When an ovarian mass is anticipated or known, following evaluation of a patient’s history and physician examination, imaging via transvaginal and often abdominal ultrasound is the very next step. This evaluation likely will include both gray-scale and color Doppler examination. The initial concern always must be to identify ovarian malignancy.

Despite morphological scoring systems as well as the use of Doppler ultrasonography, there remains a lack of agreement and acceptance. In a 2008 multicenter study, Timmerman and colleagues evaluated 1,066 patients with 1,233 persistent adnexal tumors via transvaginal grayscale and Doppler ultrasound; 73% were benign tumors, and 27% were malignant tumors. Information on 42 gray-scale ultrasound variables and 6 Doppler variables was collected and evaluated to determine which variables had the highest positive predictive value for a malignant tumor and for a benign mass (Ultrasound Obstet Gynecol. 2008 Jun. doi: 10.1002/uog.5365).

Five simple rules were selected that best predict malignancy (M-rules), as follows:

• Irregular solid tumor.
• Ascites.
• At least four papillary projections.
• Irregular multilocular-solid tumor with a greatest diameter greater than or equal to 10 cm.
• Very high color content on Doppler exam.

The following five simple rules suggested that a mass is benign (B-rules):

• Unilocular cyst.
• Largest solid component less than 7 mm.
• Acoustic shadows.
• Smooth multilocular tumor less than 10 cm.
• No detectable blood flow with Doppler exam.

Unfortunately, despite a sensitivity of 93% and specificity of 90%, and a positive and negative predictive value of 80% and 97%, these 10 simple rules were applicable to only 76% of tumors.

To assist those of us who are not gynecologic oncologists and who are often faced with having to determine whether surgery is recommended, I have elicited the expertise of Jubilee Brown, MD, professor and associate director of gynecologic oncology at the Levine Cancer Institute, Carolinas HealthCare System, in Charlotte, N.C., and the current president of the AAGL, to lead us in a review of evaluating an ovarian mass.
 

Dr. Miller is professor of obstetrics & gynecology in the department of clinical sciences, Rosalind Franklin University, North Chicago, Ill., and director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, both in Illinois. Email him at [email protected].

When an ovarian mass is anticipated or known, following evaluation of a patient’s history and physician examination, imaging via transvaginal and often abdominal ultrasound is the very next step. This evaluation likely will include both gray-scale and color Doppler examination. The initial concern always must be to identify ovarian malignancy.

Despite morphological scoring systems as well as the use of Doppler ultrasonography, there remains a lack of agreement and acceptance. In a 2008 multicenter study, Timmerman and colleagues evaluated 1,066 patients with 1,233 persistent adnexal tumors via transvaginal grayscale and Doppler ultrasound; 73% were benign tumors, and 27% were malignant tumors. Information on 42 gray-scale ultrasound variables and 6 Doppler variables was collected and evaluated to determine which variables had the highest positive predictive value for a malignant tumor and for a benign mass (Ultrasound Obstet Gynecol. 2008 Jun. doi: 10.1002/uog.5365).

Five simple rules were selected that best predict malignancy (M-rules), as follows:

• Irregular solid tumor.
• Ascites.
• At least four papillary projections.
• Irregular multilocular-solid tumor with a greatest diameter greater than or equal to 10 cm.
• Very high color content on Doppler exam.

The following five simple rules suggested that a mass is benign (B-rules):

• Unilocular cyst.
• Largest solid component less than 7 mm.
• Acoustic shadows.
• Smooth multilocular tumor less than 10 cm.
• No detectable blood flow with Doppler exam.

Unfortunately, despite a sensitivity of 93% and specificity of 90%, and a positive and negative predictive value of 80% and 97%, these 10 simple rules were applicable to only 76% of tumors.

To assist those of us who are not gynecologic oncologists and who are often faced with having to determine whether surgery is recommended, I have elicited the expertise of Jubilee Brown, MD, professor and associate director of gynecologic oncology at the Levine Cancer Institute, Carolinas HealthCare System, in Charlotte, N.C., and the current president of the AAGL, to lead us in a review of evaluating an ovarian mass.
 

Dr. Miller is professor of obstetrics & gynecology in the department of clinical sciences, Rosalind Franklin University, North Chicago, Ill., and director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, both in Illinois. Email him at [email protected].

When an ovarian mass is anticipated or known, following evaluation of a patient’s history and physician examination, imaging via transvaginal and often abdominal ultrasound is the very next step. This evaluation likely will include both gray-scale and color Doppler examination. The initial concern always must be to identify ovarian malignancy.

Despite morphological scoring systems as well as the use of Doppler ultrasonography, there remains a lack of agreement and acceptance. In a 2008 multicenter study, Timmerman and colleagues evaluated 1,066 patients with 1,233 persistent adnexal tumors via transvaginal grayscale and Doppler ultrasound; 73% were benign tumors, and 27% were malignant tumors. Information on 42 gray-scale ultrasound variables and 6 Doppler variables was collected and evaluated to determine which variables had the highest positive predictive value for a malignant tumor and for a benign mass (Ultrasound Obstet Gynecol. 2008 Jun. doi: 10.1002/uog.5365).

Five simple rules were selected that best predict malignancy (M-rules), as follows:

• Irregular solid tumor.
• Ascites.
• At least four papillary projections.
• Irregular multilocular-solid tumor with a greatest diameter greater than or equal to 10 cm.
• Very high color content on Doppler exam.

The following five simple rules suggested that a mass is benign (B-rules):

• Unilocular cyst.
• Largest solid component less than 7 mm.
• Acoustic shadows.
• Smooth multilocular tumor less than 10 cm.
• No detectable blood flow with Doppler exam.

Unfortunately, despite a sensitivity of 93% and specificity of 90%, and a positive and negative predictive value of 80% and 97%, these 10 simple rules were applicable to only 76% of tumors.

To assist those of us who are not gynecologic oncologists and who are often faced with having to determine whether surgery is recommended, I have elicited the expertise of Jubilee Brown, MD, professor and associate director of gynecologic oncology at the Levine Cancer Institute, Carolinas HealthCare System, in Charlotte, N.C., and the current president of the AAGL, to lead us in a review of evaluating an ovarian mass.
 

Dr. Miller is professor of obstetrics & gynecology in the department of clinical sciences, Rosalind Franklin University, North Chicago, Ill., and director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, both in Illinois. Email him at [email protected].

Ovarian masses are common in women of all ages. It is important not to miss even one ovarian cancer, but we must also identify masses that will resolve on their own over time to avoid overtreatment. These concurrent goals of excluding malignancy while not overtreating patients are the basis for management of the pelvic mass. Additionally, fertility preservation is important when surgery is performed in a reproductive-aged woman.

An ovarian mass may be anything from a simple functional or physiologic cyst to an endometrioma to an epithelial carcinoma, a germ-cell tumor, or a stromal tumor (the latter three of which may metastasize). Across the general population, women have a 5%-10% lifetime risk of needing surgery for a suspected ovarian mass and a 1.4% (1 in 70) risk that this mass is cancerous. The majority of ovarian cysts or masses therefore are benign.

A thorough history – including family history – and physical examination with appropriate laboratory testing and directed imaging are important first steps for the ob.gyn. Fortunately, we have guidelines and criteria governing not only when observation or surgery is warranted but also when patients should be referred to a gynecologic oncologist. By following these guidelines,¹ we are able to achieve the best outcomes.
 

Transvaginal ultrasound

A 2007 groundbreaking study led by Barbara Goff, MD, demonstrated that there are warning signs for ovarian cancer – symptoms that are significantly associated with malignancy. Dr. Goff and her coinvestigators evaluated the charts of hundreds of patients, including about 150 with ovarian cancer, and found that pelvic/abdominal pressure or pain, bloating, increase in abdominal size, and difficulty eating or feeling full were significantly and independently associated with cancer if these symptoms were present for less than a year and occurred at least 12 times per month.²

A pelvic examination is an integral part of evaluating every patient who has such concerns. That said, pelvic exams have limited ability to identify adnexal masses, especially in women who are obese – and that’s where imaging becomes especially important.

Masses generally can be considered simple or complex based on their appearance. A simple cyst is fluid-filled with thin, smooth walls and the absence of solid components or septations; it is significantly more likely to resolve on its own and is less likely to imply malignancy than a complex cyst, especially in a premenopausal woman. A complex cyst is multiseptated and/or solid – possibly with papillary projections – and is more concerning, especially if there is increased, new vascularity. Making this distinction helps us determine the risk of malignancy.

Transvaginal ultrasound (TVUS) is the preferred method for imaging, and our threshold for obtaining a TVUS should be very low. Women who have symptoms or concerns that can’t be attributed to a particular condition, and women in whom a mass can be palpated (even if asymptomatic) should have a TVUS. The imaging modality is cost effective and well tolerated by patients, does not expose the patient to ionizing radiation, and should generally be considered first-line imaging.^3,4

Size is not predictive of malignancy, but it is important for determining whether surgery is warranted. In our experience, a mass of 8-10 cm or larger on TVUS is at risk of torsion and is unlikely to resolve on its own, even in a premenopausal woman. While large masses generally require surgery, patients of any age who have simple cysts smaller than 8-10 cm generally can be followed with serial exams and ultrasound; spontaneous regression is common.

Doppler ultrasonography is useful for evaluating blood flow in and around an ovarian mass and can be helpful for confirming suspected characteristics of a mass.

Recent studies from the radiology community have looked at the utility of the resistive index – a measure of the impedance and velocity of blood flow – as a predictor of ovarian malignancy. However, we caution against using Doppler to determine whether a mass is benign or malignant, or to determine the necessity of surgery. An abnormal ovary may have what is considered to be a normal resistive index, and the resistive index of a normal ovary may fall within the abnormal range. Doppler flow can be helpful, but it must be combined with other predictive features, like solid components with flow or papillary projections within a cyst, to define a decision about surgery.^4,5

Magnetic resonance imaging can be useful in differentiating a fibroid from an ovarian mass, and a CT scan can be helpful in looking for disseminated disease when ovarian cancer is suspected based on ultrasound imaging, physical and history, and serum markers. A CT is useful, for instance, in a patient whose ovary is distended with ascites or who has upper abdominal complaints and a complex cyst. CT, PET, and MRI are not recommended in the initial evaluation of an ovarian mass.

The utility of serum biomarkers

Cancer antigen 125 (CA-125) testing may be helpful – in combination with other findings – for decision-making regarding the likelihood of malignancy and the need to refer patients. CA-125 is like Doppler in that a normal CA-125 cannot eliminate the possibility of cancer, and an abnormal CA-125 does not in and of itself imply malignancy. It’s far from a perfect cancer screening test.

CA-125 is a protein associated with epithelial ovarian malignancies, the type of ovarian cancer most commonly seen in postmenopausal women with genetic predispositions. Its specificity and positive predictive value are much higher in postmenopausal women than in average-risk premenopausal women (those without a family history or a known mutation that predisposes them to ovarian cancer). Levels of the marker are elevated in association with many nonmalignant conditions in premenopausal women – endometriosis, fibroids, and various inflammatory conditions, for instance – so the marker’s utility in this population is limited.

For women who have a family history of ovarian cancer or a known breast cancer gene 1 (BRCA1) or BRCA2 mutation, there are some data that suggest that monitoring with CA-125 measurements and TVUS may be a good approach to following patients prior to the age at which risk-reducing surgery can best be performed.

In an adolescent girl or a woman of reproductive age, we think less about epithelial cancer and more about germ-cell and stromal tumors. When a solid mass is palpated or visualized on imaging, we therefore will utilize a different set of markers; alpha-fetoprotein, L-lactate dehydrogenase, and beta-HCG, for instance, have much higher specificity than CA-125 does for germ-cell tumors in this age group and may be helpful in the evaluation. Similarly, in cases of a very large mass resembling a mucinous tumor, a carcinoembryonic antigen may be helpful.

A number of proprietary profiling technologies have been developed to determine the risk of a diagnosed mass being malignant. For instance, the OVA1 assay looks at five serum markers and scores the results, and the Risk of Ovarian Malignancy Algorithm (ROMA) combines the results of three serum markers with menopausal status into a numerical score. Both have Food and Drug Administration approval for use in women in whom surgery has been deemed necessary. These panels can be fairly predictive of risk and may be helpful – especially in rural areas – in determining which women should be referred to a gynecologic oncologist for surgery.

It is important to appreciate that an ovarian cyst or mass should never be biopsied or aspirated lest a malignant tumor confined to one ovary be potentially spread to the peritoneum.
 

Referral to a gynecologic oncologist

Postmenopausal women with a CA-125 greater than 35 U/mL should be referred, as should postmenopausal women with ascites, those with a nodular or fixed pelvic mass, and those with suspected abdominal or distant metastases (per a CT scan, for instance).

In premenopausal women, ascites, a nodular or fixed mass, and evidence of metastases also are reasons for referral to a gynecologic oncologist. CA-125, again, is much more likely to be elevated for reasons other than malignancy and therefore is not as strong a driver for referral as in postmenopausal women. Patients with markedly elevated levels, however, should probably be referred – particularly when other clinical factors also suggest the need for consultation. While there is no evidence-based threshold for CA-125 in premenopausal women, a CA-125 greater than 200 U/mL is a good cutoff for referral.

