Residents

New cases of COVID-19 rose among children for the fourth consecutive week, but the size of the increase declined for the second consecutive week, based on data from the American Academy of Pediatrics and the Children’s Hospital Association.

After new child cases jumped by 22% during the week of July 15-21, the two successive weeks have produced increases of 3.9% (July 22-29) and 1.2% (July 30-Aug. 4). The latest weekly count from all states and territories still reporting was 96,599, the AAP and CHA said in their weekly COVID report, noting that several states have stopped reporting child cases and that others are reporting every other week.

Vaccine’s summer rollout gets lukewarm reception

As a group, children aged 0-4 years have not exactly flocked to the COVID-19 vaccine. As of Aug. 2 – about 6 weeks since the vaccine was authorized for children aged 6 months to 4 years – just 3.8% of those eligible had received at least one dose. Among children aged 5-11 the corresponding number on Aug. 2 was 37.4%, and for those aged 12-17 years it was 70.3%, the CDC data show.

That 3.8% of children aged less than 5 years represents almost 756,000 initial doses. That compares with over 6 million children aged 5-11 years who had received at least one dose through the first 6 weeks of their vaccination experience and over 5 million children aged 12-15, according to the COVID Data Tracker.

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New cases of COVID-19 rose among children for the fourth consecutive week, but the size of the increase declined for the second consecutive week, based on data from the American Academy of Pediatrics and the Children’s Hospital Association.

After new child cases jumped by 22% during the week of July 15-21, the two successive weeks have produced increases of 3.9% (July 22-29) and 1.2% (July 30-Aug. 4). The latest weekly count from all states and territories still reporting was 96,599, the AAP and CHA said in their weekly COVID report, noting that several states have stopped reporting child cases and that others are reporting every other week.

Vaccine’s summer rollout gets lukewarm reception

As a group, children aged 0-4 years have not exactly flocked to the COVID-19 vaccine. As of Aug. 2 – about 6 weeks since the vaccine was authorized for children aged 6 months to 4 years – just 3.8% of those eligible had received at least one dose. Among children aged 5-11 the corresponding number on Aug. 2 was 37.4%, and for those aged 12-17 years it was 70.3%, the CDC data show.

That 3.8% of children aged less than 5 years represents almost 756,000 initial doses. That compares with over 6 million children aged 5-11 years who had received at least one dose through the first 6 weeks of their vaccination experience and over 5 million children aged 12-15, according to the COVID Data Tracker.

[email protected]

New cases of COVID-19 rose among children for the fourth consecutive week, but the size of the increase declined for the second consecutive week, based on data from the American Academy of Pediatrics and the Children’s Hospital Association.

After new child cases jumped by 22% during the week of July 15-21, the two successive weeks have produced increases of 3.9% (July 22-29) and 1.2% (July 30-Aug. 4). The latest weekly count from all states and territories still reporting was 96,599, the AAP and CHA said in their weekly COVID report, noting that several states have stopped reporting child cases and that others are reporting every other week.

Vaccine’s summer rollout gets lukewarm reception

As a group, children aged 0-4 years have not exactly flocked to the COVID-19 vaccine. As of Aug. 2 – about 6 weeks since the vaccine was authorized for children aged 6 months to 4 years – just 3.8% of those eligible had received at least one dose. Among children aged 5-11 the corresponding number on Aug. 2 was 37.4%, and for those aged 12-17 years it was 70.3%, the CDC data show.

That 3.8% of children aged less than 5 years represents almost 756,000 initial doses. That compares with over 6 million children aged 5-11 years who had received at least one dose through the first 6 weeks of their vaccination experience and over 5 million children aged 12-15, according to the COVID Data Tracker.

[email protected]

Updated clinical practice guidelines for the treatment and prevention of venous thromboembolism for patients with cancer, including those with cancer and COVID-19, have been released by the International Initiative on Thrombosis and Cancer (ITAC), an academic working group of VTE experts.

“Because patients with cancer have a baseline increased risk of VTE, compared with patients without cancer, the combination of both COVID-19 and cancer – and its effect on VTE risk and treatment – is of concern,” said the authors, led by Dominique Farge, MD, PhD, Nord Universite de Paris.

The updated 2022 ITAC guidelines cover new evidence on the treatment and prophylaxis of cancer-associated thrombosis, including for patients with cancer and COVID-19, they added.

The new guidelines were published online in The Lancet Oncology.

“Cancer-associated VTE remains an important clinical problem, associated with increased morbidity and mortality,” Dr. Farge and colleagues observed.

“The ITAC guidelines’ companion free web-based mobile application will assist the practicing clinician with decision making at various levels to provide optimal care of patients with cancer to treat and prevent VTE,” they emphasized. More information is available at itaccme.com.
 

Cancer patients with COVID

The new section of the guidelines notes that the treatment and prevention of VTE for cancer patients infected with SARS-CoV-2 remain the same as for patients without COVID.

Whether or not cancer patients with COVID-19 are hospitalized, have been discharged, or are ambulatory, they should be assessed for the risk of VTE, as should any other patient. For cancer patients with COVID-19 who are hospitalized, pharmacologic prophylaxis should be given at the same dose and anticoagulant type as for hospitalized cancer patients who do not have COVID-19.

Following discharge, VTE prophylaxis is not advised for cancer patients infected with SARS-CoV-2, and routine primary pharmacologic prophylaxis of VTE for ambulatory patients with COVID-19 is also not recommended, the authors noted.
 

Initial treatment of established VTE

Initial treatment of established VTE for up to 10 days of anticoagulation should include low-molecular-weight heparin (LMWH) when creatinine clearance is at least 30 mL/min.

“A regimen of LMWH, taken once per day, is recommended unless a twice-per-day regimen is required because of patients’ characteristics,” the authors noted. These characteristics include a high risk of bleeding, moderate renal failure, and the need for technical intervention, including surgery.

If a twice-a-day regimen is required, only enoxaparin at a dose of 1 mg/kg twice daily can be used, the authors cautioned.

For patients with a low risk of gastrointestinal or genitourinary bleeding, rivaroxaban (Xarelto) or apixaban (Eliquis) can be given in the first 10 days, as well as edoxaban (Lixiana). The latter should be started after at least 5 days of parenteral anticoagulation, provided creatinine clearance is at least 30 mL/min.

“Unfractionated heparin as well as fondaparinux (GlaxoSmithKline) can be also used for the initial treatment of established VTE when LMWH or direct oral anticoagulants are contraindicated,” Dr. Farge and colleagues wrote.

Thrombolysis can be considered on a case-by-case basis, although physicians must pay attention to specific contraindications, especially bleeding risk.

“In the initial treatment of VTE, inferior vena cava filters might be considered when anticoagulant treatment is contraindicated or, in the case of pulmonary embolism, when recurrence occurs under optimal anticoagulation,” the authors noted.
 

Maintenance VTE treatment

For maintenance therapy, which the authors define as early maintenance for up to 6 months and long-term maintenance beyond 6 months, they point out that LMWHs are preferred over vitamin K antagonists for the treatment of VTE when the creatinine clearance is again at least 30 mL/min.

Any of the direct oral anticoagulants (DOAs) – edoxaban, rivaroxaban, or apixaban – is also recommended for the same patients, provided there is no risk of inducing a strong drug-drug interaction or GI absorption is impaired.

However, the DOAs should be used with caution for patients with GI malignancies, especially upper GI cancers, because data show there is an increased risk of GI bleeding with both edoxaban and rivaroxaban.

“LMWH or direct oral anticoagulants should be used for a minimum of 6 months to treat established VTE in patients with cancer,” the authors wrote.

“After 6 months, termination or continuation of anticoagulation (LMWH, direct oral anticoagulants, or vitamin K antagonists) should be based on individual evaluation of the benefit-risk ratio,” they added.
 

Treatment of VTE recurrence

The guideline authors explain that three options can be considered in the event of VTE recurrence. These include an increase in the LMWH dose by 20%-25%, or a switch to a DOA, or, if patients are taking a DOA, a switch to an LMWH. If the patient is taking a vitamin K antagonist, it can be switched to either an LMWH or a DOA.

For treatment of catheter-related thrombosis, anticoagulant treatment is recommended for a minimum of 3 months and as long as the central venous catheter is in place. In this setting, the LMWHs are recommended.

The central venous catheter can be kept in place if it is functional, well positioned, and is not infected, provided there is good resolution of symptoms under close surveillance while anticoagulants are being administered.

In surgically treated patients, the LMWH, given once a day, to patients with a serum creatinine concentration of at least 30 mL/min can be used to prevent VTE. Alternatively, VTE can be prevented by the use low-dose unfractionated heparin, given three times a day.

“Pharmacological prophylaxis should be started 2-12 h preoperatively and continued for at least 7–10 days,” Dr. Farge and colleagues advised. In this setting, there is insufficient evidence to support the use of fondaparinux or a DOA as an alternative to an LMWH for the prophylaxis of postoperative VTE. “Use of the highest prophylactic dose of LMWH to prevent postoperative VTE in patients with cancer is recommended,” the authors advised.

Furthermore, extended prophylaxis of at least 4 weeks with LMWH is advised to prevent postoperative VTE after major abdominal or pelvic surgery. Mechanical methods are not recommended except when pharmacologic methods are contraindicated. Inferior vena cava filters are also not recommended for routine prophylaxis.
 

Patients with reduced mobility

For medically treated hospitalized patients with cancer whose mobility is reduced, the authors recommend prophylaxis with either an LMWH or fondaparinux, provided their creatinine clearance is at least 30 mL/min. These patients can also be treated with unfractionated heparin, they add.

In contrast, DOAs are not recommended – at least not routinely – in this setting, the authors cautioned. Primary pharmacologic prophylaxis of VTE with either LMWH or DOAs – either rivaroxaban or apixaban – is indicated in ambulatory patients with locally advanced or metastatic pancreatic cancer who are receiving systemic anticancer therapy, provided they are at low risk of bleeding.

However, primary pharmacologic prophylaxis with LMWH is not recommended outside of a clinical trial for patients with locally advanced or metastatic lung cancer who are undergoing systemic anticancer therapy, even for patients who are at low risk of bleeding.

For ambulatory patients who are receiving systemic anticancer therapy and who are at intermediate risk of VTE, primary prophylaxis with rivaroxaban or apixaban is recommended for those with myeloma who are receiving immunomodulatory therapy plus steroids or other systemic therapies.

In this setting, oral anticoagulants should consist of a vitamin K antagonist, given at low or therapeutic doses, or apixaban, given at prophylactic doses. Alternatively, LMWH, given at prophylactic doses, or low-dose aspirin, given at a dose of 100 mg/day, can be used.
 

Catheter-related thrombosis

Use of anticoagulation for routine prophylaxis of catheter-related thrombosis is not recommended. Catheters should be inserted on the right side in the jugular vein, and the distal extremity of the central catheter should be located at the junction of the superior vena cava and the right atrium. “In patients requiring central venous catheters, we suggest the use of implanted ports over peripheral inserted central catheter lines,” the authors noted.

The authors described a number of unique situations regarding the treatment of VTE. These situations include patients with a brain tumor, for whom treatment of established VTE should favor either LMWH or a DOA. The authors also recommended the use of LMWH or unfractionated heparin, started postoperatively, for the prevention of VTE for patients undergoing neurosurgery.

In contrast, pharmacologic prophylaxis of VTE in medically treated patients with a brain tumor who are not undergoing neurosurgery is not recommended. “In the presence of severe renal failure...we suggest using unfractionated heparin followed by early vitamin K antagonists (possibly from day 1) or LMWH adjusted to anti-Xa concentration of the treatment of established VTE,” Dr. Farge and colleagues wrote.

Anticoagulant treatment is also recommended for a minimum of 3 months for children with symptomatic catheter-related thrombosis and as long as the central venous catheter is in place. For children with acute lymphoblastic leukemia who are undergoing induction chemotherapy, LMWH is also recommended as thromboprophylaxis.

For children who require a central venous catheter, the authors suggested that physicians use implanted ports over peripherally inserted central lines.

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

Updated clinical practice guidelines for the treatment and prevention of venous thromboembolism for patients with cancer, including those with cancer and COVID-19, have been released by the International Initiative on Thrombosis and Cancer (ITAC), an academic working group of VTE experts.

“Because patients with cancer have a baseline increased risk of VTE, compared with patients without cancer, the combination of both COVID-19 and cancer – and its effect on VTE risk and treatment – is of concern,” said the authors, led by Dominique Farge, MD, PhD, Nord Universite de Paris.

The updated 2022 ITAC guidelines cover new evidence on the treatment and prophylaxis of cancer-associated thrombosis, including for patients with cancer and COVID-19, they added.

The new guidelines were published online in The Lancet Oncology.

“Cancer-associated VTE remains an important clinical problem, associated with increased morbidity and mortality,” Dr. Farge and colleagues observed.

“The ITAC guidelines’ companion free web-based mobile application will assist the practicing clinician with decision making at various levels to provide optimal care of patients with cancer to treat and prevent VTE,” they emphasized. More information is available at itaccme.com.
 

Cancer patients with COVID

The new section of the guidelines notes that the treatment and prevention of VTE for cancer patients infected with SARS-CoV-2 remain the same as for patients without COVID.

Whether or not cancer patients with COVID-19 are hospitalized, have been discharged, or are ambulatory, they should be assessed for the risk of VTE, as should any other patient. For cancer patients with COVID-19 who are hospitalized, pharmacologic prophylaxis should be given at the same dose and anticoagulant type as for hospitalized cancer patients who do not have COVID-19.

Following discharge, VTE prophylaxis is not advised for cancer patients infected with SARS-CoV-2, and routine primary pharmacologic prophylaxis of VTE for ambulatory patients with COVID-19 is also not recommended, the authors noted.
 

Initial treatment of established VTE

Initial treatment of established VTE for up to 10 days of anticoagulation should include low-molecular-weight heparin (LMWH) when creatinine clearance is at least 30 mL/min.

“A regimen of LMWH, taken once per day, is recommended unless a twice-per-day regimen is required because of patients’ characteristics,” the authors noted. These characteristics include a high risk of bleeding, moderate renal failure, and the need for technical intervention, including surgery.

If a twice-a-day regimen is required, only enoxaparin at a dose of 1 mg/kg twice daily can be used, the authors cautioned.

For patients with a low risk of gastrointestinal or genitourinary bleeding, rivaroxaban (Xarelto) or apixaban (Eliquis) can be given in the first 10 days, as well as edoxaban (Lixiana). The latter should be started after at least 5 days of parenteral anticoagulation, provided creatinine clearance is at least 30 mL/min.

“Unfractionated heparin as well as fondaparinux (GlaxoSmithKline) can be also used for the initial treatment of established VTE when LMWH or direct oral anticoagulants are contraindicated,” Dr. Farge and colleagues wrote.

Thrombolysis can be considered on a case-by-case basis, although physicians must pay attention to specific contraindications, especially bleeding risk.

“In the initial treatment of VTE, inferior vena cava filters might be considered when anticoagulant treatment is contraindicated or, in the case of pulmonary embolism, when recurrence occurs under optimal anticoagulation,” the authors noted.
 

Maintenance VTE treatment

For maintenance therapy, which the authors define as early maintenance for up to 6 months and long-term maintenance beyond 6 months, they point out that LMWHs are preferred over vitamin K antagonists for the treatment of VTE when the creatinine clearance is again at least 30 mL/min.

Any of the direct oral anticoagulants (DOAs) – edoxaban, rivaroxaban, or apixaban – is also recommended for the same patients, provided there is no risk of inducing a strong drug-drug interaction or GI absorption is impaired.

However, the DOAs should be used with caution for patients with GI malignancies, especially upper GI cancers, because data show there is an increased risk of GI bleeding with both edoxaban and rivaroxaban.

“LMWH or direct oral anticoagulants should be used for a minimum of 6 months to treat established VTE in patients with cancer,” the authors wrote.

“After 6 months, termination or continuation of anticoagulation (LMWH, direct oral anticoagulants, or vitamin K antagonists) should be based on individual evaluation of the benefit-risk ratio,” they added.
 

Treatment of VTE recurrence

The guideline authors explain that three options can be considered in the event of VTE recurrence. These include an increase in the LMWH dose by 20%-25%, or a switch to a DOA, or, if patients are taking a DOA, a switch to an LMWH. If the patient is taking a vitamin K antagonist, it can be switched to either an LMWH or a DOA.

For treatment of catheter-related thrombosis, anticoagulant treatment is recommended for a minimum of 3 months and as long as the central venous catheter is in place. In this setting, the LMWHs are recommended.

The central venous catheter can be kept in place if it is functional, well positioned, and is not infected, provided there is good resolution of symptoms under close surveillance while anticoagulants are being administered.

In surgically treated patients, the LMWH, given once a day, to patients with a serum creatinine concentration of at least 30 mL/min can be used to prevent VTE. Alternatively, VTE can be prevented by the use low-dose unfractionated heparin, given three times a day.

“Pharmacological prophylaxis should be started 2-12 h preoperatively and continued for at least 7–10 days,” Dr. Farge and colleagues advised. In this setting, there is insufficient evidence to support the use of fondaparinux or a DOA as an alternative to an LMWH for the prophylaxis of postoperative VTE. “Use of the highest prophylactic dose of LMWH to prevent postoperative VTE in patients with cancer is recommended,” the authors advised.

Furthermore, extended prophylaxis of at least 4 weeks with LMWH is advised to prevent postoperative VTE after major abdominal or pelvic surgery. Mechanical methods are not recommended except when pharmacologic methods are contraindicated. Inferior vena cava filters are also not recommended for routine prophylaxis.
 

Patients with reduced mobility

For medically treated hospitalized patients with cancer whose mobility is reduced, the authors recommend prophylaxis with either an LMWH or fondaparinux, provided their creatinine clearance is at least 30 mL/min. These patients can also be treated with unfractionated heparin, they add.

In contrast, DOAs are not recommended – at least not routinely – in this setting, the authors cautioned. Primary pharmacologic prophylaxis of VTE with either LMWH or DOAs – either rivaroxaban or apixaban – is indicated in ambulatory patients with locally advanced or metastatic pancreatic cancer who are receiving systemic anticancer therapy, provided they are at low risk of bleeding.

However, primary pharmacologic prophylaxis with LMWH is not recommended outside of a clinical trial for patients with locally advanced or metastatic lung cancer who are undergoing systemic anticancer therapy, even for patients who are at low risk of bleeding.

For ambulatory patients who are receiving systemic anticancer therapy and who are at intermediate risk of VTE, primary prophylaxis with rivaroxaban or apixaban is recommended for those with myeloma who are receiving immunomodulatory therapy plus steroids or other systemic therapies.

In this setting, oral anticoagulants should consist of a vitamin K antagonist, given at low or therapeutic doses, or apixaban, given at prophylactic doses. Alternatively, LMWH, given at prophylactic doses, or low-dose aspirin, given at a dose of 100 mg/day, can be used.
 

Catheter-related thrombosis

Use of anticoagulation for routine prophylaxis of catheter-related thrombosis is not recommended. Catheters should be inserted on the right side in the jugular vein, and the distal extremity of the central catheter should be located at the junction of the superior vena cava and the right atrium. “In patients requiring central venous catheters, we suggest the use of implanted ports over peripheral inserted central catheter lines,” the authors noted.

The authors described a number of unique situations regarding the treatment of VTE. These situations include patients with a brain tumor, for whom treatment of established VTE should favor either LMWH or a DOA. The authors also recommended the use of LMWH or unfractionated heparin, started postoperatively, for the prevention of VTE for patients undergoing neurosurgery.

In contrast, pharmacologic prophylaxis of VTE in medically treated patients with a brain tumor who are not undergoing neurosurgery is not recommended. “In the presence of severe renal failure...we suggest using unfractionated heparin followed by early vitamin K antagonists (possibly from day 1) or LMWH adjusted to anti-Xa concentration of the treatment of established VTE,” Dr. Farge and colleagues wrote.

Anticoagulant treatment is also recommended for a minimum of 3 months for children with symptomatic catheter-related thrombosis and as long as the central venous catheter is in place. For children with acute lymphoblastic leukemia who are undergoing induction chemotherapy, LMWH is also recommended as thromboprophylaxis.

For children who require a central venous catheter, the authors suggested that physicians use implanted ports over peripherally inserted central lines.

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

Updated clinical practice guidelines for the treatment and prevention of venous thromboembolism for patients with cancer, including those with cancer and COVID-19, have been released by the International Initiative on Thrombosis and Cancer (ITAC), an academic working group of VTE experts.

“Because patients with cancer have a baseline increased risk of VTE, compared with patients without cancer, the combination of both COVID-19 and cancer – and its effect on VTE risk and treatment – is of concern,” said the authors, led by Dominique Farge, MD, PhD, Nord Universite de Paris.

The updated 2022 ITAC guidelines cover new evidence on the treatment and prophylaxis of cancer-associated thrombosis, including for patients with cancer and COVID-19, they added.

The new guidelines were published online in The Lancet Oncology.

“Cancer-associated VTE remains an important clinical problem, associated with increased morbidity and mortality,” Dr. Farge and colleagues observed.

