Cleveland Clinic Journal of Medicine

Each year, millions of women undergo mammography in the hope of decreasing their risk of dying of breast cancer. The effectiveness of screening mammography, however, continues to be debated.

While most randomized controlled trials have demonstrated significantly lower mortality rates in women who undergo screening, not all trials have. Most experts agree that screening mammography programs decrease breast cancer mortality rates by 12% to 33%.^1,2 But some point out that although mammography programs clearly detect more cases of breast cancer, some proportion of this detection may include “overdiagnosis” of cancers that would not have caused morbidity or mortality, including ductal carcinoma in situ. Also, although deaths from breast cancer have decreased in the United States, at least some of the decrease may be due to more effective treatment rather than early detection.

Moreover, screening has well-documented harms. False-positive results cause alarm and expose women to needless follow-up imaging and biopsies, with their attendant inconvenience, discomfort, risks, and costs. Conversely, false-negative results (especially common in women with dense breasts) lead to missed diagnosis and a false sense of security.

How could programs and technology be improved to make screening more beneficial, both for patients and for society as a whole? A major improvement would be if mammography could be made more sensitive and specific for detecting invasive cancers, with fewer false-positive results. Lower cost and less frequent screening would also be major improvements.

Digital breast tomosynthesis (DBT), also known as 3-dimensional (3D) mammography, may be a way to improve the value of breast cancer screening programs. In 2011, the US Food and Drug Administration (FDA) approved DBT for all mammographic indications, including screening.

WHAT IS TOMOSYNTHESIS?

In DBT, the x-ray source is rotated in an arc around the patient’s breast (Figure 1), generating a 3D image.³ DBT is now routinely built into newer-generation mammography units. The 3D projections of DBT are obtained during the same breast compression required for standard 2D digital mammography. Thus, DBT requires minimal additional time on the part of the patient and the technologist.⁴

The 3D images are processed and sent to a viewing station, where a radiologist can interpret them next to 2D images. The radiologist has the ability to scroll through the DBT projections slice by slice, as in other cross-sectional imaging examinations. However, given the larger number of images compared with digital mammography, DBT requires more time for interpretation, interrupting the workflow. A population-based observational study suggested that combined digital mammography and DBT screening examinations take twice as long to interpret.⁵

The main advantage of DBT is that it can mitigate the problem of overlapping breast tissue on standard digital projections. These areas of focal asymmetry may represent suspicious masses—or merely overlapping breast parenchyma. When areas of focal asymmetry are found on 2D digital mammography without DBT, patients need to come back for further diagnostic imaging to resolve the finding.⁶ In addition, especially in women with dense breasts, areas of overlapping tissue can have a masking effect, obscuring small breast cancers.⁷

Images courtesy of Diana L. Lam, MD, University of Washington, Seattle.

For breast cancer screening, DBT is read in conjunction with standard digital mammography. By allowing examination of the breast parenchyma in thin slices, DBT decreases the interpretive issue of overlapping breast parenchyma and the masking effect, potentially leading to fewer false-positive results and higher rates of cancer detection (Figure 2).

EFFECTIVENESS OF TOMOSYNTHESIS

There is limited evidence at this time to support the addition of DBT to digital mammography for primary breast cancer screening, with no published randomized trials that assessed outcomes. However, 2 population-based trials in Europe have prospectively assessed DBT plus digital mammography as a primary screening strategy: the Screening With Tomosynthesis or Standard Mammography (STORM) trial⁸ and the Oslo tomosynthesis screening trial.⁵ Only the STORM trial reported first-year interval cancer rates, from which the sensitivity and specificity of DBT plus 2D digital mammography could be calculated and compared with those of 2D digital mammography alone.⁸

In April 2013, the Oslo tomosynthesis screening trial published interim results of its prospective cohort study of 12,631 Norwegian women ages 50 to 69.⁵ Women were invited to participate based on the availability of technical staff and imaging systems at the time of screening, and all participants underwent digital mammography and DBT. Images were read independently by 4 radiologists using a double-reader protocol.

The interim results suggest that adding DBT to digital mammography increased cancer detection rates by 31% and decreased the false-positive rate by 13% compared with 2D digital mammography alone (Table 1). However, the double-reader protocol in this study differs from typical single-reader protocols in the United States, limiting the applicability of the findings.

The STORM trial: Low sensitivity

The STORM trial is a prospective cohort study that included 7,292 women without symptoms, at average risk, age 48 and older, who participated in national breast cancer screening services in northern Italy. Each participant underwent digital mammography and DBT. The examinations were read sequentially (digital mammography first, then DBT plus digital mammography) either by a single radiologist, as is most common in the United States, or by 2 radiologists, as is standard in Europe.

Using the single-reader strategy, adding DBT significantly increased cancer detection rates and reduced the total recall rate (Table 1). Sensitivity was 85% vs 54%, and specificity was 97% vs 96%.^8,9

Of note, the sensitivity of 54% for digital mammography in the STORM trial is substantially lower than the sensitivity of digital mammography reported in the United States.¹⁰

Friedewald et al confirmed Oslo and STORM

To date, the largest US study of DBT plus digital mammography for breast cancer screening was a multicenter retrospective cohort study by Friedewald et al in 2014.¹¹ This study compared cancer detection and recall rates before and after the implementation of DBT at 13 breast centers and evaluated a total of 454,850 examinations (173,663 with DBT plus digital mammography and 281,187 with digital mammography only).

Overall, the recall rate decreased significantly after DBT was adopted and the cancer detection rate increased, findings consistent with those of the STORM and Oslo trials (Table 1). Adding DBT detected invasive cancers at a higher rate than 2D digital mammography alone (4.1/1000 vs 2.9/1,000), while there was no significant difference in ductal carcinoma in situ detection rates. This suggests that the additional cancers detected by DBT may be more clinically important. Nevertheless, the number of biopsies with negative results also increased, suggesting that adding DBT may pose potential harms.

In 2016, Rafferty et al¹² published an additional analysis of the data from Friedewald et al, concluding that adding DBT to 2D digital mammography increased the cancer detection rate more in women with heterogeneously dense breasts than in those with either nondense breasts or extremely dense breasts.¹² The reduction in recall rate was also greatest in the heterogeneously dense subgroup.

Insufficient evidence to recommend

Most other cohort studies comparing DBT and digital mammography have had findings similar to those of the European prospective studies and the large US retrospective cohort study, with the addition of DBT to mammography reducing recall rates and increasing cancer detection rates.¹³ However, many of these studies were subject to potential selection bias and did not provide information on the cancer risk of the participants. In addition, no studies have assessed clinical outcomes such as breast cancer stage at diagnosis or interval cancers, let alone breast cancer mortality.

Rigorous studies need to be done in the United States, using the standard single-reader protocol most often used in this country, to ascertain the clinical outcomes of DBT plus digital mammography for breast cancer screening for women at average risk. A 2016 review cited a dearth of high-quality US studies assessing the role of DBT in primary breast cancer.¹³

The US Preventive Services Task Force, in its 2016 guidelines for breast cancer screening, concluded that there was insufficient evidence to assess the harms and benefits of DBT as a method of breast cancer screening, including adjunctive screening in women with dense breasts.¹

Similarly, the American College of Physicians has advised against screening average-risk women for breast cancer using DBT.¹⁴

APPROVAL, DISSEMINATION, COSTS, AND CHOICE FOR PATIENTS

Even with early promising data suggesting that DBT can increase cancer detection rates and decrease false-positive results when added to routine screening mammography, the rapid diffusion of DBT into clinical practice is outpacing evidence of its effectiveness.⁴ This adoption was spurred in January 2015 when the Centers for Medicare and Medicaid Services added a Current Procedural Terminology code for DBT, allowing for additional reimbursement for it for all mammography indications.¹⁵ Still, the use of DBT in community settings is inconsistent, given the significant up-front costs associated with equipment purchases and variable reimbursement by private insurers who consider the technology experimental.