For any patient, family history of breast and/or ovarian cancer – especially in a first-degree relative – raises the risk of malignancy and should figure prominently into decision-making regarding referral. Criteria for referral are among the points discussed in the ACOG 2016 Practice Bulletin on Evaluation and Management of Adnexal Masses.¹

A note on BRCA mutations

As the American College of Obstetricians and Gynecologists says in its practice bulletin, the most important personal risk factor for ovarian cancer is a strong family history of breast or ovarian cancer. Women with such a family history can undergo genetic testing for BRCA mutations and have the opportunity to prevent ovarian cancers when mutations are detected. This simple blood test can save lives.

A modeling study we recently completed – not yet published – shows that it actually would be cost effective to do population screening with BRCA testing performed on every woman at age 30 years.

According to the National Cancer Institute website (last review: 2018), it is estimated that about 44% of women who inherit a BRCA1 mutation, and about 17% of those who inherit a BRAC2 mutation, will develop ovarian cancer by the age of 80 years. By identifying those mutations, women may undergo risk-reducing surgery at designated ages after childbearing is complete and bring their risk down to under 5%.

An international take on managing adnexal masses

• Pelvic ultrasound should include the transvaginal approach. Use Doppler imaging as indicated.
• Although simple ovarian cysts are not precursor lesions to a malignant ovarian cancer, perform a high-quality examination to make sure there are no solid/papillary structures before classifying a cyst as a simple cyst. The risk of progression to malignancy is extremely low, but some follow-up is prudent.
• The most accurate method of characterizing an ovarian mass currently is real-time pattern recognition sonography in the hands of an experienced imager.
• Pattern recognition sonography or a risk model such as the International Ovarian Tumor Analysis (IOTA) Simple Rules can be used to initially characterize an ovarian mass.
• When an ovarian lesion is classified as benign, the patient may be followed conservatively, or if indicated, surgery can be performed by a general gynecologist.
• Serial sonography can be beneficial, but there are limited prospective data to support an exact interval and duration.
• Fewer surgical interventions may result in an increase in sonographic surveillance.
• When an ovarian lesion is considered indeterminate on initial sonography, and after appropriate clinical evaluation, a “second-step” evaluation may include referral to an expert sonologist, serial sonography, application of established risk-prediction models, correlation with serum biomarkers, correlation with MRI, or referral to a gynecologic oncologist for further evaluation.

From the First International Consensus Report on Adnexal Masses: Management Recommendations

Source: Glanc P et al. J Ultrasound Med. 2017 May;36(5):849-63.

Dr. Brown reported that she had received an earlier grant from Aspira Labs, the company that developed the OVA1 assay. Dr. Miller reported that he has no relevant financial disclosures.

References

1. Obstet Gynecol. 2016 Nov. doi: 10.1097/AOG.0000000000001768.

2. Cancer. 2007 Jan 15. doi: 10.1002/cncr.22371.

3. Clin Obstet Gynecol. 2015 Mar. doi: 10.1097/GRF.0000000000000083.

4. Ultrasound Q. 2013 Mar. doi: 10.1097/RUQ.0b013e3182814d9b.

5. Ultrasound Obstet Gynecol. 2008 Jun. doi: 10.1002/uog.5365.

Ovarian masses are common in women of all ages. It is important not to miss even one ovarian cancer, but we must also identify masses that will resolve on their own over time to avoid overtreatment. These concurrent goals of excluding malignancy while not overtreating patients are the basis for management of the pelvic mass. Additionally, fertility preservation is important when surgery is performed in a reproductive-aged woman.

An ovarian mass may be anything from a simple functional or physiologic cyst to an endometrioma to an epithelial carcinoma, a germ-cell tumor, or a stromal tumor (the latter three of which may metastasize). Across the general population, women have a 5%-10% lifetime risk of needing surgery for a suspected ovarian mass and a 1.4% (1 in 70) risk that this mass is cancerous. The majority of ovarian cysts or masses therefore are benign.

A thorough history – including family history – and physical examination with appropriate laboratory testing and directed imaging are important first steps for the ob.gyn. Fortunately, we have guidelines and criteria governing not only when observation or surgery is warranted but also when patients should be referred to a gynecologic oncologist. By following these guidelines,¹ we are able to achieve the best outcomes.
 

Transvaginal ultrasound

A 2007 groundbreaking study led by Barbara Goff, MD, demonstrated that there are warning signs for ovarian cancer – symptoms that are significantly associated with malignancy. Dr. Goff and her coinvestigators evaluated the charts of hundreds of patients, including about 150 with ovarian cancer, and found that pelvic/abdominal pressure or pain, bloating, increase in abdominal size, and difficulty eating or feeling full were significantly and independently associated with cancer if these symptoms were present for less than a year and occurred at least 12 times per month.²

A pelvic examination is an integral part of evaluating every patient who has such concerns. That said, pelvic exams have limited ability to identify adnexal masses, especially in women who are obese – and that’s where imaging becomes especially important.

Masses generally can be considered simple or complex based on their appearance. A simple cyst is fluid-filled with thin, smooth walls and the absence of solid components or septations; it is significantly more likely to resolve on its own and is less likely to imply malignancy than a complex cyst, especially in a premenopausal woman. A complex cyst is multiseptated and/or solid – possibly with papillary projections – and is more concerning, especially if there is increased, new vascularity. Making this distinction helps us determine the risk of malignancy.

Transvaginal ultrasound (TVUS) is the preferred method for imaging, and our threshold for obtaining a TVUS should be very low. Women who have symptoms or concerns that can’t be attributed to a particular condition, and women in whom a mass can be palpated (even if asymptomatic) should have a TVUS. The imaging modality is cost effective and well tolerated by patients, does not expose the patient to ionizing radiation, and should generally be considered first-line imaging.^3,4

Size is not predictive of malignancy, but it is important for determining whether surgery is warranted. In our experience, a mass of 8-10 cm or larger on TVUS is at risk of torsion and is unlikely to resolve on its own, even in a premenopausal woman. While large masses generally require surgery, patients of any age who have simple cysts smaller than 8-10 cm generally can be followed with serial exams and ultrasound; spontaneous regression is common.

Doppler ultrasonography is useful for evaluating blood flow in and around an ovarian mass and can be helpful for confirming suspected characteristics of a mass.

Recent studies from the radiology community have looked at the utility of the resistive index – a measure of the impedance and velocity of blood flow – as a predictor of ovarian malignancy. However, we caution against using Doppler to determine whether a mass is benign or malignant, or to determine the necessity of surgery. An abnormal ovary may have what is considered to be a normal resistive index, and the resistive index of a normal ovary may fall within the abnormal range. Doppler flow can be helpful, but it must be combined with other predictive features, like solid components with flow or papillary projections within a cyst, to define a decision about surgery.^4,5

Magnetic resonance imaging can be useful in differentiating a fibroid from an ovarian mass, and a CT scan can be helpful in looking for disseminated disease when ovarian cancer is suspected based on ultrasound imaging, physical and history, and serum markers. A CT is useful, for instance, in a patient whose ovary is distended with ascites or who has upper abdominal complaints and a complex cyst. CT, PET, and MRI are not recommended in the initial evaluation of an ovarian mass.

The utility of serum biomarkers

Cancer antigen 125 (CA-125) testing may be helpful – in combination with other findings – for decision-making regarding the likelihood of malignancy and the need to refer patients. CA-125 is like Doppler in that a normal CA-125 cannot eliminate the possibility of cancer, and an abnormal CA-125 does not in and of itself imply malignancy. It’s far from a perfect cancer screening test.

CA-125 is a protein associated with epithelial ovarian malignancies, the type of ovarian cancer most commonly seen in postmenopausal women with genetic predispositions. Its specificity and positive predictive value are much higher in postmenopausal women than in average-risk premenopausal women (those without a family history or a known mutation that predisposes them to ovarian cancer). Levels of the marker are elevated in association with many nonmalignant conditions in premenopausal women – endometriosis, fibroids, and various inflammatory conditions, for instance – so the marker’s utility in this population is limited.

For women who have a family history of ovarian cancer or a known breast cancer gene 1 (BRCA1) or BRCA2 mutation, there are some data that suggest that monitoring with CA-125 measurements and TVUS may be a good approach to following patients prior to the age at which risk-reducing surgery can best be performed.

In an adolescent girl or a woman of reproductive age, we think less about epithelial cancer and more about germ-cell and stromal tumors. When a solid mass is palpated or visualized on imaging, we therefore will utilize a different set of markers; alpha-fetoprotein, L-lactate dehydrogenase, and beta-HCG, for instance, have much higher specificity than CA-125 does for germ-cell tumors in this age group and may be helpful in the evaluation. Similarly, in cases of a very large mass resembling a mucinous tumor, a carcinoembryonic antigen may be helpful.

A number of proprietary profiling technologies have been developed to determine the risk of a diagnosed mass being malignant. For instance, the OVA1 assay looks at five serum markers and scores the results, and the Risk of Ovarian Malignancy Algorithm (ROMA) combines the results of three serum markers with menopausal status into a numerical score. Both have Food and Drug Administration approval for use in women in whom surgery has been deemed necessary. These panels can be fairly predictive of risk and may be helpful – especially in rural areas – in determining which women should be referred to a gynecologic oncologist for surgery.

It is important to appreciate that an ovarian cyst or mass should never be biopsied or aspirated lest a malignant tumor confined to one ovary be potentially spread to the peritoneum.
 

Referral to a gynecologic oncologist

Postmenopausal women with a CA-125 greater than 35 U/mL should be referred, as should postmenopausal women with ascites, those with a nodular or fixed pelvic mass, and those with suspected abdominal or distant metastases (per a CT scan, for instance).

In premenopausal women, ascites, a nodular or fixed mass, and evidence of metastases also are reasons for referral to a gynecologic oncologist. CA-125, again, is much more likely to be elevated for reasons other than malignancy and therefore is not as strong a driver for referral as in postmenopausal women. Patients with markedly elevated levels, however, should probably be referred – particularly when other clinical factors also suggest the need for consultation. While there is no evidence-based threshold for CA-125 in premenopausal women, a CA-125 greater than 200 U/mL is a good cutoff for referral.

For any patient, family history of breast and/or ovarian cancer – especially in a first-degree relative – raises the risk of malignancy and should figure prominently into decision-making regarding referral. Criteria for referral are among the points discussed in the ACOG 2016 Practice Bulletin on Evaluation and Management of Adnexal Masses.¹

A note on BRCA mutations

As the American College of Obstetricians and Gynecologists says in its practice bulletin, the most important personal risk factor for ovarian cancer is a strong family history of breast or ovarian cancer. Women with such a family history can undergo genetic testing for BRCA mutations and have the opportunity to prevent ovarian cancers when mutations are detected. This simple blood test can save lives.

A modeling study we recently completed – not yet published – shows that it actually would be cost effective to do population screening with BRCA testing performed on every woman at age 30 years.

According to the National Cancer Institute website (last review: 2018), it is estimated that about 44% of women who inherit a BRCA1 mutation, and about 17% of those who inherit a BRAC2 mutation, will develop ovarian cancer by the age of 80 years. By identifying those mutations, women may undergo risk-reducing surgery at designated ages after childbearing is complete and bring their risk down to under 5%.

An international take on managing adnexal masses

• Pelvic ultrasound should include the transvaginal approach. Use Doppler imaging as indicated.
• Although simple ovarian cysts are not precursor lesions to a malignant ovarian cancer, perform a high-quality examination to make sure there are no solid/papillary structures before classifying a cyst as a simple cyst. The risk of progression to malignancy is extremely low, but some follow-up is prudent.
• The most accurate method of characterizing an ovarian mass currently is real-time pattern recognition sonography in the hands of an experienced imager.
• Pattern recognition sonography or a risk model such as the International Ovarian Tumor Analysis (IOTA) Simple Rules can be used to initially characterize an ovarian mass.
• When an ovarian lesion is classified as benign, the patient may be followed conservatively, or if indicated, surgery can be performed by a general gynecologist.
• Serial sonography can be beneficial, but there are limited prospective data to support an exact interval and duration.
• Fewer surgical interventions may result in an increase in sonographic surveillance.
• When an ovarian lesion is considered indeterminate on initial sonography, and after appropriate clinical evaluation, a “second-step” evaluation may include referral to an expert sonologist, serial sonography, application of established risk-prediction models, correlation with serum biomarkers, correlation with MRI, or referral to a gynecologic oncologist for further evaluation.

From the First International Consensus Report on Adnexal Masses: Management Recommendations

Source: Glanc P et al. J Ultrasound Med. 2017 May;36(5):849-63.

Dr. Brown reported that she had received an earlier grant from Aspira Labs, the company that developed the OVA1 assay. Dr. Miller reported that he has no relevant financial disclosures.

References

1. Obstet Gynecol. 2016 Nov. doi: 10.1097/AOG.0000000000001768.

2. Cancer. 2007 Jan 15. doi: 10.1002/cncr.22371.

3. Clin Obstet Gynecol. 2015 Mar. doi: 10.1097/GRF.0000000000000083.

4. Ultrasound Q. 2013 Mar. doi: 10.1097/RUQ.0b013e3182814d9b.

5. Ultrasound Obstet Gynecol. 2008 Jun. doi: 10.1002/uog.5365.

Ovarian masses are common in women of all ages. It is important not to miss even one ovarian cancer, but we must also identify masses that will resolve on their own over time to avoid overtreatment. These concurrent goals of excluding malignancy while not overtreating patients are the basis for management of the pelvic mass. Additionally, fertility preservation is important when surgery is performed in a reproductive-aged woman.