“The ITAC guidelines’ companion free web-based mobile application will assist the practicing clinician with decision making at various levels to provide optimal care of patients with cancer to treat and prevent VTE,” they emphasized. More information is available at itaccme.com.
 

Cancer patients with COVID

The new section of the guidelines notes that the treatment and prevention of VTE for cancer patients infected with SARS-CoV-2 remain the same as for patients without COVID.

Whether or not cancer patients with COVID-19 are hospitalized, have been discharged, or are ambulatory, they should be assessed for the risk of VTE, as should any other patient. For cancer patients with COVID-19 who are hospitalized, pharmacologic prophylaxis should be given at the same dose and anticoagulant type as for hospitalized cancer patients who do not have COVID-19.

Following discharge, VTE prophylaxis is not advised for cancer patients infected with SARS-CoV-2, and routine primary pharmacologic prophylaxis of VTE for ambulatory patients with COVID-19 is also not recommended, the authors noted.
 

Initial treatment of established VTE

Initial treatment of established VTE for up to 10 days of anticoagulation should include low-molecular-weight heparin (LMWH) when creatinine clearance is at least 30 mL/min.

“A regimen of LMWH, taken once per day, is recommended unless a twice-per-day regimen is required because of patients’ characteristics,” the authors noted. These characteristics include a high risk of bleeding, moderate renal failure, and the need for technical intervention, including surgery.

If a twice-a-day regimen is required, only enoxaparin at a dose of 1 mg/kg twice daily can be used, the authors cautioned.

For patients with a low risk of gastrointestinal or genitourinary bleeding, rivaroxaban (Xarelto) or apixaban (Eliquis) can be given in the first 10 days, as well as edoxaban (Lixiana). The latter should be started after at least 5 days of parenteral anticoagulation, provided creatinine clearance is at least 30 mL/min.

“Unfractionated heparin as well as fondaparinux (GlaxoSmithKline) can be also used for the initial treatment of established VTE when LMWH or direct oral anticoagulants are contraindicated,” Dr. Farge and colleagues wrote.

Thrombolysis can be considered on a case-by-case basis, although physicians must pay attention to specific contraindications, especially bleeding risk.

“In the initial treatment of VTE, inferior vena cava filters might be considered when anticoagulant treatment is contraindicated or, in the case of pulmonary embolism, when recurrence occurs under optimal anticoagulation,” the authors noted.
 

Maintenance VTE treatment

For maintenance therapy, which the authors define as early maintenance for up to 6 months and long-term maintenance beyond 6 months, they point out that LMWHs are preferred over vitamin K antagonists for the treatment of VTE when the creatinine clearance is again at least 30 mL/min.

Any of the direct oral anticoagulants (DOAs) – edoxaban, rivaroxaban, or apixaban – is also recommended for the same patients, provided there is no risk of inducing a strong drug-drug interaction or GI absorption is impaired.

However, the DOAs should be used with caution for patients with GI malignancies, especially upper GI cancers, because data show there is an increased risk of GI bleeding with both edoxaban and rivaroxaban.

“LMWH or direct oral anticoagulants should be used for a minimum of 6 months to treat established VTE in patients with cancer,” the authors wrote.

“After 6 months, termination or continuation of anticoagulation (LMWH, direct oral anticoagulants, or vitamin K antagonists) should be based on individual evaluation of the benefit-risk ratio,” they added.
 

Treatment of VTE recurrence

The guideline authors explain that three options can be considered in the event of VTE recurrence. These include an increase in the LMWH dose by 20%-25%, or a switch to a DOA, or, if patients are taking a DOA, a switch to an LMWH. If the patient is taking a vitamin K antagonist, it can be switched to either an LMWH or a DOA.

For treatment of catheter-related thrombosis, anticoagulant treatment is recommended for a minimum of 3 months and as long as the central venous catheter is in place. In this setting, the LMWHs are recommended.

The central venous catheter can be kept in place if it is functional, well positioned, and is not infected, provided there is good resolution of symptoms under close surveillance while anticoagulants are being administered.

In surgically treated patients, the LMWH, given once a day, to patients with a serum creatinine concentration of at least 30 mL/min can be used to prevent VTE. Alternatively, VTE can be prevented by the use low-dose unfractionated heparin, given three times a day.

“Pharmacological prophylaxis should be started 2-12 h preoperatively and continued for at least 7–10 days,” Dr. Farge and colleagues advised. In this setting, there is insufficient evidence to support the use of fondaparinux or a DOA as an alternative to an LMWH for the prophylaxis of postoperative VTE. “Use of the highest prophylactic dose of LMWH to prevent postoperative VTE in patients with cancer is recommended,” the authors advised.

Furthermore, extended prophylaxis of at least 4 weeks with LMWH is advised to prevent postoperative VTE after major abdominal or pelvic surgery. Mechanical methods are not recommended except when pharmacologic methods are contraindicated. Inferior vena cava filters are also not recommended for routine prophylaxis.
 

Patients with reduced mobility

For medically treated hospitalized patients with cancer whose mobility is reduced, the authors recommend prophylaxis with either an LMWH or fondaparinux, provided their creatinine clearance is at least 30 mL/min. These patients can also be treated with unfractionated heparin, they add.

In contrast, DOAs are not recommended – at least not routinely – in this setting, the authors cautioned. Primary pharmacologic prophylaxis of VTE with either LMWH or DOAs – either rivaroxaban or apixaban – is indicated in ambulatory patients with locally advanced or metastatic pancreatic cancer who are receiving systemic anticancer therapy, provided they are at low risk of bleeding.

However, primary pharmacologic prophylaxis with LMWH is not recommended outside of a clinical trial for patients with locally advanced or metastatic lung cancer who are undergoing systemic anticancer therapy, even for patients who are at low risk of bleeding.

For ambulatory patients who are receiving systemic anticancer therapy and who are at intermediate risk of VTE, primary prophylaxis with rivaroxaban or apixaban is recommended for those with myeloma who are receiving immunomodulatory therapy plus steroids or other systemic therapies.

In this setting, oral anticoagulants should consist of a vitamin K antagonist, given at low or therapeutic doses, or apixaban, given at prophylactic doses. Alternatively, LMWH, given at prophylactic doses, or low-dose aspirin, given at a dose of 100 mg/day, can be used.
 

Catheter-related thrombosis

Use of anticoagulation for routine prophylaxis of catheter-related thrombosis is not recommended. Catheters should be inserted on the right side in the jugular vein, and the distal extremity of the central catheter should be located at the junction of the superior vena cava and the right atrium. “In patients requiring central venous catheters, we suggest the use of implanted ports over peripheral inserted central catheter lines,” the authors noted.

The authors described a number of unique situations regarding the treatment of VTE. These situations include patients with a brain tumor, for whom treatment of established VTE should favor either LMWH or a DOA. The authors also recommended the use of LMWH or unfractionated heparin, started postoperatively, for the prevention of VTE for patients undergoing neurosurgery.

In contrast, pharmacologic prophylaxis of VTE in medically treated patients with a brain tumor who are not undergoing neurosurgery is not recommended. “In the presence of severe renal failure...we suggest using unfractionated heparin followed by early vitamin K antagonists (possibly from day 1) or LMWH adjusted to anti-Xa concentration of the treatment of established VTE,” Dr. Farge and colleagues wrote.

Anticoagulant treatment is also recommended for a minimum of 3 months for children with symptomatic catheter-related thrombosis and as long as the central venous catheter is in place. For children with acute lymphoblastic leukemia who are undergoing induction chemotherapy, LMWH is also recommended as thromboprophylaxis.

For children who require a central venous catheter, the authors suggested that physicians use implanted ports over peripherally inserted central lines.

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

New York City veterinarian Erin Kulick used to be a weekend warrior. Only 2½ years ago, the 38-year-old new mother played ultimate Frisbee and flag football with friends. She went for regular 30-minute runs to burn off stress.

Now, Dr. Kulick is usually so exhausted, she can’t walk nonstop for 15 minutes. She recently tried to take her 4-year-old son, Cooper, to the American Museum of Natural History for his first visit, but ended up on a bench outside the museum, sobbing in the rain, because she couldn’t even get through the first hurdle of standing in line. “I just wanted to be there with my kid,” she said.

Dr. Kulick got sick with COVID-19 at the start of the pandemic in March 2020, 9 months before the first vaccine would be approved. Now she is among the estimated one in five infected Americans, or 19%, whose symptoms developed into long COVID.

Dr. Kulick also is now vaccinated and boosted. Had a vaccine been available sooner, could it have protected her from long COVID?

Evidence is starting to show it’s likely.

“The best way not to have long COVID is not to have COVID at all,” said Leora Horwitz, MD, a professor of population health and medicine at New York University. “To the extent that vaccination can prevent you from getting COVID at all, then it helps to reduce long COVID.”

And just as vaccines reduce the risk of severe disease, hospitalization, and death, they also seem to reduce the risk of long COVID if people do get breakthrough infections. People with more serious initial illness appear more likely to have prolonged symptoms, but those with milder disease can certainly get it, too.

“You’re more likely to have long COVID with more severe disease, and we have ample evidence that vaccination reduces the severity of disease,” Dr. Horwitz said. “We also now have quite a lot of evidence that vaccination does reduce your risk of long COVID – probably because it reduces your risk of severe disease.”

There is little consensus about how much vaccines can lower the risk of long-term COVID symptoms, but several studies suggest that number lies anywhere from 15% to more than 80%.

That might seem like a big variation, but infectious disease experts argue that trying to interpret the gap isn’t as important as noticing what’s consistent across all these studies: “Vaccines do offer some protection, but it’s incomplete,” said Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System. Dr. Al-Aly, who has led several large studies on long COVID, said focusing on the fact that vaccines do offer some protection is a much better public health message than looking at the different levels of risk.

“Vaccines do a miraculous job for what they were designed to do,” said Dr. Al-Aly. “Vaccines were designed to reduce the risk of hospitalization ... and for that, vaccines are still holding up, even with all the changes in the virus.”

Still, Elena Azzolini, MD, PhD, head of the Humanitas Research Hospital’s vaccination center in Milan, thinks some studies may have underestimated the level of long COVID protection from vaccines because of limits in the study methods, such as not including enough women, who are more affected by long COVID. Her recent study, which looked at 2,560 health care professionals working in nine Italian centers from March 2020 to April 2022, focused on the risk for healthy women and men in their 20s to their 70s.

In the paper, Dr. Azzolini and associates reported that two or three doses of vaccine reduced the risk of hospitalization from COVID-19 from 42% among those who are unvaccinated to 16%-17%. In other words, they found unvaccinated people in the study were nearly three times as likely to have serious symptoms for longer than 4 weeks.

But Dr. Azzolini and Dr. Al-Aly still say that, even for the vaccinated, as long as COVID is around, masks are necessary. That’s because current vaccines don’t do enough to reduce transmission, said Dr. Al-Aly. “The only way that can really help [stop] transmission is covering our nose and mouth with a mask.”
 

How vaccinations affect people who already have long COVID

Some long COVID patients have said they got better after they get boosted, while some say they’re getting worse, said Dr. Horwitz, who is also a lead investigator at the National Institutes of Health’s flagship RECOVER program, a 4-year research project to study long COVID across the United States. (The NIH is still recruiting volunteers for these studies, which are also open to people who have never had COVID.)

One study published in the British Medical Journal analyzed survey data of more than 28,000 people infected with COVID in the United Kingdom and found a 13% reduction in long-term symptoms after a first dose of the vaccine, although it was unclear from the data if the improvement was sustained.

A second dose was associated with another 8% improvement over a 2-month period. “It’s reassuring that we see an average modest improvement in symptoms, not an average worsening in symptoms,” said Daniel Ayoubkhani, principal statistician at the U.K. Office for National Statistics and lead author of the study. Of course, the experience will differ among different people.

“It doesn’t appear that vaccination is the silver bullet that’s going to eradicate long COVID,” he said, but evidence from multiple studies suggests vaccines may help people with long-term symptoms.

Akiko Iwasaki, PhD, an immunobiologist at Yale University, New Haven, Conn., told a White House summit in July that one of the best ways to prevent long COVID is to develop the next generation of vaccines that also prevent milder cases by blocking transmission in the first place.

Back in New York, Dr. Kulick is now triple vaccinated. She’s due for a fourth dose soon but admits she’s “terrified every time” that she’s going to get sicker.

In her Facebook support group for long COVID, she reads that most people with prolonged symptoms handle it well. She has also noticed some of her symptoms eased after her first two doses of vaccine.

Since being diagnosed, Dr. Kulick learned she has a genetic condition, Ehlers-Danlos syndrome, which affects connective tissues that support skin, joints, organs, and blood vessels, and which her doctors say may have made her more prone to long COVID. She’s also being screened for autoimmune diseases, but for now, the only relief she has found has come from long COVID physical therapy, changes to her diet, and integrative medicine.

Dr. Kulick is still trying to figure out how she can get better while keeping her long hours at her veterinary job – and her health benefits. She is thankful her husband is a devoted caregiver to their son and a professional jazz musician with a schedule that allows for some flexibility.

“But it’s really hard when every week feels like I’ve run a marathon,” she said. “I can barely make it through.”

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

New York City veterinarian Erin Kulick used to be a weekend warrior. Only 2½ years ago, the 38-year-old new mother played ultimate Frisbee and flag football with friends. She went for regular 30-minute runs to burn off stress.

Now, Dr. Kulick is usually so exhausted, she can’t walk nonstop for 15 minutes. She recently tried to take her 4-year-old son, Cooper, to the American Museum of Natural History for his first visit, but ended up on a bench outside the museum, sobbing in the rain, because she couldn’t even get through the first hurdle of standing in line. “I just wanted to be there with my kid,” she said.

Dr. Kulick got sick with COVID-19 at the start of the pandemic in March 2020, 9 months before the first vaccine would be approved. Now she is among the estimated one in five infected Americans, or 19%, whose symptoms developed into long COVID.

Dr. Kulick also is now vaccinated and boosted. Had a vaccine been available sooner, could it have protected her from long COVID?

Evidence is starting to show it’s likely.

“The best way not to have long COVID is not to have COVID at all,” said Leora Horwitz, MD, a professor of population health and medicine at New York University. “To the extent that vaccination can prevent you from getting COVID at all, then it helps to reduce long COVID.”

And just as vaccines reduce the risk of severe disease, hospitalization, and death, they also seem to reduce the risk of long COVID if people do get breakthrough infections. People with more serious initial illness appear more likely to have prolonged symptoms, but those with milder disease can certainly get it, too.

“You’re more likely to have long COVID with more severe disease, and we have ample evidence that vaccination reduces the severity of disease,” Dr. Horwitz said. “We also now have quite a lot of evidence that vaccination does reduce your risk of long COVID – probably because it reduces your risk of severe disease.”

There is little consensus about how much vaccines can lower the risk of long-term COVID symptoms, but several studies suggest that number lies anywhere from 15% to more than 80%.

That might seem like a big variation, but infectious disease experts argue that trying to interpret the gap isn’t as important as noticing what’s consistent across all these studies: “Vaccines do offer some protection, but it’s incomplete,” said Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System. Dr. Al-Aly, who has led several large studies on long COVID, said focusing on the fact that vaccines do offer some protection is a much better public health message than looking at the different levels of risk.

“Vaccines do a miraculous job for what they were designed to do,” said Dr. Al-Aly. “Vaccines were designed to reduce the risk of hospitalization ... and for that, vaccines are still holding up, even with all the changes in the virus.”

Still, Elena Azzolini, MD, PhD, head of the Humanitas Research Hospital’s vaccination center in Milan, thinks some studies may have underestimated the level of long COVID protection from vaccines because of limits in the study methods, such as not including enough women, who are more affected by long COVID. Her recent study, which looked at 2,560 health care professionals working in nine Italian centers from March 2020 to April 2022, focused on the risk for healthy women and men in their 20s to their 70s.

In the paper, Dr. Azzolini and associates reported that two or three doses of vaccine reduced the risk of hospitalization from COVID-19 from 42% among those who are unvaccinated to 16%-17%. In other words, they found unvaccinated people in the study were nearly three times as likely to have serious symptoms for longer than 4 weeks.

But Dr. Azzolini and Dr. Al-Aly still say that, even for the vaccinated, as long as COVID is around, masks are necessary. That’s because current vaccines don’t do enough to reduce transmission, said Dr. Al-Aly. “The only way that can really help [stop] transmission is covering our nose and mouth with a mask.”
 

How vaccinations affect people who already have long COVID

Some long COVID patients have said they got better after they get boosted, while some say they’re getting worse, said Dr. Horwitz, who is also a lead investigator at the National Institutes of Health’s flagship RECOVER program, a 4-year research project to study long COVID across the United States. (The NIH is still recruiting volunteers for these studies, which are also open to people who have never had COVID.)

One study published in the British Medical Journal analyzed survey data of more than 28,000 people infected with COVID in the United Kingdom and found a 13% reduction in long-term symptoms after a first dose of the vaccine, although it was unclear from the data if the improvement was sustained.

A second dose was associated with another 8% improvement over a 2-month period. “It’s reassuring that we see an average modest improvement in symptoms, not an average worsening in symptoms,” said Daniel Ayoubkhani, principal statistician at the U.K. Office for National Statistics and lead author of the study. Of course, the experience will differ among different people.

“It doesn’t appear that vaccination is the silver bullet that’s going to eradicate long COVID,” he said, but evidence from multiple studies suggests vaccines may help people with long-term symptoms.

Akiko Iwasaki, PhD, an immunobiologist at Yale University, New Haven, Conn., told a White House summit in July that one of the best ways to prevent long COVID is to develop the next generation of vaccines that also prevent milder cases by blocking transmission in the first place.

Back in New York, Dr. Kulick is now triple vaccinated. She’s due for a fourth dose soon but admits she’s “terrified every time” that she’s going to get sicker.

In her Facebook support group for long COVID, she reads that most people with prolonged symptoms handle it well. She has also noticed some of her symptoms eased after her first two doses of vaccine.

Since being diagnosed, Dr. Kulick learned she has a genetic condition, Ehlers-Danlos syndrome, which affects connective tissues that support skin, joints, organs, and blood vessels, and which her doctors say may have made her more prone to long COVID. She’s also being screened for autoimmune diseases, but for now, the only relief she has found has come from long COVID physical therapy, changes to her diet, and integrative medicine.

Dr. Kulick is still trying to figure out how she can get better while keeping her long hours at her veterinary job – and her health benefits. She is thankful her husband is a devoted caregiver to their son and a professional jazz musician with a schedule that allows for some flexibility.

“But it’s really hard when every week feels like I’ve run a marathon,” she said. “I can barely make it through.”

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

New York City veterinarian Erin Kulick used to be a weekend warrior. Only 2½ years ago, the 38-year-old new mother played ultimate Frisbee and flag football with friends. She went for regular 30-minute runs to burn off stress.

Now, Dr. Kulick is usually so exhausted, she can’t walk nonstop for 15 minutes. She recently tried to take her 4-year-old son, Cooper, to the American Museum of Natural History for his first visit, but ended up on a bench outside the museum, sobbing in the rain, because she couldn’t even get through the first hurdle of standing in line. “I just wanted to be there with my kid,” she said.

Dr. Kulick got sick with COVID-19 at the start of the pandemic in March 2020, 9 months before the first vaccine would be approved. Now she is among the estimated one in five infected Americans, or 19%, whose symptoms developed into long COVID.

Dr. Kulick also is now vaccinated and boosted. Had a vaccine been available sooner, could it have protected her from long COVID?

Evidence is starting to show it’s likely.

“The best way not to have long COVID is not to have COVID at all,” said Leora Horwitz, MD, a professor of population health and medicine at New York University. “To the extent that vaccination can prevent you from getting COVID at all, then it helps to reduce long COVID.”

And just as vaccines reduce the risk of severe disease, hospitalization, and death, they also seem to reduce the risk of long COVID if people do get breakthrough infections. People with more serious initial illness appear more likely to have prolonged symptoms, but those with milder disease can certainly get it, too.

“You’re more likely to have long COVID with more severe disease, and we have ample evidence that vaccination reduces the severity of disease,” Dr. Horwitz said. “We also now have quite a lot of evidence that vaccination does reduce your risk of long COVID – probably because it reduces your risk of severe disease.”

There is little consensus about how much vaccines can lower the risk of long-term COVID symptoms, but several studies suggest that number lies anywhere from 15% to more than 80%.

That might seem like a big variation, but infectious disease experts argue that trying to interpret the gap isn’t as important as noticing what’s consistent across all these studies: “Vaccines do offer some protection, but it’s incomplete,” said Ziyad Al-Aly, MD, chief of research and development at the Veterans Affairs St. Louis Health Care System. Dr. Al-Aly, who has led several large studies on long COVID, said focusing on the fact that vaccines do offer some protection is a much better public health message than looking at the different levels of risk.

“Vaccines do a miraculous job for what they were designed to do,” said Dr. Al-Aly. “Vaccines were designed to reduce the risk of hospitalization ... and for that, vaccines are still holding up, even with all the changes in the virus.”