For the US healthcare system as a whole, it is uncertain whether the purported benefits of DBT will outweigh the additional costs associated with its use. The average reimbursement for a routine digital mammography examination is $135; adding DBT adds an average of $56 to the cost.¹⁵

Using an established, discrete-event breast cancer simulation model, a team of investigators evaluated the cost-effectiveness of combined biennial digital mammography and DBT screening compared with biennial digital mammography screening alone in US women with dense breasts.¹⁶ They found that biennial combined screening is likely to be cost-effective in US women with dense breasts. They also found that for every 2,000 women screened from age 50 to age 74, adding DBT would prevent 1 breast cancer death and 810 false-positive screening examinations.¹⁶

In addition, some have expressed concern that adding DBT to standard digital mammography increases radiation exposure. In fact, the radiation dose with DBT is similar to that with standard 2D digital mammography. Thus, when acquired together, combined digital mammography and DBT screening leads to twice the radiation dose compared with digital mammography alone.¹⁷ Nevertheless, this increased dose remains well below the FDA limits for a screening examination. In addition, the FDA has approved software that allows reconstruction of 2D synthetic views from the 3D data set, which will eventually bring radiation dose levels down to levels comparable to those of conventional digital mammography.¹⁷

Given that DBT is built into newer mammography units and is available as an add-on feature for existing units, its use is likely to increase even faster than digital mammography did when it replaced screen-film mammography in the previous decade.⁴ Its adoption by screening facilities, however, remains variable, and patients wishing to obtain combined DBT and digital mammography screening may have to travel to a different facility from their usual place of screening.¹⁸

Moreover, not all insurance companies cover DBT, resulting in additional out-of-pocket costs to the patient. It is currently unclear how individual facilities are offering DBT services, including how patients are selected for additional DBT and if they are offered the choice to add or forego DBT screening in combination with standard digital mammography.

SUMMARY: AN EMERGING TECHNOLOGY

DBT is an emerging imaging technology that allows the radiologist to view breast images in slices, as in computed tomography. DBT images can be obtained using the same breast compression that women already undergo for 2D digital mammography for breast cancer screening.

At this time, adding DBT to digital mammography screening nearly doubles the radiation exposure to the patient. However, new software is available that allows creation of synthetic 2D views from the 3D data set, resulting in radiation exposure that is similar to conventional digital mammography.

Although there are no published randomized controlled trials assessing the benefit of DBT over 2D digital mammography for breast cancer screening, prospective observational studies suggest that DBT may reduce false-positive recall rates and increase cancer detection rates when used in population-based screening programs. Assuming that additional breast cancer detection contributes to improved clinical outcomes, women with dense breasts may benefit more than women without dense breasts.

No national organizations currently recommend DBT for primary breast cancer screening. Ideally, future studies would determine whether DBT screening reduces breast cancer mortality. Since this research may not be feasible, surrogate clinical outcomes, such as a decrease in interval breast cancer rates and impact on stage at time of diagnosis, would allow us to more confidently recommend this new technology.

Each year, millions of women undergo mammography in the hope of decreasing their risk of dying of breast cancer. The effectiveness of screening mammography, however, continues to be debated.

While most randomized controlled trials have demonstrated significantly lower mortality rates in women who undergo screening, not all trials have. Most experts agree that screening mammography programs decrease breast cancer mortality rates by 12% to 33%.^1,2 But some point out that although mammography programs clearly detect more cases of breast cancer, some proportion of this detection may include “overdiagnosis” of cancers that would not have caused morbidity or mortality, including ductal carcinoma in situ. Also, although deaths from breast cancer have decreased in the United States, at least some of the decrease may be due to more effective treatment rather than early detection.

Moreover, screening has well-documented harms. False-positive results cause alarm and expose women to needless follow-up imaging and biopsies, with their attendant inconvenience, discomfort, risks, and costs. Conversely, false-negative results (especially common in women with dense breasts) lead to missed diagnosis and a false sense of security.

How could programs and technology be improved to make screening more beneficial, both for patients and for society as a whole? A major improvement would be if mammography could be made more sensitive and specific for detecting invasive cancers, with fewer false-positive results. Lower cost and less frequent screening would also be major improvements.

Digital breast tomosynthesis (DBT), also known as 3-dimensional (3D) mammography, may be a way to improve the value of breast cancer screening programs. In 2011, the US Food and Drug Administration (FDA) approved DBT for all mammographic indications, including screening.

WHAT IS TOMOSYNTHESIS?

In DBT, the x-ray source is rotated in an arc around the patient’s breast (Figure 1), generating a 3D image.³ DBT is now routinely built into newer-generation mammography units. The 3D projections of DBT are obtained during the same breast compression required for standard 2D digital mammography. Thus, DBT requires minimal additional time on the part of the patient and the technologist.⁴

The 3D images are processed and sent to a viewing station, where a radiologist can interpret them next to 2D images. The radiologist has the ability to scroll through the DBT projections slice by slice, as in other cross-sectional imaging examinations. However, given the larger number of images compared with digital mammography, DBT requires more time for interpretation, interrupting the workflow. A population-based observational study suggested that combined digital mammography and DBT screening examinations take twice as long to interpret.⁵

The main advantage of DBT is that it can mitigate the problem of overlapping breast tissue on standard digital projections. These areas of focal asymmetry may represent suspicious masses—or merely overlapping breast parenchyma. When areas of focal asymmetry are found on 2D digital mammography without DBT, patients need to come back for further diagnostic imaging to resolve the finding.⁶ In addition, especially in women with dense breasts, areas of overlapping tissue can have a masking effect, obscuring small breast cancers.⁷

Images courtesy of Diana L. Lam, MD, University of Washington, Seattle.

For breast cancer screening, DBT is read in conjunction with standard digital mammography. By allowing examination of the breast parenchyma in thin slices, DBT decreases the interpretive issue of overlapping breast parenchyma and the masking effect, potentially leading to fewer false-positive results and higher rates of cancer detection (Figure 2).

EFFECTIVENESS OF TOMOSYNTHESIS

There is limited evidence at this time to support the addition of DBT to digital mammography for primary breast cancer screening, with no published randomized trials that assessed outcomes. However, 2 population-based trials in Europe have prospectively assessed DBT plus digital mammography as a primary screening strategy: the Screening With Tomosynthesis or Standard Mammography (STORM) trial⁸ and the Oslo tomosynthesis screening trial.⁵ Only the STORM trial reported first-year interval cancer rates, from which the sensitivity and specificity of DBT plus 2D digital mammography could be calculated and compared with those of 2D digital mammography alone.⁸

In April 2013, the Oslo tomosynthesis screening trial published interim results of its prospective cohort study of 12,631 Norwegian women ages 50 to 69.⁵ Women were invited to participate based on the availability of technical staff and imaging systems at the time of screening, and all participants underwent digital mammography and DBT. Images were read independently by 4 radiologists using a double-reader protocol.

The interim results suggest that adding DBT to digital mammography increased cancer detection rates by 31% and decreased the false-positive rate by 13% compared with 2D digital mammography alone (Table 1). However, the double-reader protocol in this study differs from typical single-reader protocols in the United States, limiting the applicability of the findings.

The STORM trial: Low sensitivity

The STORM trial is a prospective cohort study that included 7,292 women without symptoms, at average risk, age 48 and older, who participated in national breast cancer screening services in northern Italy. Each participant underwent digital mammography and DBT. The examinations were read sequentially (digital mammography first, then DBT plus digital mammography) either by a single radiologist, as is most common in the United States, or by 2 radiologists, as is standard in Europe.

Using the single-reader strategy, adding DBT significantly increased cancer detection rates and reduced the total recall rate (Table 1). Sensitivity was 85% vs 54%, and specificity was 97% vs 96%.^8,9

Of note, the sensitivity of 54% for digital mammography in the STORM trial is substantially lower than the sensitivity of digital mammography reported in the United States.¹⁰

Friedewald et al confirmed Oslo and STORM

To date, the largest US study of DBT plus digital mammography for breast cancer screening was a multicenter retrospective cohort study by Friedewald et al in 2014.¹¹ This study compared cancer detection and recall rates before and after the implementation of DBT at 13 breast centers and evaluated a total of 454,850 examinations (173,663 with DBT plus digital mammography and 281,187 with digital mammography only).

Overall, the recall rate decreased significantly after DBT was adopted and the cancer detection rate increased, findings consistent with those of the STORM and Oslo trials (Table 1). Adding DBT detected invasive cancers at a higher rate than 2D digital mammography alone (4.1/1000 vs 2.9/1,000), while there was no significant difference in ductal carcinoma in situ detection rates. This suggests that the additional cancers detected by DBT may be more clinically important. Nevertheless, the number of biopsies with negative results also increased, suggesting that adding DBT may pose potential harms.

In 2016, Rafferty et al¹² published an additional analysis of the data from Friedewald et al, concluding that adding DBT to 2D digital mammography increased the cancer detection rate more in women with heterogeneously dense breasts than in those with either nondense breasts or extremely dense breasts.¹² The reduction in recall rate was also greatest in the heterogeneously dense subgroup.

Insufficient evidence to recommend

Most other cohort studies comparing DBT and digital mammography have had findings similar to those of the European prospective studies and the large US retrospective cohort study, with the addition of DBT to mammography reducing recall rates and increasing cancer detection rates.¹³ However, many of these studies were subject to potential selection bias and did not provide information on the cancer risk of the participants. In addition, no studies have assessed clinical outcomes such as breast cancer stage at diagnosis or interval cancers, let alone breast cancer mortality.