An ovarian mass may be anything from a simple functional or physiologic cyst to an endometrioma to an epithelial carcinoma, a germ-cell tumor, or a stromal tumor (the latter three of which may metastasize). Across the general population, women have a 5%-10% lifetime risk of needing surgery for a suspected ovarian mass and a 1.4% (1 in 70) risk that this mass is cancerous. The majority of ovarian cysts or masses therefore are benign.

A thorough history – including family history – and physical examination with appropriate laboratory testing and directed imaging are important first steps for the ob.gyn. Fortunately, we have guidelines and criteria governing not only when observation or surgery is warranted but also when patients should be referred to a gynecologic oncologist. By following these guidelines,¹ we are able to achieve the best outcomes.
 

Transvaginal ultrasound

A 2007 groundbreaking study led by Barbara Goff, MD, demonstrated that there are warning signs for ovarian cancer – symptoms that are significantly associated with malignancy. Dr. Goff and her coinvestigators evaluated the charts of hundreds of patients, including about 150 with ovarian cancer, and found that pelvic/abdominal pressure or pain, bloating, increase in abdominal size, and difficulty eating or feeling full were significantly and independently associated with cancer if these symptoms were present for less than a year and occurred at least 12 times per month.²

A pelvic examination is an integral part of evaluating every patient who has such concerns. That said, pelvic exams have limited ability to identify adnexal masses, especially in women who are obese – and that’s where imaging becomes especially important.

Masses generally can be considered simple or complex based on their appearance. A simple cyst is fluid-filled with thin, smooth walls and the absence of solid components or septations; it is significantly more likely to resolve on its own and is less likely to imply malignancy than a complex cyst, especially in a premenopausal woman. A complex cyst is multiseptated and/or solid – possibly with papillary projections – and is more concerning, especially if there is increased, new vascularity. Making this distinction helps us determine the risk of malignancy.

Transvaginal ultrasound (TVUS) is the preferred method for imaging, and our threshold for obtaining a TVUS should be very low. Women who have symptoms or concerns that can’t be attributed to a particular condition, and women in whom a mass can be palpated (even if asymptomatic) should have a TVUS. The imaging modality is cost effective and well tolerated by patients, does not expose the patient to ionizing radiation, and should generally be considered first-line imaging.^3,4

Size is not predictive of malignancy, but it is important for determining whether surgery is warranted. In our experience, a mass of 8-10 cm or larger on TVUS is at risk of torsion and is unlikely to resolve on its own, even in a premenopausal woman. While large masses generally require surgery, patients of any age who have simple cysts smaller than 8-10 cm generally can be followed with serial exams and ultrasound; spontaneous regression is common.

Doppler ultrasonography is useful for evaluating blood flow in and around an ovarian mass and can be helpful for confirming suspected characteristics of a mass.

Recent studies from the radiology community have looked at the utility of the resistive index – a measure of the impedance and velocity of blood flow – as a predictor of ovarian malignancy. However, we caution against using Doppler to determine whether a mass is benign or malignant, or to determine the necessity of surgery. An abnormal ovary may have what is considered to be a normal resistive index, and the resistive index of a normal ovary may fall within the abnormal range. Doppler flow can be helpful, but it must be combined with other predictive features, like solid components with flow or papillary projections within a cyst, to define a decision about surgery.^4,5

Magnetic resonance imaging can be useful in differentiating a fibroid from an ovarian mass, and a CT scan can be helpful in looking for disseminated disease when ovarian cancer is suspected based on ultrasound imaging, physical and history, and serum markers. A CT is useful, for instance, in a patient whose ovary is distended with ascites or who has upper abdominal complaints and a complex cyst. CT, PET, and MRI are not recommended in the initial evaluation of an ovarian mass.

The utility of serum biomarkers

Cancer antigen 125 (CA-125) testing may be helpful – in combination with other findings – for decision-making regarding the likelihood of malignancy and the need to refer patients. CA-125 is like Doppler in that a normal CA-125 cannot eliminate the possibility of cancer, and an abnormal CA-125 does not in and of itself imply malignancy. It’s far from a perfect cancer screening test.

CA-125 is a protein associated with epithelial ovarian malignancies, the type of ovarian cancer most commonly seen in postmenopausal women with genetic predispositions. Its specificity and positive predictive value are much higher in postmenopausal women than in average-risk premenopausal women (those without a family history or a known mutation that predisposes them to ovarian cancer). Levels of the marker are elevated in association with many nonmalignant conditions in premenopausal women – endometriosis, fibroids, and various inflammatory conditions, for instance – so the marker’s utility in this population is limited.

For women who have a family history of ovarian cancer or a known breast cancer gene 1 (BRCA1) or BRCA2 mutation, there are some data that suggest that monitoring with CA-125 measurements and TVUS may be a good approach to following patients prior to the age at which risk-reducing surgery can best be performed.

In an adolescent girl or a woman of reproductive age, we think less about epithelial cancer and more about germ-cell and stromal tumors. When a solid mass is palpated or visualized on imaging, we therefore will utilize a different set of markers; alpha-fetoprotein, L-lactate dehydrogenase, and beta-HCG, for instance, have much higher specificity than CA-125 does for germ-cell tumors in this age group and may be helpful in the evaluation. Similarly, in cases of a very large mass resembling a mucinous tumor, a carcinoembryonic antigen may be helpful.

A number of proprietary profiling technologies have been developed to determine the risk of a diagnosed mass being malignant. For instance, the OVA1 assay looks at five serum markers and scores the results, and the Risk of Ovarian Malignancy Algorithm (ROMA) combines the results of three serum markers with menopausal status into a numerical score. Both have Food and Drug Administration approval for use in women in whom surgery has been deemed necessary. These panels can be fairly predictive of risk and may be helpful – especially in rural areas – in determining which women should be referred to a gynecologic oncologist for surgery.

It is important to appreciate that an ovarian cyst or mass should never be biopsied or aspirated lest a malignant tumor confined to one ovary be potentially spread to the peritoneum.
 

Referral to a gynecologic oncologist

Postmenopausal women with a CA-125 greater than 35 U/mL should be referred, as should postmenopausal women with ascites, those with a nodular or fixed pelvic mass, and those with suspected abdominal or distant metastases (per a CT scan, for instance).

In premenopausal women, ascites, a nodular or fixed mass, and evidence of metastases also are reasons for referral to a gynecologic oncologist. CA-125, again, is much more likely to be elevated for reasons other than malignancy and therefore is not as strong a driver for referral as in postmenopausal women. Patients with markedly elevated levels, however, should probably be referred – particularly when other clinical factors also suggest the need for consultation. While there is no evidence-based threshold for CA-125 in premenopausal women, a CA-125 greater than 200 U/mL is a good cutoff for referral.

For any patient, family history of breast and/or ovarian cancer – especially in a first-degree relative – raises the risk of malignancy and should figure prominently into decision-making regarding referral. Criteria for referral are among the points discussed in the ACOG 2016 Practice Bulletin on Evaluation and Management of Adnexal Masses.¹

A note on BRCA mutations

As the American College of Obstetricians and Gynecologists says in its practice bulletin, the most important personal risk factor for ovarian cancer is a strong family history of breast or ovarian cancer. Women with such a family history can undergo genetic testing for BRCA mutations and have the opportunity to prevent ovarian cancers when mutations are detected. This simple blood test can save lives.

A modeling study we recently completed – not yet published – shows that it actually would be cost effective to do population screening with BRCA testing performed on every woman at age 30 years.

According to the National Cancer Institute website (last review: 2018), it is estimated that about 44% of women who inherit a BRCA1 mutation, and about 17% of those who inherit a BRAC2 mutation, will develop ovarian cancer by the age of 80 years. By identifying those mutations, women may undergo risk-reducing surgery at designated ages after childbearing is complete and bring their risk down to under 5%.

An international take on managing adnexal masses

• Pelvic ultrasound should include the transvaginal approach. Use Doppler imaging as indicated.
• Although simple ovarian cysts are not precursor lesions to a malignant ovarian cancer, perform a high-quality examination to make sure there are no solid/papillary structures before classifying a cyst as a simple cyst. The risk of progression to malignancy is extremely low, but some follow-up is prudent.
• The most accurate method of characterizing an ovarian mass currently is real-time pattern recognition sonography in the hands of an experienced imager.
• Pattern recognition sonography or a risk model such as the International Ovarian Tumor Analysis (IOTA) Simple Rules can be used to initially characterize an ovarian mass.
• When an ovarian lesion is classified as benign, the patient may be followed conservatively, or if indicated, surgery can be performed by a general gynecologist.
• Serial sonography can be beneficial, but there are limited prospective data to support an exact interval and duration.
• Fewer surgical interventions may result in an increase in sonographic surveillance.
• When an ovarian lesion is considered indeterminate on initial sonography, and after appropriate clinical evaluation, a “second-step” evaluation may include referral to an expert sonologist, serial sonography, application of established risk-prediction models, correlation with serum biomarkers, correlation with MRI, or referral to a gynecologic oncologist for further evaluation.

From the First International Consensus Report on Adnexal Masses: Management Recommendations

Source: Glanc P et al. J Ultrasound Med. 2017 May;36(5):849-63.

Dr. Brown reported that she had received an earlier grant from Aspira Labs, the company that developed the OVA1 assay. Dr. Miller reported that he has no relevant financial disclosures.

References

1. Obstet Gynecol. 2016 Nov. doi: 10.1097/AOG.0000000000001768.

2. Cancer. 2007 Jan 15. doi: 10.1002/cncr.22371.

3. Clin Obstet Gynecol. 2015 Mar. doi: 10.1097/GRF.0000000000000083.

4. Ultrasound Q. 2013 Mar. doi: 10.1097/RUQ.0b013e3182814d9b.

5. Ultrasound Obstet Gynecol. 2008 Jun. doi: 10.1002/uog.5365.

Case 1

A 30 year-old female with longstanding ulcerative colitis who has a history of medically refractory steroid-dependent disease and was able to achieve remission with vedolizumab for the last 5 years. Most recent objective assessment showed histologic remission. She has been using daily cannabis medicinally for the last year (high CBD:THC [cannabidiol:delta-9-tetracannabidol] concentration). She notes that she has felt better in the last year since introducing cannabis (improved stool frequency/formation, sleep quality). She inquires about discontinuing her biologic therapy in the hope of using cannabis alone to maintain remission.

Figure 1.

Case 2

A 22-year-old male with ileocolonic inflammatory Crohn’s disease escalated to adalimumab requiring an intensification of therapy to weekly dosing to normalize C-reactive protein (CRP). A recent colonoscopy showed endoscopic improvement (colonic normalization and rare aphthae in ileum). He notes clear clinical improvement, but he continues to experience diarrhea and abdominal cramping (no relationship to meals). Declines addition of immunomodulator (nervous about returning to college during the COVID-19 pandemic). He wonders whether cannabis could be effective in controlling his symptoms as he has had improvement in symptoms during his sporadic recreational cannabis exposure.

Discussion

These cases outline the challenges that providers face when managing patients with inflammatory bowel disease (IBD) when a patient would like to either substitute or incorporate cannabis into their treatment plan. Studies have shown a high prevalence of cannabis use among patients with IBD. With the restrictions surrounding the use of cannabis – either medically or recreationally – being liberalized in many states, these conversations are likely to become more frequent in your practice. However, one of the first challenges that providers face surrounding cannabis is that many patients who use cannabis do not disclose use to their health care team for fear of being judged negatively. In addition, many providers do not routinely ask about cannabis use during office visits. This might be directly related to being unprepared to have a knowledge-based discussion on the risks and benefits of cannabis use in IBD, with the same confidence present during discussion of biologic therapies.

For background, Cannabis sativa (cannabis) is composed of hundreds of phytocannabinoids, the two most common are THC and CBD. These cannabinoids act at the endocannabinoid receptors, which are expressed in the central and peripheral nervous systems and immune cells/tissues, and help explain the clinical changes experienced by cannabis users. Both THC and CBD have been studied in varying doses and routes of administration in patients with IBD, making it challenging to translate into real-world recommendations for patients. Some of the most common reported benefits of cannabis use (particularly in an IBD population) are improvement in pain, diarrhea, nausea, and joint pain. Some studies have shown overall improvement in quality of life (Figure 1).

Some common questions that arise surrounding cannabis use in IBD patients include:

1. Is it possible to stop traditional medical therapy and replace it with cannabis therapy?

No studies have directly addressed this exact question. The small studies, both randomized controlled trials and retrospective ones, have studied the effects of cannabis as adjuvant therapy only. None of the data available to date suggest that cannabis has any anti-inflammatory properties with absence of improvement in biomarkers or endoscopic measures of inflammation. In effect, any attempt to discontinue standard therapy with substitution of cannabis-based therapy should be seen as no different than simply discontinuing standard therapy. There exists the argument that – among those with moderate to severe disease – cannabis might suppress the investigation of mild symptoms which may herald a flare of disease, thus lulling the patient into a state of false stability. We do not advocate the substitution of cannabis products in place of standard medical therapy.