Still, Elena Azzolini, MD, PhD, head of the Humanitas Research Hospital’s vaccination center in Milan, thinks some studies may have underestimated the level of long COVID protection from vaccines because of limits in the study methods, such as not including enough women, who are more affected by long COVID. Her recent study, which looked at 2,560 health care professionals working in nine Italian centers from March 2020 to April 2022, focused on the risk for healthy women and men in their 20s to their 70s.

In the paper, Dr. Azzolini and associates reported that two or three doses of vaccine reduced the risk of hospitalization from COVID-19 from 42% among those who are unvaccinated to 16%-17%. In other words, they found unvaccinated people in the study were nearly three times as likely to have serious symptoms for longer than 4 weeks.

But Dr. Azzolini and Dr. Al-Aly still say that, even for the vaccinated, as long as COVID is around, masks are necessary. That’s because current vaccines don’t do enough to reduce transmission, said Dr. Al-Aly. “The only way that can really help [stop] transmission is covering our nose and mouth with a mask.”
 

How vaccinations affect people who already have long COVID

Some long COVID patients have said they got better after they get boosted, while some say they’re getting worse, said Dr. Horwitz, who is also a lead investigator at the National Institutes of Health’s flagship RECOVER program, a 4-year research project to study long COVID across the United States. (The NIH is still recruiting volunteers for these studies, which are also open to people who have never had COVID.)

One study published in the British Medical Journal analyzed survey data of more than 28,000 people infected with COVID in the United Kingdom and found a 13% reduction in long-term symptoms after a first dose of the vaccine, although it was unclear from the data if the improvement was sustained.

A second dose was associated with another 8% improvement over a 2-month period. “It’s reassuring that we see an average modest improvement in symptoms, not an average worsening in symptoms,” said Daniel Ayoubkhani, principal statistician at the U.K. Office for National Statistics and lead author of the study. Of course, the experience will differ among different people.

“It doesn’t appear that vaccination is the silver bullet that’s going to eradicate long COVID,” he said, but evidence from multiple studies suggests vaccines may help people with long-term symptoms.

Akiko Iwasaki, PhD, an immunobiologist at Yale University, New Haven, Conn., told a White House summit in July that one of the best ways to prevent long COVID is to develop the next generation of vaccines that also prevent milder cases by blocking transmission in the first place.

Back in New York, Dr. Kulick is now triple vaccinated. She’s due for a fourth dose soon but admits she’s “terrified every time” that she’s going to get sicker.

In her Facebook support group for long COVID, she reads that most people with prolonged symptoms handle it well. She has also noticed some of her symptoms eased after her first two doses of vaccine.

Since being diagnosed, Dr. Kulick learned she has a genetic condition, Ehlers-Danlos syndrome, which affects connective tissues that support skin, joints, organs, and blood vessels, and which her doctors say may have made her more prone to long COVID. She’s also being screened for autoimmune diseases, but for now, the only relief she has found has come from long COVID physical therapy, changes to her diet, and integrative medicine.

Dr. Kulick is still trying to figure out how she can get better while keeping her long hours at her veterinary job – and her health benefits. She is thankful her husband is a devoted caregiver to their son and a professional jazz musician with a schedule that allows for some flexibility.

“But it’s really hard when every week feels like I’ve run a marathon,” she said. “I can barely make it through.”

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

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

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

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

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

Emerging evidence is shedding light on the common underlying mechanisms contributing to the overlapping clinical phenomena of “long COVID,” myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (IACFSME), speakers presented data showing similar pathophysiologic abnormalities in people with systemic symptoms associated with ME/CFS who had a prior SARS-CoV-2 infection and those who did not, including individuals whose illness preceded the COVID-19 pandemic.

Core clinical diagnostic criteria for ME/CFS established by the Institute of Medicine in 2015 include substantial decrement in functioning for 6 months or longer, postexertional malaise, or a worsening of symptoms following even minor exertion (often described by patients as “crashes”), unrefreshing sleep, and cognitive dysfunction and/or orthostatic intolerance that are frequent and severe.

Long COVID has been defined in several different ways using different terminology. The U.S. Centers for Disease Control and Prevention, for example, defines “post-COVID conditions” as those continuing four or more weeks beyond first symptoms. The World Health Organization’s clinical case definition of “post COVID-19 condition” includes otherwise unexplained symptoms 3 months from COVID-19 onset and lasting longer than 2 months.

Both ME/CFS and long COVID commonly involve numerous symptoms beyond the defining ones, affecting nearly every organ system in the body, including systemic, neurocognitive, endocrine, cardiovascular, pulmonary, musculoskeletal, and gastrointestinal, with wide variation among individuals. Autonomic dysfunction is common to both conditions, particularly postural orthostatic tachycardia syndrome (POTS).

“My way of understanding these illnesses is that they’re not just multisystem illnesses, but all these interactive systems that lean on each other are dysregulated. … I would say that a very common underlying mediator of both ME/CFS and long COVID is autonomic dysfunction, and it presents as POTS,” Nancy Klimas, MD, director of the Institute for Neuro-Immune Medicine at Nova Southeastern University, Fort Lauderdale, Fla., told this news organization.

Dr. Klimas, who is also director of Clinical Immunology Research at the Miami Veterans Affairs Medical Center, added that “if basic bioenergetics are disrupted and in an oxidative-stress state [then] they have downregulated energy production at the cellular level, which seems to be the case in ME/CFS and now in long COVID.”
 

New ICD-10 codes better characterize the syndromes

New ICD-10 codes for 2023, being implemented on Oct. 1, will enable clinicians to better document all of these interrelated conditions.

Under the existing G93.3, Postviral and related fatigue syndromes, there will now be:

• G93.31 – Postviral fatigue syndrome.
• G93.32 – Myalgic encephalomyelitis/chronic fatigue syndrome (and the separate terms).
• G93.39 – Other postinfection and related fatigue syndromes.

The old R53.82, “Chronic fatigue, unspecified” code now excludes all of the above conditions.

The additional code U09.9 for “post COVID-19 condition, unspecified,” may also be used if applicable.

In addition, a new code for POTS, G90.A, which wasn’t previously mentioned in ICD-10, may also be used starting Oct. 1.

Lucinda Bateman, MD, founder and director of the Bateman Horne Center, Salt Lake City, advises using all applicable codes for a given patient. “If a patient came into my office with long COVID and met criteria for ME/CFS, we would code both, and also any other syndrome criteria that they may meet, such as POTS or fibromyalgia.

“If people use the codes appropriately, then you can understand the overlap better. It increases the likelihood of reimbursement, creates a more accurate medical record for the patient, and provides them with a better tool should they require disability benefits.”

Dr. Bateman advises in-office orthostatic evaluation for all patients with this symptom constellation, using a passive standing evaluation such as the 10-minute NASA Lean test.

“Clinicians should take the time to do orthostatic testing in these patients because it provides objective markers and will help lead us to potential interventions to help improve people’s function.”

The Bateman Horne center offers clinician resources on management of ME/CFS and related conditions.
 

How common is ME/CFS after COVID-19?

According to one published meta-analysis, the global prevalence of “post-acute sequelae of SARS-CoV-2,” defined by any symptom, is about 43% of patients overall following infection, and 49% at 120 days. Fatigue was the most commonly reported symptom, followed by memory problems. As of March 22, the World Health Organization estimated that there have been more than 470 million COVID-19 cases, which would give a figure of about 200 million people who are experiencing a wide range of long-COVID symptoms. 

On the final day of the IACFSME conference, Luis Nacul, MD, of the University of British Columbia, Vancouver, presented several sets of data from his group and others aiming to determine the proportion of individuals who develop symptoms suggestive of ME/CFS following a COVID-19 infection.   

Among a cohort of 88 adults hospitalized with confirmed SARS-CoV-2 infections during the first pandemic wave in 2020 and followed up in the respiratory clinic, rates of reported generalized fatigue were 67% at 3 months and 59.5% at 6 months. Substantial fatigue (that is, present most days and affecting activity levels) were reported by 16% at 3 months and 7% at 6 months. “This should represent in principle the maximum prevalence of cases who would meet the criteria for ME/CFS,” Dr. Nacul said.

Baseline age was indirectly associated with fatigue at 3 and 6 months, while the number of comorbidities a patient had was directly associated. Comorbidities also predicted severe fatigue at 3 months, but the numbers were too small for assessment at 6 months.

Studies involving nonhospitalized patients suggested lower rates. One meta-analysis showed 1-year rates of fatigue in 32% and cognitive impairment in 22%. Another showed very similar rates, reporting fatigue in 28% and memory/concentration difficulties in 18%-19%.   

Dr. Nacul cautioned that these figures are likely overestimates since many of the study populations are taken from respiratory or long-COVID clinics. “The evidence on ‘post-COVID fatigue syndrome’ or ME/CFS following COVID is still evolving. There is a huge need for studies looking more closely at cases meeting well-defined ME/CFS criteria. This unfortunately hasn’t been done for most studies.”
 

Immune system dysfunction appears to underlie many cases

In a keynote address during the conference, Akiko Iwasaki, PhD, of Yale University, New Haven, Conn., pointed out that long COVID and ME/CFS are among many unexplained postacute infection syndromes associated with a long list of viral pathogens, including Ebola, the prior SARS viruses, Epstein-Barr virus, and Dengue, as well as nonviral pathogens such as Coxiella burnetii (Q fever syndrome) and Borrelia (posttreatment Lyme disease syndrome).

Dr. Iwasaki cited a recent Nature Medicine review article that she coauthored on this topic with an ME/CFS patient, noting: “We really need to understand why some people are failing to recover from these types of diseases.”

Emerging evidence supports four different hypotheses regarding pathogenesis: viral reservoir/viral pathogen-associated molecular pattern molecules, autoimmunity, dysbiosis/viral reactivation, and tissue damage

“Right now, it’s too early to exclude or make any conclusions about these. We need to have an open mind to dissect these various possibilities,” she said.

Two speakers reported findings of immune dysregulation in both ME/CFS and long COVID. Wakiro Sato, MD, PhD, of the National Center of Neurology and Psychiatry, Tokyo, reported that anti–G-protein coupled receptor antibodies were found in 33 (55%) of 60 patients with long COVID, and more than 40% had peripheral immune cell profile abnormalities. These findings were similar to those found in patients with ME/CFS, published by Sato’s team (Brain Behav Immun. 2021 Mar 29. doi: 10.1016/j.bbi.2021.03.023) and other researchers in Germany.  

Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, presented data for an analysis of peripheral blood mononuclear cells from 26 donors with ME/CFS (8 with long COVID) and 24 healthy controls. In both patient groups, they found altered expression of inflammatory markers and decreases in CD8 T-cell number and function. The patients with long COVID showed evidence of sustained activation of both T-cell populations with increased CD38 and HLA-DR, associated with a compensatory increased frequency of activated CD4+CD8+ T cells.

“These results are consistent with immune dysregulation associated with overactivation and exhaustion of CD8 T cells, as observed in chronic viral infections and tumor environments,” Dr. Selin said.
 

ME/CFS and long COVID ‘frighteningly similar, if not identical’

Data for a different system derangement in long COVID and ME/CFS, the pathophysiology of exercise intolerance, were presented in another keynote talk by David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital cardiopulmonary laboratory, both in Boston. He has conducted invasive cardiopulmonary exercise testing in patients with ME/CFS and patients with long COVID.

Previously, Dr. Systrom and his team found that patients with ME/CFS have distinct defects in both ventricular filling pressure and oxygen extraction from the muscles. Neither of those are features of deconditioning, which is often blamed for exercise intolerance in people with ME/CFS. Rather, the major defect in deconditioning is decreased stroke volume and cardiac output. In ME/CFS patients, he found supranormal pulmonary blood flow, compared with VO₂ max, suggesting peripheral left-to-right shunting.

In addition, Dr. Systrom and colleagues found that a large proportion of ME/CFS patients with these peripheral vascular defects also have biopsy-demonstrated small-fiber neuropathy, suggesting that acute exercise intolerance is related to underlying autonomic nervous system dysfunction.

In Dr. Systrom and colleagues’ long COVID study, invasive cardiopulmonary exercise testing in 10 patients who had recovered from COVID-19 at least 6 months prior and did not have cardiopulmonary disease had significantly revealed reduced peak exercise aerobic capacity (VO₂ max), compared with 10 age- and sex-matched controls. The reduction in peak VO₂ was associated with impaired systemic oxygen extraction, compared with the controls, despite a preserved peak cardiac index.

The long-COVID patients also showed greater ventilatory inefficiency, which “is entirely related to hyperventilation, not intrinsic lung disease,” Dr. Systrom said, adding that while there may be subsets of patients with interstitial lung disease after acute respiratory distress syndrome, these patients didn’t have that. “This for all the world looks like ME/CFS. We think they are frighteningly similar, if not identical,” Dr. Systrom said.  

In a third study for which Dr. Systrom was a coauthor, published in Annals of Neurology, multisystem involvement was found in nine patients following mild COVID-19 infection, using standardized autonomic assessments including Valsalva maneuver, sudomotor and tilt tests, and skin biopsies for small-fiber neuropathy. The findings included cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction, small-fiber neuropathy and related dysautonomia, respiratory dysregulation, and chronic inflammation.

Dr. Systrom’s conclusion: “Dyspnea and hyperventilation are common in ME/CFS and long COVID and there is significant overlap with POTS.”

Dr. Bateman disclosed that she is conducting research for Terra Biological. Dr. Systrom said he is conducting research for Astellas.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

A variety of treatments, most already commercially available, are under investigation for treating the constellation of overlapping symptoms associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), “long COVID,” and dysautonomia.

At the virtual annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, speakers presented data for a variety of approaches to ease symptoms common across postviral conditions, such as extreme fatigue, postexertional malaise (“crash”), cognitive dysfunction (“brain fog”), orthostatic intolerance including postural orthostatic tachycardia syndrome (POTS), and chronic pain. Most of the modalities are already commercially available for other indications, although some are costly and not covered by payers for these conditions.

“Both post–acute COVID-19 syndrome and ME/CFS are forms of postinfectious viral syndromes and they have overlapping symptoms. ... In the past, patients were told ‘you have chronic fatigue syndrome but there’s nothing we can do for it.’ That certainly is not the case. There aren’t cures, but there are many management techniques to improve symptoms,” Charles W. Lapp, MD, medical director of the Hunter-Hopkins Center, Charlotte, N.C., said in an interview.

A current mainstay of treatment for ME/CFS – including that triggered by COVID-19 – is activity pacing, in which patients learn to stay within their “energy envelopes” in order to avoid postexertional malaise, a worsening of all symptoms with exertion. The use of “graded exercise” is no longer recommended, per U.K. and U.S. guidelines.

Data for the following approaches were presented at the IACFS/ME conference:
 

Pyridostigmine (mestinon, others)

Pyridostigmine, an acetylcholinesterase inhibitor, is approved for the treatment of muscle weakness resulting from myasthenia gravis and is available in generic form. It has previously been shown to produce significant improvement in both symptom burden and heart rate response in POTS.

At the IACFS/ME conference, David M. Systrom, MD, a pulmonary and critical care medicine specialist at Brigham and Women’s Hospital and director of the Massachusetts General Hospital Cardiopulmonary laboratory, both in Boston, summarized his group’s study in patients with ME/CFS using pyridostigmine as both a potential treatment for improving exercise capacity and a proof-of-concept that neurovascular dysregulation underlies exertional intolerance in the condition.

A total of 45 patients were randomized to 60 mg oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test, and a second test performed 50 minutes later. Peak VO₂ increased after pyridostigmine but decreased after placebo (+13.3 mL/min vs. –40.2 mL/min, P < .05). Cardiac output and right atrial pressure were also significantly improved with pyridostigmine and worse with placebo.

“We suggest that treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. ... Pyridostigmine may be a useful repurposed off-label treatment [for] a subset of patients with exercise intolerance,” Dr. Systrom said.

Asked to comment, Dr. Lapp said: “We’ve used Mestinon for years because it helps with POTS and also with neurally mediated hypotension. Systrom is taking it to a new level because he’s shown that it increases preload to the heart.” However, he noted that it’s unclear whether the drug will help patients who don’t have POTS specifically. On the other hand, patients rarely experience side effects from the drug.

Since the generic tablets come only in 60-mg doses, and the starting dose is 30 mg three times a day, he advised cutting the tablets in half during titration up to 60 mg three times a day.
 

Oxaloacetate (benaGene)

David Lyons Kaufman, MD, of the Center for Complex Diseases, Mountain View, Calif., summarized data from his group’s recently published open-label, nonrandomized, “proof-of-concept” study on use of the commercially available nutritional supplement anhydrous enol-oxaloacetate for treating mental and physical fatigue in 76 patients with longstanding ME/CFS and 43 with long-COVID fatigue.

Oxaloacetate is a major step in the Krebs cycle within the mitochondria that are depleted in patients with ME/CFS. It is also an energy metabolite that has multiple effects in cells and mitochondria, Dr. Kaufman explained.

Doses ranging from 500 mg twice daily up to 1,000 mg three times a day were given for 6 weeks. Up to 33% of the patients with ME/CFS and up to 46.8% of the long-COVID group achieved clinical efficacy as measured by physical and mental fatigue scores, compared with just 5.9% of historical ME/CFS controls. All doses showed highly significant improvements.

The only adverse effects were occasional dyspepsia, which was avoided by taking the supplement with food, and insomnia, resolved by having them dose at breakfast and lunch, Dr. Kaufman said.

Following those preliminary data, there is now an ongoing 90-day, randomized, placebo-controlled clinical trial of 80 patients with ME/CFS using 2,000 mg anhydrous enol-oxaloacetate per day. Endpoints include multiple objective measures.

“We have a health care crisis with long COVID, and we’ve had this smoldering crisis with ME/CFS for decades that’s never been addressed. ME/CFS and long COVID, if not identical, are certainly overlapping. ... We have to pursue these translational medicine pilot studies as rapidly as possible,” Dr. Kaufman remarked.

Dr. Lapp told this news organization that it makes sense to use constituents of the Krebs cycle to improve mitochondrial function, but the problem with oxaloacetate is its cost. Dr. Kaufman mentioned that based on the preliminary trial, the therapeutic “sweet spot” appeared to be 1,000 mg twice daily. The manufacturer’s website lists the price for a single bottle of 30 250-mg capsules at $49, or $42 if purchased via a monthly subscription.

“It’s a benign drug, and it’s over the counter. I would give it to any patient who’s got a big wallet,” Dr. Lapp quipped, adding: “If they’ve got the money, they can order it tonight.”
 

Inspiritol

Inspiritol is an investigational “nebulized, inhaled, multimechanism medication designed to treat the major symptoms of respiratory distress with antioxidant, anti-inflammatory, and broad-spectrum antiviral and antibacterial properties. Inspiritol is composed of both endogenously produced and naturally occurring, well-tolerated biochemicals,” according to the company website.

The hypothesis, Liisa K. Selin, MD, PhD, professor of pathology at the University of Massachusetts, Worcester, said at the meeting, is that “ME/CFS and long COVID-19 result from an aberrant response to an immunological trigger like infection, which results in a permanently dysregulated immune system as a result of overactivation of CD8 T cells and subsequent exhaustion.”

Inspiritol, containing five antioxidants, acts as an immune modulator to reverse the CD8 T cell exhaustion and improve symptoms. Administration by inhaler delivers it directly to the brain from the lung. It was originally designed for use in chronic obstructive pulmonary disease and asthma and has shown efficacy for acute COVID-19, Dr. Selin said.

In a preliminary study, four patients with ME/CFS and five with long COVID have been treated with Inspiritol for 2-15 months, and all have self-reported improved symptoms. Cough has been the only reported side effect.

The company is pursuing an Investigational New Drug Application for the product with the Food and Drug Administration and has several patents pending. Dr. Lapp called Inspiritol “very interesting,” and said that reversal of CD8 “exhaustion” also would appear to be a promising approach. However, he noted, “the problem is that we don’t know what’s in it.”
 

Stellate ganglion block

Injection of local anesthetic near the stellate ganglion to block activity of the entire cervical sympathetic chain has been used for nearly a century to treat a variety of sympathetically mediated conditions, including complex regional pain syndrome (CRPS), shingles, and phantom-limb pain. More recently, it has been used in a variety of other conditions, including PTSD, Raynaud’s disease, menopausal hot flashes, and hyperhidrosis.

Insurance companies typically cover it for CRPS, neuropathic upper-extremity pain, hyperhidrosis, and Raynaud’s, said Luke Liu, MD, an anesthesiologist who is founder and chief executive officer of Alaska-based pain management company Neuroversion.

Deborah Duricka, PhD, also with Neuroversion, presented results from a now-published case series of 11 patients with long COVID who underwent stellate ganglion block by a board-certified anesthesiologist, first on one side at the level of C6, then on the contralateral side the following day.

Clinically meaningful benefits were seen in at least five of the patients in fatigue, memory problems, problems concentrating, rapid heartbeat, orthostatic intolerance, sleep problems, postexertional malaise, anxiety, and depression.

