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Nebulized amphotericin B does not affect aspergillosis exacerbation-free status at 1 year
Topline
Nebulized amphotericin B does not improve exacerbation-free status at 1 year for patients with bronchopulmonary aspergillosis, though it may delay onset and incidence.
Methodology
Investigators searched PubMed and Embase databases for studies that included at least five patients with allergic bronchopulmonary aspergillosis who were managed with nebulized amphotericin B.
They included five studies, two of which were randomized controlled trials (RCTs), and three were observational studies; there was a total of 188 patients.
The primary objective of this systematic review and meta-analysis was to determine the frequency of patients remaining exacerbation free 1 year after initiating treatment with nebulized amphotericin B.
Takeaway
From the studies (one observational, two RCTs; n = 84) with exacerbation data at 1 or 2 years, the pooled proportion of patients who remained exacerbation free with nebulized amphotericin B at 1 year was 76% (I2 = 64.6%).
The pooled difference in risk with the two RCTs that assessed exacerbation-free status at 1 year was 0.33 and was not significantly different between the nebulized amphotericin B and control arms, which received nebulized saline.
Two RCTs provided the time to first exacerbation, which was significantly longer with nebulized amphotericin B than with nebulized saline (337 vs. 177 days; P = .004; I2 = 82%).
The proportion of patients who experienced two or more exacerbations was significantly lower with nebulized amphotericin B than with nebulized saline (9/33 [27.3%] vs 20/38 [52.6%]; P = .03).
In practice
Also, the proportion of subjects experiencing ≥ 2 exacerbations was also lesser with NAB than in the control,” concluded Valliappan Muthu, MD, and colleagues. However, “the ideal duration and optimal dose of LAMB for nebulization are unclear.”
Study details
“Nebulized amphotericin B for preventing exacerbations in allergic bronchopulmonary aspergillosis: A systematic review and meta-analysis” was published online in Pulmonary Pharmacology and Therapeutics.
Limitations
The current review is limited by the small number of included trials and may have a high risk of bias. Therefore, more evidence is required for the use of nebulized amphotericin B in routine care. The authors have disclosed no conflicts of interest.
A version of this article originally appeared on Medscape.com.
Topline
Nebulized amphotericin B does not improve exacerbation-free status at 1 year for patients with bronchopulmonary aspergillosis, though it may delay onset and incidence.
Methodology
Investigators searched PubMed and Embase databases for studies that included at least five patients with allergic bronchopulmonary aspergillosis who were managed with nebulized amphotericin B.
They included five studies, two of which were randomized controlled trials (RCTs), and three were observational studies; there was a total of 188 patients.
The primary objective of this systematic review and meta-analysis was to determine the frequency of patients remaining exacerbation free 1 year after initiating treatment with nebulized amphotericin B.
Takeaway
From the studies (one observational, two RCTs; n = 84) with exacerbation data at 1 or 2 years, the pooled proportion of patients who remained exacerbation free with nebulized amphotericin B at 1 year was 76% (I2 = 64.6%).
The pooled difference in risk with the two RCTs that assessed exacerbation-free status at 1 year was 0.33 and was not significantly different between the nebulized amphotericin B and control arms, which received nebulized saline.
Two RCTs provided the time to first exacerbation, which was significantly longer with nebulized amphotericin B than with nebulized saline (337 vs. 177 days; P = .004; I2 = 82%).
The proportion of patients who experienced two or more exacerbations was significantly lower with nebulized amphotericin B than with nebulized saline (9/33 [27.3%] vs 20/38 [52.6%]; P = .03).
In practice
Also, the proportion of subjects experiencing ≥ 2 exacerbations was also lesser with NAB than in the control,” concluded Valliappan Muthu, MD, and colleagues. However, “the ideal duration and optimal dose of LAMB for nebulization are unclear.”
Study details
“Nebulized amphotericin B for preventing exacerbations in allergic bronchopulmonary aspergillosis: A systematic review and meta-analysis” was published online in Pulmonary Pharmacology and Therapeutics.
Limitations
The current review is limited by the small number of included trials and may have a high risk of bias. Therefore, more evidence is required for the use of nebulized amphotericin B in routine care. The authors have disclosed no conflicts of interest.
A version of this article originally appeared on Medscape.com.
Topline
Nebulized amphotericin B does not improve exacerbation-free status at 1 year for patients with bronchopulmonary aspergillosis, though it may delay onset and incidence.
Methodology
Investigators searched PubMed and Embase databases for studies that included at least five patients with allergic bronchopulmonary aspergillosis who were managed with nebulized amphotericin B.
They included five studies, two of which were randomized controlled trials (RCTs), and three were observational studies; there was a total of 188 patients.
The primary objective of this systematic review and meta-analysis was to determine the frequency of patients remaining exacerbation free 1 year after initiating treatment with nebulized amphotericin B.
Takeaway
From the studies (one observational, two RCTs; n = 84) with exacerbation data at 1 or 2 years, the pooled proportion of patients who remained exacerbation free with nebulized amphotericin B at 1 year was 76% (I2 = 64.6%).
The pooled difference in risk with the two RCTs that assessed exacerbation-free status at 1 year was 0.33 and was not significantly different between the nebulized amphotericin B and control arms, which received nebulized saline.
Two RCTs provided the time to first exacerbation, which was significantly longer with nebulized amphotericin B than with nebulized saline (337 vs. 177 days; P = .004; I2 = 82%).
The proportion of patients who experienced two or more exacerbations was significantly lower with nebulized amphotericin B than with nebulized saline (9/33 [27.3%] vs 20/38 [52.6%]; P = .03).
In practice
Also, the proportion of subjects experiencing ≥ 2 exacerbations was also lesser with NAB than in the control,” concluded Valliappan Muthu, MD, and colleagues. However, “the ideal duration and optimal dose of LAMB for nebulization are unclear.”
Study details
“Nebulized amphotericin B for preventing exacerbations in allergic bronchopulmonary aspergillosis: A systematic review and meta-analysis” was published online in Pulmonary Pharmacology and Therapeutics.
Limitations
The current review is limited by the small number of included trials and may have a high risk of bias. Therefore, more evidence is required for the use of nebulized amphotericin B in routine care. The authors have disclosed no conflicts of interest.
A version of this article originally appeared on Medscape.com.
Comorbid respiratory disease key predictor of NTM-PD
(NTM-PD), data from a systematic review of 99 studies indicate.
NTM-PD is frequently underdiagnosed, and data on specific risk factors are lacking, especially for high-risk individuals with preexisting respiratory diseases, wrote Michael R. Loebinger, PhD, of Imperial College London, and colleagues.
“NTM-PD can be a substantial burden for patients, contributing to lung function decline and reduced health-related quality of life, and is associated with significant morbidity and mortality,” they said.
In a study published in the journal Chest, the researchers identified 99 studies published between 2011 and 2021. Of these, 24 reported an association between risk factors and NTM-PD among patients with respiratory disease compared with patients without NTM-PD and with healthy control persons without NTM-PD; these studies were included in the meta-analysis.
Overall, comorbid respiratory disease was significantly associated with an increased risk of NTM-PD, with odds ratios ranging from 4.15 for asthma to 21.43 for bronchiectasis. Other conditions significantly associated with NTM-PD risk included history of tuberculosis (odds ratio, 12.69), interstitial lung disease (OR, 6.39), and chronic obstructive pulmonary disease (COPD) (OR, 6.63).
Other factors associated with increased NTM-PD risk included inhaled corticosteroids (OR, 4.46), oral corticosteroids (OR, 3.37), and other immunosuppressants (OR, 2.60). Additional risk factors were use of anti–tumor necrosis factor-alpha for rheumatoid arthritis (OR, 2.13), solid tumors (OR, 4.66), current pneumonia (OR, 5.54), cardiovascular disease (OR, 1.73), and low body mass index (OR, 3.04).
Additional marginal or nonsignificant associations with NTM-PD risk were found for lung function, diabetes, renal disease, cancer, healthy weight, and infection with either Pseudomonas aeruginosa or Staphylococcus aureus.
Possible protective factors, though not significant, included increasing or high BMI and long-term macrolide use.
Bronchiectasis, which is associated with the highest risk of NTM-PD, was assessed in four studies. It was evaluated less frequently because it was often considered a reason for study exclusion, the researchers wrote in their discussion.
“However, many studies report high numbers of patients with nodular bronchiectatic NTM-PD and is suggested to be almost universal in patients with noncavitary NTM-PD,” they said.
The most common risk factors for NTM-PD in the included studies were the use of immunosuppressants, female sex, COPD comorbidity, and history of suspected tuberculosis.
The findings were limited by several factors, including the high level of heterogeneity among the included studies, the lack of data on attributable risk, and inconsistent definitions of NTM-PD, the researchers noted. However, the results may be useful for highlighting risk factors that could be used to identify high-risk patients and to promote early diagnosis and treatment, they said. In addition, long-term studies are needed regarding the impact of multiple potential risk factors on individual risk for NTM-PD among patients with respiratory disease, they concluded.