2. Is there a role for cannabis as adjuvant therapy in patients with IBD?

Studies to date have included only symptomatic patients with objective evidence of inflammation and assessed clinical, biochemical, or endoscopic endpoints. In Crohn’s disease, two studies showed no improvement in clinical remission rates but showed improvement in clinical response; a third study showed both improvement in clinical remission/response as well as improved quality of life. No study showed a change in disease markers of activity including CRP, fecal calprotectin, or endoscopic scoring. In one study, all patients relapsed shortly after cannabis discontinuation suggesting that, while there was benefit in symptom control, there was no improvement of the underlying chronic inflammation.

In patients with ulcerative colitis, there were two studies. One study showed no improvement and high rates of intolerance in the treatment group, while the other study reported improved disease activity but no objective improvement. The variation in results between disease states and between studies might be because of cannabis formulations. In patients with persistent symptoms despite current medical therapy, there might be a role in those patients for adjuvant therapy for improvement symptom control but not disease control. Optimization of medical therapy would still be indicated.



3. What dose and formulation of cannabis should I recommend to a patient as adjuvant therapy?

This is an excellent question and one that unfortunately we do not have the answer to. As mentioned previously, the studies have looked at varying formulations (THC alone, CBD:THC with varying percentages of THC, CBD alone) and varying routes of administration (sublingual, oral, inhalation). The IBD studies looking at CBD-alone formulations lacked clinical efficacy. In states where cannabis products have been accessible to IBD patients, no data on the product type (THC:CBD), method of administration, or prescriber preferences have been published.

4. What risks should I advise my patients about with cannabis use?

The challenge is that we don’t have large population-based studies in IBD looking at long-term risks of cannabis use. However, in the small RCT studies there were minimal reported side effects and no major adverse events over 8-10 weeks. Larger IBD population-based studies have shown that cannabis users were more likely to discontinue traditional medical therapy, and there is an increased risk for surgery in patients with Crohn’s disease. Larger studies in non-IBD patients have shown risk for addiction to other substances, diminished life achievement, increased motor vehicle accidents, chronic bronchitis, psychiatric disturbances and cannabis dependence, and cannabis hyperemesis syndrome (with an uncanny presentation resembling Crohn’s disease flare with partial small bowel obstruction). Patients should also be advised about legal implications of use (given its continued classification as a federal schedule 1 drug), possible drug interactions, and special considerations in pediatric patients (increased risk of addiction), elderly patients (increased risk of neuropsychological effects), and during pregnancy (with national obstetric society guidelines warning against use because of fetal exposure and increased risk of stillbirth).

5. What are the legal implications for providers? Patients?

As of July 2020, cannabis is available for recreational use in 12 states, for medicinal use in 28 states, and illegal in 11 states. So the answer really depends on what state the patient lives in. As a provider who might certify patients (in some medicinal states) or recommend cannabis to patients, you should consider legal and licensing implications. Again, this might vary state to state, and you should also take into account federal status. Providers acting in compliance with state laws are unlikely to have federal consequences. However, remember that malpractice insurance only covers FDA-approved medical therapies. Patients should be advised to consider the potential (although highly unlikely) to face federal prosecution and implications of use for employment, school, camp, or travel, and driving restrictions.

Take home points

• Inquire about cannabis to start the conversation.
• Know your state’s legalization status surrounding cannabis.
• Patients with IBD report improvement in symptoms and quality of life with adjuvant cannabis use; however, there is no change in disease activity.
• Encourage your patients to continue and optimize their maintenance therapy.
• Educate your patients about the legal considerations and known risks.

In conclusion, the use of cannabis in IBD patients has increased in recent years. It is important to be able to discuss the risks and benefits of use with your IBD patients. Focus on the lack of data showing that cannabis improves disease activity, and has shown benefit only in improving IBD-associated symptoms. In some patients there might be a role for adjuvant cannabis therapy to improve overall symptom control and quality of life.
 

Dr. Kinnucan is an assistant professor of medicine, division of gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor; Dr. Swaminath is an associate professor of medicine, division of gastroenterology, Lenox Hill Hospital, Northwell Health, New York.

Case 1

A 30 year-old female with longstanding ulcerative colitis who has a history of medically refractory steroid-dependent disease and was able to achieve remission with vedolizumab for the last 5 years. Most recent objective assessment showed histologic remission. She has been using daily cannabis medicinally for the last year (high CBD:THC [cannabidiol:delta-9-tetracannabidol] concentration). She notes that she has felt better in the last year since introducing cannabis (improved stool frequency/formation, sleep quality). She inquires about discontinuing her biologic therapy in the hope of using cannabis alone to maintain remission.

Figure 1.

Case 2

A 22-year-old male with ileocolonic inflammatory Crohn’s disease escalated to adalimumab requiring an intensification of therapy to weekly dosing to normalize C-reactive protein (CRP). A recent colonoscopy showed endoscopic improvement (colonic normalization and rare aphthae in ileum). He notes clear clinical improvement, but he continues to experience diarrhea and abdominal cramping (no relationship to meals). Declines addition of immunomodulator (nervous about returning to college during the COVID-19 pandemic). He wonders whether cannabis could be effective in controlling his symptoms as he has had improvement in symptoms during his sporadic recreational cannabis exposure.

Discussion

These cases outline the challenges that providers face when managing patients with inflammatory bowel disease (IBD) when a patient would like to either substitute or incorporate cannabis into their treatment plan. Studies have shown a high prevalence of cannabis use among patients with IBD. With the restrictions surrounding the use of cannabis – either medically or recreationally – being liberalized in many states, these conversations are likely to become more frequent in your practice. However, one of the first challenges that providers face surrounding cannabis is that many patients who use cannabis do not disclose use to their health care team for fear of being judged negatively. In addition, many providers do not routinely ask about cannabis use during office visits. This might be directly related to being unprepared to have a knowledge-based discussion on the risks and benefits of cannabis use in IBD, with the same confidence present during discussion of biologic therapies.

For background, Cannabis sativa (cannabis) is composed of hundreds of phytocannabinoids, the two most common are THC and CBD. These cannabinoids act at the endocannabinoid receptors, which are expressed in the central and peripheral nervous systems and immune cells/tissues, and help explain the clinical changes experienced by cannabis users. Both THC and CBD have been studied in varying doses and routes of administration in patients with IBD, making it challenging to translate into real-world recommendations for patients. Some of the most common reported benefits of cannabis use (particularly in an IBD population) are improvement in pain, diarrhea, nausea, and joint pain. Some studies have shown overall improvement in quality of life (Figure 1).

Some common questions that arise surrounding cannabis use in IBD patients include:

1. Is it possible to stop traditional medical therapy and replace it with cannabis therapy?

No studies have directly addressed this exact question. The small studies, both randomized controlled trials and retrospective ones, have studied the effects of cannabis as adjuvant therapy only. None of the data available to date suggest that cannabis has any anti-inflammatory properties with absence of improvement in biomarkers or endoscopic measures of inflammation. In effect, any attempt to discontinue standard therapy with substitution of cannabis-based therapy should be seen as no different than simply discontinuing standard therapy. There exists the argument that – among those with moderate to severe disease – cannabis might suppress the investigation of mild symptoms which may herald a flare of disease, thus lulling the patient into a state of false stability. We do not advocate the substitution of cannabis products in place of standard medical therapy.

2. Is there a role for cannabis as adjuvant therapy in patients with IBD?

Studies to date have included only symptomatic patients with objective evidence of inflammation and assessed clinical, biochemical, or endoscopic endpoints. In Crohn’s disease, two studies showed no improvement in clinical remission rates but showed improvement in clinical response; a third study showed both improvement in clinical remission/response as well as improved quality of life. No study showed a change in disease markers of activity including CRP, fecal calprotectin, or endoscopic scoring. In one study, all patients relapsed shortly after cannabis discontinuation suggesting that, while there was benefit in symptom control, there was no improvement of the underlying chronic inflammation.

In patients with ulcerative colitis, there were two studies. One study showed no improvement and high rates of intolerance in the treatment group, while the other study reported improved disease activity but no objective improvement. The variation in results between disease states and between studies might be because of cannabis formulations. In patients with persistent symptoms despite current medical therapy, there might be a role in those patients for adjuvant therapy for improvement symptom control but not disease control. Optimization of medical therapy would still be indicated.



3. What dose and formulation of cannabis should I recommend to a patient as adjuvant therapy?

This is an excellent question and one that unfortunately we do not have the answer to. As mentioned previously, the studies have looked at varying formulations (THC alone, CBD:THC with varying percentages of THC, CBD alone) and varying routes of administration (sublingual, oral, inhalation). The IBD studies looking at CBD-alone formulations lacked clinical efficacy. In states where cannabis products have been accessible to IBD patients, no data on the product type (THC:CBD), method of administration, or prescriber preferences have been published.

4. What risks should I advise my patients about with cannabis use?

The challenge is that we don’t have large population-based studies in IBD looking at long-term risks of cannabis use. However, in the small RCT studies there were minimal reported side effects and no major adverse events over 8-10 weeks. Larger IBD population-based studies have shown that cannabis users were more likely to discontinue traditional medical therapy, and there is an increased risk for surgery in patients with Crohn’s disease. Larger studies in non-IBD patients have shown risk for addiction to other substances, diminished life achievement, increased motor vehicle accidents, chronic bronchitis, psychiatric disturbances and cannabis dependence, and cannabis hyperemesis syndrome (with an uncanny presentation resembling Crohn’s disease flare with partial small bowel obstruction). Patients should also be advised about legal implications of use (given its continued classification as a federal schedule 1 drug), possible drug interactions, and special considerations in pediatric patients (increased risk of addiction), elderly patients (increased risk of neuropsychological effects), and during pregnancy (with national obstetric society guidelines warning against use because of fetal exposure and increased risk of stillbirth).

5. What are the legal implications for providers? Patients?

As of July 2020, cannabis is available for recreational use in 12 states, for medicinal use in 28 states, and illegal in 11 states. So the answer really depends on what state the patient lives in. As a provider who might certify patients (in some medicinal states) or recommend cannabis to patients, you should consider legal and licensing implications. Again, this might vary state to state, and you should also take into account federal status. Providers acting in compliance with state laws are unlikely to have federal consequences. However, remember that malpractice insurance only covers FDA-approved medical therapies. Patients should be advised to consider the potential (although highly unlikely) to face federal prosecution and implications of use for employment, school, camp, or travel, and driving restrictions.

Take home points

• Inquire about cannabis to start the conversation.
• Know your state’s legalization status surrounding cannabis.
• Patients with IBD report improvement in symptoms and quality of life with adjuvant cannabis use; however, there is no change in disease activity.
• Encourage your patients to continue and optimize their maintenance therapy.
• Educate your patients about the legal considerations and known risks.

In conclusion, the use of cannabis in IBD patients has increased in recent years. It is important to be able to discuss the risks and benefits of use with your IBD patients. Focus on the lack of data showing that cannabis improves disease activity, and has shown benefit only in improving IBD-associated symptoms. In some patients there might be a role for adjuvant cannabis therapy to improve overall symptom control and quality of life.
 

Dr. Kinnucan is an assistant professor of medicine, division of gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor; Dr. Swaminath is an associate professor of medicine, division of gastroenterology, Lenox Hill Hospital, Northwell Health, New York.

Case 1

A 30 year-old female with longstanding ulcerative colitis who has a history of medically refractory steroid-dependent disease and was able to achieve remission with vedolizumab for the last 5 years. Most recent objective assessment showed histologic remission. She has been using daily cannabis medicinally for the last year (high CBD:THC [cannabidiol:delta-9-tetracannabidol] concentration). She notes that she has felt better in the last year since introducing cannabis (improved stool frequency/formation, sleep quality). She inquires about discontinuing her biologic therapy in the hope of using cannabis alone to maintain remission.

Figure 1.

Case 2

A 22-year-old male with ileocolonic inflammatory Crohn’s disease escalated to adalimumab requiring an intensification of therapy to weekly dosing to normalize C-reactive protein (CRP). A recent colonoscopy showed endoscopic improvement (colonic normalization and rare aphthae in ileum). He notes clear clinical improvement, but he continues to experience diarrhea and abdominal cramping (no relationship to meals). Declines addition of immunomodulator (nervous about returning to college during the COVID-19 pandemic). He wonders whether cannabis could be effective in controlling his symptoms as he has had improvement in symptoms during his sporadic recreational cannabis exposure.

Discussion

These cases outline the challenges that providers face when managing patients with inflammatory bowel disease (IBD) when a patient would like to either substitute or incorporate cannabis into their treatment plan. Studies have shown a high prevalence of cannabis use among patients with IBD. With the restrictions surrounding the use of cannabis – either medically or recreationally – being liberalized in many states, these conversations are likely to become more frequent in your practice. However, one of the first challenges that providers face surrounding cannabis is that many patients who use cannabis do not disclose use to their health care team for fear of being judged negatively. In addition, many providers do not routinely ask about cannabis use during office visits. This might be directly related to being unprepared to have a knowledge-based discussion on the risks and benefits of cannabis use in IBD, with the same confidence present during discussion of biologic therapies.