Rigorous studies need to be done in the United States, using the standard single-reader protocol most often used in this country, to ascertain the clinical outcomes of DBT plus digital mammography for breast cancer screening for women at average risk. A 2016 review cited a dearth of high-quality US studies assessing the role of DBT in primary breast cancer.¹³

The US Preventive Services Task Force, in its 2016 guidelines for breast cancer screening, concluded that there was insufficient evidence to assess the harms and benefits of DBT as a method of breast cancer screening, including adjunctive screening in women with dense breasts.¹

Similarly, the American College of Physicians has advised against screening average-risk women for breast cancer using DBT.¹⁴

APPROVAL, DISSEMINATION, COSTS, AND CHOICE FOR PATIENTS

Even with early promising data suggesting that DBT can increase cancer detection rates and decrease false-positive results when added to routine screening mammography, the rapid diffusion of DBT into clinical practice is outpacing evidence of its effectiveness.⁴ This adoption was spurred in January 2015 when the Centers for Medicare and Medicaid Services added a Current Procedural Terminology code for DBT, allowing for additional reimbursement for it for all mammography indications.¹⁵ Still, the use of DBT in community settings is inconsistent, given the significant up-front costs associated with equipment purchases and variable reimbursement by private insurers who consider the technology experimental.

For the US healthcare system as a whole, it is uncertain whether the purported benefits of DBT will outweigh the additional costs associated with its use. The average reimbursement for a routine digital mammography examination is $135; adding DBT adds an average of $56 to the cost.¹⁵

Using an established, discrete-event breast cancer simulation model, a team of investigators evaluated the cost-effectiveness of combined biennial digital mammography and DBT screening compared with biennial digital mammography screening alone in US women with dense breasts.¹⁶ They found that biennial combined screening is likely to be cost-effective in US women with dense breasts. They also found that for every 2,000 women screened from age 50 to age 74, adding DBT would prevent 1 breast cancer death and 810 false-positive screening examinations.¹⁶

In addition, some have expressed concern that adding DBT to standard digital mammography increases radiation exposure. In fact, the radiation dose with DBT is similar to that with standard 2D digital mammography. Thus, when acquired together, combined digital mammography and DBT screening leads to twice the radiation dose compared with digital mammography alone.¹⁷ Nevertheless, this increased dose remains well below the FDA limits for a screening examination. In addition, the FDA has approved software that allows reconstruction of 2D synthetic views from the 3D data set, which will eventually bring radiation dose levels down to levels comparable to those of conventional digital mammography.¹⁷

Given that DBT is built into newer mammography units and is available as an add-on feature for existing units, its use is likely to increase even faster than digital mammography did when it replaced screen-film mammography in the previous decade.⁴ Its adoption by screening facilities, however, remains variable, and patients wishing to obtain combined DBT and digital mammography screening may have to travel to a different facility from their usual place of screening.¹⁸

Moreover, not all insurance companies cover DBT, resulting in additional out-of-pocket costs to the patient. It is currently unclear how individual facilities are offering DBT services, including how patients are selected for additional DBT and if they are offered the choice to add or forego DBT screening in combination with standard digital mammography.

SUMMARY: AN EMERGING TECHNOLOGY

DBT is an emerging imaging technology that allows the radiologist to view breast images in slices, as in computed tomography. DBT images can be obtained using the same breast compression that women already undergo for 2D digital mammography for breast cancer screening.

At this time, adding DBT to digital mammography screening nearly doubles the radiation exposure to the patient. However, new software is available that allows creation of synthetic 2D views from the 3D data set, resulting in radiation exposure that is similar to conventional digital mammography.

Although there are no published randomized controlled trials assessing the benefit of DBT over 2D digital mammography for breast cancer screening, prospective observational studies suggest that DBT may reduce false-positive recall rates and increase cancer detection rates when used in population-based screening programs. Assuming that additional breast cancer detection contributes to improved clinical outcomes, women with dense breasts may benefit more than women without dense breasts.

No national organizations currently recommend DBT for primary breast cancer screening. Ideally, future studies would determine whether DBT screening reduces breast cancer mortality. Since this research may not be feasible, surrogate clinical outcomes, such as a decrease in interval breast cancer rates and impact on stage at time of diagnosis, would allow us to more confidently recommend this new technology.

Each year, millions of women undergo mammography in the hope of decreasing their risk of dying of breast cancer. The effectiveness of screening mammography, however, continues to be debated.

While most randomized controlled trials have demonstrated significantly lower mortality rates in women who undergo screening, not all trials have. Most experts agree that screening mammography programs decrease breast cancer mortality rates by 12% to 33%.^1,2 But some point out that although mammography programs clearly detect more cases of breast cancer, some proportion of this detection may include “overdiagnosis” of cancers that would not have caused morbidity or mortality, including ductal carcinoma in situ. Also, although deaths from breast cancer have decreased in the United States, at least some of the decrease may be due to more effective treatment rather than early detection.

Moreover, screening has well-documented harms. False-positive results cause alarm and expose women to needless follow-up imaging and biopsies, with their attendant inconvenience, discomfort, risks, and costs. Conversely, false-negative results (especially common in women with dense breasts) lead to missed diagnosis and a false sense of security.

How could programs and technology be improved to make screening more beneficial, both for patients and for society as a whole? A major improvement would be if mammography could be made more sensitive and specific for detecting invasive cancers, with fewer false-positive results. Lower cost and less frequent screening would also be major improvements.

Digital breast tomosynthesis (DBT), also known as 3-dimensional (3D) mammography, may be a way to improve the value of breast cancer screening programs. In 2011, the US Food and Drug Administration (FDA) approved DBT for all mammographic indications, including screening.

WHAT IS TOMOSYNTHESIS?

In DBT, the x-ray source is rotated in an arc around the patient’s breast (Figure 1), generating a 3D image.³ DBT is now routinely built into newer-generation mammography units. The 3D projections of DBT are obtained during the same breast compression required for standard 2D digital mammography. Thus, DBT requires minimal additional time on the part of the patient and the technologist.⁴

The 3D images are processed and sent to a viewing station, where a radiologist can interpret them next to 2D images. The radiologist has the ability to scroll through the DBT projections slice by slice, as in other cross-sectional imaging examinations. However, given the larger number of images compared with digital mammography, DBT requires more time for interpretation, interrupting the workflow. A population-based observational study suggested that combined digital mammography and DBT screening examinations take twice as long to interpret.⁵

The main advantage of DBT is that it can mitigate the problem of overlapping breast tissue on standard digital projections. These areas of focal asymmetry may represent suspicious masses—or merely overlapping breast parenchyma. When areas of focal asymmetry are found on 2D digital mammography without DBT, patients need to come back for further diagnostic imaging to resolve the finding.⁶ In addition, especially in women with dense breasts, areas of overlapping tissue can have a masking effect, obscuring small breast cancers.⁷

Images courtesy of Diana L. Lam, MD, University of Washington, Seattle.

For breast cancer screening, DBT is read in conjunction with standard digital mammography. By allowing examination of the breast parenchyma in thin slices, DBT decreases the interpretive issue of overlapping breast parenchyma and the masking effect, potentially leading to fewer false-positive results and higher rates of cancer detection (Figure 2).

EFFECTIVENESS OF TOMOSYNTHESIS

There is limited evidence at this time to support the addition of DBT to digital mammography for primary breast cancer screening, with no published randomized trials that assessed outcomes. However, 2 population-based trials in Europe have prospectively assessed DBT plus digital mammography as a primary screening strategy: the Screening With Tomosynthesis or Standard Mammography (STORM) trial⁸ and the Oslo tomosynthesis screening trial.⁵ Only the STORM trial reported first-year interval cancer rates, from which the sensitivity and specificity of DBT plus 2D digital mammography could be calculated and compared with those of 2D digital mammography alone.⁸

In April 2013, the Oslo tomosynthesis screening trial published interim results of its prospective cohort study of 12,631 Norwegian women ages 50 to 69.⁵ Women were invited to participate based on the availability of technical staff and imaging systems at the time of screening, and all participants underwent digital mammography and DBT. Images were read independently by 4 radiologists using a double-reader protocol.

The interim results suggest that adding DBT to digital mammography increased cancer detection rates by 31% and decreased the false-positive rate by 13% compared with 2D digital mammography alone (Table 1). However, the double-reader protocol in this study differs from typical single-reader protocols in the United States, limiting the applicability of the findings.

