I know it’s taking the World Health Organization an unconscionable period of time to acknowledge that SARS-CoV-2 is airborne, but the rest of us should have gotten the message long ago and been directing our attention to air handling and ventilation. The urge to scrub and deep clean is a hard habit to break, but this nasty bug is not like influenza or a flesh eating bacteria in which deep cleaning might help. A better image to attach to a story on school reopening would be one of a custodian with a screwdriver struggling to pry open a classroom window that had been painted shut a decade ago.

Managing the inevitable

Middlebury College in Vermont and Bowdoin College here in Brunswick, Maine, are similar in many respects because they are small and situated in relatively isolated small New England towns with good track records for pandemic management. Middlebury has elected to invite all its 2,750 students back to campus, whereas Bowdoin has decided to allow only incoming first years and transfer students (for a total of about 600) to return. Both schools will institute similar testing and social distancing protocols and restrict students from access to their respective towns (“A Tale of 2 Colleges.” By Bill Burger. Inside Higher Ed, June 29,2020). It will be an interesting experiment. I’m voting for Middlebury and not because my son and daughter-in-law are alums, but because I think Middlebury seems to have acknowledged that no matter how diligent one is in creating a SARS-CoV-2–free environment at the outset, these are college kids and there will be some cases on both campuses. It is on how those inevitable realities are managed and contained that an institution should be judged.

Patience

Unfortunately, the pandemic has exposed some of our weaknesses as a nation. We always have been a restless and impatient population eager to get moving and it has driven us to greatness. Hopefully, patience will be a lesson that we will learn, along with many others.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

It turns out that a pandemic, at least this COVID-19 version, can be a challenge for folks like me who are seldom at a loss for words. The pandemic has so overwhelmed every corner of our lives that it is hard to think of another topic on which to pontificate and still not tromp on someone’s political toes. One can always write about the pandemic itself, and I’ve tried that, but as the curtain is gradually being pulled back on this crafty little germ one runs the risk of making an observation today that will be disproved in a week or 2. However, I can’t suppress my urge to write, and so I have decided to share a few brief random observations. Of course they are related to the pandemic. And of course I realize that there is a better than fifty percent chance that they will be proved wrong by the time you read my next Letters from Maine.

Under the radar

Phynart Studio/Getty Images

Two of the many mysteries about SARS-CoV-2 involve young children who as a group appear to be less easily infected than adults and even when infected seem to be less likely to spread the disease to other people, particularly adults. One explanation posited by some researchers in France is that young children are less likely to have symptoms such as cough and are less powerful speakers and so might be less likely to spew out a significant number of infected aerosolized droplets (“How to Reopen Schools: What Science and Other Countries Teach Us.” By Pam Belluck, Apoorva Mandavill, and Benedict Carey. New York Times, July 11, 2020). While there are probably several factors to explain this observation, one may be that young children are short, seldom taller than an adult waistline. I suspect the majority of aerosols they emit fall and inactivate harmlessly to the floor several feet below an adult’s nose and mouth. Regardless of the explanation, it appears to be good news for the opening of schools, at least for the early grades.

Forget the deep cleaning

There has been a glut of news stories about reopening schools, and many of these stories are accompanied by images of school custodians with buckets, mops, spray bottles, and sponges scouring desks and walls. The most recent image in our local newspaper was of someone scrubbing the underside of a desk. I know it’s taking the World Health Organization an unconscionable period of time to acknowledge that SARS-CoV-2 is airborne, but the rest of us should have gotten the message long ago and been directing our attention to air handling and ventilation. The urge to scrub and deep clean is a hard habit to break, but this nasty bug is not like influenza or a flesh eating bacteria in which deep cleaning might help. A better image to attach to a story on school reopening would be one of a custodian with a screwdriver struggling to pry open a classroom window that had been painted shut a decade ago.

Managing the inevitable

Middlebury College in Vermont and Bowdoin College here in Brunswick, Maine, are similar in many respects because they are small and situated in relatively isolated small New England towns with good track records for pandemic management. Middlebury has elected to invite all its 2,750 students back to campus, whereas Bowdoin has decided to allow only incoming first years and transfer students (for a total of about 600) to return. Both schools will institute similar testing and social distancing protocols and restrict students from access to their respective towns (“A Tale of 2 Colleges.” By Bill Burger. Inside Higher Ed, June 29,2020). It will be an interesting experiment. I’m voting for Middlebury and not because my son and daughter-in-law are alums, but because I think Middlebury seems to have acknowledged that no matter how diligent one is in creating a SARS-CoV-2–free environment at the outset, these are college kids and there will be some cases on both campuses. It is on how those inevitable realities are managed and contained that an institution should be judged.