For background, Cannabis sativa (cannabis) is composed of hundreds of phytocannabinoids, the two most common are THC and CBD. These cannabinoids act at the endocannabinoid receptors, which are expressed in the central and peripheral nervous systems and immune cells/tissues, and help explain the clinical changes experienced by cannabis users. Both THC and CBD have been studied in varying doses and routes of administration in patients with IBD, making it challenging to translate into real-world recommendations for patients. Some of the most common reported benefits of cannabis use (particularly in an IBD population) are improvement in pain, diarrhea, nausea, and joint pain. Some studies have shown overall improvement in quality of life (Figure 1).

Some common questions that arise surrounding cannabis use in IBD patients include:

1. Is it possible to stop traditional medical therapy and replace it with cannabis therapy?

No studies have directly addressed this exact question. The small studies, both randomized controlled trials and retrospective ones, have studied the effects of cannabis as adjuvant therapy only. None of the data available to date suggest that cannabis has any anti-inflammatory properties with absence of improvement in biomarkers or endoscopic measures of inflammation. In effect, any attempt to discontinue standard therapy with substitution of cannabis-based therapy should be seen as no different than simply discontinuing standard therapy. There exists the argument that – among those with moderate to severe disease – cannabis might suppress the investigation of mild symptoms which may herald a flare of disease, thus lulling the patient into a state of false stability. We do not advocate the substitution of cannabis products in place of standard medical therapy.

2. Is there a role for cannabis as adjuvant therapy in patients with IBD?

Studies to date have included only symptomatic patients with objective evidence of inflammation and assessed clinical, biochemical, or endoscopic endpoints. In Crohn’s disease, two studies showed no improvement in clinical remission rates but showed improvement in clinical response; a third study showed both improvement in clinical remission/response as well as improved quality of life. No study showed a change in disease markers of activity including CRP, fecal calprotectin, or endoscopic scoring. In one study, all patients relapsed shortly after cannabis discontinuation suggesting that, while there was benefit in symptom control, there was no improvement of the underlying chronic inflammation.

In patients with ulcerative colitis, there were two studies. One study showed no improvement and high rates of intolerance in the treatment group, while the other study reported improved disease activity but no objective improvement. The variation in results between disease states and between studies might be because of cannabis formulations. In patients with persistent symptoms despite current medical therapy, there might be a role in those patients for adjuvant therapy for improvement symptom control but not disease control. Optimization of medical therapy would still be indicated.



3. What dose and formulation of cannabis should I recommend to a patient as adjuvant therapy?

This is an excellent question and one that unfortunately we do not have the answer to. As mentioned previously, the studies have looked at varying formulations (THC alone, CBD:THC with varying percentages of THC, CBD alone) and varying routes of administration (sublingual, oral, inhalation). The IBD studies looking at CBD-alone formulations lacked clinical efficacy. In states where cannabis products have been accessible to IBD patients, no data on the product type (THC:CBD), method of administration, or prescriber preferences have been published.

4. What risks should I advise my patients about with cannabis use?

The challenge is that we don’t have large population-based studies in IBD looking at long-term risks of cannabis use. However, in the small RCT studies there were minimal reported side effects and no major adverse events over 8-10 weeks. Larger IBD population-based studies have shown that cannabis users were more likely to discontinue traditional medical therapy, and there is an increased risk for surgery in patients with Crohn’s disease. Larger studies in non-IBD patients have shown risk for addiction to other substances, diminished life achievement, increased motor vehicle accidents, chronic bronchitis, psychiatric disturbances and cannabis dependence, and cannabis hyperemesis syndrome (with an uncanny presentation resembling Crohn’s disease flare with partial small bowel obstruction). Patients should also be advised about legal implications of use (given its continued classification as a federal schedule 1 drug), possible drug interactions, and special considerations in pediatric patients (increased risk of addiction), elderly patients (increased risk of neuropsychological effects), and during pregnancy (with national obstetric society guidelines warning against use because of fetal exposure and increased risk of stillbirth).

5. What are the legal implications for providers? Patients?

As of July 2020, cannabis is available for recreational use in 12 states, for medicinal use in 28 states, and illegal in 11 states. So the answer really depends on what state the patient lives in. As a provider who might certify patients (in some medicinal states) or recommend cannabis to patients, you should consider legal and licensing implications. Again, this might vary state to state, and you should also take into account federal status. Providers acting in compliance with state laws are unlikely to have federal consequences. However, remember that malpractice insurance only covers FDA-approved medical therapies. Patients should be advised to consider the potential (although highly unlikely) to face federal prosecution and implications of use for employment, school, camp, or travel, and driving restrictions.

Take home points

• Inquire about cannabis to start the conversation.
• Know your state’s legalization status surrounding cannabis.
• Patients with IBD report improvement in symptoms and quality of life with adjuvant cannabis use; however, there is no change in disease activity.
• Encourage your patients to continue and optimize their maintenance therapy.
• Educate your patients about the legal considerations and known risks.

In conclusion, the use of cannabis in IBD patients has increased in recent years. It is important to be able to discuss the risks and benefits of use with your IBD patients. Focus on the lack of data showing that cannabis improves disease activity, and has shown benefit only in improving IBD-associated symptoms. In some patients there might be a role for adjuvant cannabis therapy to improve overall symptom control and quality of life.
 

Dr. Kinnucan is an assistant professor of medicine, division of gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor; Dr. Swaminath is an associate professor of medicine, division of gastroenterology, Lenox Hill Hospital, Northwell Health, New York.

Women are more than twice as likely as men to use antidepressants, and use among White women is at least double that of other races/ethnicities, according to a new analysis from the National Center for Health Statistics.

Here are the actual numbers: 17.7% of women and 8.4% of men used an antidepressant in the 30 days before being interviewed for the National Health and Nutrition Examination Survey (NHANES). Put them together, and it works out to 13.2% of all adults over the 4-year period from 2015 to 2018, Debra J. Brody, MPH, and Qiuping Gu, MD, PhD, said Sept. 4 in an NCHS data brief.

The racial/ethnic differences in antidepressant use were even greater, at least for women. Non-Hispanic White women had a past-30-day prevalence of 22.3%, compared with 10.0% for non-Hispanic Black women, 3.4% for non-Hispanic Asian women, and 8.9% for Hispanic women, based on the NHANES data.

The order was the same for men, but the numbers are lower. Non-Hispanic Whites had the highest antidepressant use at 10.5%, followed by non-Hispanic Blacks (5.0%), non-Hispanic Asians (2.1%), and Hispanics (4.0%). All of the differences between Whites and non-Whites were significant for both women and men, the researchers noted.

A look at trends over time shows that the gap between men and women has widened in the last 10 years. Past-30-day use among women went from 13.8% in 2009-2010 to 18.6% in 2017-2018, with a corresponding increase from 7.1% to 8.7% in men. For women, that change was significant; for men, it was not, Ms. Brody and Dr. Gu said.

The sample size averaged just over 6,000 for each of the five 2-year NHANES cycles included in the analysis. The survey includes a household interview and a physical examination at a mobile exam center.

[email protected]

Women are more than twice as likely as men to use antidepressants, and use among White women is at least double that of other races/ethnicities, according to a new analysis from the National Center for Health Statistics.

Here are the actual numbers: 17.7% of women and 8.4% of men used an antidepressant in the 30 days before being interviewed for the National Health and Nutrition Examination Survey (NHANES). Put them together, and it works out to 13.2% of all adults over the 4-year period from 2015 to 2018, Debra J. Brody, MPH, and Qiuping Gu, MD, PhD, said Sept. 4 in an NCHS data brief.

The racial/ethnic differences in antidepressant use were even greater, at least for women. Non-Hispanic White women had a past-30-day prevalence of 22.3%, compared with 10.0% for non-Hispanic Black women, 3.4% for non-Hispanic Asian women, and 8.9% for Hispanic women, based on the NHANES data.

The order was the same for men, but the numbers are lower. Non-Hispanic Whites had the highest antidepressant use at 10.5%, followed by non-Hispanic Blacks (5.0%), non-Hispanic Asians (2.1%), and Hispanics (4.0%). All of the differences between Whites and non-Whites were significant for both women and men, the researchers noted.

A look at trends over time shows that the gap between men and women has widened in the last 10 years. Past-30-day use among women went from 13.8% in 2009-2010 to 18.6% in 2017-2018, with a corresponding increase from 7.1% to 8.7% in men. For women, that change was significant; for men, it was not, Ms. Brody and Dr. Gu said.

The sample size averaged just over 6,000 for each of the five 2-year NHANES cycles included in the analysis. The survey includes a household interview and a physical examination at a mobile exam center.

[email protected]

Women are more than twice as likely as men to use antidepressants, and use among White women is at least double that of other races/ethnicities, according to a new analysis from the National Center for Health Statistics.

Here are the actual numbers: 17.7% of women and 8.4% of men used an antidepressant in the 30 days before being interviewed for the National Health and Nutrition Examination Survey (NHANES). Put them together, and it works out to 13.2% of all adults over the 4-year period from 2015 to 2018, Debra J. Brody, MPH, and Qiuping Gu, MD, PhD, said Sept. 4 in an NCHS data brief.

The racial/ethnic differences in antidepressant use were even greater, at least for women. Non-Hispanic White women had a past-30-day prevalence of 22.3%, compared with 10.0% for non-Hispanic Black women, 3.4% for non-Hispanic Asian women, and 8.9% for Hispanic women, based on the NHANES data.

The order was the same for men, but the numbers are lower. Non-Hispanic Whites had the highest antidepressant use at 10.5%, followed by non-Hispanic Blacks (5.0%), non-Hispanic Asians (2.1%), and Hispanics (4.0%). All of the differences between Whites and non-Whites were significant for both women and men, the researchers noted.

A look at trends over time shows that the gap between men and women has widened in the last 10 years. Past-30-day use among women went from 13.8% in 2009-2010 to 18.6% in 2017-2018, with a corresponding increase from 7.1% to 8.7% in men. For women, that change was significant; for men, it was not, Ms. Brody and Dr. Gu said.

The sample size averaged just over 6,000 for each of the five 2-year NHANES cycles included in the analysis. The survey includes a household interview and a physical examination at a mobile exam center.

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A nurse-led intervention aimed at reducing hospital readmission rates for systemic lupus erythematosus (SLE) is feasible but the jury is out as to whether it can achieve its primary goal, a study has found.

Copyright Kimberly Pack/Thinkstock

A paper published in Arthritis Care & Research presents the outcomes of a retrospective study using electronic health records that looked at the effect of a quality improvement initiative at the University of Colorado Hospital on readmission rates in two cohorts of 48 and 56 individuals with SLE.

Emily Bowers, MD, of the department of rheumatology at the University of Colorado at Denver, Aurora, and coauthors wrote that hospital readmission rates for SLE are as high as 36% for 30-day readmission. They are significantly higher than for other common chronic diseases such as heart failure, COPD, and diabetes. Readmission for SLE is associated with young age, ethnic or racial diversity, public health insurance, multiorgan involvement, and other comorbidities.

The intervention involved first alerting clinic nurses via the patient’s electronic medical record when the patient was discharged from hospital. The nurses would then call the patient within 48 hours to answer any questions and review their discharge information, and then consult with a rheumatologist on on-call if needed. This call was documented in the patient’s medical record.

In the preintervention cohort, there were 59 hospitalizations among 48 patients, 29% of which were followed by readmission within 30 days; 53% of these readmissions were lupus related. In the cohort that followed introduction of the intervention, there were 73 hospitalizations among 56 individuals, and 19% were followed by readmission within 30 days, 29% of which were lupus related.

After accounting for gender, age, race, and insurance type, the researchers calculated that there was an 89% higher odds of readmission in the nonintervention group than in the intervention group, but the difference was not statistically significant.

The authors noted that although the results were not statistically significant, the low cost of the intervention – requiring around 30 minutes of nursing time – meant even small reductions in the number of emergency department or hospital admissions would make it a cost-effective approach.

“Telephone outreach is an excellent method of providing additional support to patients, assessing clinical needs, reinforcing education about SLE, medications, and common complications such as drug side effects and infections, and allows for patients to ask pertinent questions to RN providers with expertise in the management of lupus,” the authors wrote.

The nurses also recorded qualitative information about the calls, which picked up some patient issues that could be addressed. For example, a patient was discharged with the wrong amount of prednisone, which the nurse was able to fix by adjusting the order and sending it to the pharmacy. Two other patients were confused by their medication instructions and were taking the medication incorrectly; the nurse arranged for the patients to come in for educational session. In another case, the nurse was able to arrange an infusion for the patient, and for one patient with concerns about infection, the nurse was able to advise that person on symptoms and how to seek care.

“To increase implementation of the intervention, we have discussed creating a discharge order set, which would include an automatic EMR message to the nurses,” the authors wrote. “Future studies should explore alternative ways of communicating with our patients after discharge, such as the use of text messaging, messaging through the patient portal in the EMR, or telehealth.”

The authors had no financial disclosures, and there was no outside financial support for the study.

SOURCE: Bowers E et al. Arthritis Care Res. 2020 Aug 29. doi: 10.1002/acr.24435.