The STORM trial: Low sensitivity

The STORM trial is a prospective cohort study that included 7,292 women without symptoms, at average risk, age 48 and older, who participated in national breast cancer screening services in northern Italy. Each participant underwent digital mammography and DBT. The examinations were read sequentially (digital mammography first, then DBT plus digital mammography) either by a single radiologist, as is most common in the United States, or by 2 radiologists, as is standard in Europe.

Using the single-reader strategy, adding DBT significantly increased cancer detection rates and reduced the total recall rate (Table 1). Sensitivity was 85% vs 54%, and specificity was 97% vs 96%.^8,9

Of note, the sensitivity of 54% for digital mammography in the STORM trial is substantially lower than the sensitivity of digital mammography reported in the United States.¹⁰

Friedewald et al confirmed Oslo and STORM

To date, the largest US study of DBT plus digital mammography for breast cancer screening was a multicenter retrospective cohort study by Friedewald et al in 2014.¹¹ This study compared cancer detection and recall rates before and after the implementation of DBT at 13 breast centers and evaluated a total of 454,850 examinations (173,663 with DBT plus digital mammography and 281,187 with digital mammography only).

Overall, the recall rate decreased significantly after DBT was adopted and the cancer detection rate increased, findings consistent with those of the STORM and Oslo trials (Table 1). Adding DBT detected invasive cancers at a higher rate than 2D digital mammography alone (4.1/1000 vs 2.9/1,000), while there was no significant difference in ductal carcinoma in situ detection rates. This suggests that the additional cancers detected by DBT may be more clinically important. Nevertheless, the number of biopsies with negative results also increased, suggesting that adding DBT may pose potential harms.

In 2016, Rafferty et al¹² published an additional analysis of the data from Friedewald et al, concluding that adding DBT to 2D digital mammography increased the cancer detection rate more in women with heterogeneously dense breasts than in those with either nondense breasts or extremely dense breasts.¹² The reduction in recall rate was also greatest in the heterogeneously dense subgroup.

Insufficient evidence to recommend

Most other cohort studies comparing DBT and digital mammography have had findings similar to those of the European prospective studies and the large US retrospective cohort study, with the addition of DBT to mammography reducing recall rates and increasing cancer detection rates.¹³ However, many of these studies were subject to potential selection bias and did not provide information on the cancer risk of the participants. In addition, no studies have assessed clinical outcomes such as breast cancer stage at diagnosis or interval cancers, let alone breast cancer mortality.

Rigorous studies need to be done in the United States, using the standard single-reader protocol most often used in this country, to ascertain the clinical outcomes of DBT plus digital mammography for breast cancer screening for women at average risk. A 2016 review cited a dearth of high-quality US studies assessing the role of DBT in primary breast cancer.¹³

The US Preventive Services Task Force, in its 2016 guidelines for breast cancer screening, concluded that there was insufficient evidence to assess the harms and benefits of DBT as a method of breast cancer screening, including adjunctive screening in women with dense breasts.¹

Similarly, the American College of Physicians has advised against screening average-risk women for breast cancer using DBT.¹⁴

APPROVAL, DISSEMINATION, COSTS, AND CHOICE FOR PATIENTS

Even with early promising data suggesting that DBT can increase cancer detection rates and decrease false-positive results when added to routine screening mammography, the rapid diffusion of DBT into clinical practice is outpacing evidence of its effectiveness.⁴ This adoption was spurred in January 2015 when the Centers for Medicare and Medicaid Services added a Current Procedural Terminology code for DBT, allowing for additional reimbursement for it for all mammography indications.¹⁵ Still, the use of DBT in community settings is inconsistent, given the significant up-front costs associated with equipment purchases and variable reimbursement by private insurers who consider the technology experimental.

For the US healthcare system as a whole, it is uncertain whether the purported benefits of DBT will outweigh the additional costs associated with its use. The average reimbursement for a routine digital mammography examination is $135; adding DBT adds an average of $56 to the cost.¹⁵

Using an established, discrete-event breast cancer simulation model, a team of investigators evaluated the cost-effectiveness of combined biennial digital mammography and DBT screening compared with biennial digital mammography screening alone in US women with dense breasts.¹⁶ They found that biennial combined screening is likely to be cost-effective in US women with dense breasts. They also found that for every 2,000 women screened from age 50 to age 74, adding DBT would prevent 1 breast cancer death and 810 false-positive screening examinations.¹⁶

In addition, some have expressed concern that adding DBT to standard digital mammography increases radiation exposure. In fact, the radiation dose with DBT is similar to that with standard 2D digital mammography. Thus, when acquired together, combined digital mammography and DBT screening leads to twice the radiation dose compared with digital mammography alone.¹⁷ Nevertheless, this increased dose remains well below the FDA limits for a screening examination. In addition, the FDA has approved software that allows reconstruction of 2D synthetic views from the 3D data set, which will eventually bring radiation dose levels down to levels comparable to those of conventional digital mammography.¹⁷

Given that DBT is built into newer mammography units and is available as an add-on feature for existing units, its use is likely to increase even faster than digital mammography did when it replaced screen-film mammography in the previous decade.⁴ Its adoption by screening facilities, however, remains variable, and patients wishing to obtain combined DBT and digital mammography screening may have to travel to a different facility from their usual place of screening.¹⁸

Moreover, not all insurance companies cover DBT, resulting in additional out-of-pocket costs to the patient. It is currently unclear how individual facilities are offering DBT services, including how patients are selected for additional DBT and if they are offered the choice to add or forego DBT screening in combination with standard digital mammography.

SUMMARY: AN EMERGING TECHNOLOGY

DBT is an emerging imaging technology that allows the radiologist to view breast images in slices, as in computed tomography. DBT images can be obtained using the same breast compression that women already undergo for 2D digital mammography for breast cancer screening.

At this time, adding DBT to digital mammography screening nearly doubles the radiation exposure to the patient. However, new software is available that allows creation of synthetic 2D views from the 3D data set, resulting in radiation exposure that is similar to conventional digital mammography.

Although there are no published randomized controlled trials assessing the benefit of DBT over 2D digital mammography for breast cancer screening, prospective observational studies suggest that DBT may reduce false-positive recall rates and increase cancer detection rates when used in population-based screening programs. Assuming that additional breast cancer detection contributes to improved clinical outcomes, women with dense breasts may benefit more than women without dense breasts.

No national organizations currently recommend DBT for primary breast cancer screening. Ideally, future studies would determine whether DBT screening reduces breast cancer mortality. Since this research may not be feasible, surrogate clinical outcomes, such as a decrease in interval breast cancer rates and impact on stage at time of diagnosis, would allow us to more confidently recommend this new technology.

Adults with leukemia, lymphoma, multiple myeloma, and other hematologic cancers are living longer, and more than 1.2 million patients with these cancers are alive in the United States.¹ Most adults with nonpediatric cancers are diagnosed in the fifth to seventh decade, and many now survive more than 5 years. The survival rate of patients with most hematologic cancers has doubled since 1974, transforming once-terminal diagnoses into chronic conditions. According to one estimate, there will be 18 million cancer survivors (all types of cancer) by 2022, and nearly 2 million of these will be survivors of hematologic cancers.²

Although survivors of hematologic cancers are at risk of complications of their cancer treatment, they often do not receive routine health maintenance and see their primary care providers only for acute issues.

Primary care providers can play a major role in monitoring the health of hematologic cancer survivors. This requires staying up-to-date on diagnosis, management, and surveillance in this group and being able to address their survivorship issues.³

In this article, we focus on survivorship considerations in patients with previously treated hematologic cancers, including childhood, adolescent, and young-adult cancers. We discuss the role of primary care in the multidisciplinary approach to the continuing care of these patients, and we review innovative technologic solutions to the challenges of delivering care to this group.

SURVIVORSHIP BEGINS AT DIAGNOSIS

The definition of cancer survivorship has changed in the last decade, particularly with hematologic cancers.⁴

Survivorship was once considered the time after the patient successfully completed cancer treatment. But most patients with hematologic cancers will likely need to continue treatment until they die, with essentially unpredictable and intermittent periods of remission and relapse. Advances in cancer treatment and supportive care have led to longer life. Thus, a commonly recognized definition of survivorship begins at diagnosis rather than later in the disease course and continues through the balance of the patient’s life.⁵

The survivorship care plan

In 2005, the Institute of Medicine released a report⁶ calling attention to cancer survivors and their special needs. At that time, a growing number of patients were not returning to their primary care physicians to receive health maintenance after completing their cancer treatment. A proposed solution was for the oncologist to develop a personalized survivorship care plan, which would help the patient understand the treatments received, the importance of health maintenance, and the need for follow-up surveillance.⁵

The survivorship care plan was originally intended for patients who had completed their cancer treatment. But patients with hematologic cancers tend to need lifelong treatment. Nevertheless, major organizations such as the American Society of Hematology and the American Society of Clinical Oncology consider a survivorship care plan an essential part of cancer care for all patients and not just those with solid tumors.⁷ The plan should consist of a written treatment summary and recommendations for follow-up care.