The study was supported by Insmed BV. Dr. Loebinger has relationships with Insmed, AstraZeneca, Chiesi, Savara, Parion, Zambon, 30T, Electromed, Recode, AN2 Therapeutics, and Armata.
A version of this article first appeared on Medscape.com.
(NTM-PD), data from a systematic review of 99 studies indicate.
NTM-PD is frequently underdiagnosed, and data on specific risk factors are lacking, especially for high-risk individuals with preexisting respiratory diseases, wrote Michael R. Loebinger, PhD, of Imperial College London, and colleagues.
“NTM-PD can be a substantial burden for patients, contributing to lung function decline and reduced health-related quality of life, and is associated with significant morbidity and mortality,” they said.
In a study published in the journal Chest, the researchers identified 99 studies published between 2011 and 2021. Of these, 24 reported an association between risk factors and NTM-PD among patients with respiratory disease compared with patients without NTM-PD and with healthy control persons without NTM-PD; these studies were included in the meta-analysis.
Overall, comorbid respiratory disease was significantly associated with an increased risk of NTM-PD, with odds ratios ranging from 4.15 for asthma to 21.43 for bronchiectasis. Other conditions significantly associated with NTM-PD risk included history of tuberculosis (odds ratio, 12.69), interstitial lung disease (OR, 6.39), and chronic obstructive pulmonary disease (COPD) (OR, 6.63).
Other factors associated with increased NTM-PD risk included inhaled corticosteroids (OR, 4.46), oral corticosteroids (OR, 3.37), and other immunosuppressants (OR, 2.60). Additional risk factors were use of anti–tumor necrosis factor-alpha for rheumatoid arthritis (OR, 2.13), solid tumors (OR, 4.66), current pneumonia (OR, 5.54), cardiovascular disease (OR, 1.73), and low body mass index (OR, 3.04).
Additional marginal or nonsignificant associations with NTM-PD risk were found for lung function, diabetes, renal disease, cancer, healthy weight, and infection with either Pseudomonas aeruginosa or Staphylococcus aureus.
Possible protective factors, though not significant, included increasing or high BMI and long-term macrolide use.
Bronchiectasis, which is associated with the highest risk of NTM-PD, was assessed in four studies. It was evaluated less frequently because it was often considered a reason for study exclusion, the researchers wrote in their discussion.
“However, many studies report high numbers of patients with nodular bronchiectatic NTM-PD and is suggested to be almost universal in patients with noncavitary NTM-PD,” they said.
The most common risk factors for NTM-PD in the included studies were the use of immunosuppressants, female sex, COPD comorbidity, and history of suspected tuberculosis.
The findings were limited by several factors, including the high level of heterogeneity among the included studies, the lack of data on attributable risk, and inconsistent definitions of NTM-PD, the researchers noted. However, the results may be useful for highlighting risk factors that could be used to identify high-risk patients and to promote early diagnosis and treatment, they said. In addition, long-term studies are needed regarding the impact of multiple potential risk factors on individual risk for NTM-PD among patients with respiratory disease, they concluded.
The study was supported by Insmed BV. Dr. Loebinger has relationships with Insmed, AstraZeneca, Chiesi, Savara, Parion, Zambon, 30T, Electromed, Recode, AN2 Therapeutics, and Armata.
A version of this article first appeared on Medscape.com.
(NTM-PD), data from a systematic review of 99 studies indicate.
NTM-PD is frequently underdiagnosed, and data on specific risk factors are lacking, especially for high-risk individuals with preexisting respiratory diseases, wrote Michael R. Loebinger, PhD, of Imperial College London, and colleagues.
“NTM-PD can be a substantial burden for patients, contributing to lung function decline and reduced health-related quality of life, and is associated with significant morbidity and mortality,” they said.
In a study published in the journal Chest, the researchers identified 99 studies published between 2011 and 2021. Of these, 24 reported an association between risk factors and NTM-PD among patients with respiratory disease compared with patients without NTM-PD and with healthy control persons without NTM-PD; these studies were included in the meta-analysis.
Overall, comorbid respiratory disease was significantly associated with an increased risk of NTM-PD, with odds ratios ranging from 4.15 for asthma to 21.43 for bronchiectasis. Other conditions significantly associated with NTM-PD risk included history of tuberculosis (odds ratio, 12.69), interstitial lung disease (OR, 6.39), and chronic obstructive pulmonary disease (COPD) (OR, 6.63).
Other factors associated with increased NTM-PD risk included inhaled corticosteroids (OR, 4.46), oral corticosteroids (OR, 3.37), and other immunosuppressants (OR, 2.60). Additional risk factors were use of anti–tumor necrosis factor-alpha for rheumatoid arthritis (OR, 2.13), solid tumors (OR, 4.66), current pneumonia (OR, 5.54), cardiovascular disease (OR, 1.73), and low body mass index (OR, 3.04).
Additional marginal or nonsignificant associations with NTM-PD risk were found for lung function, diabetes, renal disease, cancer, healthy weight, and infection with either Pseudomonas aeruginosa or Staphylococcus aureus.
Possible protective factors, though not significant, included increasing or high BMI and long-term macrolide use.
Bronchiectasis, which is associated with the highest risk of NTM-PD, was assessed in four studies. It was evaluated less frequently because it was often considered a reason for study exclusion, the researchers wrote in their discussion.
“However, many studies report high numbers of patients with nodular bronchiectatic NTM-PD and is suggested to be almost universal in patients with noncavitary NTM-PD,” they said.
The most common risk factors for NTM-PD in the included studies were the use of immunosuppressants, female sex, COPD comorbidity, and history of suspected tuberculosis.
The findings were limited by several factors, including the high level of heterogeneity among the included studies, the lack of data on attributable risk, and inconsistent definitions of NTM-PD, the researchers noted. However, the results may be useful for highlighting risk factors that could be used to identify high-risk patients and to promote early diagnosis and treatment, they said. In addition, long-term studies are needed regarding the impact of multiple potential risk factors on individual risk for NTM-PD among patients with respiratory disease, they concluded.
The study was supported by Insmed BV. Dr. Loebinger has relationships with Insmed, AstraZeneca, Chiesi, Savara, Parion, Zambon, 30T, Electromed, Recode, AN2 Therapeutics, and Armata.
A version of this article first appeared on Medscape.com.
Proteomics reveals potential targets for drug-resistant TB
TOPLINE:
Downregulation of plasma exosome-derived apolipoproteins APOA1, APOB, and APOC1 indicates DR-TB status and lipid metabolism regulation in pathogenesis.
METHODOLOGY:
Group case-controlled study assessed 17 drug resistant tuberculosis (DR-TB) and 33 non–drug resistant TB (NDR-TB) patients at The Fourth People’s Hospital of Taiyuan, China, from November 2018 to March 2019.
Plasma exosome purity and quality was determined by transmission electron microscopy, nanoparticle tracking analysis, and Western blot markers.
Proteins purified from plasma exosomes were characterized by SDS-Page with Western blotting and liquid chromatography coupled with tandem mass spectrometry techniques.
Functional proteomic differential analysis was achieved using the UniProt-GOA, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases.
TAKEAWAYS:
DR-TB patients tended to be older than NDR-TB patients.
Isolated plasma exosomes were morphologically characterized as being “close to pure.”
Differential gene expression analysis revealed 16 upregulated and 10 downregulated proteins from DR-TB compared with NDR-TB patient-derived plasma exosomes.
through their functions in lipid metabolism and protein transport.
IN PRACTICE:
Key apolipoproteins “may be involved in the pathogenesis of DR-TB via accelerating the formation of foamy macrophages and reducing the cellular uptake of anti-TB drugs.”
STUDY DETAILS:
The study led by Mingrui Wu of Shanxi (China) Medical University and colleagues was published in the July 2023 issue of Tuberculosis.
LIMITATIONS:
This study is limited by an enrollment bias of at least twice as many men to women patients for both DR-TB and NDR-TB categories, reporting of some incomplete data collection characterizing the study population, and small sample size, which did not permit stratified analysis of the five types of DR-TB.
DISCLOSURES:
The authors report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
TOPLINE:
Downregulation of plasma exosome-derived apolipoproteins APOA1, APOB, and APOC1 indicates DR-TB status and lipid metabolism regulation in pathogenesis.
METHODOLOGY:
Group case-controlled study assessed 17 drug resistant tuberculosis (DR-TB) and 33 non–drug resistant TB (NDR-TB) patients at The Fourth People’s Hospital of Taiyuan, China, from November 2018 to March 2019.
Plasma exosome purity and quality was determined by transmission electron microscopy, nanoparticle tracking analysis, and Western blot markers.
Proteins purified from plasma exosomes were characterized by SDS-Page with Western blotting and liquid chromatography coupled with tandem mass spectrometry techniques.
Functional proteomic differential analysis was achieved using the UniProt-GOA, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases.
TAKEAWAYS:
DR-TB patients tended to be older than NDR-TB patients.
Isolated plasma exosomes were morphologically characterized as being “close to pure.”