The hypothetical mechanism, she said, is that “sympathetic block prevents sympathetically driven vasoconstriction in carotid and vertebral arteries.”

Dr. Liu presented another case series of five patients with ME/CFS who underwent the procedure with ultrasound guidance, again on one side and the other side the next day. All had upper-limb autonomic issues such as Raynaud’s and/or neuropathic pain that had been refractory to more conventional treatments.

All five patients reported improvements in symptoms of ME/CFS, including energy level, cognition, pain, and postexertional malaise. One patient reported “feeling well for the first time in decades.” However, that patient relapsed after a mild viral illness 3.5 months after treatment. Some of the patients have required further treatments.

Dr. Lapp commented that, although the procedure is generally safe when performed by an experienced clinician, “Any time you do an injection like that, there’s a high risk that you could nick an artery or a vein or hit an essential nerve in the neck. That’s why it has to be done under fluoroscopy or ultrasound.”

He said he’s had a few patients undergo the procedure, mostly for CRPS, and they seem to have benefited from it. “It might increase cerebral blood flow and preload to the heart, so it might decrease ME/CFS symptoms and help with POTS as well.”

Nonetheless, Dr. Lapp said he wouldn’t consider stellate ganglion block as first-line treatment for ME/CFS or long COVID. “I think it would be for the treatment-resistant patient, when you’ve gone through all the treatments that we know and addressed all the comorbidities and they’re still not getting better.”

But, he added, it is a standard procedure. “Any pain clinic can do a stellate block.”
 

Transcutaneous auricular vagus nerve stimulation

Nicola Clague-Baker, PhD, a physiotherapist at the University of Liverpool (England), presented findings from an international survey of people with ME/CFS regarding their experience with transcutaneous auricular vagus nerve stimulation (taVNS) to manage their autonomic symptoms. The technique involves stimulation of the autonomic nervous system via the vagus nerve using electrodes applied to part of the ear. The theory is that the technique stimulates the parasympathetic nervous system and improves autonomic balance.

Two small previous trials showing benefit of vagus nerve stimulation for people with ME/CFS used more invasive and less comfortable methods of applying the stimulation rather than to the ear, Dr. Clague-Baker and colleagues noted in a poster. It has also been used successfully in treating POTS, another conference speaker noted.

A total of 131 people with ME/CFS (called simply “ME” in the United Kingdom) responded to a survey advertised on social media and websites. The majority (60%) were from the United Kingdom while the rest were from Europe, Australia, and North America. Most were female, and slightly more than half had lived with ME for 10 or more years.

The majority (72%) were still using taVNS, while 28% had stopped using it. Only 9% had used the modality for longer than a year. Respondents identified more than 30 benefits in symptoms and activities, with improvements in postexertional malaise (39%) and brain fog (37%) being the most common. One reported significant reduction in constipation.

However, respondents also mentioned more than 20 short- and long-term negatives, including headaches (15%) and long-term irritation at the site (9%). One participant reported a “big improvement in neuropathic pain, but not so much for muscles and joints.”

Overall, 80% reported that they would continue using taVNS and 67% said they would recommend it to others with ME, and 56% said that the system was mildly to very beneficial.

Dr. Lapp noted that several types of transcutaneous electrical nerve stimulation units with ear clips are sold online, and he’s seen them work well for migraine treatment. However, he cautioned that some patients have had side effects from the treatment, such as headaches and dizziness. “It’s putting an electrical current through your brain. In my mind, it’s another last-ditch measure.”

Dr. Lapp reported no financial disclosures.

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

One in eight adults (12.7%) diagnosed with COVID-19 will likely experience long-term symptoms, a large study published in The Lancet indicates.

The researchers determined that percentage by comparing long-term symptoms in people infected by SARS-CoV-2 with similar symptoms in uninfected people over the same time period.

Among the group of infected study participants in the Netherlands, 21.4% had at least one new or severely increased symptom 3-5 months after infection compared with before infection. When that group of 21.4% was compared with 8.7% of uninfected people in the same study, the researchers were able to calculate a prevalence 12.7% with long COVID.

“This finding shows that post–COVID-19 condition is an urgent problem with a mounting human toll,” the study authors wrote.

The research design was novel, two editorialists said in an accompanying commentary.

Christopher Brightling, PhD, and Rachael Evans, MBChB, PhD, of the Institute for Lung Health, University of Leicester (England), noted: “This is a major advance on prior long COVID prevalence estimates as it includes a matched uninfected group and accounts for symptoms before COVID-19 infection.”
 

Symptoms that persist

The Lancet study found that 3-5 months after COVID (compared with before COVID) and compared with the non-COVID comparison group, the symptoms that persist were chest pain, breathing difficulties, pain when breathing, muscle pain, loss of taste and/or smell, tingling extremities, lump in throat, feeling hot and cold alternately, heavy limbs, and tiredness.

The authors noted that symptoms such as brain fog were found to be relevant to long COVID after the data collection period for this paper and were not included in this research.

Researcher Aranka V. Ballering, MSc, PhD candidate, said in an interview that the researchers found fever is a symptom that is clearly present during the acute phase of the disease and it peaks the day of the COVID-19 diagnosis, but also wears off.

Loss of taste and smell, however, rapidly increases in severity when COVID-19 is diagnosed, but also persists and is still present 3-5 months after COVID.

Ms. Ballering, with the department of psychiatry at the University of Groningen (the Netherlands), said she was surprised by the sex difference made evident in their research: “Women showed more severe persistent symptoms than men.”
 

Closer to a clearer definition

The authors said their findings also pinpoint symptoms that bring us closer to a better definition of long COVID, which has many different definitions globally.

“These symptoms have the highest discriminative ability to distinguish between post–COVID-19 condition and non–COVID-19–related symptoms,” they wrote.

Researchers collected data by asking participants in the northern Netherlands, who were part of the population-based Lifelines COVID-19 study, to regularly complete digital questionnaires on 23 symptoms commonly associated with long COVID. The questionnaire was sent out 24 times to the same people between March 2020 and August 2021. At that time, people had the Alpha or earlier variants.

Participants were considered COVID-19 positive if they had either a positive test or a doctor’s diagnosis of COVID-19.

Of 76,422 study participants, the 5.5% (4,231) who had COVID were matched to 8,462 controls. Researchers accounted for sex, age, and time of completing questionnaires.
 

Effect of hospitalization, vaccination unclear

Ms. Ballering said it’s unclear from this data whether vaccination or whether a person was hospitalized would change the prevalence of persistent symptoms.

Because of the period when the data were collected, “the vast majority of our study population was not fully vaccinated,” she said.

However, she pointed to recent research that shows that immunization against COVID is only partially effective against persistent somatic symptoms after COVID.

Also, only 5% of men and 2.5% of women in the study were hospitalized as a result of COVID-19, so the findings can’t easily be generalized to hospitalized patients.

The Lifelines study was an add-on study to the multidisciplinary, prospective, population-based, observational Dutch Lifelines cohort study examining 167,729 people in the Netherlands. Almost all were White, a limitation of the study, and 58% were female. Average age was 54.

The editorialists also noted additional limitations of the study were that this research “did not fully consider the impact on mental health” and was conducted in one region in the Netherlands.

Janko Nikolich-Žugich, MD, PhD, director of the Aegis Consortium for Pandemic-Free Future and head of the immunobiology department at University of Arizona, Tucson, said in an interview that he agreed with the editorialists that a primary benefit of this study is that it corrected for symptoms people had before COVID, something other studies have not been able to do.

However, he cautioned about generalizing the results for the United States and other countries because of the lack of diversity in the study population with regard to education level, socioeconomic factors, and race. He pointed out that access issues are also different in the Netherlands, which has universal health care.

He said brain fog as a symptom of long COVID is of high interest and will be important to include in future studies that are able to extend the study period.

The work was funded by ZonMw; the Dutch Ministry of Health, Welfare, and Sport; Dutch Ministry of Economic Affairs; University Medical Center Groningen, University of Groningen; and the provinces of Drenthe, Friesland, and Groningen. The study authors and Dr. Nikolich-Žugich have reported no relevant financial relationships. Dr. Brightling has received consultancy and or grants paid to his institution from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Genentech, Roche, Sanofi, Regeneron, Mologic, and 4DPharma for asthma and chronic obstructive pulmonary disease research. Dr. Evans has received consultancy fees from AstraZeneca on the topic of long COVID and from GlaxoSmithKline on digital health, and speaker’s fees from Boehringer Ingelheim on long COVID.

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

One in eight adults (12.7%) diagnosed with COVID-19 will likely experience long-term symptoms, a large study published in The Lancet indicates.

The researchers determined that percentage by comparing long-term symptoms in people infected by SARS-CoV-2 with similar symptoms in uninfected people over the same time period.

Among the group of infected study participants in the Netherlands, 21.4% had at least one new or severely increased symptom 3-5 months after infection compared with before infection. When that group of 21.4% was compared with 8.7% of uninfected people in the same study, the researchers were able to calculate a prevalence 12.7% with long COVID.

“This finding shows that post–COVID-19 condition is an urgent problem with a mounting human toll,” the study authors wrote.

The research design was novel, two editorialists said in an accompanying commentary.

Christopher Brightling, PhD, and Rachael Evans, MBChB, PhD, of the Institute for Lung Health, University of Leicester (England), noted: “This is a major advance on prior long COVID prevalence estimates as it includes a matched uninfected group and accounts for symptoms before COVID-19 infection.”
 

Symptoms that persist

The Lancet study found that 3-5 months after COVID (compared with before COVID) and compared with the non-COVID comparison group, the symptoms that persist were chest pain, breathing difficulties, pain when breathing, muscle pain, loss of taste and/or smell, tingling extremities, lump in throat, feeling hot and cold alternately, heavy limbs, and tiredness.

The authors noted that symptoms such as brain fog were found to be relevant to long COVID after the data collection period for this paper and were not included in this research.

Researcher Aranka V. Ballering, MSc, PhD candidate, said in an interview that the researchers found fever is a symptom that is clearly present during the acute phase of the disease and it peaks the day of the COVID-19 diagnosis, but also wears off.

Loss of taste and smell, however, rapidly increases in severity when COVID-19 is diagnosed, but also persists and is still present 3-5 months after COVID.

Ms. Ballering, with the department of psychiatry at the University of Groningen (the Netherlands), said she was surprised by the sex difference made evident in their research: “Women showed more severe persistent symptoms than men.”
 

Closer to a clearer definition

The authors said their findings also pinpoint symptoms that bring us closer to a better definition of long COVID, which has many different definitions globally.

“These symptoms have the highest discriminative ability to distinguish between post–COVID-19 condition and non–COVID-19–related symptoms,” they wrote.

Researchers collected data by asking participants in the northern Netherlands, who were part of the population-based Lifelines COVID-19 study, to regularly complete digital questionnaires on 23 symptoms commonly associated with long COVID. The questionnaire was sent out 24 times to the same people between March 2020 and August 2021. At that time, people had the Alpha or earlier variants.

Participants were considered COVID-19 positive if they had either a positive test or a doctor’s diagnosis of COVID-19.

Of 76,422 study participants, the 5.5% (4,231) who had COVID were matched to 8,462 controls. Researchers accounted for sex, age, and time of completing questionnaires.
 

Effect of hospitalization, vaccination unclear

Ms. Ballering said it’s unclear from this data whether vaccination or whether a person was hospitalized would change the prevalence of persistent symptoms.

Because of the period when the data were collected, “the vast majority of our study population was not fully vaccinated,” she said.

However, she pointed to recent research that shows that immunization against COVID is only partially effective against persistent somatic symptoms after COVID.

Also, only 5% of men and 2.5% of women in the study were hospitalized as a result of COVID-19, so the findings can’t easily be generalized to hospitalized patients.

The Lifelines study was an add-on study to the multidisciplinary, prospective, population-based, observational Dutch Lifelines cohort study examining 167,729 people in the Netherlands. Almost all were White, a limitation of the study, and 58% were female. Average age was 54.

The editorialists also noted additional limitations of the study were that this research “did not fully consider the impact on mental health” and was conducted in one region in the Netherlands.

Janko Nikolich-Žugich, MD, PhD, director of the Aegis Consortium for Pandemic-Free Future and head of the immunobiology department at University of Arizona, Tucson, said in an interview that he agreed with the editorialists that a primary benefit of this study is that it corrected for symptoms people had before COVID, something other studies have not been able to do.

However, he cautioned about generalizing the results for the United States and other countries because of the lack of diversity in the study population with regard to education level, socioeconomic factors, and race. He pointed out that access issues are also different in the Netherlands, which has universal health care.

He said brain fog as a symptom of long COVID is of high interest and will be important to include in future studies that are able to extend the study period.

The work was funded by ZonMw; the Dutch Ministry of Health, Welfare, and Sport; Dutch Ministry of Economic Affairs; University Medical Center Groningen, University of Groningen; and the provinces of Drenthe, Friesland, and Groningen. The study authors and Dr. Nikolich-Žugich have reported no relevant financial relationships. Dr. Brightling has received consultancy and or grants paid to his institution from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Genentech, Roche, Sanofi, Regeneron, Mologic, and 4DPharma for asthma and chronic obstructive pulmonary disease research. Dr. Evans has received consultancy fees from AstraZeneca on the topic of long COVID and from GlaxoSmithKline on digital health, and speaker’s fees from Boehringer Ingelheim on long COVID.

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

One in eight adults (12.7%) diagnosed with COVID-19 will likely experience long-term symptoms, a large study published in The Lancet indicates.

The researchers determined that percentage by comparing long-term symptoms in people infected by SARS-CoV-2 with similar symptoms in uninfected people over the same time period.

Among the group of infected study participants in the Netherlands, 21.4% had at least one new or severely increased symptom 3-5 months after infection compared with before infection. When that group of 21.4% was compared with 8.7% of uninfected people in the same study, the researchers were able to calculate a prevalence 12.7% with long COVID.

“This finding shows that post–COVID-19 condition is an urgent problem with a mounting human toll,” the study authors wrote.

The research design was novel, two editorialists said in an accompanying commentary.

Christopher Brightling, PhD, and Rachael Evans, MBChB, PhD, of the Institute for Lung Health, University of Leicester (England), noted: “This is a major advance on prior long COVID prevalence estimates as it includes a matched uninfected group and accounts for symptoms before COVID-19 infection.”
 

Symptoms that persist

The Lancet study found that 3-5 months after COVID (compared with before COVID) and compared with the non-COVID comparison group, the symptoms that persist were chest pain, breathing difficulties, pain when breathing, muscle pain, loss of taste and/or smell, tingling extremities, lump in throat, feeling hot and cold alternately, heavy limbs, and tiredness.

The authors noted that symptoms such as brain fog were found to be relevant to long COVID after the data collection period for this paper and were not included in this research.

Researcher Aranka V. Ballering, MSc, PhD candidate, said in an interview that the researchers found fever is a symptom that is clearly present during the acute phase of the disease and it peaks the day of the COVID-19 diagnosis, but also wears off.

Loss of taste and smell, however, rapidly increases in severity when COVID-19 is diagnosed, but also persists and is still present 3-5 months after COVID.

Ms. Ballering, with the department of psychiatry at the University of Groningen (the Netherlands), said she was surprised by the sex difference made evident in their research: “Women showed more severe persistent symptoms than men.”
 

Closer to a clearer definition

The authors said their findings also pinpoint symptoms that bring us closer to a better definition of long COVID, which has many different definitions globally.

“These symptoms have the highest discriminative ability to distinguish between post–COVID-19 condition and non–COVID-19–related symptoms,” they wrote.

Researchers collected data by asking participants in the northern Netherlands, who were part of the population-based Lifelines COVID-19 study, to regularly complete digital questionnaires on 23 symptoms commonly associated with long COVID. The questionnaire was sent out 24 times to the same people between March 2020 and August 2021. At that time, people had the Alpha or earlier variants.

Participants were considered COVID-19 positive if they had either a positive test or a doctor’s diagnosis of COVID-19.

Of 76,422 study participants, the 5.5% (4,231) who had COVID were matched to 8,462 controls. Researchers accounted for sex, age, and time of completing questionnaires.
 

Effect of hospitalization, vaccination unclear

Ms. Ballering said it’s unclear from this data whether vaccination or whether a person was hospitalized would change the prevalence of persistent symptoms.

Because of the period when the data were collected, “the vast majority of our study population was not fully vaccinated,” she said.

However, she pointed to recent research that shows that immunization against COVID is only partially effective against persistent somatic symptoms after COVID.

Also, only 5% of men and 2.5% of women in the study were hospitalized as a result of COVID-19, so the findings can’t easily be generalized to hospitalized patients.

The Lifelines study was an add-on study to the multidisciplinary, prospective, population-based, observational Dutch Lifelines cohort study examining 167,729 people in the Netherlands. Almost all were White, a limitation of the study, and 58% were female. Average age was 54.

The editorialists also noted additional limitations of the study were that this research “did not fully consider the impact on mental health” and was conducted in one region in the Netherlands.

Janko Nikolich-Žugich, MD, PhD, director of the Aegis Consortium for Pandemic-Free Future and head of the immunobiology department at University of Arizona, Tucson, said in an interview that he agreed with the editorialists that a primary benefit of this study is that it corrected for symptoms people had before COVID, something other studies have not been able to do.

However, he cautioned about generalizing the results for the United States and other countries because of the lack of diversity in the study population with regard to education level, socioeconomic factors, and race. He pointed out that access issues are also different in the Netherlands, which has universal health care.

He said brain fog as a symptom of long COVID is of high interest and will be important to include in future studies that are able to extend the study period.

The work was funded by ZonMw; the Dutch Ministry of Health, Welfare, and Sport; Dutch Ministry of Economic Affairs; University Medical Center Groningen, University of Groningen; and the provinces of Drenthe, Friesland, and Groningen. The study authors and Dr. Nikolich-Žugich have reported no relevant financial relationships. Dr. Brightling has received consultancy and or grants paid to his institution from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Genentech, Roche, Sanofi, Regeneron, Mologic, and 4DPharma for asthma and chronic obstructive pulmonary disease research. Dr. Evans has received consultancy fees from AstraZeneca on the topic of long COVID and from GlaxoSmithKline on digital health, and speaker’s fees from Boehringer Ingelheim on long COVID.

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

New COVID-19 vaccine boosters, targeting new Omicron strains of the virus, are expected to roll out across the United States in September – a month ahead of schedule, the Biden administration announced this week.

Moderna has signed a $1.74 billion federal contract to supply 66 million initial doses of the “bivalent” booster, which includes the original “ancestral” virus strain and elements of the Omicron BA.4 and BA.5 variants. Pfizer also announced a $3.2 billion U.S. agreement for another 105 million shots. Both vaccine suppliers have signed options to provide millions more boosters in the months ahead.

About 83.5% of Americans have received at least one COVID-19 shot, with 71.5% fully vaccinated with the initial series, 48% receiving one booster shot, and 31% two boosters, according to the CDC. With about 130,000 new COVID cases per day, and about 440 deaths, officials say the updated boosters may help rein in those figures by targeting the highly transmissible and widely circulating Omicron strains.

Federal health officials are still hammering out details of guidelines and recommendations of who should get the boosters, which are expected to come from the CDC and FDA. For now, authorities have decided not to expand eligibility for second boosters of the existing vaccines – now recommended only for adults over 50 and those 12 and older with immune deficiencies. Children 5 through 11 are advised to receive a single booster, 5 months after their initial vaccine series.

For a preview of what to expect from the CDC and FDA, this news organization spoke with Keri Althoff, PhD, an epidemiologist at Johns Hopkins University, Baltimore.
 

Q: Based on what we know now, who should be getting one of these new bivalent boosters?A: Of course, there is a process here regarding the specific recommendations, but it appears there will likely be a recommendation for all individuals to get this bivalent booster, similar to the first booster. And there will likely be a recommended time frame as to time since the last booster.

Right now, we have a recommendation for adults over the age of 50 or adults who are at higher risk for severe COVID-related illness [to get] a second booster. For them, there will probably be a timeline that says you should get the booster if you’re X amount of months or more from your second booster; or X amount of months or more from your first booster, if you’ve only had one.

Q: What about pregnant women or those being treated for chronic health conditions?A: I would imagine that once this bivalent booster becomes available, it will be recommended for all adults.

Q: And for children?A: That’s a good question. It’s something I have been digging into, [and] I think parents are really interested in this. Most kids, 5 and above, are supposed to be boosted with one shot right now, if they’re X amount of days from their primary vaccine series. Of course those 6 months to 4.99 years are not yet eligible [for boosters].

As a parent, I would love to see my children become eligible for the bivalent booster. It would be great if these boosters are conveying some additional protection that the kids could get access to before we send them off to school this fall. But there are questions as to whether or not that is going to happen.

Q: If you never received a booster, but only the preliminary vaccine series, do you need to get those earlier boosters before having the new bivalent booster shot?A: I don’t think they will likely make that a requirement – to restrict the bivalent booster only to those who are already boosted or up to date on their vaccines at the time the bivalent booster becomes available. But that will be up to the [CDC] vaccine recommendation committee to decide.