EFFECTS OF HEMATOLOGIC CANCER AND ITS TREATMENT

Hematologic cancers and their treatment put patients at risk of many complications, including endocrinopathies, such as hypothyroidism or diabetes secondary to chronic steroid and immunosuppressant use, and cardiovascular events, such as congestive heart failure and stroke due to high-dose chemotherapy. Survivors are also at risk of secondary cancers and recurrence of the primary cancer.^8–15

Despite the gravity of a cancer diagnosis, cancer patients do not always adhere to a healthy lifestyle. A survey of over 400,000 cancer survivors found that 15% were current cigarette smokers, 27.5% were obese, and 31.5% had not engaged in physical activity during the previous 30 days.¹⁶

THE PRIMARY CARE CLINICIAN AND SURVIVORSHIP CARE

Many hematologic oncology practices include not only medical oncologists but also ancillary team members such as nurse practitioners, nurse specialists, physician assistants, registered nurses, and in some cases a social worker or nutritionist. Patients with hematologic cancers often rely on this team for most of their care while undergoing cancer treatment.

Depending on the type of cancer, and especially after a period of stable disease or remission, some patients transition away from the oncology team, particularly if they live far away, and receive care from their local primary care clinician.

Although the Institute for Medicine intended the survivorship care plan⁶ to be a patient-focused tool, primary care providers can benefit from it too. In survey of oncologists and primary care providers in the United States,¹⁷ 49% of the 1,130 oncologists said they almost always provided care plans to patients, and 85% perceived a greater benefit for primary care providers to have these plans than for cancer survivors. However, only 13% of the 1,120 primary care providers surveyed said they consistently received a care plan from the oncologist. The study suggests that oncologists should make a better effort to share these plans with primary care providers to enhance the coordination of care.

COMPONENTS OF A SURVIVORSHIP CARE PLAN AND SELF-MANAGEMENT

Although personalized survivorship care plans are not routinely used in patients with blood cancers,¹⁸ they are as important in hematologic cancer survivors as in patients with solid tumors.

The plan should consist of a treatment summary and information on essential components of a healthy lifestyle and should take into consideration coordination of care among primary and other providers, health maintenance recommendations, information on early detection and screening, and psychosocial welfare. Guidance on preventive screening for physical, financial, and psychosocial well-being should be generated by the oncology team or primary care provider and can be helpful to patients and caregivers as they navigate the healthcare system. (See https://cancercontrol.cancer.gov/pdf/ASCO-Survivorship-Care-Plan.pdf for a sample survivorship care plan.)

Although patients with hematologic cancer often have a highly variable course with multiple periods of remission and relapse, the survivorship care plan and treatment summary are essential components of their ongoing care.

Self-management of chronic illness refers to daily activities to keep the illness under control, minimize its impact on physical health and function, and help the patient cope with the psychosocial sequelae of the illness.¹⁹ Empowering patients and their caregivers to take control of their health is an essential component of survivorship care. Patients and caregivers can be valuable partners to primary care providers and the oncology team in ongoing care to ensure proper testing and monitoring for secondary illnesses.

Implementation of a survivorship care plan can be facilitated by integrating the plan and treatment summaries into the patient’s electronic medical record and encouraging the patient to be a part of the process.²⁰ Many electronic medical record systems such as Epic can automatically fill in treatment summaries and provide patients access to a survivorship care plan tailored to their needs, but these features are not routinely used, and output can be lengthy and hard to follow.^21,22

There has been a surge in research in information technology and care plan delivery since the Health Information Technology for Economic and Clinical Health (HITECH) Act was passed in 2009,²³ specifically in innovative strategies to proactively screen for, assess, and manage disease- and treatment-related symptoms in cancer survivors. As a result, patients and families can be more engaged in their care, and providers can better guide survivorship concerns.

Providers can create their own survivorship care plans or use electronic resources to generate one. The American Society of Clinical Oncology and the National Comprehensive Cancer Network provide printed templates in which the patient, primary care provider, or oncology team can complete a care plan. Newer electronic platforms such as the Carevive system are also available. Brief electronic outcome questionnaires can be completed by the patient at home or in the waiting room to assess symptoms, evaluate health maintenance practices, and generate a plan of care to review with the patient.

EMERGING TECHNOLOGY: TELEMEDICINE, VIRTUAL VISITS

Technology can help patients and the healthcare team in survivorship monitoring. Telemedicine, the exchange of medical information via electronic communication, includes video conferencing for patient consultations, transmission of still images, patient portals, and remote monitoring of vital signs.²⁴

This technology is critical to deliver high-quality acute and chronic care to patients in remote or rural areas, locally to patients unable to travel to the clinic, and internationally.^25–28 As patients become more technologically savvy, providers can try novel strategies to provide patients access to care. As of September 2015, there were at least 165,000 health applications (apps) for smartphones to help patients better manage aspects of their care such as diet, exercise, blood pressure, and blood sugar levels.²⁹

Video technology such as Express Care Online allows patients to connect with their healthcare providers for video and virtual visits without having to leave home or take time off from work. It also allows oncology providers to have virtual face-to-face contact with patients undergoing treatment phases, and primary care providers to have easier contact with patients during maintenance and remission phases. This technology allows for earlier detection of illness and provides broader access to care. Virtual visits may even prevent needless hospitalization in some cases or, conversely, alert the physician to tell the patient with alarming symptoms of an acute event, that it is time to go to the hospital.

SURVEILLANCE FOR LATE TREATMENT EFFECTS

Guidelines for surveillance for late treatment effects include the following:

• Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer³⁰
• National Comprehensive Cancer Network Guidelines for Age-Related Recommendations: Adolescent and Young Adult Oncology³¹
• National Comprehensive Cancer Network Guidelines for Treatment of Cancer by Site and Survivorship³¹
• American Society for Blood and Marrow Transplantation, for survivors of hematopoietic cell transplantation.³²

Survivors of childhood blood cancers are at increased risk of cardiac effects of high-dose or anthracycline chemotherapy (eg, doxorubicin for lymphoma, idarubicin for leukemia), skin cancer, sex-specific cancers (breast cancer, cervical cancer, prostate cancer), and osteoporosis.^5,30,33,34

For adult survivors of childhood cancers, it is generally recommended to screen for secondary conditions according to the US Preventive Services Task Force. The clinician must also consider the age at cancer diagnosis (child, young adult, or adult), the length of time since chemotherapy (months vs years), and the type of chemotherapy received.

A myriad of recommendations exist according to cancer type, location, stage, and age at diagnosis, but no clear consensus for screening exists. The major survivorship surveillance guidelines of the Children’s Oncology Group, National Comprehensive Cancer Network, and American Society for Blood and Marrow Transplantation are very detailed and lengthy and therefore not user-friendly for the busy clinician. While these guidelines contain minor differences as to what to test for and when to test, they differ mainly in considerations of the length of exposure to chemotherapy and radiation (eg, children, young adults, and older adults), length of time from completion of treatment to assessment of late complications, and whether the patient underwent hematopoietic stem cell transplant.^35,36

Table 1 reviews hematologic malignancies and conditions that blood cancer survivors are at risk for and general routine screening recommendations.^{5,22,30,33,34,36–39} In general, an assessment by a healthcare provider is recommended annually to screen for late effects of cancer and its treatment. Most important are screening for cardiac toxicity, giving immunizations, and preventing second cancers.

Table 1 reflects general recommendations for healthcare screening in childhood, adolescent, or young adult cancer survivors who see adult primary care physicians and for adult cancer survivors (acute leukemias, lymphomas, and multiple myeloma).

Table 2 focuses on screening and prevention specifically after hematopoietic cell transplantation.^30,32 These tables are not meant to be all-inclusive but to provide evidence-based recommendations for health surveillance at a glance.

SURVIVORS NEED ONGOING CARE

Recent successes in the treatment of hematologic cancers have led to dramatic changes in the overall health of these patients. In many instances, cancer survivors in the United States are considered to have a chronic illness with survival rates surpassing those in the past. A longer life span is counterbalanced by cumulative physical, financial, and psychosocial issues that require a multidisciplinary team to monitor and manage.

Childhood cancer survivors face the same psychosocial and financial issues as survivors of adult-onset cancers and are at heightened risk of preventable conditions. Ultimately, it is up to the survivor to self-manage many long-term treatment-related symptoms.