Differential gene expression analysis revealed 16 upregulated and 10 downregulated proteins from DR-TB compared with NDR-TB patient-derived plasma exosomes.
through their functions in lipid metabolism and protein transport.
IN PRACTICE:
Key apolipoproteins “may be involved in the pathogenesis of DR-TB via accelerating the formation of foamy macrophages and reducing the cellular uptake of anti-TB drugs.”
STUDY DETAILS:
The study led by Mingrui Wu of Shanxi (China) Medical University and colleagues was published in the July 2023 issue of Tuberculosis.
LIMITATIONS:
This study is limited by an enrollment bias of at least twice as many men to women patients for both DR-TB and NDR-TB categories, reporting of some incomplete data collection characterizing the study population, and small sample size, which did not permit stratified analysis of the five types of DR-TB.
DISCLOSURES:
The authors report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
TOPLINE:
Downregulation of plasma exosome-derived apolipoproteins APOA1, APOB, and APOC1 indicates DR-TB status and lipid metabolism regulation in pathogenesis.
METHODOLOGY:
Group case-controlled study assessed 17 drug resistant tuberculosis (DR-TB) and 33 non–drug resistant TB (NDR-TB) patients at The Fourth People’s Hospital of Taiyuan, China, from November 2018 to March 2019.
Plasma exosome purity and quality was determined by transmission electron microscopy, nanoparticle tracking analysis, and Western blot markers.
Proteins purified from plasma exosomes were characterized by SDS-Page with Western blotting and liquid chromatography coupled with tandem mass spectrometry techniques.
Functional proteomic differential analysis was achieved using the UniProt-GOA, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING databases.
TAKEAWAYS:
DR-TB patients tended to be older than NDR-TB patients.
Isolated plasma exosomes were morphologically characterized as being “close to pure.”
Differential gene expression analysis revealed 16 upregulated and 10 downregulated proteins from DR-TB compared with NDR-TB patient-derived plasma exosomes.
through their functions in lipid metabolism and protein transport.
IN PRACTICE:
Key apolipoproteins “may be involved in the pathogenesis of DR-TB via accelerating the formation of foamy macrophages and reducing the cellular uptake of anti-TB drugs.”
STUDY DETAILS:
The study led by Mingrui Wu of Shanxi (China) Medical University and colleagues was published in the July 2023 issue of Tuberculosis.
LIMITATIONS:
This study is limited by an enrollment bias of at least twice as many men to women patients for both DR-TB and NDR-TB categories, reporting of some incomplete data collection characterizing the study population, and small sample size, which did not permit stratified analysis of the five types of DR-TB.
DISCLOSURES:
The authors report no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
New drugs in primary care: Lessons learned from COVID-19
SAN DIEGO – – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.
Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.
Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
Understanding the mechanism of action
Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.
“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.
“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.
Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.
Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.
Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.
When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.
Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.
“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.
Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
Effective in real world, but less so than in clinical trials
The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.
A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
Many drug-drug interactions, but they can be managed
Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.
To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.
This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.
To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:
- Prescribe an alternative COVID therapy.
- Temporarily withhold concomitant medication if clinically appropriate.
- Adjust the dose of concomitant medication and monitor for adverse effects.
Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
Important considerations
Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.
He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.
Dr. Smetana and Dr. Kiefl reported no disclosures.
SAN DIEGO – – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.
Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.
Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
Understanding the mechanism of action
Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.
“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.
“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.
Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.
Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.
Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.
When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.
Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.
“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.
Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
Effective in real world, but less so than in clinical trials
The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.
A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
Many drug-drug interactions, but they can be managed
Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.
To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.
This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.
To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:
- Prescribe an alternative COVID therapy.
- Temporarily withhold concomitant medication if clinically appropriate.
- Adjust the dose of concomitant medication and monitor for adverse effects.
Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
Important considerations
Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.
He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.
Dr. Smetana and Dr. Kiefl reported no disclosures.
SAN DIEGO – – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.
Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.
Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
Understanding the mechanism of action
Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.
“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.
“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.
Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.
Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.
Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.
When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.
Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.
“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.
Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
Effective in real world, but less so than in clinical trials
The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.
A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
Many drug-drug interactions, but they can be managed
Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.
To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.
This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.
To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:
- Prescribe an alternative COVID therapy.
- Temporarily withhold concomitant medication if clinically appropriate.
- Adjust the dose of concomitant medication and monitor for adverse effects.
Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
Important considerations
Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.
He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.
Dr. Smetana and Dr. Kiefl reported no disclosures.
AT INTERNAL MEDICINE 2023
Tyrosine kinase inhibitors – a new weapon against respiratory viruses?
Five different nonreceptor tyrosine kinase inhibitors were effective against viral replication of pandemic viruses and seasonal influenza viruses in an ex vivo lung model.
Influenza viruses remain a high cause of morbidity and mortality worldwide as viral mutations outwit vaccine efficacy, Robert Meineke, PhD, of the University of Veterinary Medicine in Hannover, Germany, and colleagues wrote.
“As with previous influenza pandemics and the current SARS-CoV-2 pandemic, effective vaccines are not readily available at early stages of a pandemic,” they noted. To help manage the limitations of timing and effectiveness of current vaccines, the researchers proposed repurposing nonreceptor tyrosine kinase inhibitors (NRTKIs) to block seasonal flu and COVID-19 viral replication.
In a study published in iScience, the researchers identified six NRTKIs currently approved by the U.S. Food and Drug Administration that showed in vitro inhibition of both pandemic viruses (H1N1) and seasonal influenza viruses (H3N2). These included defactinib, acalabrutinib, saracatinib, and bosutinib, all of which reduced hPCLS infectivity by approximately 50%. In addition, ibrutinib and bosutinib had the largest impact on viral titers. The antiviral effects of NRTKIs appeared to be independent of multiplicity of infection.
The researchers then tested the NRIKIs on an ex vivo model of human precision-cut lung slices to validate the effects of NRTKIs as antivirals against influenza A viruses (IAVs).
In this model, the highest peak titers were achieved at 48 hpi following infection with virus strains NL09 and NL11. The hPCLS models also showed consistent tolerability to 1x concentrations. “Our cytotoxicity cut-off was 20% of the positive control treatment; none of the NRTKIs surpassed this cutoff at [1x] max,” the researchers wrote.
Five of the six identified NRTKIs were validated in the ex vivo setting. All five reduced viral titers by at least 10-fold to more than 1,000-fold. Of these, ibrutinib, bosutinib, and bosutinib showed a significant effect at all concentrations, while treatments with acalabrutinib and defactinib were significant at 24 hpi and 48 hpi. The NRTKs also showed a high genetic barrier against emerging resistant virus mutations.
The study demonstrates the ability of NRTKIs to target kinases required for replication of IAV, the researchers wrote, and that NRTKIs “represent promising drugs for the development of the next generation of antivirals.”
More research is needed to determine the therapeutic window given that NRTKIs are targeting host factors versus virus-targeted antivirals, but the advantages of NRTKIs include localized delivery that can limit possible cytotoxic effects, and their safety and bioavailability are well established, they said.
The findings were limited by several factors including the use of lung tissue mainly from older donors with lung cancer, the researchers noted. However, this population could be considered at increased risk for IAVs and therefore the data are more clinically applicable.
In addition, “because many viruses utilize the same (or related) host kinases to facilitate replication and transmission, our studies have broader implications for the potential use of these SMKIs to treat infections by other viruses,” they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Five different nonreceptor tyrosine kinase inhibitors were effective against viral replication of pandemic viruses and seasonal influenza viruses in an ex vivo lung model.
Influenza viruses remain a high cause of morbidity and mortality worldwide as viral mutations outwit vaccine efficacy, Robert Meineke, PhD, of the University of Veterinary Medicine in Hannover, Germany, and colleagues wrote.
“As with previous influenza pandemics and the current SARS-CoV-2 pandemic, effective vaccines are not readily available at early stages of a pandemic,” they noted. To help manage the limitations of timing and effectiveness of current vaccines, the researchers proposed repurposing nonreceptor tyrosine kinase inhibitors (NRTKIs) to block seasonal flu and COVID-19 viral replication.
In a study published in iScience, the researchers identified six NRTKIs currently approved by the U.S. Food and Drug Administration that showed in vitro inhibition of both pandemic viruses (H1N1) and seasonal influenza viruses (H3N2). These included defactinib, acalabrutinib, saracatinib, and bosutinib, all of which reduced hPCLS infectivity by approximately 50%. In addition, ibrutinib and bosutinib had the largest impact on viral titers. The antiviral effects of NRTKIs appeared to be independent of multiplicity of infection.
The researchers then tested the NRIKIs on an ex vivo model of human precision-cut lung slices to validate the effects of NRTKIs as antivirals against influenza A viruses (IAVs).
In this model, the highest peak titers were achieved at 48 hpi following infection with virus strains NL09 and NL11. The hPCLS models also showed consistent tolerability to 1x concentrations. “Our cytotoxicity cut-off was 20% of the positive control treatment; none of the NRTKIs surpassed this cutoff at [1x] max,” the researchers wrote.
Five of the six identified NRTKIs were validated in the ex vivo setting. All five reduced viral titers by at least 10-fold to more than 1,000-fold. Of these, ibrutinib, bosutinib, and bosutinib showed a significant effect at all concentrations, while treatments with acalabrutinib and defactinib were significant at 24 hpi and 48 hpi. The NRTKs also showed a high genetic barrier against emerging resistant virus mutations.
The study demonstrates the ability of NRTKIs to target kinases required for replication of IAV, the researchers wrote, and that NRTKIs “represent promising drugs for the development of the next generation of antivirals.”
More research is needed to determine the therapeutic window given that NRTKIs are targeting host factors versus virus-targeted antivirals, but the advantages of NRTKIs include localized delivery that can limit possible cytotoxic effects, and their safety and bioavailability are well established, they said.
The findings were limited by several factors including the use of lung tissue mainly from older donors with lung cancer, the researchers noted. However, this population could be considered at increased risk for IAVs and therefore the data are more clinically applicable.
In addition, “because many viruses utilize the same (or related) host kinases to facilitate replication and transmission, our studies have broader implications for the potential use of these SMKIs to treat infections by other viruses,” they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Five different nonreceptor tyrosine kinase inhibitors were effective against viral replication of pandemic viruses and seasonal influenza viruses in an ex vivo lung model.
Influenza viruses remain a high cause of morbidity and mortality worldwide as viral mutations outwit vaccine efficacy, Robert Meineke, PhD, of the University of Veterinary Medicine in Hannover, Germany, and colleagues wrote.
“As with previous influenza pandemics and the current SARS-CoV-2 pandemic, effective vaccines are not readily available at early stages of a pandemic,” they noted. To help manage the limitations of timing and effectiveness of current vaccines, the researchers proposed repurposing nonreceptor tyrosine kinase inhibitors (NRTKIs) to block seasonal flu and COVID-19 viral replication.
In a study published in iScience, the researchers identified six NRTKIs currently approved by the U.S. Food and Drug Administration that showed in vitro inhibition of both pandemic viruses (H1N1) and seasonal influenza viruses (H3N2). These included defactinib, acalabrutinib, saracatinib, and bosutinib, all of which reduced hPCLS infectivity by approximately 50%. In addition, ibrutinib and bosutinib had the largest impact on viral titers. The antiviral effects of NRTKIs appeared to be independent of multiplicity of infection.
The researchers then tested the NRIKIs on an ex vivo model of human precision-cut lung slices to validate the effects of NRTKIs as antivirals against influenza A viruses (IAVs).
In this model, the highest peak titers were achieved at 48 hpi following infection with virus strains NL09 and NL11. The hPCLS models also showed consistent tolerability to 1x concentrations. “Our cytotoxicity cut-off was 20% of the positive control treatment; none of the NRTKIs surpassed this cutoff at [1x] max,” the researchers wrote.
Five of the six identified NRTKIs were validated in the ex vivo setting. All five reduced viral titers by at least 10-fold to more than 1,000-fold. Of these, ibrutinib, bosutinib, and bosutinib showed a significant effect at all concentrations, while treatments with acalabrutinib and defactinib were significant at 24 hpi and 48 hpi. The NRTKs also showed a high genetic barrier against emerging resistant virus mutations.
The study demonstrates the ability of NRTKIs to target kinases required for replication of IAV, the researchers wrote, and that NRTKIs “represent promising drugs for the development of the next generation of antivirals.”
More research is needed to determine the therapeutic window given that NRTKIs are targeting host factors versus virus-targeted antivirals, but the advantages of NRTKIs include localized delivery that can limit possible cytotoxic effects, and their safety and bioavailability are well established, they said.
The findings were limited by several factors including the use of lung tissue mainly from older donors with lung cancer, the researchers noted. However, this population could be considered at increased risk for IAVs and therefore the data are more clinically applicable.
In addition, “because many viruses utilize the same (or related) host kinases to facilitate replication and transmission, our studies have broader implications for the potential use of these SMKIs to treat infections by other viruses,” they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM ISCIENCE
COVID can mimic prostate cancer symptoms
This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter painkillers are not helping, you’d think, “check for metastases,” right?
That patient was me in late January 2023.
As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.
With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.
To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6.
But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit.
The COVID effect
I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study2 of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.
Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.
That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
COVID-19 pain
What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies3 have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.
To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.
References
1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.
2. Cinislioglu AE et al. Urology. 2022;159:16-21.
3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.
Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.
A version of this article first appeared on Medscape.com.
This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter painkillers are not helping, you’d think, “check for metastases,” right?
That patient was me in late January 2023.
As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.
With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.
To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6.
But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit.
The COVID effect
I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study2 of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.
Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.
That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
COVID-19 pain
What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies3 have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.
To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.
References
1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.
2. Cinislioglu AE et al. Urology. 2022;159:16-21.
3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.
Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.
A version of this article first appeared on Medscape.com.
This patient has a strong likelihood of aggressive prostate cancer, right? If that same patient also presents with severe, burning bone pain with no precipitating trauma to the area and rest and over-the-counter painkillers are not helping, you’d think, “check for metastases,” right?
That patient was me in late January 2023.
As a research scientist member of the American Urological Association, I knew enough to know I had to consult my urologist ASAP.
With the above symptoms, I’ll admit I was scared. Fortunately, if that’s the right word, I was no stranger to a rapid, dramatic spike in PSA. In 2021 I was temporarily living in a new city, and I wanted to form a relationship with a good local urologist. The urologist that I was referred to gave me a thorough consultation, including a vigorous digital rectal exam (DRE) and sent me across the street for a blood draw.
To my shock, my PSA had spiked over 2 points, to 9.9 from 7.8 a few months earlier. I freaked. Had my 3-cm tumor burst out into an aggressive cancer? Research on PubMed provided an array of studies showing what could cause PSA to suddenly rise, including a DRE performed 72 hours before the blood draw.1 A week later, my PSA was back down to its normal 7.6.
But in January 2023, I had none of those previously reported experiences that could suddenly trigger a spike in PSA, like a DRE or riding on a thin bicycle seat for a few hours before the lab visit.
The COVID effect
I went back to PubMed and found a new circumstance that could cause a surge in PSA: COVID-19. A recent study2 of 91 men with benign prostatic hypertrophy by researchers in Turkey found that PSA spiked from 0 to 5 points during the COVID infection period and up to 2 points higher 3 months after the infection had cleared. I had tested positive for COVID-19 in mid-December 2022, 4 weeks before my 9.9 PSA reading.
Using Google translate, I communicated with the team in Turkey and found out that the PSA spike can last up to 6 months.
That study helps explain why my PSA dropped over 1.5 points to 8.5 just 2 weeks after the 9.9 reading, with the expectation that it would return to its previous normal of 7.8 within 6 months of infection with SARS-CoV-2. To be safe, my urologist scheduled another PSA test in May, along with an updated multiparametric MRI, which may be followed by an in-bore MRI-guided biopsy of the 3-cm tumor if the mass has enlarged.
COVID-19 pain
What about my burning bone pain in my upper right humerus and right rotator cuff that was not precipitated by trauma or strain? A radiograph found no evidence of metastasis, thank goodness. And my research showed that several studies3 have found that COVID-19 can cause burning musculoskeletal pain, including enthesopathy, which is what I had per the radiology report. So my PSA spike and searing pain were likely consequences of the infection.
To avoid the risk for a gross misdiagnosis after a radical spike in PSA, the informed urologist should ask the patient if he has had COVID-19 in the previous 6 months. Overlooking that question could lead to the wrong diagnostic decisions about a rapid jump in PSA or unexplained bone pain.
References
1. Bossens MM et al. Eur J Cancer. 1995;31A:682-5.
2. Cinislioglu AE et al. Urology. 2022;159:16-21.
3. Ciaffi J et al. Joint Bone Spine. 2021;88:105158.
Dr. Keller is founder of the Keller Research Institute, Jacksonville, Fla. He reported serving as a research scientist for the American Urological Association, serving on the advisory board of Active Surveillance Patient’s International, and serving on the boards of numerous nonprofit organizations.
A version of this article first appeared on Medscape.com.
NOVIDs: Do some have the genes to dodge COVID?
As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.
There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”
Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.
He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
How many NOVIDs?
As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.
As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.
But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.
Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
Resistance research
In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”
Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.
Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.
“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’
“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.
He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.
“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.
Genetic resistance has been found for other diseases, such as HIV.
“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.
However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”
What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”
Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.
The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.
The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
The testing ... or lack thereof factor
The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.
“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”
Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
Susceptibility research
“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.
Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.
More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
NOVIDs’ habits run the gamut
As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.
Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.
He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”
And does he worry his number will eventually be up? “Not at this point, no,” he said.
Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.
“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”
However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.
Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.
Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.
Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.
When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”
One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.
In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.
She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”
Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.
At this point, she said she doesn’t worry about getting infected but remains careful.
Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
Bragging rights?
Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it.
And what about those who wear a “NOVID” T-shirt?