A nurse-led intervention aimed at reducing hospital readmission rates for systemic lupus erythematosus (SLE) is feasible but the jury is out as to whether it can achieve its primary goal, a study has found.

Copyright Kimberly Pack/Thinkstock

A paper published in Arthritis Care & Research presents the outcomes of a retrospective study using electronic health records that looked at the effect of a quality improvement initiative at the University of Colorado Hospital on readmission rates in two cohorts of 48 and 56 individuals with SLE.

Emily Bowers, MD, of the department of rheumatology at the University of Colorado at Denver, Aurora, and coauthors wrote that hospital readmission rates for SLE are as high as 36% for 30-day readmission. They are significantly higher than for other common chronic diseases such as heart failure, COPD, and diabetes. Readmission for SLE is associated with young age, ethnic or racial diversity, public health insurance, multiorgan involvement, and other comorbidities.

The intervention involved first alerting clinic nurses via the patient’s electronic medical record when the patient was discharged from hospital. The nurses would then call the patient within 48 hours to answer any questions and review their discharge information, and then consult with a rheumatologist on on-call if needed. This call was documented in the patient’s medical record.

In the preintervention cohort, there were 59 hospitalizations among 48 patients, 29% of which were followed by readmission within 30 days; 53% of these readmissions were lupus related. In the cohort that followed introduction of the intervention, there were 73 hospitalizations among 56 individuals, and 19% were followed by readmission within 30 days, 29% of which were lupus related.

After accounting for gender, age, race, and insurance type, the researchers calculated that there was an 89% higher odds of readmission in the nonintervention group than in the intervention group, but the difference was not statistically significant.

The authors noted that although the results were not statistically significant, the low cost of the intervention – requiring around 30 minutes of nursing time – meant even small reductions in the number of emergency department or hospital admissions would make it a cost-effective approach.

“Telephone outreach is an excellent method of providing additional support to patients, assessing clinical needs, reinforcing education about SLE, medications, and common complications such as drug side effects and infections, and allows for patients to ask pertinent questions to RN providers with expertise in the management of lupus,” the authors wrote.

The nurses also recorded qualitative information about the calls, which picked up some patient issues that could be addressed. For example, a patient was discharged with the wrong amount of prednisone, which the nurse was able to fix by adjusting the order and sending it to the pharmacy. Two other patients were confused by their medication instructions and were taking the medication incorrectly; the nurse arranged for the patients to come in for educational session. In another case, the nurse was able to arrange an infusion for the patient, and for one patient with concerns about infection, the nurse was able to advise that person on symptoms and how to seek care.

“To increase implementation of the intervention, we have discussed creating a discharge order set, which would include an automatic EMR message to the nurses,” the authors wrote. “Future studies should explore alternative ways of communicating with our patients after discharge, such as the use of text messaging, messaging through the patient portal in the EMR, or telehealth.”

The authors had no financial disclosures, and there was no outside financial support for the study.

SOURCE: Bowers E et al. Arthritis Care Res. 2020 Aug 29. doi: 10.1002/acr.24435.

A nurse-led intervention aimed at reducing hospital readmission rates for systemic lupus erythematosus (SLE) is feasible but the jury is out as to whether it can achieve its primary goal, a study has found.

Copyright Kimberly Pack/Thinkstock

A paper published in Arthritis Care & Research presents the outcomes of a retrospective study using electronic health records that looked at the effect of a quality improvement initiative at the University of Colorado Hospital on readmission rates in two cohorts of 48 and 56 individuals with SLE.

Emily Bowers, MD, of the department of rheumatology at the University of Colorado at Denver, Aurora, and coauthors wrote that hospital readmission rates for SLE are as high as 36% for 30-day readmission. They are significantly higher than for other common chronic diseases such as heart failure, COPD, and diabetes. Readmission for SLE is associated with young age, ethnic or racial diversity, public health insurance, multiorgan involvement, and other comorbidities.

The intervention involved first alerting clinic nurses via the patient’s electronic medical record when the patient was discharged from hospital. The nurses would then call the patient within 48 hours to answer any questions and review their discharge information, and then consult with a rheumatologist on on-call if needed. This call was documented in the patient’s medical record.

In the preintervention cohort, there were 59 hospitalizations among 48 patients, 29% of which were followed by readmission within 30 days; 53% of these readmissions were lupus related. In the cohort that followed introduction of the intervention, there were 73 hospitalizations among 56 individuals, and 19% were followed by readmission within 30 days, 29% of which were lupus related.

After accounting for gender, age, race, and insurance type, the researchers calculated that there was an 89% higher odds of readmission in the nonintervention group than in the intervention group, but the difference was not statistically significant.

The authors noted that although the results were not statistically significant, the low cost of the intervention – requiring around 30 minutes of nursing time – meant even small reductions in the number of emergency department or hospital admissions would make it a cost-effective approach.

“Telephone outreach is an excellent method of providing additional support to patients, assessing clinical needs, reinforcing education about SLE, medications, and common complications such as drug side effects and infections, and allows for patients to ask pertinent questions to RN providers with expertise in the management of lupus,” the authors wrote.

The nurses also recorded qualitative information about the calls, which picked up some patient issues that could be addressed. For example, a patient was discharged with the wrong amount of prednisone, which the nurse was able to fix by adjusting the order and sending it to the pharmacy. Two other patients were confused by their medication instructions and were taking the medication incorrectly; the nurse arranged for the patients to come in for educational session. In another case, the nurse was able to arrange an infusion for the patient, and for one patient with concerns about infection, the nurse was able to advise that person on symptoms and how to seek care.

“To increase implementation of the intervention, we have discussed creating a discharge order set, which would include an automatic EMR message to the nurses,” the authors wrote. “Future studies should explore alternative ways of communicating with our patients after discharge, such as the use of text messaging, messaging through the patient portal in the EMR, or telehealth.”

The authors had no financial disclosures, and there was no outside financial support for the study.

SOURCE: Bowers E et al. Arthritis Care Res. 2020 Aug 29. doi: 10.1002/acr.24435.

Key clinical point: Higher Expanded Disability Status Scale (EDSS) score is associated with an unfavorable urologic course in patients with multiple sclerosis (MS), and increased postvoid residual volume (PVR) correlates with male gender, EDSS, and disease course.

Major finding: The presence of lower urinary tract symptoms (LUTS) was more frequently associated with a primary progressive disease course (P = .040), a higher level of disability (mean EDSS of 6.4, P = .011), and urinary tract infection (P = .002). PVR values were higher in patients with LUTS vs. those without (P = .011). Increased PVR correlated with male gender (P less than .001), EDSS score (P = .005), and disease course (P = .041). Higher PVR correlated with incontinence (P = .007), chronic urinary retention (P less than .001), incomplete emptying (P = .015), and diminished stream intensity (P = .040).

Study details: The findings are based on a study of 501 patients with clinically definite MS (68.9% females; mean age: 56.0 ± 12.3 years).

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Citation: Monti Bragadin M et al. Mult Scler Relat Disord. 2020 Jul 5. doi: 10.1016/j.msard.2020.102378.

Key clinical point: Higher Expanded Disability Status Scale (EDSS) score is associated with an unfavorable urologic course in patients with multiple sclerosis (MS), and increased postvoid residual volume (PVR) correlates with male gender, EDSS, and disease course.

Major finding: The presence of lower urinary tract symptoms (LUTS) was more frequently associated with a primary progressive disease course (P = .040), a higher level of disability (mean EDSS of 6.4, P = .011), and urinary tract infection (P = .002). PVR values were higher in patients with LUTS vs. those without (P = .011). Increased PVR correlated with male gender (P less than .001), EDSS score (P = .005), and disease course (P = .041). Higher PVR correlated with incontinence (P = .007), chronic urinary retention (P less than .001), incomplete emptying (P = .015), and diminished stream intensity (P = .040).

Study details: The findings are based on a study of 501 patients with clinically definite MS (68.9% females; mean age: 56.0 ± 12.3 years).

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Citation: Monti Bragadin M et al. Mult Scler Relat Disord. 2020 Jul 5. doi: 10.1016/j.msard.2020.102378.

Key clinical point: Higher Expanded Disability Status Scale (EDSS) score is associated with an unfavorable urologic course in patients with multiple sclerosis (MS), and increased postvoid residual volume (PVR) correlates with male gender, EDSS, and disease course.

Major finding: The presence of lower urinary tract symptoms (LUTS) was more frequently associated with a primary progressive disease course (P = .040), a higher level of disability (mean EDSS of 6.4, P = .011), and urinary tract infection (P = .002). PVR values were higher in patients with LUTS vs. those without (P = .011). Increased PVR correlated with male gender (P less than .001), EDSS score (P = .005), and disease course (P = .041). Higher PVR correlated with incontinence (P = .007), chronic urinary retention (P less than .001), incomplete emptying (P = .015), and diminished stream intensity (P = .040).

Study details: The findings are based on a study of 501 patients with clinically definite MS (68.9% females; mean age: 56.0 ± 12.3 years).

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Citation: Monti Bragadin M et al. Mult Scler Relat Disord. 2020 Jul 5. doi: 10.1016/j.msard.2020.102378.

Key clinical point: In patients with relapsing-remitting multiple sclerosis (RRMS), initiating high-efficacy disease-modifying therapies (heDMT) lowers the risk of Expanded Disability Status Scale (EDSS) score worsening and relapses compared to initiating medium-efficacy DMT (meDMT).

Major finding: The absolute probabilities of a 6-month confirmed EDSS score worsening at 2- and 4-year follow-ups were 11.5% and 16.7% for heDMT initiators and 18.3% and 30.1% for meDMT initiators, respectively (hazard ratio [HR], 0.53; P = .006). The heDMT initiators had a lower probability of a first relapse than meDMT initiators (HR, 0.50; 95% confidence interval, 0.37-0.67).

Study details: In this Danish population-based study, 194 patients with RRMS starting initial therapy with heDMT were matched to 194 patients starting meDMT.

Disclosures: There was no targeted funding. The presenting author reported receiving support for congress participation from Roche.

Citation: Buron MD et al. Neurology. 2020 Jul 7. doi: 10.1212/WNL.0000000000010135.

Key clinical point: In patients with relapsing-remitting multiple sclerosis (RRMS), initiating high-efficacy disease-modifying therapies (heDMT) lowers the risk of Expanded Disability Status Scale (EDSS) score worsening and relapses compared to initiating medium-efficacy DMT (meDMT).

Major finding: The absolute probabilities of a 6-month confirmed EDSS score worsening at 2- and 4-year follow-ups were 11.5% and 16.7% for heDMT initiators and 18.3% and 30.1% for meDMT initiators, respectively (hazard ratio [HR], 0.53; P = .006). The heDMT initiators had a lower probability of a first relapse than meDMT initiators (HR, 0.50; 95% confidence interval, 0.37-0.67).

Study details: In this Danish population-based study, 194 patients with RRMS starting initial therapy with heDMT were matched to 194 patients starting meDMT.

Disclosures: There was no targeted funding. The presenting author reported receiving support for congress participation from Roche.

Citation: Buron MD et al. Neurology. 2020 Jul 7. doi: 10.1212/WNL.0000000000010135.

Key clinical point: In patients with relapsing-remitting multiple sclerosis (RRMS), initiating high-efficacy disease-modifying therapies (heDMT) lowers the risk of Expanded Disability Status Scale (EDSS) score worsening and relapses compared to initiating medium-efficacy DMT (meDMT).

Major finding: The absolute probabilities of a 6-month confirmed EDSS score worsening at 2- and 4-year follow-ups were 11.5% and 16.7% for heDMT initiators and 18.3% and 30.1% for meDMT initiators, respectively (hazard ratio [HR], 0.53; P = .006). The heDMT initiators had a lower probability of a first relapse than meDMT initiators (HR, 0.50; 95% confidence interval, 0.37-0.67).

Study details: In this Danish population-based study, 194 patients with RRMS starting initial therapy with heDMT were matched to 194 patients starting meDMT.

Disclosures: There was no targeted funding. The presenting author reported receiving support for congress participation from Roche.

Citation: Buron MD et al. Neurology. 2020 Jul 7. doi: 10.1212/WNL.0000000000010135.

Key clinical point: Switching to personalized extended interval dosing of natalizumab did not result in recurrence of disease activity in stable patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: 84% of study patients extended the dosing interval from the standard 4 weeks to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI], 0-7.4%) during follow-up. No patient developed new/enlarging T2 lesions or relapses during the 1-year follow-up and 1-year extension phase.

Study details: The findings are based on a prospective, multicenter, single-arm trial of 61 patients with RRMS.

Disclosures: The study was funded by the Brain Foundation Netherlands. The presenting author had no disclosures. Some of the coauthors reported ties with pharmaceutical companies.

Citation: van Kempen ZLE et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000009995.

Key clinical point: Switching to personalized extended interval dosing of natalizumab did not result in recurrence of disease activity in stable patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: 84% of study patients extended the dosing interval from the standard 4 weeks to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI], 0-7.4%) during follow-up. No patient developed new/enlarging T2 lesions or relapses during the 1-year follow-up and 1-year extension phase.

Study details: The findings are based on a prospective, multicenter, single-arm trial of 61 patients with RRMS.

Disclosures: The study was funded by the Brain Foundation Netherlands. The presenting author had no disclosures. Some of the coauthors reported ties with pharmaceutical companies.