Q: Are there any new risks associated with these boosters, since they were developed so rapidly?A: No. We continue to monitor this technology, and with all the mRNA vaccines that have been delivered, you have seen all that monitoring play out with the detection, for example, of different forms of inflammation of the heart tissue and who that may impact. So, those monitoring systems work, and they work really, really well, so we can detect those things. And we know these vaccines are definitely safe.

Q: Some health experts are concerned “vaccine fatigue” will have an impact on the booster campaign. What’s your take?A: We have seen this fatigue in the proportion of individuals who are boosted with a first booster and even boosted with a second. But having those earlier boosters along with this new bivalent booster is important, because essentially, what we’re doing is really priming the immune system.

We’re trying to expedite the process of getting people’s immune system up to speed so that when the virus comes our way – as we know it will, because [of] these Omicron strains that are highly infectious and really whipping through our communities – we’re able to get the highest level of population immunity, you don’t end up in the hospital.

Q: What other challenges do you see in persuading Americans to get another round of boosters?A: One of the things that I’ve been hearing a lot, which I get very nervous about, is people saying: “Oh, I got fully vaccinated, I did or did not get the booster, and I had COVID anyway and it was really nothing, it didn’t feel like much to me, and so I’m not going to be boosted anymore.” We are not in a place quite yet where those guidelines are being rolled back in any way, shape, or form. We still have highly vulnerable people to severe disease and death in our communities, and we’re seeing hundreds of deaths every day.

There are consequences, even if it isn’t in severity of disease, meaning hospitalization and death. And let’s not let the actual quality of the vaccine being so successful that it can keep you out of the hospital. Don’t mistake that for “I don’t need another one.”

Q: Unlike the flu shot, which is reformulated each year to match circulating strains, the new COVID boosters offer protection against older strains as well as the newer ones. Why?A: It’s all about creating a broader immune response in individuals so that as more strains emerge, which they likely will, we can create a broader population immune response [to all strains]. Our individual bodies are seeing differences in these strains through vaccination that helps everyone stay healthy.

Q: There haven’t been clinical trials of these new mRNA boosters. How strong is the evidence that they will be effective against the emerging Omicron variants?A: There have been some studies – some great studies – looking at things like neutralizing antibodies, which we use as a surrogate for clinical trials. But that is not the same as studying the outcome of interest, which would be hospitalizations. So, part of the challenge is to be able to say: “Okay, this is what we know about the safety and effectiveness of the prior vaccines ... and how can we relate that to outcomes with these new boosters at an earlier stage [before] clinical data is available?”

Q: How long will the new boosters’ protections last – do we know yet?A: That timing is still a question, but of course what plays a big role in that is what COVID strains are circulating. If we prep these boosters that are Omicron specific, and then we have something totally new emerge ... we have to be more nimble because the variants are outpacing what we’re able to do.

This turns out to be a bit of a game of probability – the more infection we have, the more replication of the virus; the more replication, the more opportunity for mutations and subsequent variants.

Q: What about a combined flu-COVID vaccine; is that on the horizon?A: My children, who like most children do not like vaccines, always tell me: “Mom, why can’t they just put the influenza vaccine and the COVID vaccine into the same shot?” And I’m like: “Oh, from your lips to some scientist’s ears.”

At a time like this, where mRNA technology has totally disrupted what we can do with vaccines, in such a good way, I think we should push for the limits, because that would be incredible.

Q: If you’ve received a non-mRNA COVID vaccine, like those produced by Johnson & Johnson and Novavax, should you also get an mRNA booster?A: Right now, the CDC guidelines do state that if your primary vaccine series was not with an mRNA vaccine then being boosted with an mRNA is a fine thing to do, and it’s actually encouraged. So that’s not going to change with the bivalent booster.

Q: Is it okay to get a flu shot and a COVID booster at the same time, as the Centers for Disease Control and Prevention has recommended with past vaccines?A: I don’t anticipate there being recommendations against that. But I would also say watch for the recommendations that come out this fall on the bivalent boosters.

I do hope in the recommendations the CDC makes about the COVID boosters, they will say think about also getting your influenza vaccine, too. You could also get your COVID booster first, then by October get your influenza vaccine.

Q: Once you’re fully boosted, is it safe to stop wearing a mask, social distancing, avoiding crowded indoor spaces, and taking other precautions to avoid COVID-19?A: The virus is going to do what it does, which is infect whomever it can, and make them sick. So, if you see a lot of community transmission – you know who is ill with COVID in your kids’ schools, you know in your workplace and when people go out – that still signals there’s some increases in the circulation of virus. So, look at that to understand what your risk is.

If you know someone or have a colleague who is currently pregnant or immune suppressed, think about how you can protect them with mask-wearing, even if it’s just when you’re in one-on-one closed-door meetings with that individual.

So, your masking question is an important one, and it’s important for people to continue to hang onto those masks and wear them the week before you go see Grandma, for instance, to further reduce your risk so you don’t bring anything to here.

The high-level community risk nationwide is high right now. COVID is here.

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

New COVID-19 vaccine boosters, targeting new Omicron strains of the virus, are expected to roll out across the United States in September – a month ahead of schedule, the Biden administration announced this week.

Moderna has signed a $1.74 billion federal contract to supply 66 million initial doses of the “bivalent” booster, which includes the original “ancestral” virus strain and elements of the Omicron BA.4 and BA.5 variants. Pfizer also announced a $3.2 billion U.S. agreement for another 105 million shots. Both vaccine suppliers have signed options to provide millions more boosters in the months ahead.

About 83.5% of Americans have received at least one COVID-19 shot, with 71.5% fully vaccinated with the initial series, 48% receiving one booster shot, and 31% two boosters, according to the CDC. With about 130,000 new COVID cases per day, and about 440 deaths, officials say the updated boosters may help rein in those figures by targeting the highly transmissible and widely circulating Omicron strains.

Federal health officials are still hammering out details of guidelines and recommendations of who should get the boosters, which are expected to come from the CDC and FDA. For now, authorities have decided not to expand eligibility for second boosters of the existing vaccines – now recommended only for adults over 50 and those 12 and older with immune deficiencies. Children 5 through 11 are advised to receive a single booster, 5 months after their initial vaccine series.

For a preview of what to expect from the CDC and FDA, this news organization spoke with Keri Althoff, PhD, an epidemiologist at Johns Hopkins University, Baltimore.
 

Q: Based on what we know now, who should be getting one of these new bivalent boosters?A: Of course, there is a process here regarding the specific recommendations, but it appears there will likely be a recommendation for all individuals to get this bivalent booster, similar to the first booster. And there will likely be a recommended time frame as to time since the last booster.

Right now, we have a recommendation for adults over the age of 50 or adults who are at higher risk for severe COVID-related illness [to get] a second booster. For them, there will probably be a timeline that says you should get the booster if you’re X amount of months or more from your second booster; or X amount of months or more from your first booster, if you’ve only had one.

Q: What about pregnant women or those being treated for chronic health conditions?A: I would imagine that once this bivalent booster becomes available, it will be recommended for all adults.

Q: And for children?A: That’s a good question. It’s something I have been digging into, [and] I think parents are really interested in this. Most kids, 5 and above, are supposed to be boosted with one shot right now, if they’re X amount of days from their primary vaccine series. Of course those 6 months to 4.99 years are not yet eligible [for boosters].

As a parent, I would love to see my children become eligible for the bivalent booster. It would be great if these boosters are conveying some additional protection that the kids could get access to before we send them off to school this fall. But there are questions as to whether or not that is going to happen.

Q: If you never received a booster, but only the preliminary vaccine series, do you need to get those earlier boosters before having the new bivalent booster shot?A: I don’t think they will likely make that a requirement – to restrict the bivalent booster only to those who are already boosted or up to date on their vaccines at the time the bivalent booster becomes available. But that will be up to the [CDC] vaccine recommendation committee to decide.

Q: Are there any new risks associated with these boosters, since they were developed so rapidly?A: No. We continue to monitor this technology, and with all the mRNA vaccines that have been delivered, you have seen all that monitoring play out with the detection, for example, of different forms of inflammation of the heart tissue and who that may impact. So, those monitoring systems work, and they work really, really well, so we can detect those things. And we know these vaccines are definitely safe.

Q: Some health experts are concerned “vaccine fatigue” will have an impact on the booster campaign. What’s your take?A: We have seen this fatigue in the proportion of individuals who are boosted with a first booster and even boosted with a second. But having those earlier boosters along with this new bivalent booster is important, because essentially, what we’re doing is really priming the immune system.

We’re trying to expedite the process of getting people’s immune system up to speed so that when the virus comes our way – as we know it will, because [of] these Omicron strains that are highly infectious and really whipping through our communities – we’re able to get the highest level of population immunity, you don’t end up in the hospital.

Q: What other challenges do you see in persuading Americans to get another round of boosters?A: One of the things that I’ve been hearing a lot, which I get very nervous about, is people saying: “Oh, I got fully vaccinated, I did or did not get the booster, and I had COVID anyway and it was really nothing, it didn’t feel like much to me, and so I’m not going to be boosted anymore.” We are not in a place quite yet where those guidelines are being rolled back in any way, shape, or form. We still have highly vulnerable people to severe disease and death in our communities, and we’re seeing hundreds of deaths every day.

There are consequences, even if it isn’t in severity of disease, meaning hospitalization and death. And let’s not let the actual quality of the vaccine being so successful that it can keep you out of the hospital. Don’t mistake that for “I don’t need another one.”

Q: Unlike the flu shot, which is reformulated each year to match circulating strains, the new COVID boosters offer protection against older strains as well as the newer ones. Why?A: It’s all about creating a broader immune response in individuals so that as more strains emerge, which they likely will, we can create a broader population immune response [to all strains]. Our individual bodies are seeing differences in these strains through vaccination that helps everyone stay healthy.

Q: There haven’t been clinical trials of these new mRNA boosters. How strong is the evidence that they will be effective against the emerging Omicron variants?A: There have been some studies – some great studies – looking at things like neutralizing antibodies, which we use as a surrogate for clinical trials. But that is not the same as studying the outcome of interest, which would be hospitalizations. So, part of the challenge is to be able to say: “Okay, this is what we know about the safety and effectiveness of the prior vaccines ... and how can we relate that to outcomes with these new boosters at an earlier stage [before] clinical data is available?”

Q: How long will the new boosters’ protections last – do we know yet?A: That timing is still a question, but of course what plays a big role in that is what COVID strains are circulating. If we prep these boosters that are Omicron specific, and then we have something totally new emerge ... we have to be more nimble because the variants are outpacing what we’re able to do.

This turns out to be a bit of a game of probability – the more infection we have, the more replication of the virus; the more replication, the more opportunity for mutations and subsequent variants.

Q: What about a combined flu-COVID vaccine; is that on the horizon?A: My children, who like most children do not like vaccines, always tell me: “Mom, why can’t they just put the influenza vaccine and the COVID vaccine into the same shot?” And I’m like: “Oh, from your lips to some scientist’s ears.”

At a time like this, where mRNA technology has totally disrupted what we can do with vaccines, in such a good way, I think we should push for the limits, because that would be incredible.

Q: If you’ve received a non-mRNA COVID vaccine, like those produced by Johnson & Johnson and Novavax, should you also get an mRNA booster?A: Right now, the CDC guidelines do state that if your primary vaccine series was not with an mRNA vaccine then being boosted with an mRNA is a fine thing to do, and it’s actually encouraged. So that’s not going to change with the bivalent booster.

Q: Is it okay to get a flu shot and a COVID booster at the same time, as the Centers for Disease Control and Prevention has recommended with past vaccines?A: I don’t anticipate there being recommendations against that. But I would also say watch for the recommendations that come out this fall on the bivalent boosters.

I do hope in the recommendations the CDC makes about the COVID boosters, they will say think about also getting your influenza vaccine, too. You could also get your COVID booster first, then by October get your influenza vaccine.

Q: Once you’re fully boosted, is it safe to stop wearing a mask, social distancing, avoiding crowded indoor spaces, and taking other precautions to avoid COVID-19?A: The virus is going to do what it does, which is infect whomever it can, and make them sick. So, if you see a lot of community transmission – you know who is ill with COVID in your kids’ schools, you know in your workplace and when people go out – that still signals there’s some increases in the circulation of virus. So, look at that to understand what your risk is.

If you know someone or have a colleague who is currently pregnant or immune suppressed, think about how you can protect them with mask-wearing, even if it’s just when you’re in one-on-one closed-door meetings with that individual.

So, your masking question is an important one, and it’s important for people to continue to hang onto those masks and wear them the week before you go see Grandma, for instance, to further reduce your risk so you don’t bring anything to here.

The high-level community risk nationwide is high right now. COVID is here.

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

New COVID-19 vaccine boosters, targeting new Omicron strains of the virus, are expected to roll out across the United States in September – a month ahead of schedule, the Biden administration announced this week.

Moderna has signed a $1.74 billion federal contract to supply 66 million initial doses of the “bivalent” booster, which includes the original “ancestral” virus strain and elements of the Omicron BA.4 and BA.5 variants. Pfizer also announced a $3.2 billion U.S. agreement for another 105 million shots. Both vaccine suppliers have signed options to provide millions more boosters in the months ahead.

About 83.5% of Americans have received at least one COVID-19 shot, with 71.5% fully vaccinated with the initial series, 48% receiving one booster shot, and 31% two boosters, according to the CDC. With about 130,000 new COVID cases per day, and about 440 deaths, officials say the updated boosters may help rein in those figures by targeting the highly transmissible and widely circulating Omicron strains.

Federal health officials are still hammering out details of guidelines and recommendations of who should get the boosters, which are expected to come from the CDC and FDA. For now, authorities have decided not to expand eligibility for second boosters of the existing vaccines – now recommended only for adults over 50 and those 12 and older with immune deficiencies. Children 5 through 11 are advised to receive a single booster, 5 months after their initial vaccine series.

For a preview of what to expect from the CDC and FDA, this news organization spoke with Keri Althoff, PhD, an epidemiologist at Johns Hopkins University, Baltimore.
 

Q: Based on what we know now, who should be getting one of these new bivalent boosters?A: Of course, there is a process here regarding the specific recommendations, but it appears there will likely be a recommendation for all individuals to get this bivalent booster, similar to the first booster. And there will likely be a recommended time frame as to time since the last booster.

Right now, we have a recommendation for adults over the age of 50 or adults who are at higher risk for severe COVID-related illness [to get] a second booster. For them, there will probably be a timeline that says you should get the booster if you’re X amount of months or more from your second booster; or X amount of months or more from your first booster, if you’ve only had one.

Q: What about pregnant women or those being treated for chronic health conditions?A: I would imagine that once this bivalent booster becomes available, it will be recommended for all adults.

Q: And for children?A: That’s a good question. It’s something I have been digging into, [and] I think parents are really interested in this. Most kids, 5 and above, are supposed to be boosted with one shot right now, if they’re X amount of days from their primary vaccine series. Of course those 6 months to 4.99 years are not yet eligible [for boosters].

As a parent, I would love to see my children become eligible for the bivalent booster. It would be great if these boosters are conveying some additional protection that the kids could get access to before we send them off to school this fall. But there are questions as to whether or not that is going to happen.

Q: If you never received a booster, but only the preliminary vaccine series, do you need to get those earlier boosters before having the new bivalent booster shot?A: I don’t think they will likely make that a requirement – to restrict the bivalent booster only to those who are already boosted or up to date on their vaccines at the time the bivalent booster becomes available. But that will be up to the [CDC] vaccine recommendation committee to decide.

Q: Are there any new risks associated with these boosters, since they were developed so rapidly?A: No. We continue to monitor this technology, and with all the mRNA vaccines that have been delivered, you have seen all that monitoring play out with the detection, for example, of different forms of inflammation of the heart tissue and who that may impact. So, those monitoring systems work, and they work really, really well, so we can detect those things. And we know these vaccines are definitely safe.

Q: Some health experts are concerned “vaccine fatigue” will have an impact on the booster campaign. What’s your take?A: We have seen this fatigue in the proportion of individuals who are boosted with a first booster and even boosted with a second. But having those earlier boosters along with this new bivalent booster is important, because essentially, what we’re doing is really priming the immune system.

We’re trying to expedite the process of getting people’s immune system up to speed so that when the virus comes our way – as we know it will, because [of] these Omicron strains that are highly infectious and really whipping through our communities – we’re able to get the highest level of population immunity, you don’t end up in the hospital.

Q: What other challenges do you see in persuading Americans to get another round of boosters?A: One of the things that I’ve been hearing a lot, which I get very nervous about, is people saying: “Oh, I got fully vaccinated, I did or did not get the booster, and I had COVID anyway and it was really nothing, it didn’t feel like much to me, and so I’m not going to be boosted anymore.” We are not in a place quite yet where those guidelines are being rolled back in any way, shape, or form. We still have highly vulnerable people to severe disease and death in our communities, and we’re seeing hundreds of deaths every day.

There are consequences, even if it isn’t in severity of disease, meaning hospitalization and death. And let’s not let the actual quality of the vaccine being so successful that it can keep you out of the hospital. Don’t mistake that for “I don’t need another one.”

Q: Unlike the flu shot, which is reformulated each year to match circulating strains, the new COVID boosters offer protection against older strains as well as the newer ones. Why?A: It’s all about creating a broader immune response in individuals so that as more strains emerge, which they likely will, we can create a broader population immune response [to all strains]. Our individual bodies are seeing differences in these strains through vaccination that helps everyone stay healthy.

Q: There haven’t been clinical trials of these new mRNA boosters. How strong is the evidence that they will be effective against the emerging Omicron variants?A: There have been some studies – some great studies – looking at things like neutralizing antibodies, which we use as a surrogate for clinical trials. But that is not the same as studying the outcome of interest, which would be hospitalizations. So, part of the challenge is to be able to say: “Okay, this is what we know about the safety and effectiveness of the prior vaccines ... and how can we relate that to outcomes with these new boosters at an earlier stage [before] clinical data is available?”

Q: How long will the new boosters’ protections last – do we know yet?A: That timing is still a question, but of course what plays a big role in that is what COVID strains are circulating. If we prep these boosters that are Omicron specific, and then we have something totally new emerge ... we have to be more nimble because the variants are outpacing what we’re able to do.

This turns out to be a bit of a game of probability – the more infection we have, the more replication of the virus; the more replication, the more opportunity for mutations and subsequent variants.

Q: What about a combined flu-COVID vaccine; is that on the horizon?A: My children, who like most children do not like vaccines, always tell me: “Mom, why can’t they just put the influenza vaccine and the COVID vaccine into the same shot?” And I’m like: “Oh, from your lips to some scientist’s ears.”

At a time like this, where mRNA technology has totally disrupted what we can do with vaccines, in such a good way, I think we should push for the limits, because that would be incredible.

Q: If you’ve received a non-mRNA COVID vaccine, like those produced by Johnson & Johnson and Novavax, should you also get an mRNA booster?A: Right now, the CDC guidelines do state that if your primary vaccine series was not with an mRNA vaccine then being boosted with an mRNA is a fine thing to do, and it’s actually encouraged. So that’s not going to change with the bivalent booster.

Q: Is it okay to get a flu shot and a COVID booster at the same time, as the Centers for Disease Control and Prevention has recommended with past vaccines?A: I don’t anticipate there being recommendations against that. But I would also say watch for the recommendations that come out this fall on the bivalent boosters.

I do hope in the recommendations the CDC makes about the COVID boosters, they will say think about also getting your influenza vaccine, too. You could also get your COVID booster first, then by October get your influenza vaccine.

Q: Once you’re fully boosted, is it safe to stop wearing a mask, social distancing, avoiding crowded indoor spaces, and taking other precautions to avoid COVID-19?A: The virus is going to do what it does, which is infect whomever it can, and make them sick. So, if you see a lot of community transmission – you know who is ill with COVID in your kids’ schools, you know in your workplace and when people go out – that still signals there’s some increases in the circulation of virus. So, look at that to understand what your risk is.

If you know someone or have a colleague who is currently pregnant or immune suppressed, think about how you can protect them with mask-wearing, even if it’s just when you’re in one-on-one closed-door meetings with that individual.

So, your masking question is an important one, and it’s important for people to continue to hang onto those masks and wear them the week before you go see Grandma, for instance, to further reduce your risk so you don’t bring anything to here.

The high-level community risk nationwide is high right now. COVID is here.

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

When Joel Fram woke up on the morning of March 12, 2020, he had a pretty good idea why he felt so lousy.

He lives in New York, where the first wave of the coronavirus was tearing through the city. “I instantly knew,” said the 55-year-old Broadway music director. It was COVID-19.

What started with a general sense of having been hit by a truck soon included a sore throat and such severe fatigue that he once fell asleep in the middle of sending a text to his sister. The final symptoms were chest tightness and trouble breathing.

And then he started to feel better. “By mid-April, my body was feeling essentially back to normal,” he said.

So he did what would have been smart after almost any other illness: He began working out. That didn’t last long. “It felt like someone pulled the carpet out from under me,” he remembered. “I couldn’t walk three blocks without getting breathless and fatigued.”

That was the first indication Mr. Fram had long COVID.

According to the National Center for Health Statistics, at least 7.5% of American adults – close to 20 million people – have symptoms of long COVID. And for almost all of those people, a growing body of evidence shows that exercise will make their symptoms worse.

COVID-19 patients who had the most severe illness will struggle the most with exercise later, according to a review published in June from researchers at the University of California, San Francisco. But even people with mild symptoms can struggle to regain their previous levels of fitness.

“We have participants in our study who had relatively mild acute symptoms and went on to have really profound decreases in their ability to exercise,” said Matthew S. Durstenfeld, MD, a cardiologist at UCSF and principal author of the review.

Most people with long COVID will have lower-than-expected scores on tests of aerobic fitness, as shown by Yale researchers in a study published in August 2021.

“Some amount of that is due to deconditioning,” Dr. Durstenfeld said. “You’re not feeling well, so you’re not exercising to the same degree you might have been before you got infected.”

In a study published in April, people with long COVID told researchers at Britain’s University of Leeds they spent 93% less time in physical activity than they did before their infection.

But multiple studies have found deconditioning is not entirely – or even mostly – to blame.

A 2021 study found that 89% of participants with long COVID had postexertional malaise (PEM), which happens when a patient’s symptoms get worse after they do even minor physical or mental activities. According to the CDC, postexertional malaise can hit as long as 12-48 hours after the activity, and it can take people up to 2 weeks to fully recover.

Unfortunately, the advice patients get from their doctors sometimes makes the problem worse.
 

How long COVID defies simple solutions

Long COVID is a “dynamic disability” that requires health professionals to go off script when a patient’s symptoms don’t respond in a predictable way to treatment, said David Putrino, PhD, a neuroscientist, physical therapist, and director of rehabilitation innovation for the Mount Sinai Health System in New York.

“We’re not so good at dealing with somebody who, for all intents and purposes, can appear healthy and nondisabled on one day and be completely debilitated the next day,” he said.

Dr. Putrino said more than half of his clinic’s long-COVID patients told his team they had at least one of these persistent problems:

• Fatigue (82%).
• Brain fog (67%).
• Headache (60%).
• Sleep problems (59%).
• Dizziness (54%).

And 86% said exercise worsened their symptoms.

The symptoms are similar to what doctors see with illnesses such as lupus, Lyme disease, and chronic fatigue syndrome – something many experts compare long COVID to. Researchers and medical professionals still don’t know exactly how COVID-19 causes those symptoms. But there are some theories.
 

Potential causes of long-COVID symptoms

Dr. Putrino said it is possible the virus enters a patient’s cells and hijacks the mitochondria – a part of the cell that provides energy. It can linger there for weeks or months – something known as viral persistence.

“All of a sudden, the body’s getting less energy for itself, even though it’s producing the same amount, or even a little more,” he said. And there is a consequence to this extra stress on the cells. “Creating energy isn’t free. You’re producing more waste products, which puts your body in a state of oxidative stress,” Dr. Putrino said. Oxidative stress damages cells as molecules interact with oxygen in harmful ways.

“The other big mechanism is autonomic dysfunction,” Dr. Putrino said. It’s marked by breathing problems, heart palpitations, and other glitches in areas most healthy people never have to think about. About 70% of long-COVID patients at Mount Sinai’s clinic have some degree of autonomic dysfunction, he said.

For a person with autonomic dysfunction, something as basic as changing posture can trigger a storm of cytokines, a chemical messenger that tells the immune system where and how to respond to challenges like an injury or infection.

“Suddenly, you have this on-off switch,” Dr. Putrino said. “You go straight to ‘fight or flight,’ ” with a surge of adrenaline and a spiking heart rate, “then plunge back to ‘rest or digest.’ You go from fired up to so sleepy, you can’t keep your eyes open.”

A patient with viral persistence and one with autonomic dysfunction may have the same negative reaction to exercise, even though the triggers are completely different.
 

So how can doctors help long-COVID patients?

The first step, Dr. Putrino said, is to understand the difference between long COVID and a long recovery from COVID-19 infection.

Many of the patients in the latter group still have symptoms 4 weeks after their first infection. “At 4 weeks, yeah, they’re still feeling symptoms, but that’s not long COVID,” he said. “That’s just taking a while to get over a viral infection.”

Fitness advice is simple for those people: Take it easy at first, and gradually increase the amount and intensity of aerobic exercise and strength training.

But that advice would be disastrous for someone who meets Dr. Putrino’s stricter definition of long COVID: “Three to 4 months out from initial infection, they’re experiencing severe fatigue, exertional symptoms, cognitive symptoms, heart palpitations, shortness of breath,” he said.

“Our clinic is extraordinarily cautious with exercise” for those patients, he said.

In Dr. Putrino’s experience, about 20%-30% of patients will make significant progress after 12 weeks. “They’re feeling more or less like they felt pre-COVID,” he said.

The unluckiest 10%-20% won’t make any progress at all. Any type of therapy, even if it’s as simple as moving their legs from a flat position, worsens their symptoms.

The majority – 50%-60% – will have some improvement in their symptoms. But then progress will stop, for reasons researchers are still trying to figure out.

“My sense is that gradually increasing your exercise is still good advice for the vast majority of people,” UCSF’s Dr. Durstenfeld said.

Ideally, that exercise will be supervised by someone trained in cardiac, pulmonary, and/or autonomic rehabilitation – a specialized type of therapy aimed at resyncing the autonomic nervous system that governs breathing and other unconscious functions, he said. But those therapies are rarely covered by insurance, which means most long-COVID patients are on their own.

Dr. Durstenfeld said it’s important that patients keep trying and not give up. “With slow and steady progress, a lot of people can get profoundly better,” he said.

Mr. Fram, who’s worked with careful supervision, says he’s getting closer to something like his pre-COVID-19 life.

But he’s not there yet. Long COVID, he said, “affects my life every single day.”

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

When Joel Fram woke up on the morning of March 12, 2020, he had a pretty good idea why he felt so lousy.

He lives in New York, where the first wave of the coronavirus was tearing through the city. “I instantly knew,” said the 55-year-old Broadway music director. It was COVID-19.

What started with a general sense of having been hit by a truck soon included a sore throat and such severe fatigue that he once fell asleep in the middle of sending a text to his sister. The final symptoms were chest tightness and trouble breathing.

And then he started to feel better. “By mid-April, my body was feeling essentially back to normal,” he said.

So he did what would have been smart after almost any other illness: He began working out. That didn’t last long. “It felt like someone pulled the carpet out from under me,” he remembered. “I couldn’t walk three blocks without getting breathless and fatigued.”

That was the first indication Mr. Fram had long COVID.

According to the National Center for Health Statistics, at least 7.5% of American adults – close to 20 million people – have symptoms of long COVID. And for almost all of those people, a growing body of evidence shows that exercise will make their symptoms worse.

COVID-19 patients who had the most severe illness will struggle the most with exercise later, according to a review published in June from researchers at the University of California, San Francisco. But even people with mild symptoms can struggle to regain their previous levels of fitness.

“We have participants in our study who had relatively mild acute symptoms and went on to have really profound decreases in their ability to exercise,” said Matthew S. Durstenfeld, MD, a cardiologist at UCSF and principal author of the review.

Most people with long COVID will have lower-than-expected scores on tests of aerobic fitness, as shown by Yale researchers in a study published in August 2021.

“Some amount of that is due to deconditioning,” Dr. Durstenfeld said. “You’re not feeling well, so you’re not exercising to the same degree you might have been before you got infected.”

In a study published in April, people with long COVID told researchers at Britain’s University of Leeds they spent 93% less time in physical activity than they did before their infection.

But multiple studies have found deconditioning is not entirely – or even mostly – to blame.

A 2021 study found that 89% of participants with long COVID had postexertional malaise (PEM), which happens when a patient’s symptoms get worse after they do even minor physical or mental activities. According to the CDC, postexertional malaise can hit as long as 12-48 hours after the activity, and it can take people up to 2 weeks to fully recover.

Unfortunately, the advice patients get from their doctors sometimes makes the problem worse.
 

How long COVID defies simple solutions

Long COVID is a “dynamic disability” that requires health professionals to go off script when a patient’s symptoms don’t respond in a predictable way to treatment, said David Putrino, PhD, a neuroscientist, physical therapist, and director of rehabilitation innovation for the Mount Sinai Health System in New York.

“We’re not so good at dealing with somebody who, for all intents and purposes, can appear healthy and nondisabled on one day and be completely debilitated the next day,” he said.

Dr. Putrino said more than half of his clinic’s long-COVID patients told his team they had at least one of these persistent problems:

• Fatigue (82%).
• Brain fog (67%).
• Headache (60%).
• Sleep problems (59%).
• Dizziness (54%).

And 86% said exercise worsened their symptoms.

The symptoms are similar to what doctors see with illnesses such as lupus, Lyme disease, and chronic fatigue syndrome – something many experts compare long COVID to. Researchers and medical professionals still don’t know exactly how COVID-19 causes those symptoms. But there are some theories.
 

Potential causes of long-COVID symptoms

Dr. Putrino said it is possible the virus enters a patient’s cells and hijacks the mitochondria – a part of the cell that provides energy. It can linger there for weeks or months – something known as viral persistence.

“All of a sudden, the body’s getting less energy for itself, even though it’s producing the same amount, or even a little more,” he said. And there is a consequence to this extra stress on the cells. “Creating energy isn’t free. You’re producing more waste products, which puts your body in a state of oxidative stress,” Dr. Putrino said. Oxidative stress damages cells as molecules interact with oxygen in harmful ways.

“The other big mechanism is autonomic dysfunction,” Dr. Putrino said. It’s marked by breathing problems, heart palpitations, and other glitches in areas most healthy people never have to think about. About 70% of long-COVID patients at Mount Sinai’s clinic have some degree of autonomic dysfunction, he said.

For a person with autonomic dysfunction, something as basic as changing posture can trigger a storm of cytokines, a chemical messenger that tells the immune system where and how to respond to challenges like an injury or infection.

“Suddenly, you have this on-off switch,” Dr. Putrino said. “You go straight to ‘fight or flight,’ ” with a surge of adrenaline and a spiking heart rate, “then plunge back to ‘rest or digest.’ You go from fired up to so sleepy, you can’t keep your eyes open.”

A patient with viral persistence and one with autonomic dysfunction may have the same negative reaction to exercise, even though the triggers are completely different.
 

So how can doctors help long-COVID patients?

The first step, Dr. Putrino said, is to understand the difference between long COVID and a long recovery from COVID-19 infection.

Many of the patients in the latter group still have symptoms 4 weeks after their first infection. “At 4 weeks, yeah, they’re still feeling symptoms, but that’s not long COVID,” he said. “That’s just taking a while to get over a viral infection.”

Fitness advice is simple for those people: Take it easy at first, and gradually increase the amount and intensity of aerobic exercise and strength training.

But that advice would be disastrous for someone who meets Dr. Putrino’s stricter definition of long COVID: “Three to 4 months out from initial infection, they’re experiencing severe fatigue, exertional symptoms, cognitive symptoms, heart palpitations, shortness of breath,” he said.

“Our clinic is extraordinarily cautious with exercise” for those patients, he said.

In Dr. Putrino’s experience, about 20%-30% of patients will make significant progress after 12 weeks. “They’re feeling more or less like they felt pre-COVID,” he said.

The unluckiest 10%-20% won’t make any progress at all. Any type of therapy, even if it’s as simple as moving their legs from a flat position, worsens their symptoms.

The majority – 50%-60% – will have some improvement in their symptoms. But then progress will stop, for reasons researchers are still trying to figure out.

“My sense is that gradually increasing your exercise is still good advice for the vast majority of people,” UCSF’s Dr. Durstenfeld said.

Ideally, that exercise will be supervised by someone trained in cardiac, pulmonary, and/or autonomic rehabilitation – a specialized type of therapy aimed at resyncing the autonomic nervous system that governs breathing and other unconscious functions, he said. But those therapies are rarely covered by insurance, which means most long-COVID patients are on their own.

Dr. Durstenfeld said it’s important that patients keep trying and not give up. “With slow and steady progress, a lot of people can get profoundly better,” he said.

Mr. Fram, who’s worked with careful supervision, says he’s getting closer to something like his pre-COVID-19 life.

But he’s not there yet. Long COVID, he said, “affects my life every single day.”

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

When Joel Fram woke up on the morning of March 12, 2020, he had a pretty good idea why he felt so lousy.

He lives in New York, where the first wave of the coronavirus was tearing through the city. “I instantly knew,” said the 55-year-old Broadway music director. It was COVID-19.

What started with a general sense of having been hit by a truck soon included a sore throat and such severe fatigue that he once fell asleep in the middle of sending a text to his sister. The final symptoms were chest tightness and trouble breathing.

And then he started to feel better. “By mid-April, my body was feeling essentially back to normal,” he said.

So he did what would have been smart after almost any other illness: He began working out. That didn’t last long. “It felt like someone pulled the carpet out from under me,” he remembered. “I couldn’t walk three blocks without getting breathless and fatigued.”

That was the first indication Mr. Fram had long COVID.

According to the National Center for Health Statistics, at least 7.5% of American adults – close to 20 million people – have symptoms of long COVID. And for almost all of those people, a growing body of evidence shows that exercise will make their symptoms worse.

COVID-19 patients who had the most severe illness will struggle the most with exercise later, according to a review published in June from researchers at the University of California, San Francisco. But even people with mild symptoms can struggle to regain their previous levels of fitness.

“We have participants in our study who had relatively mild acute symptoms and went on to have really profound decreases in their ability to exercise,” said Matthew S. Durstenfeld, MD, a cardiologist at UCSF and principal author of the review.

Most people with long COVID will have lower-than-expected scores on tests of aerobic fitness, as shown by Yale researchers in a study published in August 2021.

“Some amount of that is due to deconditioning,” Dr. Durstenfeld said. “You’re not feeling well, so you’re not exercising to the same degree you might have been before you got infected.”

In a study published in April, people with long COVID told researchers at Britain’s University of Leeds they spent 93% less time in physical activity than they did before their infection.

But multiple studies have found deconditioning is not entirely – or even mostly – to blame.

A 2021 study found that 89% of participants with long COVID had postexertional malaise (PEM), which happens when a patient’s symptoms get worse after they do even minor physical or mental activities. According to the CDC, postexertional malaise can hit as long as 12-48 hours after the activity, and it can take people up to 2 weeks to fully recover.

Unfortunately, the advice patients get from their doctors sometimes makes the problem worse.
 

How long COVID defies simple solutions

Long COVID is a “dynamic disability” that requires health professionals to go off script when a patient’s symptoms don’t respond in a predictable way to treatment, said David Putrino, PhD, a neuroscientist, physical therapist, and director of rehabilitation innovation for the Mount Sinai Health System in New York.

“We’re not so good at dealing with somebody who, for all intents and purposes, can appear healthy and nondisabled on one day and be completely debilitated the next day,” he said.

Dr. Putrino said more than half of his clinic’s long-COVID patients told his team they had at least one of these persistent problems:

• Fatigue (82%).
• Brain fog (67%).
• Headache (60%).
• Sleep problems (59%).
• Dizziness (54%).

And 86% said exercise worsened their symptoms.

The symptoms are similar to what doctors see with illnesses such as lupus, Lyme disease, and chronic fatigue syndrome – something many experts compare long COVID to. Researchers and medical professionals still don’t know exactly how COVID-19 causes those symptoms. But there are some theories.
 

Potential causes of long-COVID symptoms

Dr. Putrino said it is possible the virus enters a patient’s cells and hijacks the mitochondria – a part of the cell that provides energy. It can linger there for weeks or months – something known as viral persistence.

“All of a sudden, the body’s getting less energy for itself, even though it’s producing the same amount, or even a little more,” he said. And there is a consequence to this extra stress on the cells. “Creating energy isn’t free. You’re producing more waste products, which puts your body in a state of oxidative stress,” Dr. Putrino said. Oxidative stress damages cells as molecules interact with oxygen in harmful ways.

“The other big mechanism is autonomic dysfunction,” Dr. Putrino said. It’s marked by breathing problems, heart palpitations, and other glitches in areas most healthy people never have to think about. About 70% of long-COVID patients at Mount Sinai’s clinic have some degree of autonomic dysfunction, he said.

For a person with autonomic dysfunction, something as basic as changing posture can trigger a storm of cytokines, a chemical messenger that tells the immune system where and how to respond to challenges like an injury or infection.

“Suddenly, you have this on-off switch,” Dr. Putrino said. “You go straight to ‘fight or flight,’ ” with a surge of adrenaline and a spiking heart rate, “then plunge back to ‘rest or digest.’ You go from fired up to so sleepy, you can’t keep your eyes open.”

A patient with viral persistence and one with autonomic dysfunction may have the same negative reaction to exercise, even though the triggers are completely different.
 

So how can doctors help long-COVID patients?

The first step, Dr. Putrino said, is to understand the difference between long COVID and a long recovery from COVID-19 infection.

Many of the patients in the latter group still have symptoms 4 weeks after their first infection. “At 4 weeks, yeah, they’re still feeling symptoms, but that’s not long COVID,” he said. “That’s just taking a while to get over a viral infection.”

Fitness advice is simple for those people: Take it easy at first, and gradually increase the amount and intensity of aerobic exercise and strength training.

But that advice would be disastrous for someone who meets Dr. Putrino’s stricter definition of long COVID: “Three to 4 months out from initial infection, they’re experiencing severe fatigue, exertional symptoms, cognitive symptoms, heart palpitations, shortness of breath,” he said.

“Our clinic is extraordinarily cautious with exercise” for those patients, he said.

In Dr. Putrino’s experience, about 20%-30% of patients will make significant progress after 12 weeks. “They’re feeling more or less like they felt pre-COVID,” he said.

The unluckiest 10%-20% won’t make any progress at all. Any type of therapy, even if it’s as simple as moving their legs from a flat position, worsens their symptoms.

The majority – 50%-60% – will have some improvement in their symptoms. But then progress will stop, for reasons researchers are still trying to figure out.

“My sense is that gradually increasing your exercise is still good advice for the vast majority of people,” UCSF’s Dr. Durstenfeld said.

Ideally, that exercise will be supervised by someone trained in cardiac, pulmonary, and/or autonomic rehabilitation – a specialized type of therapy aimed at resyncing the autonomic nervous system that governs breathing and other unconscious functions, he said. But those therapies are rarely covered by insurance, which means most long-COVID patients are on their own.

Dr. Durstenfeld said it’s important that patients keep trying and not give up. “With slow and steady progress, a lot of people can get profoundly better,” he said.

Mr. Fram, who’s worked with careful supervision, says he’s getting closer to something like his pre-COVID-19 life.

But he’s not there yet. Long COVID, he said, “affects my life every single day.”

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

An AI-guided analysis of more than 1,000 human lung transcriptomic datasets found that COVID-19 resembles idiopathic pulmonary fibrosis (IPF) at a fundamental level, according to a study published in eBiomedicine, part of The Lancet Discovery Science.

In the aftermath of COVID-19, a significant number of patients develop a fibrotic lung disease, for which insights into pathogenesis, disease models, or treatment options are lacking, according to researchers Dr. Sinha and colleagues. This long-haul form of the disease culminates in a fibrotic type of interstitial lung disease (ILD). While the actual prevalence of post–COVID-19 ILD (PCLD) is still emerging, early analysis indicates that more than a third of COVID-19 survivors develop fibrotic abnormalities, according to the authors.

Previous research has shown that one of the important determinants for PCLD is the duration of disease. Among patients who developed fibrosis, approximately 4% of patients had a disease duration of less than 1 week; approximately 24% had a disease duration between 1 and 3 weeks; and around 61% had a disease duration longer than 3 weeks, the authors stated.

The lung transcriptomic datasets compared in their study were associated with various lung conditions. The researchers used two viral pandemic signatures (ViP and sViP) and one COVID lung-derived signature. They found that the resemblances included that COVID-19 recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric), and the AT2 cytopathic changes, for example, injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP).

In laboratory experiments, Dr. Sinha and colleagues were able to induce these same immunocytopathic features in preclinical COVID-19 models (human adult lung organoid and hamster) and to reverse them in the hamster model with effective anti–CoV-2 therapeutics.

PPI-network analyses pinpointed endoplasmic reticulum (ER) stress as one of the shared early triggers of both IPF and COVID-19, and immunohistochemistry studies validated the same in the lungs of deceased subjects with COVID-19 and the SARS-CoV-2–challenged hamster lungs. Additionally, lungs from transgenic mice, in which ER stress was induced specifically in the AT2 cells, faithfully recapitulated the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.

“In this work, we found that a blood-based gene expression biomarker, which works for prognostication in COVID, also works for IPF,” stated corresponding author Pradipta Ghosh, MD, professor in the departments of medicine and cellular and molecular medicine, University of California, San Diego. “If proven in prospective studies, this biomarker could indicate who is at greatest risk for progressive fibrosis and may require lung transplantation,” she said in an interview.

Dr. Ghosh stated further, “When it comes to therapeutics in COVID lung or IPF, we also found that shared fundamental pathogenic mechanisms present excellent opportunities for developing therapeutics that can arrest the fibrogenic drivers in both diseases. One clue that emerged is a specific cytokine that is at the heart of the smoldering inflammation which is invariably associated with fibrosis. That is interleukin 15 [IL-15] and its receptor.” Dr. Ghosh observed that there are two Food and Drug Administration–approved drugs for IPF. “None are very effective in arresting this invariably fatal disease. Hence, finding better options to treat IPF is an urgent and an unmet need.”

Preclinical testing of hypotheses, Dr. Ghosh said, is next on the path to clinical trials. “We have the advantage of using human lung organoids (mini-lungs grown using stem cells) in a dish, adding additional cells to the system (like fibroblasts and immune cells), infecting them with the virus, or subjecting them to the IL-15 cytokine and monitoring lung fibrosis progression in a dish. Anti–IL-15 therapy can then be initiated to observe reversal of the fibrogenic cascade.” Hamsters have also been shown to provide appropriate models for mimicking lung fibrosis, Dr. Ghosh said. 

“The report by Sinha and colleagues describes the fascinating similarities between drivers of post-COVID lung disease and idiopathic pulmonary fibrosis,” stated David Bowton, MD, professor emeritus, section on critical care, department of anesthesiology, Wake Forest University, Winston-Salem, N.C., in an interview. He added that, “Central to the mechanisms of induction of fibrosis in both disorders appears to be endoplasmic reticulum stress in alveolar type II cells (AT2). ER stress induces the unfolded protein response (UPR) that halts protein translation and promotes the degradation of misfolded proteins. Prolonged UPR can reprogram the cell or trigger apoptosis pathways. ER stress in the lung has been reported in a variety of cell lines including AT2 in IPF, bronchial and alveolar epithelial cells in asthma and [chronic obstructive pulmonary disease], and endothelial cells in pulmonary hypertension.”

Dr. Bowton commented further, including a caution, “Sinha and colleagues suggest that the identification of these gene signatures and mechanisms will be a fruitful avenue for developing effective therapeutics for IPF and other fibrotic lung diseases. I am hopeful that these data may offer clues that expedite this process.  However, the redundancy of triggers for effector pathways in biologic systems argues that, even if successful, this will be [a] long and fraught process.”

The research study was supported by National Institutes of Health grants and funding from the Tobacco-Related Disease Research Program.

Dr. Sinha, Dr. Ghosh, and Dr. Bowton reported no relevant disclosures.

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

An AI-guided analysis of more than 1,000 human lung transcriptomic datasets found that COVID-19 resembles idiopathic pulmonary fibrosis (IPF) at a fundamental level, according to a study published in eBiomedicine, part of The Lancet Discovery Science.

In the aftermath of COVID-19, a significant number of patients develop a fibrotic lung disease, for which insights into pathogenesis, disease models, or treatment options are lacking, according to researchers Dr. Sinha and colleagues. This long-haul form of the disease culminates in a fibrotic type of interstitial lung disease (ILD). While the actual prevalence of post–COVID-19 ILD (PCLD) is still emerging, early analysis indicates that more than a third of COVID-19 survivors develop fibrotic abnormalities, according to the authors.

Previous research has shown that one of the important determinants for PCLD is the duration of disease. Among patients who developed fibrosis, approximately 4% of patients had a disease duration of less than 1 week; approximately 24% had a disease duration between 1 and 3 weeks; and around 61% had a disease duration longer than 3 weeks, the authors stated.

The lung transcriptomic datasets compared in their study were associated with various lung conditions. The researchers used two viral pandemic signatures (ViP and sViP) and one COVID lung-derived signature. They found that the resemblances included that COVID-19 recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric), and the AT2 cytopathic changes, for example, injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP).

In laboratory experiments, Dr. Sinha and colleagues were able to induce these same immunocytopathic features in preclinical COVID-19 models (human adult lung organoid and hamster) and to reverse them in the hamster model with effective anti–CoV-2 therapeutics.

PPI-network analyses pinpointed endoplasmic reticulum (ER) stress as one of the shared early triggers of both IPF and COVID-19, and immunohistochemistry studies validated the same in the lungs of deceased subjects with COVID-19 and the SARS-CoV-2–challenged hamster lungs. Additionally, lungs from transgenic mice, in which ER stress was induced specifically in the AT2 cells, faithfully recapitulated the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.

“In this work, we found that a blood-based gene expression biomarker, which works for prognostication in COVID, also works for IPF,” stated corresponding author Pradipta Ghosh, MD, professor in the departments of medicine and cellular and molecular medicine, University of California, San Diego. “If proven in prospective studies, this biomarker could indicate who is at greatest risk for progressive fibrosis and may require lung transplantation,” she said in an interview.

Dr. Ghosh stated further, “When it comes to therapeutics in COVID lung or IPF, we also found that shared fundamental pathogenic mechanisms present excellent opportunities for developing therapeutics that can arrest the fibrogenic drivers in both diseases. One clue that emerged is a specific cytokine that is at the heart of the smoldering inflammation which is invariably associated with fibrosis. That is interleukin 15 [IL-15] and its receptor.” Dr. Ghosh observed that there are two Food and Drug Administration–approved drugs for IPF. “None are very effective in arresting this invariably fatal disease. Hence, finding better options to treat IPF is an urgent and an unmet need.”

Preclinical testing of hypotheses, Dr. Ghosh said, is next on the path to clinical trials. “We have the advantage of using human lung organoids (mini-lungs grown using stem cells) in a dish, adding additional cells to the system (like fibroblasts and immune cells), infecting them with the virus, or subjecting them to the IL-15 cytokine and monitoring lung fibrosis progression in a dish. Anti–IL-15 therapy can then be initiated to observe reversal of the fibrogenic cascade.” Hamsters have also been shown to provide appropriate models for mimicking lung fibrosis, Dr. Ghosh said. 

“The report by Sinha and colleagues describes the fascinating similarities between drivers of post-COVID lung disease and idiopathic pulmonary fibrosis,” stated David Bowton, MD, professor emeritus, section on critical care, department of anesthesiology, Wake Forest University, Winston-Salem, N.C., in an interview. He added that, “Central to the mechanisms of induction of fibrosis in both disorders appears to be endoplasmic reticulum stress in alveolar type II cells (AT2). ER stress induces the unfolded protein response (UPR) that halts protein translation and promotes the degradation of misfolded proteins. Prolonged UPR can reprogram the cell or trigger apoptosis pathways. ER stress in the lung has been reported in a variety of cell lines including AT2 in IPF, bronchial and alveolar epithelial cells in asthma and [chronic obstructive pulmonary disease], and endothelial cells in pulmonary hypertension.”

Dr. Bowton commented further, including a caution, “Sinha and colleagues suggest that the identification of these gene signatures and mechanisms will be a fruitful avenue for developing effective therapeutics for IPF and other fibrotic lung diseases. I am hopeful that these data may offer clues that expedite this process.  However, the redundancy of triggers for effector pathways in biologic systems argues that, even if successful, this will be [a] long and fraught process.”

The research study was supported by National Institutes of Health grants and funding from the Tobacco-Related Disease Research Program.

Dr. Sinha, Dr. Ghosh, and Dr. Bowton reported no relevant disclosures.

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

An AI-guided analysis of more than 1,000 human lung transcriptomic datasets found that COVID-19 resembles idiopathic pulmonary fibrosis (IPF) at a fundamental level, according to a study published in eBiomedicine, part of The Lancet Discovery Science.

In the aftermath of COVID-19, a significant number of patients develop a fibrotic lung disease, for which insights into pathogenesis, disease models, or treatment options are lacking, according to researchers Dr. Sinha and colleagues. This long-haul form of the disease culminates in a fibrotic type of interstitial lung disease (ILD). While the actual prevalence of post–COVID-19 ILD (PCLD) is still emerging, early analysis indicates that more than a third of COVID-19 survivors develop fibrotic abnormalities, according to the authors.

Previous research has shown that one of the important determinants for PCLD is the duration of disease. Among patients who developed fibrosis, approximately 4% of patients had a disease duration of less than 1 week; approximately 24% had a disease duration between 1 and 3 weeks; and around 61% had a disease duration longer than 3 weeks, the authors stated.

The lung transcriptomic datasets compared in their study were associated with various lung conditions. The researchers used two viral pandemic signatures (ViP and sViP) and one COVID lung-derived signature. They found that the resemblances included that COVID-19 recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric), and the AT2 cytopathic changes, for example, injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP).

In laboratory experiments, Dr. Sinha and colleagues were able to induce these same immunocytopathic features in preclinical COVID-19 models (human adult lung organoid and hamster) and to reverse them in the hamster model with effective anti–CoV-2 therapeutics.

PPI-network analyses pinpointed endoplasmic reticulum (ER) stress as one of the shared early triggers of both IPF and COVID-19, and immunohistochemistry studies validated the same in the lungs of deceased subjects with COVID-19 and the SARS-CoV-2–challenged hamster lungs. Additionally, lungs from transgenic mice, in which ER stress was induced specifically in the AT2 cells, faithfully recapitulated the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.

“In this work, we found that a blood-based gene expression biomarker, which works for prognostication in COVID, also works for IPF,” stated corresponding author Pradipta Ghosh, MD, professor in the departments of medicine and cellular and molecular medicine, University of California, San Diego. “If proven in prospective studies, this biomarker could indicate who is at greatest risk for progressive fibrosis and may require lung transplantation,” she said in an interview.

Dr. Ghosh stated further, “When it comes to therapeutics in COVID lung or IPF, we also found that shared fundamental pathogenic mechanisms present excellent opportunities for developing therapeutics that can arrest the fibrogenic drivers in both diseases. One clue that emerged is a specific cytokine that is at the heart of the smoldering inflammation which is invariably associated with fibrosis. That is interleukin 15 [IL-15] and its receptor.” Dr. Ghosh observed that there are two Food and Drug Administration–approved drugs for IPF. “None are very effective in arresting this invariably fatal disease. Hence, finding better options to treat IPF is an urgent and an unmet need.”

Preclinical testing of hypotheses, Dr. Ghosh said, is next on the path to clinical trials. “We have the advantage of using human lung organoids (mini-lungs grown using stem cells) in a dish, adding additional cells to the system (like fibroblasts and immune cells), infecting them with the virus, or subjecting them to the IL-15 cytokine and monitoring lung fibrosis progression in a dish. Anti–IL-15 therapy can then be initiated to observe reversal of the fibrogenic cascade.” Hamsters have also been shown to provide appropriate models for mimicking lung fibrosis, Dr. Ghosh said. 

“The report by Sinha and colleagues describes the fascinating similarities between drivers of post-COVID lung disease and idiopathic pulmonary fibrosis,” stated David Bowton, MD, professor emeritus, section on critical care, department of anesthesiology, Wake Forest University, Winston-Salem, N.C., in an interview. He added that, “Central to the mechanisms of induction of fibrosis in both disorders appears to be endoplasmic reticulum stress in alveolar type II cells (AT2). ER stress induces the unfolded protein response (UPR) that halts protein translation and promotes the degradation of misfolded proteins. Prolonged UPR can reprogram the cell or trigger apoptosis pathways. ER stress in the lung has been reported in a variety of cell lines including AT2 in IPF, bronchial and alveolar epithelial cells in asthma and [chronic obstructive pulmonary disease], and endothelial cells in pulmonary hypertension.”

Dr. Bowton commented further, including a caution, “Sinha and colleagues suggest that the identification of these gene signatures and mechanisms will be a fruitful avenue for developing effective therapeutics for IPF and other fibrotic lung diseases. I am hopeful that these data may offer clues that expedite this process.  However, the redundancy of triggers for effector pathways in biologic systems argues that, even if successful, this will be [a] long and fraught process.”

The research study was supported by National Institutes of Health grants and funding from the Tobacco-Related Disease Research Program.

Dr. Sinha, Dr. Ghosh, and Dr. Bowton reported no relevant disclosures.

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

We all have friends or relatives who, somehow, have managed to avoid catching COVID-19, which has infected more than 91.5 million Americans. You may even be one of the lucky ones yourself.

But health experts are saying: Not so fast. A mounting pile of scientific evidence suggests millions of Americans have been infected with the virus without ever even knowing it because they didn’t have symptoms or had mild cases they mistook for a cold or allergies.

The upshot: These silent COVID-19 cases reflect a hidden side of the pandemic that may be helping to drive new surges and viral variants.

Still, infectious disease experts say there is little doubt that some people have indeed managed to avoid COVID-19 infection altogether, and they are trying to understand why.

Several recent studies have suggested certain genetic and immune system traits may better protect this group of people against the coronavirus, making them less likely than others to be infected or seriously sickened. Researchers around the world are now studying these seemingly super-immune people for clues to what makes them so special, with an eye toward better vaccines, treatments, and prevention strategies.

Infectious disease specialists say both types of cases – those unknowingly infected by COVID-19 and people who’ve avoided the virus altogether – matter greatly to public health, more than 2 years into the pandemic.

“It’s definitely true that some people have had COVID and don’t realize it,” says Stephen Kissler, PhD, an infectious disease researcher with the Harvard T.H. Chan School of Public Health, Boston. “It is potentially good news if there’s more immunity in the population than we realize.”

But he says that being able to identify genetic and other factors that may offer some people protection against COVID-19 is an “exciting prospect” that could help find out who’s most at risk and improve efforts to get the pandemic under control.

Some studies have found a person’s genetic profile, past exposure to other COVID-like viruses, allergies, and even drugs they take for other conditions may all provide some defense – even for people who have not been vaccinated, don’t use masks, or don’t practice social distancing.

A person’s medical history and genetics may help decide their risk from new diseases, meaning “we may be able to help identify people who are at especially high risk from infection,” Dr. Kissler says. “That knowledge could help those people better shield themselves from infection and get quicker access to treatment and vaccines, if necessary. … We don’t yet know, but studies are ongoing for these things.”

Amesh Adalja, MD, an infectious disease specialist with the Johns Hopkins Center for Health Security, Baltimore, agrees that emerging research on people who’ve avoided infection offers the chance of new public health strategies to combat COVID-19.

“I’m sure there is some subset of people who are [COVID] negative,” he says. “So what explains that phenomenon, especially if that person was out there getting significant exposures?”
 

Have you had COVID without knowing it?

In a media briefing late last month, White House COVID-19 Response Coordinator Ashish Jha, MD, said more than 70% of the U.S. population has had the virus, according to the latest CDC data. That’s up from 33.5% in December.

But the actual number of people in the U.S. who have been infected with SARS-CoV-2, the scientific name for the virus that causes COVID-19, is likely to be much higher due to cases without symptoms that are unreported, experts say.

Since the early days of the pandemic, researchers have tried to put a number on these hidden cases, but that figure has been evolving and a clear consensus has not emerged.

In September 2020, a study published in the Annals of Internal Medicine said “approximately 40% to 45% of those infected with SARS-CoV-2 will remain asymptomatic.”

A follow-up analysis of 95 studies, published last December, reached similar findings, estimating that more than 40% of COVID-19 infections didn’t come with symptoms.

To get a better handle on the issue, CDC officials have been working with the American Red Cross and other blood banks to track COVID-19 antibodies – proteins your body makes after exposure to the virus to fight off an infection – in donors who said they have never had COVID-19.

While that joint effort is still ongoing, early findings say the number of donors with antibodies from COVID-19 infection increased in blood donors from 3.5% in July 2020 to at least 20.2% in May 2021. Since then, those percentages have soared, in part due to the introduction of vaccines, which also make the body produce COVID-19 antibodies.

The most current findings show that 83.3% of donors have combined COVID infection– and vaccine-induced antibodies in their blood. Those findings are based on 1.4 million blood donations.

Health experts say all of these studies are strong evidence that many COVID-19 cases continue to go undetected. In fact, the University of Washington Institute for Health Metrics and Evaluation estimates that only 7% of positive COVID-19 cases in the U.S. are being detected. That means case rates are actually 14.5 times higher than the official count of 131,000 new COVID infections each day, according to the Centers for Disease Control and Prevention, which reports the virus is still killing about 440 Americans daily.

So, why is all this important, in terms of public health?

Experts say people are more likely to be cautious if they know COVID-19 cases are high where they live, work, and play. On the other hand, if they believe case rates in their communities are lower than they actually are, they may be less likely to get vaccinated and boosted, wear masks indoors, avoid crowded indoor spaces, and take other precautions to fend off infection.
 

How do some avoid infection altogether?

In addition to tracking cases that go unreported and don’t have symptoms, infectious disease experts have also been trying to figure out why some people have managed to avoid getting the highly contagious virus.

Several leading lines of research have produced promising early results – suggesting that a person’s genetic makeup, past exposure to less-lethal coronaviruses, allergies, and even certain drugs they take for other conditions may all provide at least some protection against COVID.

“Our study showed that there are many human genes – hundreds of genes – that can impact SARS-CoV-2 infection,” says Neville Sanjana, PhD, a geneticist at New York University and the New York Genome Center who co-led the study. “With a better understanding of host genetic factors, we can find new kinds of therapies that target these host factors to block infection.”

In addition, he says several studies show some drugs that regulate genes, such as the breast cancer drug tamoxifen, also appear to knock down COVID-19 risk. He suggests such drugs, already approved by the Food and Drug Administration, might be “repurposed” to target the virus.

Studies in other countries show that patients taking tamoxifen before the pandemic were protected against severe COVID-19, Dr. Sanjana says. “That was a really cool thing, highlighting the power of harnessing host genetics. The virus critically depends on our genes to complete key parts of its life cycle.”

The NYU research findings echo other studies that have been published in recent months.

In July, a team of researchers led by the National Cancer Institute identified a genetic factor that appears to determine how severe an infection will be. In a study involving 3,000 people, they found that two gene changes, or mutations, that decrease the expression of a gene called OAS1 boosted the risk of hospitalization from COVID-19. OAS1 is part of the immune system’s response to viral infections.

As a result, developing a genetic therapy designed to increase the OAS1 gene’s expression might reduce the risk of severe disease.

“It’s very natural to get infected once you are exposed. There’s no magic bullet for that. But after you get infected, how you’re going to respond to this infection, that’s what is going to be affected by your genetic variants,” said Ludmila Prokunina-Olsson, PhD, the study’s lead researcher and chief of the National Cancer Institute’s Laboratory of Translational Genomics, Bethesda, Md., in an interview with NBC News.

Benjamin tenOever, PhD, a New York University virologist who co-authored the 2020 research, says the new genetic research is promising, but he believes it’s unlikely scientists will be able to identify a single gene responsible for actually preventing a COVID-19 infection.

“On the flip side, we have identified many genes that makes the disease worse,” he says.
 

T cells ‘remember’ past viral infections

As Dr. tenOever and Dr. Sanjana suggest, another intriguing line of research has found that prior viral infections may prime the body’s immune system to fight COVID-19.

Four other common coronaviruses – aside from SARS-CoV-2 – infect people worldwide, typically causing mild to moderate upper respiratory illnesses like the common cold, says Alessandro Sette, PhD, an infectious disease expert and vaccine researcher with the La Jolla (Calif.) Institute for Immunology.

In a recent study published in Science, he and his team found past infection with these other coronaviruses may give some protection against SARS-CoV-2.

T cells – white blood cells that act like immunological ninjas to ferret out and fight infections – appear to maintain a kind of “biological memory” of coronaviruses they have seen before and can mount an attack on similar pathogens, such SARS-CoV-2, Dr. Sette says.

The new work builds on a prior research he helped lead that found 40%-60% of people never exposed to SARS-CoV-2 had T cells that reacted to the virus – with their immune systems recognizing fragments of a virus they had never seen before.

Dr. Sette says his research shows that people whose T cells have this “preexisting memory” of past coronavirus exposures also tend to respond better to vaccination for reasons not yet well understood.

“The question is, at which point will there be enough immunity from vaccination, repeated infections from other coronaviruses, but also some of the variants of the SARS-CoV-2 … where infections become less frequent? We’re not there yet,” he says.

In addition to these exciting genetic and T-cell findings, other research has suggested low-grade inflammation from allergies – a key part of the body’s immune response to foreign substances – may also give some people an extra leg up, in terms of avoiding COVID infection.

Last May, a study of 1,400 households published in The Journal of Allergy and Clinical Immunology found that having a food allergy cut the risk of COVID-19 infection in half.

The researchers said it’s unclear why allergies may reduce the risk of infection, but they noted that people with food allergies express fewer ACE2 receptors on the surface of their airway cells, making it harder for the virus to enter cells.
 

The big picture: Prevention still your best bet

So, what’s the takeaway from all of this emerging research?

New York University’s Dr. tenOever says that while genes, T cells and allergies may offer some protection against COVID, tried-and-true precautions – vaccination, wearing masks, avoiding crowded indoor spaces, and social distancing – are likely to provide a greater defense.

He believes these precautions are likely why he and his family have never contracted COVID-19.

“I was tested weekly, as were my kids at school,” he says. “We definitely never got COVID, despite the fact that we live in New York City and I worked in a hospital every single day of the pandemic.”

Ziyad Al-Aly, MD, an infectious disease specialist and director of clinical epidemiology at Washington University in St. Louis, agrees that the new research on COVID-19 is intriguing but won’t likely result in practical changes in the approach to fighting the virus in the near term.

“Getting a deeper understanding of potential genetic factors or other characteristics – that could really help us understand why the virus just comes and goes without any ill effects in some people, and in other people it produces really serious disease,” he says. “That will really help us eventually to design better vaccines to prevent it or reduce severity or even [treat] people who get severe disease.”

In the meantime, Dr. Al-Aly says, “it’s still best to do everything you can to avoid infection in the first place – even if you’re vaccinated or previously infected, you should really try to avoid reinfection.”

That means sit outside if you can when visiting a restaurant. Wear a mask on a plane, even though it’s not required. And get vaccinated and boosted.

“In the future, there may be more tools to address this pandemic, but that’s really the best advice for now,” Dr. Al-Aly says.

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

We all have friends or relatives who, somehow, have managed to avoid catching COVID-19, which has infected more than 91.5 million Americans. You may even be one of the lucky ones yourself.

But health experts are saying: Not so fast. A mounting pile of scientific evidence suggests millions of Americans have been infected with the virus without ever even knowing it because they didn’t have symptoms or had mild cases they mistook for a cold or allergies.

The upshot: These silent COVID-19 cases reflect a hidden side of the pandemic that may be helping to drive new surges and viral variants.

Still, infectious disease experts say there is little doubt that some people have indeed managed to avoid COVID-19 infection altogether, and they are trying to understand why.

Several recent studies have suggested certain genetic and immune system traits may better protect this group of people against the coronavirus, making them less likely than others to be infected or seriously sickened. Researchers around the world are now studying these seemingly super-immune people for clues to what makes them so special, with an eye toward better vaccines, treatments, and prevention strategies.

Infectious disease specialists say both types of cases – those unknowingly infected by COVID-19 and people who’ve avoided the virus altogether – matter greatly to public health, more than 2 years into the pandemic.

“It’s definitely true that some people have had COVID and don’t realize it,” says Stephen Kissler, PhD, an infectious disease researcher with the Harvard T.H. Chan School of Public Health, Boston. “It is potentially good news if there’s more immunity in the population than we realize.”

But he says that being able to identify genetic and other factors that may offer some people protection against COVID-19 is an “exciting prospect” that could help find out who’s most at risk and improve efforts to get the pandemic under control.

Some studies have found a person’s genetic profile, past exposure to other COVID-like viruses, allergies, and even drugs they take for other conditions may all provide some defense – even for people who have not been vaccinated, don’t use masks, or don’t practice social distancing.

A person’s medical history and genetics may help decide their risk from new diseases, meaning “we may be able to help identify people who are at especially high risk from infection,” Dr. Kissler says. “That knowledge could help those people better shield themselves from infection and get quicker access to treatment and vaccines, if necessary. … We don’t yet know, but studies are ongoing for these things.”

Amesh Adalja, MD, an infectious disease specialist with the Johns Hopkins Center for Health Security, Baltimore, agrees that emerging research on people who’ve avoided infection offers the chance of new public health strategies to combat COVID-19.

“I’m sure there is some subset of people who are [COVID] negative,” he says. “So what explains that phenomenon, especially if that person was out there getting significant exposures?”
 

Have you had COVID without knowing it?

In a media briefing late last month, White House COVID-19 Response Coordinator Ashish Jha, MD, said more than 70% of the U.S. population has had the virus, according to the latest CDC data. That’s up from 33.5% in December.

But the actual number of people in the U.S. who have been infected with SARS-CoV-2, the scientific name for the virus that causes COVID-19, is likely to be much higher due to cases without symptoms that are unreported, experts say.

Since the early days of the pandemic, researchers have tried to put a number on these hidden cases, but that figure has been evolving and a clear consensus has not emerged.

In September 2020, a study published in the Annals of Internal Medicine said “approximately 40% to 45% of those infected with SARS-CoV-2 will remain asymptomatic.”

A follow-up analysis of 95 studies, published last December, reached similar findings, estimating that more than 40% of COVID-19 infections didn’t come with symptoms.

To get a better handle on the issue, CDC officials have been working with the American Red Cross and other blood banks to track COVID-19 antibodies – proteins your body makes after exposure to the virus to fight off an infection – in donors who said they have never had COVID-19.

While that joint effort is still ongoing, early findings say the number of donors with antibodies from COVID-19 infection increased in blood donors from 3.5% in July 2020 to at least 20.2% in May 2021. Since then, those percentages have soared, in part due to the introduction of vaccines, which also make the body produce COVID-19 antibodies.

The most current findings show that 83.3% of donors have combined COVID infection– and vaccine-induced antibodies in their blood. Those findings are based on 1.4 million blood donations.

Health experts say all of these studies are strong evidence that many COVID-19 cases continue to go undetected. In fact, the University of Washington Institute for Health Metrics and Evaluation estimates that only 7% of positive COVID-19 cases in the U.S. are being detected. That means case rates are actually 14.5 times higher than the official count of 131,000 new COVID infections each day, according to the Centers for Disease Control and Prevention, which reports the virus is still killing about 440 Americans daily.

So, why is all this important, in terms of public health?

Experts say people are more likely to be cautious if they know COVID-19 cases are high where they live, work, and play. On the other hand, if they believe case rates in their communities are lower than they actually are, they may be less likely to get vaccinated and boosted, wear masks indoors, avoid crowded indoor spaces, and take other precautions to fend off infection.
 

How do some avoid infection altogether?

In addition to tracking cases that go unreported and don’t have symptoms, infectious disease experts have also been trying to figure out why some people have managed to avoid getting the highly contagious virus.

Several leading lines of research have produced promising early results – suggesting that a person’s genetic makeup, past exposure to less-lethal coronaviruses, allergies, and even certain drugs they take for other conditions may all provide at least some protection against COVID.

“Our study showed that there are many human genes – hundreds of genes – that can impact SARS-CoV-2 infection,” says Neville Sanjana, PhD, a geneticist at New York University and the New York Genome Center who co-led the study. “With a better understanding of host genetic factors, we can find new kinds of therapies that target these host factors to block infection.”

In addition, he says several studies show some drugs that regulate genes, such as the breast cancer drug tamoxifen, also appear to knock down COVID-19 risk. He suggests such drugs, already approved by the Food and Drug Administration, might be “repurposed” to target the virus.

Studies in other countries show that patients taking tamoxifen before the pandemic were protected against severe COVID-19, Dr. Sanjana says. “That was a really cool thing, highlighting the power of harnessing host genetics. The virus critically depends on our genes to complete key parts of its life cycle.”

The NYU research findings echo other studies that have been published in recent months.

In July, a team of researchers led by the National Cancer Institute identified a genetic factor that appears to determine how severe an infection will be. In a study involving 3,000 people, they found that two gene changes, or mutations, that decrease the expression of a gene called OAS1 boosted the risk of hospitalization from COVID-19. OAS1 is part of the immune system’s response to viral infections.

As a result, developing a genetic therapy designed to increase the OAS1 gene’s expression might reduce the risk of severe disease.

“It’s very natural to get infected once you are exposed. There’s no magic bullet for that. But after you get infected, how you’re going to respond to this infection, that’s what is going to be affected by your genetic variants,” said Ludmila Prokunina-Olsson, PhD, the study’s lead researcher and chief of the National Cancer Institute’s Laboratory of Translational Genomics, Bethesda, Md., in an interview with NBC News.

Benjamin tenOever, PhD, a New York University virologist who co-authored the 2020 research, says the new genetic research is promising, but he believes it’s unlikely scientists will be able to identify a single gene responsible for actually preventing a COVID-19 infection.

“On the flip side, we have identified many genes that makes the disease worse,” he says.
 

T cells ‘remember’ past viral infections

As Dr. tenOever and Dr. Sanjana suggest, another intriguing line of research has found that prior viral infections may prime the body’s immune system to fight COVID-19.

Four other common coronaviruses – aside from SARS-CoV-2 – infect people worldwide, typically causing mild to moderate upper respiratory illnesses like the common cold, says Alessandro Sette, PhD, an infectious disease expert and vaccine researcher with the La Jolla (Calif.) Institute for Immunology.

In a recent study published in Science, he and his team found past infection with these other coronaviruses may give some protection against SARS-CoV-2.

T cells – white blood cells that act like immunological ninjas to ferret out and fight infections – appear to maintain a kind of “biological memory” of coronaviruses they have seen before and can mount an attack on similar pathogens, such SARS-CoV-2, Dr. Sette says.

The new work builds on a prior research he helped lead that found 40%-60% of people never exposed to SARS-CoV-2 had T cells that reacted to the virus – with their immune systems recognizing fragments of a virus they had never seen before.

Dr. Sette says his research shows that people whose T cells have this “preexisting memory” of past coronavirus exposures also tend to respond better to vaccination for reasons not yet well understood.

“The question is, at which point will there be enough immunity from vaccination, repeated infections from other coronaviruses, but also some of the variants of the SARS-CoV-2 … where infections become less frequent? We’re not there yet,” he says.

In addition to these exciting genetic and T-cell findings, other research has suggested low-grade inflammation from allergies – a key part of the body’s immune response to foreign substances – may also give some people an extra leg up, in terms of avoiding COVID infection.

Last May, a study of 1,400 households published in The Journal of Allergy and Clinical Immunology found that having a food allergy cut the risk of COVID-19 infection in half.

The researchers said it’s unclear why allergies may reduce the risk of infection, but they noted that people with food allergies express fewer ACE2 receptors on the surface of their airway cells, making it harder for the virus to enter cells.
 

The big picture: Prevention still your best bet

So, what’s the takeaway from all of this emerging research?

New York University’s Dr. tenOever says that while genes, T cells and allergies may offer some protection against COVID, tried-and-true precautions – vaccination, wearing masks, avoiding crowded indoor spaces, and social distancing – are likely to provide a greater defense.

He believes these precautions are likely why he and his family have never contracted COVID-19.

“I was tested weekly, as were my kids at school,” he says. “We definitely never got COVID, despite the fact that we live in New York City and I worked in a hospital every single day of the pandemic.”

Ziyad Al-Aly, MD, an infectious disease specialist and director of clinical epidemiology at Washington University in St. Louis, agrees that the new research on COVID-19 is intriguing but won’t likely result in practical changes in the approach to fighting the virus in the near term.

“Getting a deeper understanding of potential genetic factors or other characteristics – that could really help us understand why the virus just comes and goes without any ill effects in some people, and in other people it produces really serious disease,” he says. “That will really help us eventually to design better vaccines to prevent it or reduce severity or even [treat] people who get severe disease.”

In the meantime, Dr. Al-Aly says, “it’s still best to do everything you can to avoid infection in the first place – even if you’re vaccinated or previously infected, you should really try to avoid reinfection.”

That means sit outside if you can when visiting a restaurant. Wear a mask on a plane, even though it’s not required. And get vaccinated and boosted.

“In the future, there may be more tools to address this pandemic, but that’s really the best advice for now,” Dr. Al-Aly says.

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

We all have friends or relatives who, somehow, have managed to avoid catching COVID-19, which has infected more than 91.5 million Americans. You may even be one of the lucky ones yourself.

But health experts are saying: Not so fast. A mounting pile of scientific evidence suggests millions of Americans have been infected with the virus without ever even knowing it because they didn’t have symptoms or had mild cases they mistook for a cold or allergies.

The upshot: These silent COVID-19 cases reflect a hidden side of the pandemic that may be helping to drive new surges and viral variants.

Still, infectious disease experts say there is little doubt that some people have indeed managed to avoid COVID-19 infection altogether, and they are trying to understand why.

Several recent studies have suggested certain genetic and immune system traits may better protect this group of people against the coronavirus, making them less likely than others to be infected or seriously sickened. Researchers around the world are now studying these seemingly super-immune people for clues to what makes them so special, with an eye toward better vaccines, treatments, and prevention strategies.

Infectious disease specialists say both types of cases – those unknowingly infected by COVID-19 and people who’ve avoided the virus altogether – matter greatly to public health, more than 2 years into the pandemic.

“It’s definitely true that some people have had COVID and don’t realize it,” says Stephen Kissler, PhD, an infectious disease researcher with the Harvard T.H. Chan School of Public Health, Boston. “It is potentially good news if there’s more immunity in the population than we realize.”

But he says that being able to identify genetic and other factors that may offer some people protection against COVID-19 is an “exciting prospect” that could help find out who’s most at risk and improve efforts to get the pandemic under control.

Some studies have found a person’s genetic profile, past exposure to other COVID-like viruses, allergies, and even drugs they take for other conditions may all provide some defense – even for people who have not been vaccinated, don’t use masks, or don’t practice social distancing.

A person’s medical history and genetics may help decide their risk from new diseases, meaning “we may be able to help identify people who are at especially high risk from infection,” Dr. Kissler says. “That knowledge could help those people better shield themselves from infection and get quicker access to treatment and vaccines, if necessary. … We don’t yet know, but studies are ongoing for these things.”

Amesh Adalja, MD, an infectious disease specialist with the Johns Hopkins Center for Health Security, Baltimore, agrees that emerging research on people who’ve avoided infection offers the chance of new public health strategies to combat COVID-19.

“I’m sure there is some subset of people who are [COVID] negative,” he says. “So what explains that phenomenon, especially if that person was out there getting significant exposures?”
 

Have you had COVID without knowing it?

In a media briefing late last month, White House COVID-19 Response Coordinator Ashish Jha, MD, said more than 70% of the U.S. population has had the virus, according to the latest CDC data. That’s up from 33.5% in December.

But the actual number of people in the U.S. who have been infected with SARS-CoV-2, the scientific name for the virus that causes COVID-19, is likely to be much higher due to cases without symptoms that are unreported, experts say.

Since the early days of the pandemic, researchers have tried to put a number on these hidden cases, but that figure has been evolving and a clear consensus has not emerged.

In September 2020, a study published in the Annals of Internal Medicine said “approximately 40% to 45% of those infected with SARS-CoV-2 will remain asymptomatic.”

A follow-up analysis of 95 studies, published last December, reached similar findings, estimating that more than 40% of COVID-19 infections didn’t come with symptoms.

To get a better handle on the issue, CDC officials have been working with the American Red Cross and other blood banks to track COVID-19 antibodies – proteins your body makes after exposure to the virus to fight off an infection – in donors who said they have never had COVID-19.

While that joint effort is still ongoing, early findings say the number of donors with antibodies from COVID-19 infection increased in blood donors from 3.5% in July 2020 to at least 20.2% in May 2021. Since then, those percentages have soared, in part due to the introduction of vaccines, which also make the body produce COVID-19 antibodies.

The most current findings show that 83.3% of donors have combined COVID infection– and vaccine-induced antibodies in their blood. Those findings are based on 1.4 million blood donations.

Health experts say all of these studies are strong evidence that many COVID-19 cases continue to go undetected. In fact, the University of Washington Institute for Health Metrics and Evaluation estimates that only 7% of positive COVID-19 cases in the U.S. are being detected. That means case rates are actually 14.5 times higher than the official count of 131,000 new COVID infections each day, according to the Centers for Disease Control and Prevention, which reports the virus is still killing about 440 Americans daily.

So, why is all this important, in terms of public health?

Experts say people are more likely to be cautious if they know COVID-19 cases are high where they live, work, and play. On the other hand, if they believe case rates in their communities are lower than they actually are, they may be less likely to get vaccinated and boosted, wear masks indoors, avoid crowded indoor spaces, and take other precautions to fend off infection.
 

How do some avoid infection altogether?

In addition to tracking cases that go unreported and don’t have symptoms, infectious disease experts have also been trying to figure out why some people have managed to avoid getting the highly contagious virus.

Several leading lines of research have produced promising early results – suggesting that a person’s genetic makeup, past exposure to less-lethal coronaviruses, allergies, and even certain drugs they take for other conditions may all provide at least some protection against COVID.

“Our study showed that there are many human genes – hundreds of genes – that can impact SARS-CoV-2 infection,” says Neville Sanjana, PhD, a geneticist at New York University and the New York Genome Center who co-led the study. “With a better understanding of host genetic factors, we can find new kinds of therapies that target these host factors to block infection.”

In addition, he says several studies show some drugs that regulate genes, such as the breast cancer drug tamoxifen, also appear to knock down COVID-19 risk. He suggests such drugs, already approved by the Food and Drug Administration, might be “repurposed” to target the virus.

Studies in other countries show that patients taking tamoxifen before the pandemic were protected against severe COVID-19, Dr. Sanjana says. “That was a really cool thing, highlighting the power of harnessing host genetics. The virus critically depends on our genes to complete key parts of its life cycle.”

The NYU research findings echo other studies that have been published in recent months.

In July, a team of researchers led by the National Cancer Institute identified a genetic factor that appears to determine how severe an infection will be. In a study involving 3,000 people, they found that two gene changes, or mutations, that decrease the expression of a gene called OAS1 boosted the risk of hospitalization from COVID-19. OAS1 is part of the immune system’s response to viral infections.

As a result, developing a genetic therapy designed to increase the OAS1 gene’s expression might reduce the risk of severe disease.

“It’s very natural to get infected once you are exposed. There’s no magic bullet for that. But after you get infected, how you’re going to respond to this infection, that’s what is going to be affected by your genetic variants,” said Ludmila Prokunina-Olsson, PhD, the study’s lead researcher and chief of the National Cancer Institute’s Laboratory of Translational Genomics, Bethesda, Md., in an interview with NBC News.

Benjamin tenOever, PhD, a New York University virologist who co-authored the 2020 research, says the new genetic research is promising, but he believes it’s unlikely scientists will be able to identify a single gene responsible for actually preventing a COVID-19 infection.

“On the flip side, we have identified many genes that makes the disease worse,” he says.
 

T cells ‘remember’ past viral infections

As Dr. tenOever and Dr. Sanjana suggest, another intriguing line of research has found that prior viral infections may prime the body’s immune system to fight COVID-19.

Four other common coronaviruses – aside from SARS-CoV-2 – infect people worldwide, typically causing mild to moderate upper respiratory illnesses like the common cold, says Alessandro Sette, PhD, an infectious disease expert and vaccine researcher with the La Jolla (Calif.) Institute for Immunology.

In a recent study published in Science, he and his team found past infection with these other coronaviruses may give some protection against SARS-CoV-2.

T cells – white blood cells that act like immunological ninjas to ferret out and fight infections – appear to maintain a kind of “biological memory” of coronaviruses they have seen before and can mount an attack on similar pathogens, such SARS-CoV-2, Dr. Sette says.

The new work builds on a prior research he helped lead that found 40%-60% of people never exposed to SARS-CoV-2 had T cells that reacted to the virus – with their immune systems recognizing fragments of a virus they had never seen before.

Dr. Sette says his research shows that people whose T cells have this “preexisting memory” of past coronavirus exposures also tend to respond better to vaccination for reasons not yet well understood.

“The question is, at which point will there be enough immunity from vaccination, repeated infections from other coronaviruses, but also some of the variants of the SARS-CoV-2 … where infections become less frequent? We’re not there yet,” he says.

In addition to these exciting genetic and T-cell findings, other research has suggested low-grade inflammation from allergies – a key part of the body’s immune response to foreign substances – may also give some people an extra leg up, in terms of avoiding COVID infection.

Last May, a study of 1,400 households published in The Journal of Allergy and Clinical Immunology found that having a food allergy cut the risk of COVID-19 infection in half.

The researchers said it’s unclear why allergies may reduce the risk of infection, but they noted that people with food allergies express fewer ACE2 receptors on the surface of their airway cells, making it harder for the virus to enter cells.
 

The big picture: Prevention still your best bet

So, what’s the takeaway from all of this emerging research?

New York University’s Dr. tenOever says that while genes, T cells and allergies may offer some protection against COVID, tried-and-true precautions – vaccination, wearing masks, avoiding crowded indoor spaces, and social distancing – are likely to provide a greater defense.

He believes these precautions are likely why he and his family have never contracted COVID-19.

“I was tested weekly, as were my kids at school,” he says. “We definitely never got COVID, despite the fact that we live in New York City and I worked in a hospital every single day of the pandemic.”

Ziyad Al-Aly, MD, an infectious disease specialist and director of clinical epidemiology at Washington University in St. Louis, agrees that the new research on COVID-19 is intriguing but won’t likely result in practical changes in the approach to fighting the virus in the near term.

“Getting a deeper understanding of potential genetic factors or other characteristics – that could really help us understand why the virus just comes and goes without any ill effects in some people, and in other people it produces really serious disease,” he says. “That will really help us eventually to design better vaccines to prevent it or reduce severity or even [treat] people who get severe disease.”

In the meantime, Dr. Al-Aly says, “it’s still best to do everything you can to avoid infection in the first place – even if you’re vaccinated or previously infected, you should really try to avoid reinfection.”

That means sit outside if you can when visiting a restaurant. Wear a mask on a plane, even though it’s not required. And get vaccinated and boosted.

“In the future, there may be more tools to address this pandemic, but that’s really the best advice for now,” Dr. Al-Aly says.

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