A survivorship care plan and treatment summary to guide the patient, primary provider, and oncology team is an essential component of quality care. Screening guidelines vary according to the age at treatment and length of time from therapy, but general screening and the use of technology and information technology solutions to deliver care can help survivors. These solutions have the potential to transform healthcare delivery in the future and provide the opportunity for ongoing, comprehensive care.

Adults with leukemia, lymphoma, multiple myeloma, and other hematologic cancers are living longer, and more than 1.2 million patients with these cancers are alive in the United States.¹ Most adults with nonpediatric cancers are diagnosed in the fifth to seventh decade, and many now survive more than 5 years. The survival rate of patients with most hematologic cancers has doubled since 1974, transforming once-terminal diagnoses into chronic conditions. According to one estimate, there will be 18 million cancer survivors (all types of cancer) by 2022, and nearly 2 million of these will be survivors of hematologic cancers.²

Although survivors of hematologic cancers are at risk of complications of their cancer treatment, they often do not receive routine health maintenance and see their primary care providers only for acute issues.

Primary care providers can play a major role in monitoring the health of hematologic cancer survivors. This requires staying up-to-date on diagnosis, management, and surveillance in this group and being able to address their survivorship issues.³

In this article, we focus on survivorship considerations in patients with previously treated hematologic cancers, including childhood, adolescent, and young-adult cancers. We discuss the role of primary care in the multidisciplinary approach to the continuing care of these patients, and we review innovative technologic solutions to the challenges of delivering care to this group.

SURVIVORSHIP BEGINS AT DIAGNOSIS

The definition of cancer survivorship has changed in the last decade, particularly with hematologic cancers.⁴

Survivorship was once considered the time after the patient successfully completed cancer treatment. But most patients with hematologic cancers will likely need to continue treatment until they die, with essentially unpredictable and intermittent periods of remission and relapse. Advances in cancer treatment and supportive care have led to longer life. Thus, a commonly recognized definition of survivorship begins at diagnosis rather than later in the disease course and continues through the balance of the patient’s life.⁵

The survivorship care plan

In 2005, the Institute of Medicine released a report⁶ calling attention to cancer survivors and their special needs. At that time, a growing number of patients were not returning to their primary care physicians to receive health maintenance after completing their cancer treatment. A proposed solution was for the oncologist to develop a personalized survivorship care plan, which would help the patient understand the treatments received, the importance of health maintenance, and the need for follow-up surveillance.⁵

The survivorship care plan was originally intended for patients who had completed their cancer treatment. But patients with hematologic cancers tend to need lifelong treatment. Nevertheless, major organizations such as the American Society of Hematology and the American Society of Clinical Oncology consider a survivorship care plan an essential part of cancer care for all patients and not just those with solid tumors.⁷ The plan should consist of a written treatment summary and recommendations for follow-up care.

EFFECTS OF HEMATOLOGIC CANCER AND ITS TREATMENT

Hematologic cancers and their treatment put patients at risk of many complications, including endocrinopathies, such as hypothyroidism or diabetes secondary to chronic steroid and immunosuppressant use, and cardiovascular events, such as congestive heart failure and stroke due to high-dose chemotherapy. Survivors are also at risk of secondary cancers and recurrence of the primary cancer.^8–15

Despite the gravity of a cancer diagnosis, cancer patients do not always adhere to a healthy lifestyle. A survey of over 400,000 cancer survivors found that 15% were current cigarette smokers, 27.5% were obese, and 31.5% had not engaged in physical activity during the previous 30 days.¹⁶

THE PRIMARY CARE CLINICIAN AND SURVIVORSHIP CARE

Many hematologic oncology practices include not only medical oncologists but also ancillary team members such as nurse practitioners, nurse specialists, physician assistants, registered nurses, and in some cases a social worker or nutritionist. Patients with hematologic cancers often rely on this team for most of their care while undergoing cancer treatment.

Depending on the type of cancer, and especially after a period of stable disease or remission, some patients transition away from the oncology team, particularly if they live far away, and receive care from their local primary care clinician.

Although the Institute for Medicine intended the survivorship care plan⁶ to be a patient-focused tool, primary care providers can benefit from it too. In survey of oncologists and primary care providers in the United States,¹⁷ 49% of the 1,130 oncologists said they almost always provided care plans to patients, and 85% perceived a greater benefit for primary care providers to have these plans than for cancer survivors. However, only 13% of the 1,120 primary care providers surveyed said they consistently received a care plan from the oncologist. The study suggests that oncologists should make a better effort to share these plans with primary care providers to enhance the coordination of care.

COMPONENTS OF A SURVIVORSHIP CARE PLAN AND SELF-MANAGEMENT

Although personalized survivorship care plans are not routinely used in patients with blood cancers,¹⁸ they are as important in hematologic cancer survivors as in patients with solid tumors.

The plan should consist of a treatment summary and information on essential components of a healthy lifestyle and should take into consideration coordination of care among primary and other providers, health maintenance recommendations, information on early detection and screening, and psychosocial welfare. Guidance on preventive screening for physical, financial, and psychosocial well-being should be generated by the oncology team or primary care provider and can be helpful to patients and caregivers as they navigate the healthcare system. (See https://cancercontrol.cancer.gov/pdf/ASCO-Survivorship-Care-Plan.pdf for a sample survivorship care plan.)

Although patients with hematologic cancer often have a highly variable course with multiple periods of remission and relapse, the survivorship care plan and treatment summary are essential components of their ongoing care.

Self-management of chronic illness refers to daily activities to keep the illness under control, minimize its impact on physical health and function, and help the patient cope with the psychosocial sequelae of the illness.¹⁹ Empowering patients and their caregivers to take control of their health is an essential component of survivorship care. Patients and caregivers can be valuable partners to primary care providers and the oncology team in ongoing care to ensure proper testing and monitoring for secondary illnesses.

Implementation of a survivorship care plan can be facilitated by integrating the plan and treatment summaries into the patient’s electronic medical record and encouraging the patient to be a part of the process.²⁰ Many electronic medical record systems such as Epic can automatically fill in treatment summaries and provide patients access to a survivorship care plan tailored to their needs, but these features are not routinely used, and output can be lengthy and hard to follow.^21,22

There has been a surge in research in information technology and care plan delivery since the Health Information Technology for Economic and Clinical Health (HITECH) Act was passed in 2009,²³ specifically in innovative strategies to proactively screen for, assess, and manage disease- and treatment-related symptoms in cancer survivors. As a result, patients and families can be more engaged in their care, and providers can better guide survivorship concerns.

Providers can create their own survivorship care plans or use electronic resources to generate one. The American Society of Clinical Oncology and the National Comprehensive Cancer Network provide printed templates in which the patient, primary care provider, or oncology team can complete a care plan. Newer electronic platforms such as the Carevive system are also available. Brief electronic outcome questionnaires can be completed by the patient at home or in the waiting room to assess symptoms, evaluate health maintenance practices, and generate a plan of care to review with the patient.

EMERGING TECHNOLOGY: TELEMEDICINE, VIRTUAL VISITS

Technology can help patients and the healthcare team in survivorship monitoring. Telemedicine, the exchange of medical information via electronic communication, includes video conferencing for patient consultations, transmission of still images, patient portals, and remote monitoring of vital signs.²⁴

This technology is critical to deliver high-quality acute and chronic care to patients in remote or rural areas, locally to patients unable to travel to the clinic, and internationally.^25–28 As patients become more technologically savvy, providers can try novel strategies to provide patients access to care. As of September 2015, there were at least 165,000 health applications (apps) for smartphones to help patients better manage aspects of their care such as diet, exercise, blood pressure, and blood sugar levels.²⁹

Video technology such as Express Care Online allows patients to connect with their healthcare providers for video and virtual visits without having to leave home or take time off from work. It also allows oncology providers to have virtual face-to-face contact with patients undergoing treatment phases, and primary care providers to have easier contact with patients during maintenance and remission phases. This technology allows for earlier detection of illness and provides broader access to care. Virtual visits may even prevent needless hospitalization in some cases or, conversely, alert the physician to tell the patient with alarming symptoms of an acute event, that it is time to go to the hospital.