Citation: van Kempen ZLE et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000009995.

Key clinical point: Switching to personalized extended interval dosing of natalizumab did not result in recurrence of disease activity in stable patients with relapsing-remitting multiple sclerosis (RRMS).

Major finding: 84% of study patients extended the dosing interval from the standard 4 weeks to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI], 0-7.4%) during follow-up. No patient developed new/enlarging T2 lesions or relapses during the 1-year follow-up and 1-year extension phase.

Study details: The findings are based on a prospective, multicenter, single-arm trial of 61 patients with RRMS.

Disclosures: The study was funded by the Brain Foundation Netherlands. The presenting author had no disclosures. Some of the coauthors reported ties with pharmaceutical companies.

Citation: van Kempen ZLE et al. Neurology. 2020 Jul 20. doi: 10.1212/WNL.0000000000009995.

Key clinical point: Disease-modifying therapies (DMTs) are associated with improvements in disability outcomes in patients with active relapses during secondary progressive multiple sclerosis (SPMS).

Major finding: Patients who experienced superimposed relapses during SPMS and received DMTs had a greater proportion of time with a reduced Multiple Sclerosis Severity Score (MSSS) progression slope during SPMS (per 25% increase in proportion of time receiving treatment, β = −0.025; P less than .001 for low-efficacy; β = −0.022; P = .06 for medium-efficacy; and β = −0.034; P = .002 for high-efficacy therapies).

Study details: An observational cohort study of 1,621 patients with active SPMS from the international MSBase registry.

Disclosures: The study was supported by grants from the National Health and Medical Research Council. The MSBase Foundation receives funding from Bayer, bioCSL, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. The presenting author reported receiving travel compensation from Merck outside the submitted work.

Citation: Lizak N et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2453.

Key clinical point: Disease-modifying therapies (DMTs) are associated with improvements in disability outcomes in patients with active relapses during secondary progressive multiple sclerosis (SPMS).

Major finding: Patients who experienced superimposed relapses during SPMS and received DMTs had a greater proportion of time with a reduced Multiple Sclerosis Severity Score (MSSS) progression slope during SPMS (per 25% increase in proportion of time receiving treatment, β = −0.025; P less than .001 for low-efficacy; β = −0.022; P = .06 for medium-efficacy; and β = −0.034; P = .002 for high-efficacy therapies).

Study details: An observational cohort study of 1,621 patients with active SPMS from the international MSBase registry.

Disclosures: The study was supported by grants from the National Health and Medical Research Council. The MSBase Foundation receives funding from Bayer, bioCSL, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. The presenting author reported receiving travel compensation from Merck outside the submitted work.

Citation: Lizak N et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2453.

Key clinical point: Disease-modifying therapies (DMTs) are associated with improvements in disability outcomes in patients with active relapses during secondary progressive multiple sclerosis (SPMS).

Major finding: Patients who experienced superimposed relapses during SPMS and received DMTs had a greater proportion of time with a reduced Multiple Sclerosis Severity Score (MSSS) progression slope during SPMS (per 25% increase in proportion of time receiving treatment, β = −0.025; P less than .001 for low-efficacy; β = −0.022; P = .06 for medium-efficacy; and β = −0.034; P = .002 for high-efficacy therapies).

Study details: An observational cohort study of 1,621 patients with active SPMS from the international MSBase registry.

Disclosures: The study was supported by grants from the National Health and Medical Research Council. The MSBase Foundation receives funding from Bayer, bioCSL, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. The presenting author reported receiving travel compensation from Merck outside the submitted work.

Citation: Lizak N et al. JAMA Neurol. 2020 Jul 27. doi: 10.1001/jamaneurol.2020.2453.

About 22% of children with COVID-19 infections were asymptomatic, and 66% of the symptomatic children had unrecognized symptoms at the time of diagnosis, based on data from a case series of 91 confirmed cases.

South_agency/Getty Images

Although recent reports suggest that COVID-19 infections in children are generally mild, data on the full spectrum of illness and duration of viral RNA in children are limited, wrote Mi Seon Han, MD, PhD, of Seoul (South Korea) Metropolitan Government–Seoul National University Boramae Medical Center, and colleagues.

To examine the full clinical course and duration of COVID-19 RNA detectability in children with confirmed infections, the researchers reviewed data from 91 individuals with confirmed infections. The children ranged in age from 27 days to 18 years, and 58% were male. The children were monitored at 20 hospitals and 2 isolation facilities for a mean 21.9 days. The findings were published in JAMA Pediatrics.

Overall, COVID-19 viral RNA was present in the study population for a mean 17.6 days, with testing done at a median interval of 3 days. A total of 20 children (22%) were asymptomatic throughout the study period. In these children, viral RNA was detected for a mean 14 days.

“The major hurdle implicated in this study in diagnosing and treating children with COVID-19 is that a considerable number of children are asymptomatic, and even if symptoms are present, they are unrecognized and overlooked before COVID-19 is diagnosed,” the researchers noted.

Of the 71 symptomatic children, 47 (66%) had unrecognized symptoms prior to diagnosis, 18 (25%) developed symptoms after diagnosis, and 6 (9%) were diagnosed at the time of symptom onset. The symptomatic children were symptomatic for a median of 11 days; 43 (61%) remained symptomatic at 7 days’ follow-up after the study period, 27 (38%) were symptomatic at 14 days, and 7 (10%) were symptomatic at 21 days.

A total of 41 children had upper respiratory infections (58%) and 22 children (24%) had lower respiratory tract infections. No difference in the duration of virus RNA was detected between children with upper respiratory tract infections and lower respiratory tract infections (average, 18.7 days vs. 19.9 days).

Among the symptomatic children, 46 (65%) had mild cases and 20 (28%) had moderate cases.

For treatment, 14 children (15%) received lopinavir-ritonavir and/or hydroxychloroquine. Two patients had severe illness and received oxygen via nasal prong, without the need for mechanical ventilation. All the children in the case series recovered from their infections with no fatalities.

The study’s main limitation was the inability to analyze the transmission potential of the children because of the quarantine and isolation policies in Korea, the researchers noted. In addition, the researchers did not perform follow-up testing at consistent intervals, so the duration of COVID-19 RNA detection may be inexact.

However, the results suggest “that suspecting and diagnosing COVID-19 in children based on their symptoms without epidemiologic information and virus testing is very challenging,” the researchers emphasized.

“Most of the children with COVID-19 have silent disease, but SARS-CoV-2 RNA can still be detected in the respiratory tract for a prolonged period,” they wrote. More research is needed to explore the potential for disease transmission by children in the community, and increased surveillance with laboratory screening can help identify children with unrecognized infections.

The study is the first known to focus on the frequency of asymptomatic infection in children and the duration of symptoms in both asymptomatic and symptomatic children, Roberta L. DeBiasi, MD, and Meghan Delaney, DO, both affiliated with Children’s National Hospital and Research Institute, Washington, and George Washington University, Washington, wrote in an accompanying editorial. The structure of the Korean public health system “allowed for the sequential observation, testing (median testing interval of every 3 days), and comparison of 91 asymptomatic, presymptomatic, and symptomatic children with mild to moderate upper and lower respiratory tract infection, identified primarily by contact tracing from laboratory-proven cases.”

Two take-home points from the study are that not all infected children are symptomatic, and the duration of symptoms in those who are varies widely, they noted. “Interestingly, this study aligns with adult data in which up to 40% of adults may remain asymptomatic in the face of infection.”

However, “The third and most important take-home point from this study relates to the duration of viral shedding in infected pediatric patients,” Dr. DeBiasi and Dr. Delaney said (JAMA Pediatr. 2020 Aug 28. doi: 10.1001/jamapediatrics.2020.3996).

“Fully half of symptomatic children with both upper and lower tract disease were still shedding virus at 21 days. These are striking data, particularly since 86 of 88 diagnosed children (98%) either had no symptoms or mild or moderate disease,” they explained. The results highlight the need for improvements in qualitative molecular testing and formal studies to identify differences in results from different testing scenarios, such as hospital entry, preprocedure screening, and symptomatic testing. In addition, “these findings are highly relevant to the development of public health strategies to mitigate and contain spread within communities, particularly as affected communities begin their recovery phases.”

The study is important because “schools are opening, and we don’t know what is going to happen,” Michael E. Pichichero, MD, of Rochester General Hospital, N.Y., said in an interview.

“Clinicians, parents, students, school administrators and politicians are worried,” he said. “This study adds to others recently published, bringing into focus the challenges to several suppositions that existed when the COVID-19 pandemic began and over the summer.”

“This study of 91 Korean children tells us that taking a child’s temperature as a screening tool to decide if they may enter school will not be a highly successful strategy,” he said. “Many children are without fever and asymptomatic when infected and contagious. The notion that children shed less virus or shed it for shorter lengths of time we keep learning from this type of research is not true. In another recent study the authors found that children shed as much of the SARS-CoV-2 virus as an adult in the ICU on a ventilator.”

Dr. Pichichero said he was not surprised by the study findings. “A similar paper was published last week in the Journal of Pediatrics from Massachusetts General Hospital, so the findings in the JAMA paper are similar to what has been reported in the United States.”

“Availability of testing will continue to be a challenge in some communities,” said Dr. Pichichero. “Here in the Rochester, New York, area we will use a screening questionnaire based on the CDC [Centers for Disease Control and Prevention] symptom criteria of SARS-CoV-2 infections to decide whom to test.”

As for additional research, “We have so much more to learn about SARS-CoV-2 in children,” he emphasized. “The focus has been on adults because the morbidity and mortality has been greatest in adults, especially the elderly and those with compromised health.”

“The National Institutes of Health has issued a call for more research in children to characterize the spectrum of SARS-CoV-2 illness, including the multisystem inflammatory syndrome in children [MIS-C] and try to identify biomarkers and/or biosignatures for a prognostic algorithm to predict the longitudinal risk of disease severity after a child is exposed to and may be infected with SARS-CoV-2,” said Dr. Pichichero. “NIH has asked researchers to answer the following questions.”

• Why do children have milder illness?
• Are there differences in childhood biology (e.g., gender, puberty, etc.) that contribute to illness severity?
• Are there genetic host differences associated with different disease severity phenotypes, including MIS-C?
• Are there innate mucosal, humoral, cellular and other adaptive immune profiles that are associated with reduced or increased risk of progressive disease, including previous coronavirus infections?
• Will SARS-CoV-2 reinfection cause worse disease as seen with antibody-dependent enhancement (ADE) in other viral infections (e.g., dengue)? Will future vaccines carry a risk of the ADE phenomenon?
• Does substance use (e.g., nicotine, marijuana) exacerbate or trigger MIS-C through immune activation?

“We have no knowledge yet about SARS-CoV-2 vaccination of children, especially young children,” Dr. Pichichero emphasized. “There are different types of vaccines – messenger RNA, adenovirus vector and purified spike proteins of the virus – among others, but questions remain: Will the vaccines work in children? What about side effects? Will the antibodies and cellular immunity protect partially or completely?”

The researchers and editorialists had no financial conflicts to disclose. Dr. Pichichero had no financial conflicts to disclose.

SOURCE: Han MS et al. JAMA Pediatr. 2020 Aug 28. doi:10.1001/jamapediatrics.2020.3988.

About 22% of children with COVID-19 infections were asymptomatic, and 66% of the symptomatic children had unrecognized symptoms at the time of diagnosis, based on data from a case series of 91 confirmed cases.

South_agency/Getty Images

Although recent reports suggest that COVID-19 infections in children are generally mild, data on the full spectrum of illness and duration of viral RNA in children are limited, wrote Mi Seon Han, MD, PhD, of Seoul (South Korea) Metropolitan Government–Seoul National University Boramae Medical Center, and colleagues.

To examine the full clinical course and duration of COVID-19 RNA detectability in children with confirmed infections, the researchers reviewed data from 91 individuals with confirmed infections. The children ranged in age from 27 days to 18 years, and 58% were male. The children were monitored at 20 hospitals and 2 isolation facilities for a mean 21.9 days. The findings were published in JAMA Pediatrics.

Overall, COVID-19 viral RNA was present in the study population for a mean 17.6 days, with testing done at a median interval of 3 days. A total of 20 children (22%) were asymptomatic throughout the study period. In these children, viral RNA was detected for a mean 14 days.

“The major hurdle implicated in this study in diagnosing and treating children with COVID-19 is that a considerable number of children are asymptomatic, and even if symptoms are present, they are unrecognized and overlooked before COVID-19 is diagnosed,” the researchers noted.

Of the 71 symptomatic children, 47 (66%) had unrecognized symptoms prior to diagnosis, 18 (25%) developed symptoms after diagnosis, and 6 (9%) were diagnosed at the time of symptom onset. The symptomatic children were symptomatic for a median of 11 days; 43 (61%) remained symptomatic at 7 days’ follow-up after the study period, 27 (38%) were symptomatic at 14 days, and 7 (10%) were symptomatic at 21 days.

A total of 41 children had upper respiratory infections (58%) and 22 children (24%) had lower respiratory tract infections. No difference in the duration of virus RNA was detected between children with upper respiratory tract infections and lower respiratory tract infections (average, 18.7 days vs. 19.9 days).