“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”
Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.
Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■
A version of this article first appeared on Medscape.com.
As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.
There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”
Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.
He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
How many NOVIDs?
As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.
As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.
But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.
Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
Resistance research
In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”
Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.
Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.
“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’
“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.
He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.
“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.
Genetic resistance has been found for other diseases, such as HIV.
“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.
However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”
What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”
Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.
The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.
The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
The testing ... or lack thereof factor
The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.
“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”
Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
Susceptibility research
“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.
Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.
More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
NOVIDs’ habits run the gamut
As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.
Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.
He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”
And does he worry his number will eventually be up? “Not at this point, no,” he said.
Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.
“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”
However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.
Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.
Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.
Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.
When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”
One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.
In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.
She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”
Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.
At this point, she said she doesn’t worry about getting infected but remains careful.
Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
Bragging rights?
Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it.
And what about those who wear a “NOVID” T-shirt?
“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”
Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.
Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■
A version of this article first appeared on Medscape.com.
As a field service representative for a slot machine company, Ryan Alexander, 37, of Louisville, Ky., spends his working hours in casinos, covering a large territory including Norfolk, Va., Indianapolis, and Charlotte. Social distancing in the casinos is not the norm. Despite all this up-close contact with people, he said he is still COVID-free, 3 years into the pandemic.
There was one nervous night when his temperature rose to 101° F, and he figured the virus had caught up with him. “I took a test and was fine,” he said, relieved that the result was negative. The fever disappeared, and he was back to normal soon. “Maybe it was just an exhausting day.”
Mr. Alexander is one of those people who have managed – or at least think they have managed – to avoid getting COVID-19.
He is, some say, a NOVID. While some scientists cringe at the term, it’s caught on to describe these virus super-dodgers. Online entrepreneurs offer NOVID-19 T-shirts, masks, and stickers, in case these super-healthy or super-lucky folks want to publicize their good luck. On Twitter, NOVIDs share stories of how they’ve done it.
How many NOVIDs?
As of March 16, according to the CDC, almost 104 million cases of COVID – about one-third of the U.S. population – have been reported, but many cases are known to go unreported. About half of American adults surveyed said they have had COVID, according to a December report by the COVID States Project, a multiuniversity effort to supply pandemic data.
As the numbers settle over time, though, it becomes clearer that some in the U.S. have apparently managed to avoid the virus.
But some scientists bristle at the term NOVIDs. They prefer the term “resisters,” according to Elena Hsieh, MD, associate professor of pediatrics and immunology at the University of Colorado at Denver, Aurora. Currently, she said, there is much more information on who is more susceptible to contracting severe COVID than who is resistant.
Dr. Hsieh is one of the regional coordinators for the COVID Human Genetic Effort, an international consortium of more than 250 researchers and doctors dedicated to discovering the genetic and immunological bases of the forms of SARS-CoV-2 infection. These researchers and others are looking for explanations for why some people get severe COVID while others seem resistant despite repeated exposure.
Resistance research
In determining explanations for resistance to infection, “the needle in the haystack that we are looking for is a change in the genetic code that would allow for you to avoid entry of the virus into the cell,” Dr. Hsieh said. “That is what being resistant to infection is.”
Part of the reason it’s so difficult to study resistance is defining a resister, she said. While many people consider themselves among that group because they’re been exposed multiple times – even with close family members infected and sick, yet they still felt fine – that doesn’t necessarily make them a resister, she said.
Those people could have been infected but remained without symptoms. “Resistance means the virus was inside you, it was near your cell and it did not infect your cell,” Dr. Hsieh said.
“I don’t think we know a lot so far,” Dr. Hsieh said about resisters. “I do believe that, just like there are genetic defects that make someone more susceptible, there are likely to be genetic defects that make somebody less susceptible.’’
“To identify genetic variants that are protective is a really challenging thing to do,” agreed Peter K. Gregersen, MD, professor of genetics at the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, N.Y. Dr. Gregersen is also a regional coordinator for the COVID Human Genetic Effort.
He suspects the number found to be truly resistant to COVID – versus dodging it so far – is going to be very small or not found at all.
“It may exist for COVID or it may not,” he said. Some people may simply have what he calls a robust immune response in the upper part of the throat, perhaps killing off the virus quickly as soon as it enters, so they don’t get a positive test.
Genetic resistance has been found for other diseases, such as HIV.
“For HIV, scientists have been able to identify a specific gene that codes for a protein that can prevent individuals from getting infected,” said Sabrina Assoumou, MD, MPH, professor of medicine at Boston University, who researches HIV.
However, she said, “we haven’t yet found a similar gene or protein that can prevent people from getting infected with SARS-CoV-2.”
What has been found “is that some people might have a mutation in a gene that encodes for what’s called human leukocyte antigen (HLA),” Dr. Assoumou said. HLA, a molecule found on the surface of most cells, has a crucial role in the immune response to foreign substances. “A mutation in HLA can make people less likely to have symptoms if they get infected. Individuals still get infected, but they are less likely to have symptoms.”
Other research has found that those with food allergies are also less likely to be infected. The researchers have speculated that the inflammation characteristic of allergic conditions may reduce levels of a protein called the ACE2 receptor on the surface of airway cells. The SARS-CoV-2 virus uses the receptor to enter the cells, so if levels are low, that could reduce the ability of the virus to infect people.
The COVID Human Genetic Effort continues to search for participants, both those who were admitted to a hospital or repeatedly seen at a hospital because of COVID, as well as those who did not get infected, even after “intense and repeated” exposure.
The number of people likely to be resistant is much smaller, Dr. Hsieh said, than the number of people susceptible to severe disease.
The testing ... or lack thereof factor
The timing of testing and a person’s “infection profile” may be factors in people incorrectly declaring themselves NOVIDs, said Anne Wyllie, PhD, a research scientist in epidemiology at the Yale School of Public Health in New Haven, Conn., and a codeveloper of a saliva PCR test for COVID.
“Infection profiles can vary between individuals,” she said. For some, the infection may start in the lower respiratory tract, others in the higher respiratory tract. “Depending on where the virus takes up residence, that can affect test results.”
Then there’s the following-instructions factor. “It’s very likely that due to tests not being done at the right time, with the right sample, or not repeated if there is ongoing evidence of symptoms, that there are individuals out there who believe they are NOVIDs but just missed catching their infection at the window of opportunity.” Dr. Wyllie said.
Susceptibility research
“The part we have proven is the genetic defect that would make you more susceptible to having severe disease,” Dr. Hsieh said.
Many published papers report that inherited and/or autoimmune deficiencies of type I interferon immunity, important for combating viral infections and modulating the immune response, can be a significant cause of life-threatening COVID pneumonia.
More recently, researchers, including Jean-Laurent Casanova, MD, PhD, professor at Rockefeller University, New York, and cofounder of the COVID Human Genome Effort, reported that deficiencies in a gene that plays a role in built-in immunity (the early response), and a gene involved in signaling within the immune cells, impair interferon production and may be the basis of severe COVID pneumonia.
NOVIDs’ habits run the gamut
As scientists continue their research, the NOVIDs have their own ideas about why they’ve dodged the pandemic bullet, and they have a variety of approaches to handling the pandemic now.
Ryan Alexander, the field rep who travels to casinos, is up to date on his vaccinations and has gotten all the recommended COVID shots. “I was wearing a mask when told to wear masks,” he said.
He still observes the social distance habit but lives life. “I’ve been to three or four concerts in the past couple of years.”
And does he worry his number will eventually be up? “Not at this point, no,” he said.
Joe Asher, 46, said he has not gotten COVID despite being in contact with about 100 people a day, on average. He works as a bartender at an Evansville, Ind., brewery.
“On a Friday night, we can get 500 people,” he said. “I feel like almost everyone at the brewery got it. There’s no way I wasn’t exposed to it all the time.”
However, he said, his coworkers who did get sick were very cautious about not infecting others, partly to help protect a coworker’s family with newborn twins, so that may have helped him stay uninfected, too.
Mr. Asher said he’s in good physical shape, and he’s worked around the public for a long time, so figures maybe that has strengthened his immune system. He’s always been careful about handwashing and said he’s perhaps a bit more conscious of germs than others might be.
Roselyn Mena, 68, a retired teacher in Richmond, Calif., about 16 miles northeast of San Francisco, said she’s managed to avoid the virus even though her husband, Jesus Mena, got infected, as did her two adult children. Now, she remains vigilant about wearing a mask. She tries not to eat inside at restaurants. “I’m super careful,” she said.
Besides her teacher training, Ms. Mena had training as a medical assistant and learned a lot about sanitizing methods. She gets an annual flu shot, washes her hands often, and uses hand sanitizer.
When she shops, she will ask salespeople not wearing masks to please mask. “Only one refused, and she got someone else [to wait on her].”
One reason she is always careful about hygiene, Ms. Mena said, is that “when I get a cold, I get really sick. It last and lasts.” Now, she does worry she might still get it, she said, with the prospect of getting long COVID driving that worry.
In the beginning of the pandemic, Rhonda Fleming, 68, of Los Angeles, lived in a “COVID bubble,” interacting with just a few close family members. As cases went down, she enlarged the bubble. Her two grown daughters got infected, but her granddaughter did not.
She has been vigilant about masking, she said, “and I do still mask in public places.” She has a mask wardrobe, including basic black as well as glittery masks for dressier occasions. “I always carry a mask because inevitably, a cougher surrounds me.”
Now, she will bypass restaurants if she doesn’t feel comfortable with the environment, choosing ones with good air flow. When she flew to Mexico recently, she masked on the plane.
At this point, she said she doesn’t worry about getting infected but remains careful.
Recently, two friends, who have been as diligent as she has about precautions, got infected, “and they don’t know how they got it.”
Bragging rights?
Until researchers separate out the true resisters from those who claim to be, some NOVIDs are simply quietly grateful for their luck, while others mention their COVID-free status to anyone who asks or who will listen, and are proud of it.
And what about those who wear a “NOVID” T-shirt?
“I would think they have a need to convey to the world they are different, perhaps special, because they beat COVID,” said Richard B. Joelson, a New York–based doctor of social work, a psychotherapist, and the author of Help Me! A Psychotherapist’s Tried-and-True Techniques for a Happier Relationship with Yourself and the People You Love. “They didn’t beat COVID, they just didn’t get it.”
Or they may be relieved they didn’t get sick, he said, because they feel defeated when they do. So “it’s a source of pride.” It might be the same people who tell anyone who will listen they never need a doctor or take no medicines, he said.
Even though science may prove many NOVIDs are inaccurate when they call themselves resisters, Dr. Hsieh understands the temptation to talk about it. “It’s kind of cool to think you are supernatural,” she said. “It’s much more attractive than being susceptible. It’s a lot sexier.” ■
A version of this article first appeared on Medscape.com.
Factors linked with increased VTE risk in COVID outpatients
Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.
The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
Nearly 400,000 patients studied
Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.
VTE risk was low overall for ambulatory COVID patients.
“It is a reassuring study,” Dr. Fang said in an interview.
The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
Factors linked with high VTE risk
They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m2.
The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
Are routine anticoagulants justified?
Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.
“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
Mild COVID VTE risk similar to general population
The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.
Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.
Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
Physicians should inform patients of their higher risk
“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.
”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.
Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
Unanswered questions
Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.
However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.
One is the change in the COVID variant landscape.
“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.
The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.
Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”
Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.
Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.
The research was funded through Patient-Centered Outcomes Research Institute.
Dr. Hopkins reports no relevant financial relationships.
Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.
The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
Nearly 400,000 patients studied
Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.
VTE risk was low overall for ambulatory COVID patients.
“It is a reassuring study,” Dr. Fang said in an interview.
The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
Factors linked with high VTE risk
They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m2.
The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
Are routine anticoagulants justified?
Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.
“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
Mild COVID VTE risk similar to general population
The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.
Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.
Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
Physicians should inform patients of their higher risk
“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.
”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.
Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
Unanswered questions
Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.
However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.
One is the change in the COVID variant landscape.
“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.
The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.
Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”
Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.
Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.
The research was funded through Patient-Centered Outcomes Research Institute.
Dr. Hopkins reports no relevant financial relationships.
Though VTE risk is well studied and significant in those hospitalized with COVID, little is known about the risk in the outpatient setting, said the authors of the new research published online in JAMA Network Open.
The study was conducted at two integrated health care delivery systems in northern and southern California. Data were gathered from the Kaiser Permanente Virtual Data Warehouse and electronic health records.
Nearly 400,000 patients studied
Researchers, led by Margaret Fang, MD, with the division of hospital medicine, University of California, San Francisco, identified 398,530 outpatients with COVID-19 from Jan. 1, 2020, through Jan. 31, 2021.
VTE risk was low overall for ambulatory COVID patients.
“It is a reassuring study,” Dr. Fang said in an interview.
The researchers found that the risk is highest in the first 30 days after COVID-19 diagnosis (unadjusted rate, 0.58; 95% confidence interval, 0.51-0.67 per 100 person-years vs. 0.09; 95% CI, 0.08-0.11 per 100 person-years after 30 days).
Factors linked with high VTE risk
They also found that several factors were linked with a higher risk of blood clots in the study population, including being at least 55 years old; being male; having a history of blood clots or thrombophilia; and a body mass index (BMI) of at least 30 kg/m2.
The authors write, “These findings may help identify subsets of patients with COVID-19 who could benefit from VTE preventive strategies and more intensive short-term surveillance.”
Are routine anticoagulants justified?
Previously, randomized clinical trials have found that hospitalized patients with moderate COVID-19 may benefit from therapeutically dosed heparin anticoagulants but that therapeutic anticoagulation had no net benefit – and perhaps could even harm – patients who were critically ill with COVID.
“[M]uch less is known about the optimal thromboprophylaxis strategy for people with milder presentations of COVID-19 who do not require hospitalization,” they write.
Mild COVID VTE risk similar to general population
The authors note that rates of blood clots linked with COVID-19 are not much higher than the average blood clot rate in the general population, which is about 0.1-0.2 per 100 person-years.
Therefore, the results don’t justify routine administration of anticoagulation given the costs, inconvenience, and bleeding risks, they acknowledge.
Dr. Fang told this publication that it’s hard to know what to tell patients, given the overall low VTE risk. She said their study wasn’t designed to advise when to give prophylaxis.
Physicians should inform patients of their higher risk
“We should tell our patients who fall into these risk categories that blood clot is a concern after the development of COVID, especially in those first 30 days. And some people might benefit from increased surveillance,” Dr. Fang said.
”I think this study would support ongoing studies that look at whether selected patients benefit from VTE prophylaxis, for example low-dose anticoagulants,” she said.
Dr. Fang said the subgroup factors they found increased risk of blood clots for all patients, not just COVID-19 patients. It’s not clear why factors such as being male may increase blood clot risk, though that is consistent with previous literature, but higher risk with higher BMI might be related to a combination of inflammation or decreased mobility, she said.
Unanswered questions
Robert H. Hopkins Jr., MD, says the study helps answer a couple of important questions – that the VTE risk in nonhospitalized COVID-19 patients is low and when and for which patients risk may be highest.
However, there are several unanswered questions that argue against routine initiation of anticoagulants, notes the professor of internal medicine and pediatrics chief, division of general internal medicine, at University of Arkansas for Medical Sciences, Little Rock.
One is the change in the COVID variant landscape.
“We do not know whether rates of VTE are same or lower or higher with current circulating variants,” Dr. Hopkins said.
The authors acknowledge this as a limitation. Study data predate Omicron and subvariants, which appear to lower clinical severity, so it’s unclear whether VTE risk is different in this Omicron era.
Dr. Hopkins added another unknown: “We do not know whether vaccination affects rates of VTE in ambulatory breakthrough infection.”
Dr. Hopkins and the authors also note the lack of a control group in the study, to better compare risk.
Coauthor Dr. Prasad reports consultant fees from EpiExcellence LLC outside the submitted work. Coauthor Dr. Go reports grants paid to the division of research, Kaiser Permanente Northern California, from CSL Behring, Novartis, Bristol Meyers Squibb/Pfizer Alliance, and Janssen outside the submitted work.
The research was funded through Patient-Centered Outcomes Research Institute.
Dr. Hopkins reports no relevant financial relationships.
FROM JAMA NETWORK OPEN
Are early childhood viral infections linked with asthma?
MARSEILLE, France – It is well known that viral infections, especially respiratory syncytial virus (RSV) and rhinovirus (RV), exacerbate symptoms of asthma. But could they also play a part in triggering the onset of asthma?
The link between RSV and RV infections in early childhood and the development of asthma symptoms is well established, said Camille Taillé, MD, PhD, of the department of respiratory medicine and the rare diseases center of excellence at Bichat Hospital, Paris. But getting asthma is probably not just a matter of having a viral infection at a young age or of having a severe form of it. Gene polymorphisms, immune system disorders, and preexisting atopy are also associated with the risk of asthma. This was the focus of the 27th French-language respiratory medicine conference, held in Marseille, France.
RV and RSV
Persons with asthma are vulnerable to certain viral respiratory infections, in particular the flu and RV, which can exacerbate asthma symptoms. Inhaled corticosteroids have an overall protective effect against viral-induced exacerbations. For worsening asthma symptoms during an epidemic or pandemic, there is no contraindication to inhaled or oral corticosteroids.
Young children from the time of birth to 4 years of age are particularly susceptible to viral respiratory infections. According to data from France’s clinical surveillance network, Sentinelles, from the period covering winter 2021-2022, the rate of incidence per 100,000 inhabitants was systematically greater for the 0 to 4-year age range than for older age ranges.
Of the most common viruses that infect young children, RV, the virus that causes the common cold, is a nonenveloped RNA virus from the enterovirus family. There are 160 types, which are classified into three strains (A, B, and C). Of those strains, A and C confer the most severe infections. The virus is highly variable, which makes developing a vaccine challenging. The virus circulates year round, usually peaking in the fall and at the end of spring. RSV is an RNA virus that is classed as a respiratory virus. It comprises two serotypes: type A and B. Almost all children will have been infected with RSV by the time they are 2 years old. Epidemics occur each year during winter or in early spring in temperate climates. Vaccines are currently being developed and will soon be marketed. A monoclonal antibody (palivizumab), which targets fusion proteins of the virus, is available as prophylactic treatment for at-risk children.
RSV infection
During an RSV infection, the severe inflammation of the bronchial and alveolar wall causes acute respiratory distress. “But not all infants will develop severe forms of bronchiolitis,” said Dr. Taillé. “The risk factors for the severe form of the illness are well known: being under 6 months of age, prematurity, comorbidities (neurovascular, cardiovascular, respiratory, etc.), history of a stay in a neonatal intensive care unit at birth, living in low socioeconomic status towns, and exposure to smoking.”
Asthma development
The issue of whether or not viral diseases cause asthma has been the subject of intense debate. The studies are starting to stack up, however. They seem to show that RSV or RV infections are associated with the risk of subsequent asthma development. “For example, in a study published in 2022,” said Dr. Taillé, “in children admitted with an RSV infection, 60% of those who had been admitted to neonatal intensive care presented with symptoms of asthma between 3 and 6 years of age, compared with 18% of those who had had a milder case of RSV (admitted to nonintensive care settings). A serious RSV infection is a risk factor for later development of asthma.”
However, the link between RSV and later onset of asthma is also seen in milder cases of the infection. The American COAST study was designed to examine the effect of childhood respiratory infections on the risk of developing asthma. Researchers followed 259 newborns prospectively for 1, 3, and 6 years. To qualify, at least one parent was required to have respiratory allergies (defined as one or more positive aeroallergen skin tests) or a history of physician-diagnosed asthma. Regular samples taken during infectious episodes identified a virus in 90% of cases.
“We now know that RSV is not the only pathogen responsible for bronchiolitis. RV is often found, now that it can routinely be detected by PCR tests,” said Dr. Taillé. In the COAST study, the onset of wheezing during an RSV or RV infection in children aged 0-3 years was associated with an increased risk of asthma at 6 years of age. Globally, 28% of children infected by either virus were deemed to have asthma at 6 years of age. “There is clearly a link between having had a respiratory virus like RV or RSV and getting asthma symptoms at 6 years of age,” said Dr. Taillé. “What’s more, the effect of RV is not changed in this study by allergic sensitization.”
Many articles have been published on this topic. The results of cohort studies, from Japan to Finland and the United States, Italy, and Australia, are consistent with each other. Persons who have contracted RV or RSV are more likely to suffer from recurrent wheezing or asthma, especially if the infection is contracted in infancy or if it is severe. “Some studies even suggest that viral-induced asthma is more severe,” said Dr. Taillé. “For example, a Scottish study ... showed that children with a previous history of RSV infection had more hospital admissions and required more medication than asthmatics with no history of an RSV infection, suggesting the link between a previous history of RSV infection and the development of a more severe form of asthma.”
Reaching adulthood
Few longitudinal cohorts explore this issue in adulthood. A relatively old study reported an increased rate of asthma among adults who had required hospital admission for bronchiolitis in early childhood, as well as the effect on respiratory function. A 2023 study of the effects of respiratory illnesses in childhood reported similar findings. The authors evaluated lung structure and function via CT scans of 39 patients aged 26 years and concluded that participants who had been infected with RSV in childhood presented with increased air trapping, which is suggestive of airway abnormalities, possibly linked to a direct effect of viruses on lung development.
Mechanisms of action
“The real question is understanding if it’s the virus itself that causes asthma, or if the virus is simply uncovering underlying asthma in predisposed children,” said Dr. Taillé. From 30% to 40% of children who have had RSV will go on to develop wheezing or asthma in childhood. This observation suggests that there are factors favoring the development of asthma after infection with RSV. It has been shown that there is a genetic predisposition for RV. The roles of cigarette smoke, air pollution, environmental exposures to allergens, rapid urbanization, low vitamin D levels, low maternal omega-3 long-chain polyunsaturated fatty acid levels, maternal stress, and depression have also been highlighted.
It would seem that RSV and RV are a bit different. RV is thought to be associated with the development of asthma and wheezing, especially in people with a preexisting atopy or a reduced interferon immune response, while RSV, which occurs at a younger age and among the most vulnerable populations, seems to act independently of a person’s predisposition to allergies. RV stands out from other viral factors, owing to its tendency to create a Th2-biased inflammatory environment and its association with specific risk genes in people predisposed to asthma development (CDHR3).
Dr. Taillé has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MARSEILLE, France – It is well known that viral infections, especially respiratory syncytial virus (RSV) and rhinovirus (RV), exacerbate symptoms of asthma. But could they also play a part in triggering the onset of asthma?
The link between RSV and RV infections in early childhood and the development of asthma symptoms is well established, said Camille Taillé, MD, PhD, of the department of respiratory medicine and the rare diseases center of excellence at Bichat Hospital, Paris. But getting asthma is probably not just a matter of having a viral infection at a young age or of having a severe form of it. Gene polymorphisms, immune system disorders, and preexisting atopy are also associated with the risk of asthma. This was the focus of the 27th French-language respiratory medicine conference, held in Marseille, France.
RV and RSV
Persons with asthma are vulnerable to certain viral respiratory infections, in particular the flu and RV, which can exacerbate asthma symptoms. Inhaled corticosteroids have an overall protective effect against viral-induced exacerbations. For worsening asthma symptoms during an epidemic or pandemic, there is no contraindication to inhaled or oral corticosteroids.
Young children from the time of birth to 4 years of age are particularly susceptible to viral respiratory infections. According to data from France’s clinical surveillance network, Sentinelles, from the period covering winter 2021-2022, the rate of incidence per 100,000 inhabitants was systematically greater for the 0 to 4-year age range than for older age ranges.
Of the most common viruses that infect young children, RV, the virus that causes the common cold, is a nonenveloped RNA virus from the enterovirus family. There are 160 types, which are classified into three strains (A, B, and C). Of those strains, A and C confer the most severe infections. The virus is highly variable, which makes developing a vaccine challenging. The virus circulates year round, usually peaking in the fall and at the end of spring. RSV is an RNA virus that is classed as a respiratory virus. It comprises two serotypes: type A and B. Almost all children will have been infected with RSV by the time they are 2 years old. Epidemics occur each year during winter or in early spring in temperate climates. Vaccines are currently being developed and will soon be marketed. A monoclonal antibody (palivizumab), which targets fusion proteins of the virus, is available as prophylactic treatment for at-risk children.
RSV infection
During an RSV infection, the severe inflammation of the bronchial and alveolar wall causes acute respiratory distress. “But not all infants will develop severe forms of bronchiolitis,” said Dr. Taillé. “The risk factors for the severe form of the illness are well known: being under 6 months of age, prematurity, comorbidities (neurovascular, cardiovascular, respiratory, etc.), history of a stay in a neonatal intensive care unit at birth, living in low socioeconomic status towns, and exposure to smoking.”
Asthma development
The issue of whether or not viral diseases cause asthma has been the subject of intense debate. The studies are starting to stack up, however. They seem to show that RSV or RV infections are associated with the risk of subsequent asthma development. “For example, in a study published in 2022,” said Dr. Taillé, “in children admitted with an RSV infection, 60% of those who had been admitted to neonatal intensive care presented with symptoms of asthma between 3 and 6 years of age, compared with 18% of those who had had a milder case of RSV (admitted to nonintensive care settings). A serious RSV infection is a risk factor for later development of asthma.”
However, the link between RSV and later onset of asthma is also seen in milder cases of the infection. The American COAST study was designed to examine the effect of childhood respiratory infections on the risk of developing asthma. Researchers followed 259 newborns prospectively for 1, 3, and 6 years. To qualify, at least one parent was required to have respiratory allergies (defined as one or more positive aeroallergen skin tests) or a history of physician-diagnosed asthma. Regular samples taken during infectious episodes identified a virus in 90% of cases.
“We now know that RSV is not the only pathogen responsible for bronchiolitis. RV is often found, now that it can routinely be detected by PCR tests,” said Dr. Taillé. In the COAST study, the onset of wheezing during an RSV or RV infection in children aged 0-3 years was associated with an increased risk of asthma at 6 years of age. Globally, 28% of children infected by either virus were deemed to have asthma at 6 years of age. “There is clearly a link between having had a respiratory virus like RV or RSV and getting asthma symptoms at 6 years of age,” said Dr. Taillé. “What’s more, the effect of RV is not changed in this study by allergic sensitization.”
Many articles have been published on this topic. The results of cohort studies, from Japan to Finland and the United States, Italy, and Australia, are consistent with each other. Persons who have contracted RV or RSV are more likely to suffer from recurrent wheezing or asthma, especially if the infection is contracted in infancy or if it is severe. “Some studies even suggest that viral-induced asthma is more severe,” said Dr. Taillé. “For example, a Scottish study ... showed that children with a previous history of RSV infection had more hospital admissions and required more medication than asthmatics with no history of an RSV infection, suggesting the link between a previous history of RSV infection and the development of a more severe form of asthma.”
Reaching adulthood
Few longitudinal cohorts explore this issue in adulthood. A relatively old study reported an increased rate of asthma among adults who had required hospital admission for bronchiolitis in early childhood, as well as the effect on respiratory function. A 2023 study of the effects of respiratory illnesses in childhood reported similar findings. The authors evaluated lung structure and function via CT scans of 39 patients aged 26 years and concluded that participants who had been infected with RSV in childhood presented with increased air trapping, which is suggestive of airway abnormalities, possibly linked to a direct effect of viruses on lung development.
Mechanisms of action
“The real question is understanding if it’s the virus itself that causes asthma, or if the virus is simply uncovering underlying asthma in predisposed children,” said Dr. Taillé. From 30% to 40% of children who have had RSV will go on to develop wheezing or asthma in childhood. This observation suggests that there are factors favoring the development of asthma after infection with RSV. It has been shown that there is a genetic predisposition for RV. The roles of cigarette smoke, air pollution, environmental exposures to allergens, rapid urbanization, low vitamin D levels, low maternal omega-3 long-chain polyunsaturated fatty acid levels, maternal stress, and depression have also been highlighted.
It would seem that RSV and RV are a bit different. RV is thought to be associated with the development of asthma and wheezing, especially in people with a preexisting atopy or a reduced interferon immune response, while RSV, which occurs at a younger age and among the most vulnerable populations, seems to act independently of a person’s predisposition to allergies. RV stands out from other viral factors, owing to its tendency to create a Th2-biased inflammatory environment and its association with specific risk genes in people predisposed to asthma development (CDHR3).
Dr. Taillé has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MARSEILLE, France – It is well known that viral infections, especially respiratory syncytial virus (RSV) and rhinovirus (RV), exacerbate symptoms of asthma. But could they also play a part in triggering the onset of asthma?
The link between RSV and RV infections in early childhood and the development of asthma symptoms is well established, said Camille Taillé, MD, PhD, of the department of respiratory medicine and the rare diseases center of excellence at Bichat Hospital, Paris. But getting asthma is probably not just a matter of having a viral infection at a young age or of having a severe form of it. Gene polymorphisms, immune system disorders, and preexisting atopy are also associated with the risk of asthma. This was the focus of the 27th French-language respiratory medicine conference, held in Marseille, France.
RV and RSV
Persons with asthma are vulnerable to certain viral respiratory infections, in particular the flu and RV, which can exacerbate asthma symptoms. Inhaled corticosteroids have an overall protective effect against viral-induced exacerbations. For worsening asthma symptoms during an epidemic or pandemic, there is no contraindication to inhaled or oral corticosteroids.
Young children from the time of birth to 4 years of age are particularly susceptible to viral respiratory infections. According to data from France’s clinical surveillance network, Sentinelles, from the period covering winter 2021-2022, the rate of incidence per 100,000 inhabitants was systematically greater for the 0 to 4-year age range than for older age ranges.
Of the most common viruses that infect young children, RV, the virus that causes the common cold, is a nonenveloped RNA virus from the enterovirus family. There are 160 types, which are classified into three strains (A, B, and C). Of those strains, A and C confer the most severe infections. The virus is highly variable, which makes developing a vaccine challenging. The virus circulates year round, usually peaking in the fall and at the end of spring. RSV is an RNA virus that is classed as a respiratory virus. It comprises two serotypes: type A and B. Almost all children will have been infected with RSV by the time they are 2 years old. Epidemics occur each year during winter or in early spring in temperate climates. Vaccines are currently being developed and will soon be marketed. A monoclonal antibody (palivizumab), which targets fusion proteins of the virus, is available as prophylactic treatment for at-risk children.
RSV infection
During an RSV infection, the severe inflammation of the bronchial and alveolar wall causes acute respiratory distress. “But not all infants will develop severe forms of bronchiolitis,” said Dr. Taillé. “The risk factors for the severe form of the illness are well known: being under 6 months of age, prematurity, comorbidities (neurovascular, cardiovascular, respiratory, etc.), history of a stay in a neonatal intensive care unit at birth, living in low socioeconomic status towns, and exposure to smoking.”
Asthma development
The issue of whether or not viral diseases cause asthma has been the subject of intense debate. The studies are starting to stack up, however. They seem to show that RSV or RV infections are associated with the risk of subsequent asthma development. “For example, in a study published in 2022,” said Dr. Taillé, “in children admitted with an RSV infection, 60% of those who had been admitted to neonatal intensive care presented with symptoms of asthma between 3 and 6 years of age, compared with 18% of those who had had a milder case of RSV (admitted to nonintensive care settings). A serious RSV infection is a risk factor for later development of asthma.”
However, the link between RSV and later onset of asthma is also seen in milder cases of the infection. The American COAST study was designed to examine the effect of childhood respiratory infections on the risk of developing asthma. Researchers followed 259 newborns prospectively for 1, 3, and 6 years. To qualify, at least one parent was required to have respiratory allergies (defined as one or more positive aeroallergen skin tests) or a history of physician-diagnosed asthma. Regular samples taken during infectious episodes identified a virus in 90% of cases.
“We now know that RSV is not the only pathogen responsible for bronchiolitis. RV is often found, now that it can routinely be detected by PCR tests,” said Dr. Taillé. In the COAST study, the onset of wheezing during an RSV or RV infection in children aged 0-3 years was associated with an increased risk of asthma at 6 years of age. Globally, 28% of children infected by either virus were deemed to have asthma at 6 years of age. “There is clearly a link between having had a respiratory virus like RV or RSV and getting asthma symptoms at 6 years of age,” said Dr. Taillé. “What’s more, the effect of RV is not changed in this study by allergic sensitization.”
Many articles have been published on this topic. The results of cohort studies, from Japan to Finland and the United States, Italy, and Australia, are consistent with each other. Persons who have contracted RV or RSV are more likely to suffer from recurrent wheezing or asthma, especially if the infection is contracted in infancy or if it is severe. “Some studies even suggest that viral-induced asthma is more severe,” said Dr. Taillé. “For example, a Scottish study ... showed that children with a previous history of RSV infection had more hospital admissions and required more medication than asthmatics with no history of an RSV infection, suggesting the link between a previous history of RSV infection and the development of a more severe form of asthma.”
Reaching adulthood
Few longitudinal cohorts explore this issue in adulthood. A relatively old study reported an increased rate of asthma among adults who had required hospital admission for bronchiolitis in early childhood, as well as the effect on respiratory function. A 2023 study of the effects of respiratory illnesses in childhood reported similar findings. The authors evaluated lung structure and function via CT scans of 39 patients aged 26 years and concluded that participants who had been infected with RSV in childhood presented with increased air trapping, which is suggestive of airway abnormalities, possibly linked to a direct effect of viruses on lung development.
Mechanisms of action
“The real question is understanding if it’s the virus itself that causes asthma, or if the virus is simply uncovering underlying asthma in predisposed children,” said Dr. Taillé. From 30% to 40% of children who have had RSV will go on to develop wheezing or asthma in childhood. This observation suggests that there are factors favoring the development of asthma after infection with RSV. It has been shown that there is a genetic predisposition for RV. The roles of cigarette smoke, air pollution, environmental exposures to allergens, rapid urbanization, low vitamin D levels, low maternal omega-3 long-chain polyunsaturated fatty acid levels, maternal stress, and depression have also been highlighted.
It would seem that RSV and RV are a bit different. RV is thought to be associated with the development of asthma and wheezing, especially in people with a preexisting atopy or a reduced interferon immune response, while RSV, which occurs at a younger age and among the most vulnerable populations, seems to act independently of a person’s predisposition to allergies. RV stands out from other viral factors, owing to its tendency to create a Th2-biased inflammatory environment and its association with specific risk genes in people predisposed to asthma development (CDHR3).
Dr. Taillé has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
‘Breakthrough’ study: Diabetes drug helps prevent long COVID
with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.
In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection.
“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.
Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.
The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.
The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.
The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.
Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant.
The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.
Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.
The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.
When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.
Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.
At the same time, the study authors caution that more research is needed.
“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”
Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.
Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.
The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.
“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals.
Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.
“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”
Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19.
Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”
“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”
A version of this article first appeared on WebMD.com.
with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.
In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection.
“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.
Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.
The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.
The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.
The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.
Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant.
The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.
Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.
The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.
When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.
Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.
At the same time, the study authors caution that more research is needed.
“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”
Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.
Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.
The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.
“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals.
Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.
“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”
Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19.
Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”
“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”
A version of this article first appeared on WebMD.com.
with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.
In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection.
“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.
Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.
The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.
The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.
The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.
Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant.
The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.
Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.
The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.
When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.
Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.
At the same time, the study authors caution that more research is needed.
“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”
Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.
Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.
The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.
“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals.
Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.
“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”
Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19.
Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”
“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”
A version of this article first appeared on WebMD.com.