Patience

Unfortunately, the pandemic has exposed some of our weaknesses as a nation. We always have been a restless and impatient population eager to get moving and it has driven us to greatness. Hopefully, patience will be a lesson that we will learn, along with many others.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Hospitalized cancer patients have a high risk of nosocomial COVID-19 that is associated with increased mortality, so these patients should be treated in COVID-free zones, according to researchers.

In an observational study of patients with COVID-19 and cancer, 19% of patients had COVID-19 acquired during a non-COVID-related hospital stay, and 81% had community-acquired COVID-19.

At a median follow-up of 23 days, the overall mortality rate was 28%. However, the all-cause mortality rate in patients with nosocomial COVID-19 was more than double that of patients with community-acquired COVID-19, at 47% and 23%, respectively.

Arielle Elkrief, MD, of the University of Montreal, reported these results during the AACR virtual meeting: COVID-19 and Cancer.

“This is the first report that describes a high rate of hospital-acquired COVID-19 in patients with cancer, at a rate of 19%,” Dr. Elkrief said. “This was associated with high mortality in both univariate and multivariate analyses.”

The study included 250 adults and 3 children with COVID-19 and cancer who were identified between March 3 and May 23, 2020. They ranged in age from 4 to 95 years, but the median age was 73 years.

All patients had either laboratory-confirmed (95%) or presumed COVID-19 (5%) and invasive cancer. The most common cancer types were similar to those seen in the general population. Lung and breast cancer were the most common, followed by lymphoma, prostate cancer, and colorectal cancer. Most patients were on active anticancer therapy, most often chemotherapy.

Most patients (n = 236) were residents of Quebec, but 17 patients were residents of British Columbia.

“It is important to note that Quebec was one of the most heavily affected areas in North America at the time of the study,” Dr. Elkrief said.
 

Outcomes by group

There were 206 patients (81%) who had community-acquired COVID-19 and 47 (19%) who had nosocomial COVID-19. The two groups were similar with respect to sex, performance status, and cancer stage. A small trend toward more patients on active therapy was seen in the nosocomial group, but the difference did not reach statistical significance.

The median overall survival was 27 days in the nosocomial group and 71 days in the community-acquired group (hazard ratio, 2.2; P = .002).

A multivariate analysis showed that nosocomial infection was “strongly and independently associated with death,” Dr. Elkrief said. “Other risk factors for poor prognosis included age, poor [performance] status, and advanced stage of cancer.”

There were no significant differences between the hospital-acquired and community-acquired groups for other outcomes, including oxygen requirements (43% and 47%, respectively), ICU admission (13% and 11%), need for mechanical ventilation (6% and 5%), or length of stay (median, 9.5 days and 8.5 days).

The low rate of ICU admission, considering the mortality rate of 28%, “could reflect that patients with cancer are less likely to be admitted to the ICU,” Dr. Elkrief noted.
 

Applying the findings to practice

The findings reinforce the importance of adherence to stringent infection control guidelines to protect vulnerable patients, such as those with cancer, Dr. Elkrief said.

In ambulatory settings, this means decreasing in-person visits through increased use of teleconsultations, and for those who need to be seen in person, screening for symptoms or use of polymerase chain reaction testing should be used when resources are available, she said.

“Similar principles apply to chemotherapy treatment units,” Dr. Elkrief said. She added that staff must avoid cross-contamination between COVID and COVID-free zones, and that “dedicated personnel and equipment should be maintained and separate between these two zones.

“Adequate protective personal equipment and strict hand hygiene protocols are also of utmost importance,” Dr. Elkrief said. “The threat of COVID-19 is not behind us, and so we continue to enforce these strategies to protect our patients.”

Session moderator Gypsyamber D’Souza, PhD, an infectious disease epidemiologist at Johns Hopkins University in Baltimore, raised the question of whether the high nosocomial infection and death rate in this study was related to patients having more severe disease because of underlying comorbidities.

Dr. Elkrief explained that the overall mortality rate was indeed higher than the 13% reported in other studies, and it may reflect an overrepresentation of hospitalized or more severely ill patients in the cohort.

However, the investigators made every effort to include all patients with both cancer and COVID-19 by using systematic screening of inpatient and outpatients lists and registries.

Further, the multivariate analysis included both inpatients and outpatients and adjusted for known negative prognostic factors for COVID-19 outcomes. These included increasing age, poor performance status, and different comorbidities.

The finding that nosocomial infection was an independent predictor of death “pushed us to look at nosocomial infection as a new independent risk factor,” Dr. Elkrief said.

Dr. Elkrief reported grant support from AstraZeneca. Dr. D’Souza did not report any disclosures.

[email protected]

SOURCE: Elkrief A et al. AACR: COVID and Cancer, Abstract S12-01.

Hospitalized cancer patients have a high risk of nosocomial COVID-19 that is associated with increased mortality, so these patients should be treated in COVID-free zones, according to researchers.

In an observational study of patients with COVID-19 and cancer, 19% of patients had COVID-19 acquired during a non-COVID-related hospital stay, and 81% had community-acquired COVID-19.

At a median follow-up of 23 days, the overall mortality rate was 28%. However, the all-cause mortality rate in patients with nosocomial COVID-19 was more than double that of patients with community-acquired COVID-19, at 47% and 23%, respectively.

Arielle Elkrief, MD, of the University of Montreal, reported these results during the AACR virtual meeting: COVID-19 and Cancer.

“This is the first report that describes a high rate of hospital-acquired COVID-19 in patients with cancer, at a rate of 19%,” Dr. Elkrief said. “This was associated with high mortality in both univariate and multivariate analyses.”

The study included 250 adults and 3 children with COVID-19 and cancer who were identified between March 3 and May 23, 2020. They ranged in age from 4 to 95 years, but the median age was 73 years.

All patients had either laboratory-confirmed (95%) or presumed COVID-19 (5%) and invasive cancer. The most common cancer types were similar to those seen in the general population. Lung and breast cancer were the most common, followed by lymphoma, prostate cancer, and colorectal cancer. Most patients were on active anticancer therapy, most often chemotherapy.

Most patients (n = 236) were residents of Quebec, but 17 patients were residents of British Columbia.

“It is important to note that Quebec was one of the most heavily affected areas in North America at the time of the study,” Dr. Elkrief said.
 

Outcomes by group

There were 206 patients (81%) who had community-acquired COVID-19 and 47 (19%) who had nosocomial COVID-19. The two groups were similar with respect to sex, performance status, and cancer stage. A small trend toward more patients on active therapy was seen in the nosocomial group, but the difference did not reach statistical significance.

The median overall survival was 27 days in the nosocomial group and 71 days in the community-acquired group (hazard ratio, 2.2; P = .002).

A multivariate analysis showed that nosocomial infection was “strongly and independently associated with death,” Dr. Elkrief said. “Other risk factors for poor prognosis included age, poor [performance] status, and advanced stage of cancer.”

There were no significant differences between the hospital-acquired and community-acquired groups for other outcomes, including oxygen requirements (43% and 47%, respectively), ICU admission (13% and 11%), need for mechanical ventilation (6% and 5%), or length of stay (median, 9.5 days and 8.5 days).

The low rate of ICU admission, considering the mortality rate of 28%, “could reflect that patients with cancer are less likely to be admitted to the ICU,” Dr. Elkrief noted.
 

Applying the findings to practice

The findings reinforce the importance of adherence to stringent infection control guidelines to protect vulnerable patients, such as those with cancer, Dr. Elkrief said.

In ambulatory settings, this means decreasing in-person visits through increased use of teleconsultations, and for those who need to be seen in person, screening for symptoms or use of polymerase chain reaction testing should be used when resources are available, she said.

“Similar principles apply to chemotherapy treatment units,” Dr. Elkrief said. She added that staff must avoid cross-contamination between COVID and COVID-free zones, and that “dedicated personnel and equipment should be maintained and separate between these two zones.

“Adequate protective personal equipment and strict hand hygiene protocols are also of utmost importance,” Dr. Elkrief said. “The threat of COVID-19 is not behind us, and so we continue to enforce these strategies to protect our patients.”

Session moderator Gypsyamber D’Souza, PhD, an infectious disease epidemiologist at Johns Hopkins University in Baltimore, raised the question of whether the high nosocomial infection and death rate in this study was related to patients having more severe disease because of underlying comorbidities.

Dr. Elkrief explained that the overall mortality rate was indeed higher than the 13% reported in other studies, and it may reflect an overrepresentation of hospitalized or more severely ill patients in the cohort.

However, the investigators made every effort to include all patients with both cancer and COVID-19 by using systematic screening of inpatient and outpatients lists and registries.

Further, the multivariate analysis included both inpatients and outpatients and adjusted for known negative prognostic factors for COVID-19 outcomes. These included increasing age, poor performance status, and different comorbidities.

The finding that nosocomial infection was an independent predictor of death “pushed us to look at nosocomial infection as a new independent risk factor,” Dr. Elkrief said.

Dr. Elkrief reported grant support from AstraZeneca. Dr. D’Souza did not report any disclosures.

[email protected]

SOURCE: Elkrief A et al. AACR: COVID and Cancer, Abstract S12-01.

Hospitalized cancer patients have a high risk of nosocomial COVID-19 that is associated with increased mortality, so these patients should be treated in COVID-free zones, according to researchers.

In an observational study of patients with COVID-19 and cancer, 19% of patients had COVID-19 acquired during a non-COVID-related hospital stay, and 81% had community-acquired COVID-19.

At a median follow-up of 23 days, the overall mortality rate was 28%. However, the all-cause mortality rate in patients with nosocomial COVID-19 was more than double that of patients with community-acquired COVID-19, at 47% and 23%, respectively.

Arielle Elkrief, MD, of the University of Montreal, reported these results during the AACR virtual meeting: COVID-19 and Cancer.

“This is the first report that describes a high rate of hospital-acquired COVID-19 in patients with cancer, at a rate of 19%,” Dr. Elkrief said. “This was associated with high mortality in both univariate and multivariate analyses.”

The study included 250 adults and 3 children with COVID-19 and cancer who were identified between March 3 and May 23, 2020. They ranged in age from 4 to 95 years, but the median age was 73 years.

All patients had either laboratory-confirmed (95%) or presumed COVID-19 (5%) and invasive cancer. The most common cancer types were similar to those seen in the general population. Lung and breast cancer were the most common, followed by lymphoma, prostate cancer, and colorectal cancer. Most patients were on active anticancer therapy, most often chemotherapy.

Most patients (n = 236) were residents of Quebec, but 17 patients were residents of British Columbia.

“It is important to note that Quebec was one of the most heavily affected areas in North America at the time of the study,” Dr. Elkrief said.
 

Outcomes by group

There were 206 patients (81%) who had community-acquired COVID-19 and 47 (19%) who had nosocomial COVID-19. The two groups were similar with respect to sex, performance status, and cancer stage. A small trend toward more patients on active therapy was seen in the nosocomial group, but the difference did not reach statistical significance.

The median overall survival was 27 days in the nosocomial group and 71 days in the community-acquired group (hazard ratio, 2.2; P = .002).

A multivariate analysis showed that nosocomial infection was “strongly and independently associated with death,” Dr. Elkrief said. “Other risk factors for poor prognosis included age, poor [performance] status, and advanced stage of cancer.”

There were no significant differences between the hospital-acquired and community-acquired groups for other outcomes, including oxygen requirements (43% and 47%, respectively), ICU admission (13% and 11%), need for mechanical ventilation (6% and 5%), or length of stay (median, 9.5 days and 8.5 days).

The low rate of ICU admission, considering the mortality rate of 28%, “could reflect that patients with cancer are less likely to be admitted to the ICU,” Dr. Elkrief noted.
 

Applying the findings to practice

The findings reinforce the importance of adherence to stringent infection control guidelines to protect vulnerable patients, such as those with cancer, Dr. Elkrief said.

In ambulatory settings, this means decreasing in-person visits through increased use of teleconsultations, and for those who need to be seen in person, screening for symptoms or use of polymerase chain reaction testing should be used when resources are available, she said.

“Similar principles apply to chemotherapy treatment units,” Dr. Elkrief said. She added that staff must avoid cross-contamination between COVID and COVID-free zones, and that “dedicated personnel and equipment should be maintained and separate between these two zones.

“Adequate protective personal equipment and strict hand hygiene protocols are also of utmost importance,” Dr. Elkrief said. “The threat of COVID-19 is not behind us, and so we continue to enforce these strategies to protect our patients.”

Session moderator Gypsyamber D’Souza, PhD, an infectious disease epidemiologist at Johns Hopkins University in Baltimore, raised the question of whether the high nosocomial infection and death rate in this study was related to patients having more severe disease because of underlying comorbidities.

Dr. Elkrief explained that the overall mortality rate was indeed higher than the 13% reported in other studies, and it may reflect an overrepresentation of hospitalized or more severely ill patients in the cohort.

However, the investigators made every effort to include all patients with both cancer and COVID-19 by using systematic screening of inpatient and outpatients lists and registries.

Further, the multivariate analysis included both inpatients and outpatients and adjusted for known negative prognostic factors for COVID-19 outcomes. These included increasing age, poor performance status, and different comorbidities.

The finding that nosocomial infection was an independent predictor of death “pushed us to look at nosocomial infection as a new independent risk factor,” Dr. Elkrief said.

Dr. Elkrief reported grant support from AstraZeneca. Dr. D’Souza did not report any disclosures.

[email protected]

SOURCE: Elkrief A et al. AACR: COVID and Cancer, Abstract S12-01.

Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.

Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.

The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.

The study was published online July 23 in The FEBS Journal.

Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.

Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.

Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.

Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.

Key findings

A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).

The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.

“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.

“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.

In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.

The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).

After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).

Implications and future plans

The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.

Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.

“A compelling case”

“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.

Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.

However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”

“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
 

More confounders likely?

“I think the study is of interest,” Naveed Sattar, PhD,  professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.

“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.

For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.

“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”

Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
 

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

Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.

Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.

The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.

The study was published online July 23 in The FEBS Journal.

Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.

Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.

Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.

Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.

Key findings

A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).

The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.

“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.

“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.

In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.

The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).

After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).

Implications and future plans

The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.

Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.

“A compelling case”

“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.

Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.

However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”

“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
 

More confounders likely?

“I think the study is of interest,” Naveed Sattar, PhD,  professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.

“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.

For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.

“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”

Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
 

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

Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.

Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.

The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.

The study was published online July 23 in The FEBS Journal.

Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.

Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.

Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.

Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.

Key findings

A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).

The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.

“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.

“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.

In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.

The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).

After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).

Implications and future plans

The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.

Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.

“A compelling case”

“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.

Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.

However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”

“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
 

More confounders likely?

“I think the study is of interest,” Naveed Sattar, PhD,  professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.

“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.

For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.

“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”

Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
 

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

Sleep difficulties during the COVID-19 crisis may be exacerbated by media overexposure and other factors causing fear and stress, according to findings from a large survey of French individuals.

klebercordeiro/Getty Images

“Physicians usually recommend coping with sleep disorders by exercising, going outside, avoiding screen time, and having a regular schedule – all recommendations difficult to apply during lockdown. Being forced to stay home and the ensuing boredom and loneliness may have led to increased [media exposure], especially among disadvantaged people and overexposure to media COVID-19 content may have contributed to fright and emotional distress,” Damien Leger of the Centre du Sommeil et de la Vigilance, Hôtel Dieu APHP, Université de Paris, and his colleagues wrote in the journal Sleep.

The investigators analyzed data from survey respondents about their sleep problems since the COVID-19 lockdown and other topics such as employment, daily activities, and sleep medications. The survey was part of a large research project, COCONEL, that has been developed to study the French population on a variety of behaviors and comprises 750,000 permanent panelists who respond to surveys. The survey was sent to random sample of panelists with no topic label to avoid selection bias. Of the 25,800 surveys sent, 1,005 responses were recorded.

Respondents were classified as having severe sleep problems if they reported that their daytime activities were affected or if their sleeping medications had increased since the lockdown. While 73% of respondents reported poor sleep in the 8 previous days, 25% reported severe sleep problems, and 54% reported that their sleep problems had worsened during the COVID-19 lockdown.

A media exposure score was created with a Likert scale (strongly agree, agree, disagree, strongly disagree) about media exposures of different types. The investigators also queried respondents about the degree to which they found media coverage of the pandemic provoked a fear response. Overall, 68% of respondents agreed that media images and stories about COVD-19 were frightening.

The researchers found a strong association between severe sleeping problems and a high media exposure score (risk ratio, 1.49; 95% confidence interval, 1.10-2.01; P < .05).

In addition, trepidation and fear from media exposure to COVID-19 news were also associated with severe sleep problems (RR, 1.27; 95% CI, 0.92-1.75; P < .05). “Suffering from sleep problems may have increased media use at night, and thus increased stress and/or psychological distress and reinforced sleeping problems,” the investigators wrote.

Not surprisingly, respondents with financial difficulties due to the pandemic also reported severe sleeping difficulties (RR, 1.99; 95% CI, 1.49-2.65; P < .05).

For individuals who have been treated for sleep problems, the COVID-19 pandemic may ratchet up their sleep challenges. The strongest association with severe sleep problems was found in those respondents who were already taking sleeping medications before the pandemic (RR, 2.72; 95% CI, 2.04-3.61; P < .05).

The COCONEL survey has been funded by the French and National Agency for Research, the Fondation de France, and the National Research Institute for Sustainable Development.

[email protected]

SOURCE: Leger D et al. Sleep. 2020, Jul 25. doi: 10.1093/sleep/zsaa125.

Sleep difficulties during the COVID-19 crisis may be exacerbated by media overexposure and other factors causing fear and stress, according to findings from a large survey of French individuals.

klebercordeiro/Getty Images

“Physicians usually recommend coping with sleep disorders by exercising, going outside, avoiding screen time, and having a regular schedule – all recommendations difficult to apply during lockdown. Being forced to stay home and the ensuing boredom and loneliness may have led to increased [media exposure], especially among disadvantaged people and overexposure to media COVID-19 content may have contributed to fright and emotional distress,” Damien Leger of the Centre du Sommeil et de la Vigilance, Hôtel Dieu APHP, Université de Paris, and his colleagues wrote in the journal Sleep.

The investigators analyzed data from survey respondents about their sleep problems since the COVID-19 lockdown and other topics such as employment, daily activities, and sleep medications. The survey was part of a large research project, COCONEL, that has been developed to study the French population on a variety of behaviors and comprises 750,000 permanent panelists who respond to surveys. The survey was sent to random sample of panelists with no topic label to avoid selection bias. Of the 25,800 surveys sent, 1,005 responses were recorded.

Respondents were classified as having severe sleep problems if they reported that their daytime activities were affected or if their sleeping medications had increased since the lockdown. While 73% of respondents reported poor sleep in the 8 previous days, 25% reported severe sleep problems, and 54% reported that their sleep problems had worsened during the COVID-19 lockdown.

A media exposure score was created with a Likert scale (strongly agree, agree, disagree, strongly disagree) about media exposures of different types. The investigators also queried respondents about the degree to which they found media coverage of the pandemic provoked a fear response. Overall, 68% of respondents agreed that media images and stories about COVD-19 were frightening.

The researchers found a strong association between severe sleeping problems and a high media exposure score (risk ratio, 1.49; 95% confidence interval, 1.10-2.01; P < .05).

In addition, trepidation and fear from media exposure to COVID-19 news were also associated with severe sleep problems (RR, 1.27; 95% CI, 0.92-1.75; P < .05). “Suffering from sleep problems may have increased media use at night, and thus increased stress and/or psychological distress and reinforced sleeping problems,” the investigators wrote.

Not surprisingly, respondents with financial difficulties due to the pandemic also reported severe sleeping difficulties (RR, 1.99; 95% CI, 1.49-2.65; P < .05).

For individuals who have been treated for sleep problems, the COVID-19 pandemic may ratchet up their sleep challenges. The strongest association with severe sleep problems was found in those respondents who were already taking sleeping medications before the pandemic (RR, 2.72; 95% CI, 2.04-3.61; P < .05).

The COCONEL survey has been funded by the French and National Agency for Research, the Fondation de France, and the National Research Institute for Sustainable Development.

[email protected]

SOURCE: Leger D et al. Sleep. 2020, Jul 25. doi: 10.1093/sleep/zsaa125.

Sleep difficulties during the COVID-19 crisis may be exacerbated by media overexposure and other factors causing fear and stress, according to findings from a large survey of French individuals.

klebercordeiro/Getty Images

“Physicians usually recommend coping with sleep disorders by exercising, going outside, avoiding screen time, and having a regular schedule – all recommendations difficult to apply during lockdown. Being forced to stay home and the ensuing boredom and loneliness may have led to increased [media exposure], especially among disadvantaged people and overexposure to media COVID-19 content may have contributed to fright and emotional distress,” Damien Leger of the Centre du Sommeil et de la Vigilance, Hôtel Dieu APHP, Université de Paris, and his colleagues wrote in the journal Sleep.

The investigators analyzed data from survey respondents about their sleep problems since the COVID-19 lockdown and other topics such as employment, daily activities, and sleep medications. The survey was part of a large research project, COCONEL, that has been developed to study the French population on a variety of behaviors and comprises 750,000 permanent panelists who respond to surveys. The survey was sent to random sample of panelists with no topic label to avoid selection bias. Of the 25,800 surveys sent, 1,005 responses were recorded.

Respondents were classified as having severe sleep problems if they reported that their daytime activities were affected or if their sleeping medications had increased since the lockdown. While 73% of respondents reported poor sleep in the 8 previous days, 25% reported severe sleep problems, and 54% reported that their sleep problems had worsened during the COVID-19 lockdown.

A media exposure score was created with a Likert scale (strongly agree, agree, disagree, strongly disagree) about media exposures of different types. The investigators also queried respondents about the degree to which they found media coverage of the pandemic provoked a fear response. Overall, 68% of respondents agreed that media images and stories about COVD-19 were frightening.

The researchers found a strong association between severe sleeping problems and a high media exposure score (risk ratio, 1.49; 95% confidence interval, 1.10-2.01; P < .05).

In addition, trepidation and fear from media exposure to COVID-19 news were also associated with severe sleep problems (RR, 1.27; 95% CI, 0.92-1.75; P < .05). “Suffering from sleep problems may have increased media use at night, and thus increased stress and/or psychological distress and reinforced sleeping problems,” the investigators wrote.

Not surprisingly, respondents with financial difficulties due to the pandemic also reported severe sleeping difficulties (RR, 1.99; 95% CI, 1.49-2.65; P < .05).

For individuals who have been treated for sleep problems, the COVID-19 pandemic may ratchet up their sleep challenges. The strongest association with severe sleep problems was found in those respondents who were already taking sleeping medications before the pandemic (RR, 2.72; 95% CI, 2.04-3.61; P < .05).

The COCONEL survey has been funded by the French and National Agency for Research, the Fondation de France, and the National Research Institute for Sustainable Development.

[email protected]

SOURCE: Leger D et al. Sleep. 2020, Jul 25. doi: 10.1093/sleep/zsaa125.

Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

[email protected]

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.

Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

[email protected]

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.

Systemic bevacizumab is safe and highly effective for the management of chronic bleeding and anemia in patients with hereditary hemorrhagic telangiectasia (HHT), according to findings from an international observational study.

In 238 patients from 12 international centers who were treated with bevacizumab for a median of 12 months, mean hemoglobin levels increased by 3.2 g/dL (mean pre- and posttreatment levels, 8.6 vs. 11.8 g/dL), and epistaxis severity scores (ESS) decreased by a mean of 3.4 points (pre- and posttreatment scores, 6.8 vs. 3.4 points), Hanny Al-Samkari, MD, reported at the International Society on Thrombosis and Haemostasis virtual congress.

As established in prior studies, the minimal clinically important difference in the ESS, a well-validated 10-point bleeding score in HHT, is 0.71 points; the mean reduction seen in this study was 4.75 times that, noted Dr. Al-Samkari, a clinical investigator and hematologist at Massachusetts General Hospital, Boston.

Further, the median number of red blood cell units transfused during the first year of treatment decreased by 82%, compared with the 6 months prior to treatment (9.0 vs. 0 units), and median iron infusions decreased by 70% during the same period (8.0 vs. 2.0 infusions), he said, adding that these improvements occurred within the first 6 months of treatment and were maintained through 12 months.

Study subjects were adults with a mean age of 63 years who were treated with systemic bevacizumab, a vascular endothelial growth factor receptor (VEGF) monoclonal antibody, between 2011 and 2019 for the primary indication of moderate to severe chronic HHT-related bleeding and anemia. Treatment involved four to eight induction infusions – typically at a dose of 5 mg/kg and given 4 weeks apart – followed by bevacizumab maintenance, either as continuous or scheduled maintenance at 4-, 8-, or 12-week intervals regardless of symptoms, or on an as-needed basis, with 2-6 infusions for signs or symptoms of rebleeding.

Patients received a median of 11 infusions, and 181 received maintenance treatment, including continuous or scheduled maintenance in 136 patients and as-needed maintenance in 45 patients, Dr. Al-Samkari said.

The treatment was generally well tolerated; the most common adverse events during 344 patient-years of treatment were hypertension, fatigue, and proteinuria. No fatal treatment-related adverse events occurred, and no increase in adverse events occurred with longer treatment, he noted

Venous thromboembolism occurred in five patients, including two patients who had “provoked events immediately following joint replacement surgery,” he said.

Thirteen patients (5%) discontinued treatment – 11 for inadequate effect and 2 for side effects, he noted.

Subgroup analyses showed that outcomes were similar regardless of underlying pathogenic mutation, but among those receiving bevacizumab maintenance, the continuous approach, compared with as-needed maintenance, was associated with greater improvement in hemoglobin (10.8 vs. 12.3 g/dL) and ESS (mean, 4.96 vs. 2.88) during months 7-12 of treatment, “which is the time most reflective of the effect of maintenance,” he said.

HHT, also known as Osler-Weber-Rendu disease, is a “rare, genetic, progressive, multisystem bleeding disorder resulting from disorder of angiogenesis,” Dr. Al-Samkari explained, adding that the condition is characterized by severe, recurrent epistaxis and chronic gastrointestinal bleeding.

“Bleeding frequently leads to iron deficiency anemia, which may be severe and dependent on regular iron infusions and/or blood transfusions,” he said.

Though rare, it is the second most common bleeding disorder worldwide, with a prevalence about twice that of hemophilia A and six times that of hemophilia B.

“Despite this, it has no FDA-approved therapies,” he said. “The current mainstay of care is surgical or procedural local hemostatic intervention – which is usually temporizing – and hematological support in the form of blood and iron.”

However, given that the underlying genetic defects that cause HHT result in elevations in VEGF, targeting VEGF with existing antiangiogenic agents is a promising approach.

In fact, several centers have been using bevacizumab for several years as an off-label treatment for bleeding in this setting, and while scattered case reports and small case series suggest efficacy, no “large or definitive studies” have been conducted, and safety hasn’t been carefully evaluated, he said.

To that end, the International Hereditary Hemorrhagic Telangiectasia Intravenous Bevacizumab Investigative Team (InHIBIT) was formed. The current report, “the largest study of antiangiogenic therapy to date in HHT,” represents the results of the InHIBIT-Bleed study, the first completed by the team. The next study will address bevacizumab for the treatment of high-output cardiac failure in HHT (the InHIBIT-HF study), Dr. Al-Samkari said.

Though limited by its retrospective nature and lack of a unified treatment protocol, the InHIBIT-Bleed study provides important information and is strengthened by the large cohort size, especially given that HHT is a rare disease, and by other factors, such as the substantial number of patient-years of treatment.

“Bevacizumab was effective in the management of severe HHT-related epistaxis and GI bleeds,” he said, noting the “significant and striking improvements” on a variety of measures.

Questioned about the durability of treatment effects after treatment discontinuation, Dr. Al-Samkari said outcomes are variable, “highly patient dependent,” and “something that we really need to investigate thoroughly.”

As for the potential for anti-VEGF therapy for bleeding in certain non-HHT settings, session moderator Michael Makris, MD, professor of haemostasis and thrombosis at the University of Sheffield, England, said the possibilities are intriguing.

“I work with lots of patients with von Willebrand disease and angiodysplasia,” he said, adding that angiodysplasia-related bleeding in type 2A von Willebrand disease is a major issue.

Dr. Al-Samkari agreed that the possibility is worth exploring.

“We have looked at this in a small number of patients, and the jury is still out,” he said. “But there is a publication in Gastroenterology – Albitar et al. – that evaluated bevacizumab in patients without HHT [who had] angiodysplasias from other causes – not specifically in type 2 von Willebrand syndrome ... and did find that it was effective at causing the angiodysplasias to regress, hemoglobin to improve.

“So the non-HHT use of this agent is certainly an important one [and] we do have retrospective evidence in a small group of patients who don’t have HHT, who do have angiodysplasias and bleeding, that it may be effective as well.”

Dr. Al-Samkari reported receiving research support and/or consulting fees from Agios, Amgen, and Dova.

[email protected]

SOURCE: Al-Samkari H et al. ISTH 2020, Abstract OC 09.2.