Among the symptomatic children, 46 (65%) had mild cases and 20 (28%) had moderate cases.

For treatment, 14 children (15%) received lopinavir-ritonavir and/or hydroxychloroquine. Two patients had severe illness and received oxygen via nasal prong, without the need for mechanical ventilation. All the children in the case series recovered from their infections with no fatalities.

The study’s main limitation was the inability to analyze the transmission potential of the children because of the quarantine and isolation policies in Korea, the researchers noted. In addition, the researchers did not perform follow-up testing at consistent intervals, so the duration of COVID-19 RNA detection may be inexact.

However, the results suggest “that suspecting and diagnosing COVID-19 in children based on their symptoms without epidemiologic information and virus testing is very challenging,” the researchers emphasized.

“Most of the children with COVID-19 have silent disease, but SARS-CoV-2 RNA can still be detected in the respiratory tract for a prolonged period,” they wrote. More research is needed to explore the potential for disease transmission by children in the community, and increased surveillance with laboratory screening can help identify children with unrecognized infections.

The study is the first known to focus on the frequency of asymptomatic infection in children and the duration of symptoms in both asymptomatic and symptomatic children, Roberta L. DeBiasi, MD, and Meghan Delaney, DO, both affiliated with Children’s National Hospital and Research Institute, Washington, and George Washington University, Washington, wrote in an accompanying editorial. The structure of the Korean public health system “allowed for the sequential observation, testing (median testing interval of every 3 days), and comparison of 91 asymptomatic, presymptomatic, and symptomatic children with mild to moderate upper and lower respiratory tract infection, identified primarily by contact tracing from laboratory-proven cases.”

Two take-home points from the study are that not all infected children are symptomatic, and the duration of symptoms in those who are varies widely, they noted. “Interestingly, this study aligns with adult data in which up to 40% of adults may remain asymptomatic in the face of infection.”

However, “The third and most important take-home point from this study relates to the duration of viral shedding in infected pediatric patients,” Dr. DeBiasi and Dr. Delaney said (JAMA Pediatr. 2020 Aug 28. doi: 10.1001/jamapediatrics.2020.3996).

“Fully half of symptomatic children with both upper and lower tract disease were still shedding virus at 21 days. These are striking data, particularly since 86 of 88 diagnosed children (98%) either had no symptoms or mild or moderate disease,” they explained. The results highlight the need for improvements in qualitative molecular testing and formal studies to identify differences in results from different testing scenarios, such as hospital entry, preprocedure screening, and symptomatic testing. In addition, “these findings are highly relevant to the development of public health strategies to mitigate and contain spread within communities, particularly as affected communities begin their recovery phases.”

The study is important because “schools are opening, and we don’t know what is going to happen,” Michael E. Pichichero, MD, of Rochester General Hospital, N.Y., said in an interview.

“Clinicians, parents, students, school administrators and politicians are worried,” he said. “This study adds to others recently published, bringing into focus the challenges to several suppositions that existed when the COVID-19 pandemic began and over the summer.”

“This study of 91 Korean children tells us that taking a child’s temperature as a screening tool to decide if they may enter school will not be a highly successful strategy,” he said. “Many children are without fever and asymptomatic when infected and contagious. The notion that children shed less virus or shed it for shorter lengths of time we keep learning from this type of research is not true. In another recent study the authors found that children shed as much of the SARS-CoV-2 virus as an adult in the ICU on a ventilator.”

Dr. Pichichero said he was not surprised by the study findings. “A similar paper was published last week in the Journal of Pediatrics from Massachusetts General Hospital, so the findings in the JAMA paper are similar to what has been reported in the United States.”

“Availability of testing will continue to be a challenge in some communities,” said Dr. Pichichero. “Here in the Rochester, New York, area we will use a screening questionnaire based on the CDC [Centers for Disease Control and Prevention] symptom criteria of SARS-CoV-2 infections to decide whom to test.”

As for additional research, “We have so much more to learn about SARS-CoV-2 in children,” he emphasized. “The focus has been on adults because the morbidity and mortality has been greatest in adults, especially the elderly and those with compromised health.”

“The National Institutes of Health has issued a call for more research in children to characterize the spectrum of SARS-CoV-2 illness, including the multisystem inflammatory syndrome in children [MIS-C] and try to identify biomarkers and/or biosignatures for a prognostic algorithm to predict the longitudinal risk of disease severity after a child is exposed to and may be infected with SARS-CoV-2,” said Dr. Pichichero. “NIH has asked researchers to answer the following questions.”

• Why do children have milder illness?
• Are there differences in childhood biology (e.g., gender, puberty, etc.) that contribute to illness severity?
• Are there genetic host differences associated with different disease severity phenotypes, including MIS-C?
• Are there innate mucosal, humoral, cellular and other adaptive immune profiles that are associated with reduced or increased risk of progressive disease, including previous coronavirus infections?
• Will SARS-CoV-2 reinfection cause worse disease as seen with antibody-dependent enhancement (ADE) in other viral infections (e.g., dengue)? Will future vaccines carry a risk of the ADE phenomenon?
• Does substance use (e.g., nicotine, marijuana) exacerbate or trigger MIS-C through immune activation?

“We have no knowledge yet about SARS-CoV-2 vaccination of children, especially young children,” Dr. Pichichero emphasized. “There are different types of vaccines – messenger RNA, adenovirus vector and purified spike proteins of the virus – among others, but questions remain: Will the vaccines work in children? What about side effects? Will the antibodies and cellular immunity protect partially or completely?”

The researchers and editorialists had no financial conflicts to disclose. Dr. Pichichero had no financial conflicts to disclose.

SOURCE: Han MS et al. JAMA Pediatr. 2020 Aug 28. doi:10.1001/jamapediatrics.2020.3988.

About 22% of children with COVID-19 infections were asymptomatic, and 66% of the symptomatic children had unrecognized symptoms at the time of diagnosis, based on data from a case series of 91 confirmed cases.

South_agency/Getty Images

Although recent reports suggest that COVID-19 infections in children are generally mild, data on the full spectrum of illness and duration of viral RNA in children are limited, wrote Mi Seon Han, MD, PhD, of Seoul (South Korea) Metropolitan Government–Seoul National University Boramae Medical Center, and colleagues.

To examine the full clinical course and duration of COVID-19 RNA detectability in children with confirmed infections, the researchers reviewed data from 91 individuals with confirmed infections. The children ranged in age from 27 days to 18 years, and 58% were male. The children were monitored at 20 hospitals and 2 isolation facilities for a mean 21.9 days. The findings were published in JAMA Pediatrics.

Overall, COVID-19 viral RNA was present in the study population for a mean 17.6 days, with testing done at a median interval of 3 days. A total of 20 children (22%) were asymptomatic throughout the study period. In these children, viral RNA was detected for a mean 14 days.

“The major hurdle implicated in this study in diagnosing and treating children with COVID-19 is that a considerable number of children are asymptomatic, and even if symptoms are present, they are unrecognized and overlooked before COVID-19 is diagnosed,” the researchers noted.

Of the 71 symptomatic children, 47 (66%) had unrecognized symptoms prior to diagnosis, 18 (25%) developed symptoms after diagnosis, and 6 (9%) were diagnosed at the time of symptom onset. The symptomatic children were symptomatic for a median of 11 days; 43 (61%) remained symptomatic at 7 days’ follow-up after the study period, 27 (38%) were symptomatic at 14 days, and 7 (10%) were symptomatic at 21 days.

A total of 41 children had upper respiratory infections (58%) and 22 children (24%) had lower respiratory tract infections. No difference in the duration of virus RNA was detected between children with upper respiratory tract infections and lower respiratory tract infections (average, 18.7 days vs. 19.9 days).

Among the symptomatic children, 46 (65%) had mild cases and 20 (28%) had moderate cases.

For treatment, 14 children (15%) received lopinavir-ritonavir and/or hydroxychloroquine. Two patients had severe illness and received oxygen via nasal prong, without the need for mechanical ventilation. All the children in the case series recovered from their infections with no fatalities.

The study’s main limitation was the inability to analyze the transmission potential of the children because of the quarantine and isolation policies in Korea, the researchers noted. In addition, the researchers did not perform follow-up testing at consistent intervals, so the duration of COVID-19 RNA detection may be inexact.

However, the results suggest “that suspecting and diagnosing COVID-19 in children based on their symptoms without epidemiologic information and virus testing is very challenging,” the researchers emphasized.

“Most of the children with COVID-19 have silent disease, but SARS-CoV-2 RNA can still be detected in the respiratory tract for a prolonged period,” they wrote. More research is needed to explore the potential for disease transmission by children in the community, and increased surveillance with laboratory screening can help identify children with unrecognized infections.

The study is the first known to focus on the frequency of asymptomatic infection in children and the duration of symptoms in both asymptomatic and symptomatic children, Roberta L. DeBiasi, MD, and Meghan Delaney, DO, both affiliated with Children’s National Hospital and Research Institute, Washington, and George Washington University, Washington, wrote in an accompanying editorial. The structure of the Korean public health system “allowed for the sequential observation, testing (median testing interval of every 3 days), and comparison of 91 asymptomatic, presymptomatic, and symptomatic children with mild to moderate upper and lower respiratory tract infection, identified primarily by contact tracing from laboratory-proven cases.”

Two take-home points from the study are that not all infected children are symptomatic, and the duration of symptoms in those who are varies widely, they noted. “Interestingly, this study aligns with adult data in which up to 40% of adults may remain asymptomatic in the face of infection.”

However, “The third and most important take-home point from this study relates to the duration of viral shedding in infected pediatric patients,” Dr. DeBiasi and Dr. Delaney said (JAMA Pediatr. 2020 Aug 28. doi: 10.1001/jamapediatrics.2020.3996).

“Fully half of symptomatic children with both upper and lower tract disease were still shedding virus at 21 days. These are striking data, particularly since 86 of 88 diagnosed children (98%) either had no symptoms or mild or moderate disease,” they explained. The results highlight the need for improvements in qualitative molecular testing and formal studies to identify differences in results from different testing scenarios, such as hospital entry, preprocedure screening, and symptomatic testing. In addition, “these findings are highly relevant to the development of public health strategies to mitigate and contain spread within communities, particularly as affected communities begin their recovery phases.”

The study is important because “schools are opening, and we don’t know what is going to happen,” Michael E. Pichichero, MD, of Rochester General Hospital, N.Y., said in an interview.

“Clinicians, parents, students, school administrators and politicians are worried,” he said. “This study adds to others recently published, bringing into focus the challenges to several suppositions that existed when the COVID-19 pandemic began and over the summer.”

“This study of 91 Korean children tells us that taking a child’s temperature as a screening tool to decide if they may enter school will not be a highly successful strategy,” he said. “Many children are without fever and asymptomatic when infected and contagious. The notion that children shed less virus or shed it for shorter lengths of time we keep learning from this type of research is not true. In another recent study the authors found that children shed as much of the SARS-CoV-2 virus as an adult in the ICU on a ventilator.”

Dr. Pichichero said he was not surprised by the study findings. “A similar paper was published last week in the Journal of Pediatrics from Massachusetts General Hospital, so the findings in the JAMA paper are similar to what has been reported in the United States.”

“Availability of testing will continue to be a challenge in some communities,” said Dr. Pichichero. “Here in the Rochester, New York, area we will use a screening questionnaire based on the CDC [Centers for Disease Control and Prevention] symptom criteria of SARS-CoV-2 infections to decide whom to test.”

As for additional research, “We have so much more to learn about SARS-CoV-2 in children,” he emphasized. “The focus has been on adults because the morbidity and mortality has been greatest in adults, especially the elderly and those with compromised health.”

“The National Institutes of Health has issued a call for more research in children to characterize the spectrum of SARS-CoV-2 illness, including the multisystem inflammatory syndrome in children [MIS-C] and try to identify biomarkers and/or biosignatures for a prognostic algorithm to predict the longitudinal risk of disease severity after a child is exposed to and may be infected with SARS-CoV-2,” said Dr. Pichichero. “NIH has asked researchers to answer the following questions.”

• Why do children have milder illness?
• Are there differences in childhood biology (e.g., gender, puberty, etc.) that contribute to illness severity?
• Are there genetic host differences associated with different disease severity phenotypes, including MIS-C?
• Are there innate mucosal, humoral, cellular and other adaptive immune profiles that are associated with reduced or increased risk of progressive disease, including previous coronavirus infections?
• Will SARS-CoV-2 reinfection cause worse disease as seen with antibody-dependent enhancement (ADE) in other viral infections (e.g., dengue)? Will future vaccines carry a risk of the ADE phenomenon?
• Does substance use (e.g., nicotine, marijuana) exacerbate or trigger MIS-C through immune activation?

“We have no knowledge yet about SARS-CoV-2 vaccination of children, especially young children,” Dr. Pichichero emphasized. “There are different types of vaccines – messenger RNA, adenovirus vector and purified spike proteins of the virus – among others, but questions remain: Will the vaccines work in children? What about side effects? Will the antibodies and cellular immunity protect partially or completely?”

The researchers and editorialists had no financial conflicts to disclose. Dr. Pichichero had no financial conflicts to disclose.

SOURCE: Han MS et al. JAMA Pediatr. 2020 Aug 28. doi:10.1001/jamapediatrics.2020.3988.