SURVEILLANCE FOR LATE TREATMENT EFFECTS

Guidelines for surveillance for late treatment effects include the following:

• Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer³⁰
• National Comprehensive Cancer Network Guidelines for Age-Related Recommendations: Adolescent and Young Adult Oncology³¹
• National Comprehensive Cancer Network Guidelines for Treatment of Cancer by Site and Survivorship³¹
• American Society for Blood and Marrow Transplantation, for survivors of hematopoietic cell transplantation.³²

Survivors of childhood blood cancers are at increased risk of cardiac effects of high-dose or anthracycline chemotherapy (eg, doxorubicin for lymphoma, idarubicin for leukemia), skin cancer, sex-specific cancers (breast cancer, cervical cancer, prostate cancer), and osteoporosis.^5,30,33,34

For adult survivors of childhood cancers, it is generally recommended to screen for secondary conditions according to the US Preventive Services Task Force. The clinician must also consider the age at cancer diagnosis (child, young adult, or adult), the length of time since chemotherapy (months vs years), and the type of chemotherapy received.

A myriad of recommendations exist according to cancer type, location, stage, and age at diagnosis, but no clear consensus for screening exists. The major survivorship surveillance guidelines of the Children’s Oncology Group, National Comprehensive Cancer Network, and American Society for Blood and Marrow Transplantation are very detailed and lengthy and therefore not user-friendly for the busy clinician. While these guidelines contain minor differences as to what to test for and when to test, they differ mainly in considerations of the length of exposure to chemotherapy and radiation (eg, children, young adults, and older adults), length of time from completion of treatment to assessment of late complications, and whether the patient underwent hematopoietic stem cell transplant.^35,36

Table 1 reviews hematologic malignancies and conditions that blood cancer survivors are at risk for and general routine screening recommendations.^{5,22,30,33,34,36–39} In general, an assessment by a healthcare provider is recommended annually to screen for late effects of cancer and its treatment. Most important are screening for cardiac toxicity, giving immunizations, and preventing second cancers.

Table 1 reflects general recommendations for healthcare screening in childhood, adolescent, or young adult cancer survivors who see adult primary care physicians and for adult cancer survivors (acute leukemias, lymphomas, and multiple myeloma).

Table 2 focuses on screening and prevention specifically after hematopoietic cell transplantation.^30,32 These tables are not meant to be all-inclusive but to provide evidence-based recommendations for health surveillance at a glance.

SURVIVORS NEED ONGOING CARE

Recent successes in the treatment of hematologic cancers have led to dramatic changes in the overall health of these patients. In many instances, cancer survivors in the United States are considered to have a chronic illness with survival rates surpassing those in the past. A longer life span is counterbalanced by cumulative physical, financial, and psychosocial issues that require a multidisciplinary team to monitor and manage.

Childhood cancer survivors face the same psychosocial and financial issues as survivors of adult-onset cancers and are at heightened risk of preventable conditions. Ultimately, it is up to the survivor to self-manage many long-term treatment-related symptoms.

A survivorship care plan and treatment summary to guide the patient, primary provider, and oncology team is an essential component of quality care. Screening guidelines vary according to the age at treatment and length of time from therapy, but general screening and the use of technology and information technology solutions to deliver care can help survivors. These solutions have the potential to transform healthcare delivery in the future and provide the opportunity for ongoing, comprehensive care.

Adults with leukemia, lymphoma, multiple myeloma, and other hematologic cancers are living longer, and more than 1.2 million patients with these cancers are alive in the United States.¹ Most adults with nonpediatric cancers are diagnosed in the fifth to seventh decade, and many now survive more than 5 years. The survival rate of patients with most hematologic cancers has doubled since 1974, transforming once-terminal diagnoses into chronic conditions. According to one estimate, there will be 18 million cancer survivors (all types of cancer) by 2022, and nearly 2 million of these will be survivors of hematologic cancers.²

Although survivors of hematologic cancers are at risk of complications of their cancer treatment, they often do not receive routine health maintenance and see their primary care providers only for acute issues.

Primary care providers can play a major role in monitoring the health of hematologic cancer survivors. This requires staying up-to-date on diagnosis, management, and surveillance in this group and being able to address their survivorship issues.³

In this article, we focus on survivorship considerations in patients with previously treated hematologic cancers, including childhood, adolescent, and young-adult cancers. We discuss the role of primary care in the multidisciplinary approach to the continuing care of these patients, and we review innovative technologic solutions to the challenges of delivering care to this group.

SURVIVORSHIP BEGINS AT DIAGNOSIS

The definition of cancer survivorship has changed in the last decade, particularly with hematologic cancers.⁴

Survivorship was once considered the time after the patient successfully completed cancer treatment. But most patients with hematologic cancers will likely need to continue treatment until they die, with essentially unpredictable and intermittent periods of remission and relapse. Advances in cancer treatment and supportive care have led to longer life. Thus, a commonly recognized definition of survivorship begins at diagnosis rather than later in the disease course and continues through the balance of the patient’s life.⁵

The survivorship care plan

In 2005, the Institute of Medicine released a report⁶ calling attention to cancer survivors and their special needs. At that time, a growing number of patients were not returning to their primary care physicians to receive health maintenance after completing their cancer treatment. A proposed solution was for the oncologist to develop a personalized survivorship care plan, which would help the patient understand the treatments received, the importance of health maintenance, and the need for follow-up surveillance.⁵

The survivorship care plan was originally intended for patients who had completed their cancer treatment. But patients with hematologic cancers tend to need lifelong treatment. Nevertheless, major organizations such as the American Society of Hematology and the American Society of Clinical Oncology consider a survivorship care plan an essential part of cancer care for all patients and not just those with solid tumors.⁷ The plan should consist of a written treatment summary and recommendations for follow-up care.

EFFECTS OF HEMATOLOGIC CANCER AND ITS TREATMENT

Hematologic cancers and their treatment put patients at risk of many complications, including endocrinopathies, such as hypothyroidism or diabetes secondary to chronic steroid and immunosuppressant use, and cardiovascular events, such as congestive heart failure and stroke due to high-dose chemotherapy. Survivors are also at risk of secondary cancers and recurrence of the primary cancer.^8–15

Despite the gravity of a cancer diagnosis, cancer patients do not always adhere to a healthy lifestyle. A survey of over 400,000 cancer survivors found that 15% were current cigarette smokers, 27.5% were obese, and 31.5% had not engaged in physical activity during the previous 30 days.¹⁶

THE PRIMARY CARE CLINICIAN AND SURVIVORSHIP CARE

Many hematologic oncology practices include not only medical oncologists but also ancillary team members such as nurse practitioners, nurse specialists, physician assistants, registered nurses, and in some cases a social worker or nutritionist. Patients with hematologic cancers often rely on this team for most of their care while undergoing cancer treatment.

Depending on the type of cancer, and especially after a period of stable disease or remission, some patients transition away from the oncology team, particularly if they live far away, and receive care from their local primary care clinician.

Although the Institute for Medicine intended the survivorship care plan⁶ to be a patient-focused tool, primary care providers can benefit from it too. In survey of oncologists and primary care providers in the United States,¹⁷ 49% of the 1,130 oncologists said they almost always provided care plans to patients, and 85% perceived a greater benefit for primary care providers to have these plans than for cancer survivors. However, only 13% of the 1,120 primary care providers surveyed said they consistently received a care plan from the oncologist. The study suggests that oncologists should make a better effort to share these plans with primary care providers to enhance the coordination of care.

COMPONENTS OF A SURVIVORSHIP CARE PLAN AND SELF-MANAGEMENT

Although personalized survivorship care plans are not routinely used in patients with blood cancers,¹⁸ they are as important in hematologic cancer survivors as in patients with solid tumors.

The plan should consist of a treatment summary and information on essential components of a healthy lifestyle and should take into consideration coordination of care among primary and other providers, health maintenance recommendations, information on early detection and screening, and psychosocial welfare. Guidance on preventive screening for physical, financial, and psychosocial well-being should be generated by the oncology team or primary care provider and can be helpful to patients and caregivers as they navigate the healthcare system. (See https://cancercontrol.cancer.gov/pdf/ASCO-Survivorship-Care-Plan.pdf for a sample survivorship care plan.)

Although patients with hematologic cancer often have a highly variable course with multiple periods of remission and relapse, the survivorship care plan and treatment summary are essential components of their ongoing care.

Self-management of chronic illness refers to daily activities to keep the illness under control, minimize its impact on physical health and function, and help the patient cope with the psychosocial sequelae of the illness.¹⁹ Empowering patients and their caregivers to take control of their health is an essential component of survivorship care. Patients and caregivers can be valuable partners to primary care providers and the oncology team in ongoing care to ensure proper testing and monitoring for secondary illnesses.

Implementation of a survivorship care plan can be facilitated by integrating the plan and treatment summaries into the patient’s electronic medical record and encouraging the patient to be a part of the process.²⁰ Many electronic medical record systems such as Epic can automatically fill in treatment summaries and provide patients access to a survivorship care plan tailored to their needs, but these features are not routinely used, and output can be lengthy and hard to follow.^21,22

There has been a surge in research in information technology and care plan delivery since the Health Information Technology for Economic and Clinical Health (HITECH) Act was passed in 2009,²³ specifically in innovative strategies to proactively screen for, assess, and manage disease- and treatment-related symptoms in cancer survivors. As a result, patients and families can be more engaged in their care, and providers can better guide survivorship concerns.

Providers can create their own survivorship care plans or use electronic resources to generate one. The American Society of Clinical Oncology and the National Comprehensive Cancer Network provide printed templates in which the patient, primary care provider, or oncology team can complete a care plan. Newer electronic platforms such as the Carevive system are also available. Brief electronic outcome questionnaires can be completed by the patient at home or in the waiting room to assess symptoms, evaluate health maintenance practices, and generate a plan of care to review with the patient.

EMERGING TECHNOLOGY: TELEMEDICINE, VIRTUAL VISITS

Technology can help patients and the healthcare team in survivorship monitoring. Telemedicine, the exchange of medical information via electronic communication, includes video conferencing for patient consultations, transmission of still images, patient portals, and remote monitoring of vital signs.²⁴

This technology is critical to deliver high-quality acute and chronic care to patients in remote or rural areas, locally to patients unable to travel to the clinic, and internationally.^25–28 As patients become more technologically savvy, providers can try novel strategies to provide patients access to care. As of September 2015, there were at least 165,000 health applications (apps) for smartphones to help patients better manage aspects of their care such as diet, exercise, blood pressure, and blood sugar levels.²⁹

Video technology such as Express Care Online allows patients to connect with their healthcare providers for video and virtual visits without having to leave home or take time off from work. It also allows oncology providers to have virtual face-to-face contact with patients undergoing treatment phases, and primary care providers to have easier contact with patients during maintenance and remission phases. This technology allows for earlier detection of illness and provides broader access to care. Virtual visits may even prevent needless hospitalization in some cases or, conversely, alert the physician to tell the patient with alarming symptoms of an acute event, that it is time to go to the hospital.

SURVEILLANCE FOR LATE TREATMENT EFFECTS

Guidelines for surveillance for late treatment effects include the following:

• Children’s Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer³⁰
• National Comprehensive Cancer Network Guidelines for Age-Related Recommendations: Adolescent and Young Adult Oncology³¹
• National Comprehensive Cancer Network Guidelines for Treatment of Cancer by Site and Survivorship³¹
• American Society for Blood and Marrow Transplantation, for survivors of hematopoietic cell transplantation.³²

Survivors of childhood blood cancers are at increased risk of cardiac effects of high-dose or anthracycline chemotherapy (eg, doxorubicin for lymphoma, idarubicin for leukemia), skin cancer, sex-specific cancers (breast cancer, cervical cancer, prostate cancer), and osteoporosis.^5,30,33,34

For adult survivors of childhood cancers, it is generally recommended to screen for secondary conditions according to the US Preventive Services Task Force. The clinician must also consider the age at cancer diagnosis (child, young adult, or adult), the length of time since chemotherapy (months vs years), and the type of chemotherapy received.

A myriad of recommendations exist according to cancer type, location, stage, and age at diagnosis, but no clear consensus for screening exists. The major survivorship surveillance guidelines of the Children’s Oncology Group, National Comprehensive Cancer Network, and American Society for Blood and Marrow Transplantation are very detailed and lengthy and therefore not user-friendly for the busy clinician. While these guidelines contain minor differences as to what to test for and when to test, they differ mainly in considerations of the length of exposure to chemotherapy and radiation (eg, children, young adults, and older adults), length of time from completion of treatment to assessment of late complications, and whether the patient underwent hematopoietic stem cell transplant.^35,36

Table 1 reviews hematologic malignancies and conditions that blood cancer survivors are at risk for and general routine screening recommendations.^{5,22,30,33,34,36–39} In general, an assessment by a healthcare provider is recommended annually to screen for late effects of cancer and its treatment. Most important are screening for cardiac toxicity, giving immunizations, and preventing second cancers.

Table 1 reflects general recommendations for healthcare screening in childhood, adolescent, or young adult cancer survivors who see adult primary care physicians and for adult cancer survivors (acute leukemias, lymphomas, and multiple myeloma).

Table 2 focuses on screening and prevention specifically after hematopoietic cell transplantation.^30,32 These tables are not meant to be all-inclusive but to provide evidence-based recommendations for health surveillance at a glance.

SURVIVORS NEED ONGOING CARE

Recent successes in the treatment of hematologic cancers have led to dramatic changes in the overall health of these patients. In many instances, cancer survivors in the United States are considered to have a chronic illness with survival rates surpassing those in the past. A longer life span is counterbalanced by cumulative physical, financial, and psychosocial issues that require a multidisciplinary team to monitor and manage.

Childhood cancer survivors face the same psychosocial and financial issues as survivors of adult-onset cancers and are at heightened risk of preventable conditions. Ultimately, it is up to the survivor to self-manage many long-term treatment-related symptoms.

A survivorship care plan and treatment summary to guide the patient, primary provider, and oncology team is an essential component of quality care. Screening guidelines vary according to the age at treatment and length of time from therapy, but general screening and the use of technology and information technology solutions to deliver care can help survivors. These solutions have the potential to transform healthcare delivery in the future and provide the opportunity for ongoing, comprehensive care.

A healthy 16-year-old boy presented with muscle pain and weakness in the chest and both arms after performing 50 push-ups daily for 3 days, and the symptoms did not seem to improve after 3 days.

EXERCISE-INDUCED RHABDOMYOLYSIS

Approximately 50% of patients with rhabdomyolysis present with the characteristic triad of myalgia (84%), muscle weakness (73%), and dark urine (80%), and 8.1% to 52% present with muscle swelling.¹ Rhabdomyolysis may be caused by exercise,² and risk factors include physical deconditioning, high ambient temperature, high humidity, impaired sweating (due to anticholinergic drugs), sickle cell trait, and hypokalemia from sweating.² Pain and swelling of the affected focal muscles is the chief complaint.³

Although acute renal failure in exercise-induced rhabdomyolysis is rare, failure to recognize rhabdomyolysis can cause diagnostic delay and inappropriate treatment.⁴

In healthy people, exercise-induced muscle damage begins to resolve within 1 to 3 days.^5,6 Physicians should suspect exercise-induced rhabdomyolysis in patients with prolonged muscle swelling and tenderness in affected muscles that lasts longer than expected.⁷

A healthy 16-year-old boy presented with muscle pain and weakness in the chest and both arms after performing 50 push-ups daily for 3 days, and the symptoms did not seem to improve after 3 days.

EXERCISE-INDUCED RHABDOMYOLYSIS

Approximately 50% of patients with rhabdomyolysis present with the characteristic triad of myalgia (84%), muscle weakness (73%), and dark urine (80%), and 8.1% to 52% present with muscle swelling.¹ Rhabdomyolysis may be caused by exercise,² and risk factors include physical deconditioning, high ambient temperature, high humidity, impaired sweating (due to anticholinergic drugs), sickle cell trait, and hypokalemia from sweating.² Pain and swelling of the affected focal muscles is the chief complaint.³

Although acute renal failure in exercise-induced rhabdomyolysis is rare, failure to recognize rhabdomyolysis can cause diagnostic delay and inappropriate treatment.⁴

In healthy people, exercise-induced muscle damage begins to resolve within 1 to 3 days.^5,6 Physicians should suspect exercise-induced rhabdomyolysis in patients with prolonged muscle swelling and tenderness in affected muscles that lasts longer than expected.⁷

A healthy 16-year-old boy presented with muscle pain and weakness in the chest and both arms after performing 50 push-ups daily for 3 days, and the symptoms did not seem to improve after 3 days.

EXERCISE-INDUCED RHABDOMYOLYSIS

Approximately 50% of patients with rhabdomyolysis present with the characteristic triad of myalgia (84%), muscle weakness (73%), and dark urine (80%), and 8.1% to 52% present with muscle swelling.¹ Rhabdomyolysis may be caused by exercise,² and risk factors include physical deconditioning, high ambient temperature, high humidity, impaired sweating (due to anticholinergic drugs), sickle cell trait, and hypokalemia from sweating.² Pain and swelling of the affected focal muscles is the chief complaint.³

Although acute renal failure in exercise-induced rhabdomyolysis is rare, failure to recognize rhabdomyolysis can cause diagnostic delay and inappropriate treatment.⁴

In healthy people, exercise-induced muscle damage begins to resolve within 1 to 3 days.^5,6 Physicians should suspect exercise-induced rhabdomyolysis in patients with prolonged muscle swelling and tenderness in affected muscles that lasts longer than expected.⁷

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS