Q) The billing consultant who came to our office said we can increase our reimbursements if we also provide education to our patients with chronic kidney disease (CKD). Is she right?

In 2010, under an omnibus bill, kidney disease education (KDE) classes were added as a Medicare benefit. These are for patients with stage 4 CKD (glomerular filtration rate, 15-30 mL/min) and are to be taught by a qualified instructor (MD, PA, NP, or CNS).

The classes can be taught on the same day as an evaluation/management visit (ie, a regular office visit) and are compensated by the hour. (Side note: Medicare defines an hour as 31 minutes—yes, 31 minutes; Medicare takes for granted that you will also need time to chart!) You can teach two classes in the same day. Thus, if you wanted to, you could have a patient arrive for an office visit, then teach two 31-minute classes, and bill all three for the same day. The entire visit could be 75 minutes (although this may be exhausting for this population).

You can conduct the classes in a number of settings, including nursing homes, hospitals, skilled nursing facilities, the office, or even the patient’s home. Many PAs and NPs have taught these classes to hospitalized patients who have lost kidney function due to an acute insult (ie, medications, dehydration, contrast).

Each Medicare recipient has a lifetime benefit of six KDE classes. The CPT billing code is G0420 for an individual class and G0421 for a group class. You must make sure you also code for the stage 4 CKD diagnosis (code: 585.4).

Congress stipulated KDE classes must include information on causes, symptoms, and treatments and comprise a posttest at a specific health literacy level. To make it simple, the National Kidney Foundation Council of Advanced Practitioners (NKF-CAP) has developed two free Power-Point slide decks for clinicians to use in KDE classes (available at www.kidney.org/professionals/CAP/sub_resources#kde). References and updated peer-reviewed guidelines are included. You can print the slides for your patients and/or share the program with your colleagues.

Many nephrology practitioners teach the two slide sets over and over, because patients only retain one-third of the info we provide them on a given day. So if you teach each slide set three times, you have six lifetime classes—and hopefully the patient will have retained everything.

One caveat: Before you initiate KDE classes for a specific patient, check with the patient’s nephrology group (we hope at stage 4 the patient has a nephrologist) to see if they are providing the education. —KZ and JD

Kim Zuber, PA-C, MSPS, DFAAPA
American Academy of Nephrology PAs

Jane S. Davis, CRNP, DNP
Division of Nephrology at the University of Alabama
National Kidney Foundation's Council of Advanced Practitioners

Q) The billing consultant who came to our office said we can increase our reimbursements if we also provide education to our patients with chronic kidney disease (CKD). Is she right?

In 2010, under an omnibus bill, kidney disease education (KDE) classes were added as a Medicare benefit. These are for patients with stage 4 CKD (glomerular filtration rate, 15-30 mL/min) and are to be taught by a qualified instructor (MD, PA, NP, or CNS).

The classes can be taught on the same day as an evaluation/management visit (ie, a regular office visit) and are compensated by the hour. (Side note: Medicare defines an hour as 31 minutes—yes, 31 minutes; Medicare takes for granted that you will also need time to chart!) You can teach two classes in the same day. Thus, if you wanted to, you could have a patient arrive for an office visit, then teach two 31-minute classes, and bill all three for the same day. The entire visit could be 75 minutes (although this may be exhausting for this population).

You can conduct the classes in a number of settings, including nursing homes, hospitals, skilled nursing facilities, the office, or even the patient’s home. Many PAs and NPs have taught these classes to hospitalized patients who have lost kidney function due to an acute insult (ie, medications, dehydration, contrast).

Each Medicare recipient has a lifetime benefit of six KDE classes. The CPT billing code is G0420 for an individual class and G0421 for a group class. You must make sure you also code for the stage 4 CKD diagnosis (code: 585.4).

Congress stipulated KDE classes must include information on causes, symptoms, and treatments and comprise a posttest at a specific health literacy level. To make it simple, the National Kidney Foundation Council of Advanced Practitioners (NKF-CAP) has developed two free Power-Point slide decks for clinicians to use in KDE classes (available at www.kidney.org/professionals/CAP/sub_resources#kde). References and updated peer-reviewed guidelines are included. You can print the slides for your patients and/or share the program with your colleagues.

Many nephrology practitioners teach the two slide sets over and over, because patients only retain one-third of the info we provide them on a given day. So if you teach each slide set three times, you have six lifetime classes—and hopefully the patient will have retained everything.

One caveat: Before you initiate KDE classes for a specific patient, check with the patient’s nephrology group (we hope at stage 4 the patient has a nephrologist) to see if they are providing the education. —KZ and JD

Kim Zuber, PA-C, MSPS, DFAAPA
American Academy of Nephrology PAs

Jane S. Davis, CRNP, DNP
Division of Nephrology at the University of Alabama
National Kidney Foundation's Council of Advanced Practitioners

Q) The billing consultant who came to our office said we can increase our reimbursements if we also provide education to our patients with chronic kidney disease (CKD). Is she right?

In 2010, under an omnibus bill, kidney disease education (KDE) classes were added as a Medicare benefit. These are for patients with stage 4 CKD (glomerular filtration rate, 15-30 mL/min) and are to be taught by a qualified instructor (MD, PA, NP, or CNS).

The classes can be taught on the same day as an evaluation/management visit (ie, a regular office visit) and are compensated by the hour. (Side note: Medicare defines an hour as 31 minutes—yes, 31 minutes; Medicare takes for granted that you will also need time to chart!) You can teach two classes in the same day. Thus, if you wanted to, you could have a patient arrive for an office visit, then teach two 31-minute classes, and bill all three for the same day. The entire visit could be 75 minutes (although this may be exhausting for this population).

You can conduct the classes in a number of settings, including nursing homes, hospitals, skilled nursing facilities, the office, or even the patient’s home. Many PAs and NPs have taught these classes to hospitalized patients who have lost kidney function due to an acute insult (ie, medications, dehydration, contrast).

Each Medicare recipient has a lifetime benefit of six KDE classes. The CPT billing code is G0420 for an individual class and G0421 for a group class. You must make sure you also code for the stage 4 CKD diagnosis (code: 585.4).

Congress stipulated KDE classes must include information on causes, symptoms, and treatments and comprise a posttest at a specific health literacy level. To make it simple, the National Kidney Foundation Council of Advanced Practitioners (NKF-CAP) has developed two free Power-Point slide decks for clinicians to use in KDE classes (available at www.kidney.org/professionals/CAP/sub_resources#kde). References and updated peer-reviewed guidelines are included. You can print the slides for your patients and/or share the program with your colleagues.

Many nephrology practitioners teach the two slide sets over and over, because patients only retain one-third of the info we provide them on a given day. So if you teach each slide set three times, you have six lifetime classes—and hopefully the patient will have retained everything.

One caveat: Before you initiate KDE classes for a specific patient, check with the patient’s nephrology group (we hope at stage 4 the patient has a nephrologist) to see if they are providing the education. —KZ and JD

Kim Zuber, PA-C, MSPS, DFAAPA
American Academy of Nephrology PAs

Jane S. Davis, CRNP, DNP
Division of Nephrology at the University of Alabama
National Kidney Foundation's Council of Advanced Practitioners

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD

Photo courtesy of ASH

ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.

Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.

The research suggested these patients will not benefit from further chemotherapy intensification.

Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).

She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.

Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).

At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.

Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.

Response and survival

Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.

Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.

For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).

Survival according to cytogenetics

Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).

And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.

For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).

For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).

For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).

For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).

Survival according to risk group and MRD

The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.

“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.

“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”

The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).

Standard-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.

High-risk group

Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.

Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.

Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.

In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.

She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.

And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.

CASE 1 › George D is a 67-year-old patient who has never smoked and who has no history of malignancy. An x-ray of his ribs performed after a fall shows a 13-mm solitary nodule in his right upper lung.

CASE 2 › Cathy B is a healthy 80-year-old with no history of smoking. During a trip to the emergency department for chest pain, she had a computed tomography (CT) scan of her chest. While the chest pain was subsequently attributed to gastroesophageal reflux, the CT revealed a 9-mm part solid nodule that was 75% solid.

How should the physicians caring for each of these patients proceed with their care?

The widespread use of sensitive imaging techniques often leads to the incidental discovery of unrelated—but possibly significant—pulmonary findings. Pulmonary nodules are incidentally discovered on an estimated 0.09% to 0.2% of all chest x-rays, 13% of all chest CT angiograms,¹ 31% of all cardiac CTs performed for coronary calcium scoring,² and up to 50% of thin-section chest CT scans.¹

The widespread implementation of the US Preventive Services Task Force recommendations on lung cancer screening has further expanded the number of patients in whom asymptomatic pulmonary nodules will be detected. As a result, family physicians (FPs) will frequently encounter this challenging clinical dilemma and will need to:

• assess the patient’s risk profile
• address the patient’s concerns about malignancy while eliciting his or her preference for management
• minimize the risks of surveillance testing
• minimize patient distress while ensuring compliance with a follow-up that may extend up to 4 years
• determine when it’s appropriate to refer the patient to a pulmonologist and/or pulmonary nodule clinic or registry.

Taking these steps, however, can be challenging. In interviews, 15 primary care clinicians who care for patients with pulmonary nodules expressed concerns about limitations in time, knowledge, and resources, as well as a fear about such patients “falling through the cracks.”³ Familiarity with current evidence-based guidelines such as those from the American College of Chest Physicians (ACCP) and knowledge of emerging data on the management of various types of nodules are imperative.

To that end, this review will fill in the information gaps and provide guidance on how best to communicate what is known about a particular type of nodule with the patient who has one. (See “What to say to improve joint decision-making.”^4-7) But first, a word about terminology.

Solid vs subsolid pulmonary nodules

Solid pulmonary nodules. Traditionally, the term “solitary pulmonary nodule” has been used to describe a single, well-circumscribed, radiographic opacity that measures up to 3 cm in diameter and is completely surrounded by aerated lung.^1,8 The term “solitary” is now less useful because increasingly sensitive imaging techniques often reveal more than one nodule. In the absence of evidence of features that strongly suggest a benign etiology, these are now commonly referred to as indeterminate solid nodules.

If a solid nodule shows evidence of malignant growth on serial imaging, nonsurgical biopsy or surgical resection is recommended.

Subsolid nodules are pulmonary nodules that have unique characteristics and require separate guidelines for management. Subsolid nodules include pure ground glass nodules (GGNs) and part solid nodules. GGNs are focal nodular areas of increased lung attenuation through which normal parenchymal structures such as airways, vessels, and interlobular septa can be visualized.^1,8 Part solid nodules have a solid component. They are usually, but not necessarily, >50% ground glass in appearance.

Lung masses. Focal pulmonary lesions >3 cm in diameter are called lung masses and are presumed to be malignant (bronchogenic carcinoma) unless proven otherwise.^1,8

The specific approach to evaluating and monitoring a pulmonary nodule varies depending on whether the nodule is solid or subsolid and other factors, including the nodule’s size.

Monitoring solid nodules

Monitoring of an indeterminate solid nodule is largely determined by the patient’s risk profile and the characteristics of the identified nodule.¹ Independent patient predictors of malignancy include older age, smoking status, and history of prior malignancy (>5 years ago). Less established predictors are the presence of moderate or severe obstructive lung disease and exposure to particulate or sulfur oxide-related pollution.⁹

Patients who have an indeterminate nodule identified on chest x-ray should undergo a chest CT scan, preferably with thin sections through the nodule to help characterize it.¹ Nodule characteristics that can help predict a patient’s risk of malignancy include the size (>8 mm confers higher risk), malignant rate of growth, edge characteristics (spiculation or irregular edges), thickness of the wall of a cavitary pulmonary nodule (≥16 mm has a likelihood ratio [LR] 37.97 of malignancy), and the location of the nodule (upper or middle lobe [LR=1.2 to 1.6]). ¹⁰ A lack of growth over 2 years and a benign pattern of calcification eliminate the need for further evaluation.

Validated tools to help guide decision-making. Although many physicians estimate pretest probability of malignancy intuitively, validated tools are readily available and can help in clinical decision-making.¹¹ One such tool is the Mayo model, which is available at http://reference.medscape.com/calculator/solitary-pulmonary-nodule-risk. This model takes into account the patient’s age, smoking status, history of cancer, and characteristics of the nodule.

Solid nodules >8 mm to 3 cm

For a patient with a solid nodule >8 mm to 3 cm, ACCP guidelines suggest that physicians estimate the pretest probability of malignancy qualitatively using their clinical judgment and/or quantitatively by using a validated model, such as the Mayo model described above.

Based on the patient’s probability of malignancy, management options include continued CT surveillance, positron emission tomography (PET) imaging, CT-guided needle lung biopsy, bronchoscopy with biopsy, or surgical wedge resection (ALGORITHM 1).¹

CT surveillance is recommended for individuals:

• with very low (<5%) probability of malignancy
• with low to moderate (5% to 30%) or moderate to high (31% to 65%) probability of malignancy with negative functional imaging (PET)
• with high probability of malignancy (>65%) when needle biopsy is nondiagnostic and the lesion is not hypermetabolic on PET scan.

Surveillance is also recommended when a fully informed patient prefers nonaggressive management. The intervals for serial CT in this population are at 3 to 6 months, 9 to 12 months, and 18 to 24 months.

In an individual with a solid indeterminate nodule with a high probability of malignancy (>65%), functional imaging should not be performed to characterize the nodule. It may, however, be performed for staging.

Time for biopsy or resection? If a nodule shows evidence of malignant growth on serial imaging, nonsurgical biopsy (CT scan-guided transthoracic needle biopsy, bronchoscopy guided by fluoroscopy, endobronchial ultrasound, electromagnetic navigation bronchoscopy, or virtual bronchoscopy navigation) or surgical resection is recommended.

Nonsurgical biopsy is also recommended when the patient’s pretest probability and imaging test results are discordant, when a benign diagnosis requires specific medical treatment, or if a fully informed patient desires proof of diagnosis prior to surgery.

Thoracoscopy with wedge resection is the gold standard for diagnosis of a malignant nodule. It is recommended:

• when the clinical probability of malignancy is high (>65%)
• when the nodule is intensely hypermetabolic by PET scan or positive by other functional imaging tests
• when nonsurgical biopsy is suggestive of malignancy
• when a fully informed patient prefers a definitive diagnostic procedure.

CASE 1 › The FP contacts Mr. D and advises that he get a chest CT to better characterize his pulmonary nodule. A thin-slice CT of the lung reveals that the 13-mm solid nodule in the right upper lobe has spiculated margins. According to the Mayo risk calculator, Mr. D is at moderate risk of malignancy (32.5%). Mr. D and his physician discuss the findings and possible management options, and Mr. D opts to have a PET scan. The FP gives Mr. D literature on pulmonary nodules and contact information for the provider team. A PET scan shows negative uptake. Mr. D and his physician discuss CT surveillance and nonsurgical biopsy. He opts for CT surveillance. The next CT is scheduled for 3 months.

Solid nodules ≤8 mm

Management of these lesions generally follows the consensus-based guidelines that were first published by the Fleischner Society and subsequently endorsed by the ACCP.¹ The 2 main determinants that guide management of nodules ≤8 mm are the patient’s risk factors for cancer and nodule size (ALGORITHM 2).¹ The Fleischner guidelines pertain only to patients older than age 35 with no current extra pulmonary malignancy or unexplained fevers. The ACCP guidelines, although similar, do not include these limitations. Patient risk factors include history of smoking, older age, and a history of malignancy.¹

Patients with no risk factors for malignancy. The frequency of surveillance CT is determined by the size of the nodule. Nodules ≤4 mm do not need to be followed. For nodules >4 mm to 6 mm, a repeat CT in 12 months is recommended with no follow-up if stable. For nodules >6 to <8 mm, repeat CT is recommended at 6 to 12 months, and again between 18 and 24 months if unchanged.¹Patients with one or more risk factors for malignancy. Nodules ≤4 mm should be reevaluated at 12 months in patients with one or more risk factors; no additional follow-up is needed if unchanged. For nodules >4 mm to 6 mm, CT should be repeated between 6 and 12 months and again between 18 and 24 months. Nodules >6 mm to <8 mm should be followed initially between 3 to 6 months, then between 9 and 12 months and again at 24 months if unchanged.¹

Subsolid nodules have a high prevalence of premalignant and malignant disease.

Subsolid nodules require a different approach

Subsolid nodules have a high prevalence of premalignant and malignant disease (adenocarcinoma in situ, minimally invasive adenocarcinoma, and adenocarcinoma). Studies have reported subsolid nodule malignancy rates ranging from 20% to 75%.^11-15 This wide range may be a function of different nodule sizes or rates of biopsy. The prevalence increases even further in nodules with a part solid component.

These factors, plus challenges in measuring serial growth on CT and the uncertain prognosis of untreated premalignant disease, make it necessary to have separate guidelines for managing subsolid nodules. The Fleischner Society, National Comprehensive Cancer Network, and the American College of Radiology (LungRads) each have differing recommendations on the frequency of follow-up for different-sized subsolid nodules. Newer studies favor a more conservative approach.¹⁶ Here we describe the current ACCP guidelines for managing subsolid nodules (ALGORITHM 3).¹

GGNs. In an individual with a pure GGN ≤5 mm in diameter, no further evaluation is recommended. In an individual with a pure GGN >5 mm in diameter, annual surveillance with chest CT for at least 3 years is recommended.¹

Part solid nodules. In an individual with a part solid nodule ≤8 mm, conduct CT surveillance at 3, 12, and 24 months and then annually for an additional one to 3 years. In a patient with a part solid nodule >8 mm to 15 mm, repeat chest CT at 3 months followed by a PET scan, nonsurgical biopsy, and/or surgical resection if the nodule persists. A patient with a part solid nodule >15 mm should undergo a PET scan, nonsurgical biopsy, and/or surgical resection.

CASE 2 › Ms. G is seen in the office by her FP, and they discuss management options. A repeat CT is done in 3 months and shows a persistent, unchanged nodule. Ms. G opts for a transthoracic biopsy, which reveals adenocarcinoma. Following a PET scan, which shows no evidence of metastasis, curative surgical wedge resection is done.

Multiple subsolid nodules. In a patient who has a dominant nodule and one or more additional nodules, each nodule should be evaluated individually, according to recommendations from the Fleischner Society (the ACCP currently does not have guidelines for managing multiple subsolid nodules). An individual with multiple GGNs that all measure ≤5 mm should receive CT exams at 2 and 4 years.¹³ A patient with multiple GGNs that include at least one nodule >5 mm but no dominant nodule should undergo follow-up CT at 3 months and annual CT surveillance for at least 3 years.¹³

CORRESPONDENCE
Samina Yunus, MD, MPH, Cleveland Clinic, Family Medicine, 551 East Washington Street, Chagrin Falls, OH 44022; [email protected].

CASE 1 › George D is a 67-year-old patient who has never smoked and who has no history of malignancy. An x-ray of his ribs performed after a fall shows a 13-mm solitary nodule in his right upper lung.

CASE 2 › Cathy B is a healthy 80-year-old with no history of smoking. During a trip to the emergency department for chest pain, she had a computed tomography (CT) scan of her chest. While the chest pain was subsequently attributed to gastroesophageal reflux, the CT revealed a 9-mm part solid nodule that was 75% solid.

How should the physicians caring for each of these patients proceed with their care?

The widespread use of sensitive imaging techniques often leads to the incidental discovery of unrelated—but possibly significant—pulmonary findings. Pulmonary nodules are incidentally discovered on an estimated 0.09% to 0.2% of all chest x-rays, 13% of all chest CT angiograms,¹ 31% of all cardiac CTs performed for coronary calcium scoring,² and up to 50% of thin-section chest CT scans.¹

The widespread implementation of the US Preventive Services Task Force recommendations on lung cancer screening has further expanded the number of patients in whom asymptomatic pulmonary nodules will be detected. As a result, family physicians (FPs) will frequently encounter this challenging clinical dilemma and will need to:

• assess the patient’s risk profile
• address the patient’s concerns about malignancy while eliciting his or her preference for management
• minimize the risks of surveillance testing
• minimize patient distress while ensuring compliance with a follow-up that may extend up to 4 years
• determine when it’s appropriate to refer the patient to a pulmonologist and/or pulmonary nodule clinic or registry.

Taking these steps, however, can be challenging. In interviews, 15 primary care clinicians who care for patients with pulmonary nodules expressed concerns about limitations in time, knowledge, and resources, as well as a fear about such patients “falling through the cracks.”³ Familiarity with current evidence-based guidelines such as those from the American College of Chest Physicians (ACCP) and knowledge of emerging data on the management of various types of nodules are imperative.

To that end, this review will fill in the information gaps and provide guidance on how best to communicate what is known about a particular type of nodule with the patient who has one. (See “What to say to improve joint decision-making.”^4-7) But first, a word about terminology.

Solid vs subsolid pulmonary nodules

Solid pulmonary nodules. Traditionally, the term “solitary pulmonary nodule” has been used to describe a single, well-circumscribed, radiographic opacity that measures up to 3 cm in diameter and is completely surrounded by aerated lung.^1,8 The term “solitary” is now less useful because increasingly sensitive imaging techniques often reveal more than one nodule. In the absence of evidence of features that strongly suggest a benign etiology, these are now commonly referred to as indeterminate solid nodules.

If a solid nodule shows evidence of malignant growth on serial imaging, nonsurgical biopsy or surgical resection is recommended.

Subsolid nodules are pulmonary nodules that have unique characteristics and require separate guidelines for management. Subsolid nodules include pure ground glass nodules (GGNs) and part solid nodules. GGNs are focal nodular areas of increased lung attenuation through which normal parenchymal structures such as airways, vessels, and interlobular septa can be visualized.^1,8 Part solid nodules have a solid component. They are usually, but not necessarily, >50% ground glass in appearance.

Lung masses. Focal pulmonary lesions >3 cm in diameter are called lung masses and are presumed to be malignant (bronchogenic carcinoma) unless proven otherwise.^1,8

The specific approach to evaluating and monitoring a pulmonary nodule varies depending on whether the nodule is solid or subsolid and other factors, including the nodule’s size.

Monitoring solid nodules

Monitoring of an indeterminate solid nodule is largely determined by the patient’s risk profile and the characteristics of the identified nodule.¹ Independent patient predictors of malignancy include older age, smoking status, and history of prior malignancy (>5 years ago). Less established predictors are the presence of moderate or severe obstructive lung disease and exposure to particulate or sulfur oxide-related pollution.⁹

Patients who have an indeterminate nodule identified on chest x-ray should undergo a chest CT scan, preferably with thin sections through the nodule to help characterize it.¹ Nodule characteristics that can help predict a patient’s risk of malignancy include the size (>8 mm confers higher risk), malignant rate of growth, edge characteristics (spiculation or irregular edges), thickness of the wall of a cavitary pulmonary nodule (≥16 mm has a likelihood ratio [LR] 37.97 of malignancy), and the location of the nodule (upper or middle lobe [LR=1.2 to 1.6]). ¹⁰ A lack of growth over 2 years and a benign pattern of calcification eliminate the need for further evaluation.

Validated tools to help guide decision-making. Although many physicians estimate pretest probability of malignancy intuitively, validated tools are readily available and can help in clinical decision-making.¹¹ One such tool is the Mayo model, which is available at http://reference.medscape.com/calculator/solitary-pulmonary-nodule-risk. This model takes into account the patient’s age, smoking status, history of cancer, and characteristics of the nodule.

Solid nodules >8 mm to 3 cm

For a patient with a solid nodule >8 mm to 3 cm, ACCP guidelines suggest that physicians estimate the pretest probability of malignancy qualitatively using their clinical judgment and/or quantitatively by using a validated model, such as the Mayo model described above.

Based on the patient’s probability of malignancy, management options include continued CT surveillance, positron emission tomography (PET) imaging, CT-guided needle lung biopsy, bronchoscopy with biopsy, or surgical wedge resection (ALGORITHM 1).¹

CT surveillance is recommended for individuals:

• with very low (<5%) probability of malignancy
• with low to moderate (5% to 30%) or moderate to high (31% to 65%) probability of malignancy with negative functional imaging (PET)
• with high probability of malignancy (>65%) when needle biopsy is nondiagnostic and the lesion is not hypermetabolic on PET scan.

Surveillance is also recommended when a fully informed patient prefers nonaggressive management. The intervals for serial CT in this population are at 3 to 6 months, 9 to 12 months, and 18 to 24 months.

In an individual with a solid indeterminate nodule with a high probability of malignancy (>65%), functional imaging should not be performed to characterize the nodule. It may, however, be performed for staging.

Time for biopsy or resection? If a nodule shows evidence of malignant growth on serial imaging, nonsurgical biopsy (CT scan-guided transthoracic needle biopsy, bronchoscopy guided by fluoroscopy, endobronchial ultrasound, electromagnetic navigation bronchoscopy, or virtual bronchoscopy navigation) or surgical resection is recommended.

Nonsurgical biopsy is also recommended when the patient’s pretest probability and imaging test results are discordant, when a benign diagnosis requires specific medical treatment, or if a fully informed patient desires proof of diagnosis prior to surgery.

Thoracoscopy with wedge resection is the gold standard for diagnosis of a malignant nodule. It is recommended:

• when the clinical probability of malignancy is high (>65%)
• when the nodule is intensely hypermetabolic by PET scan or positive by other functional imaging tests
• when nonsurgical biopsy is suggestive of malignancy
• when a fully informed patient prefers a definitive diagnostic procedure.

CASE 1 › The FP contacts Mr. D and advises that he get a chest CT to better characterize his pulmonary nodule. A thin-slice CT of the lung reveals that the 13-mm solid nodule in the right upper lobe has spiculated margins. According to the Mayo risk calculator, Mr. D is at moderate risk of malignancy (32.5%). Mr. D and his physician discuss the findings and possible management options, and Mr. D opts to have a PET scan. The FP gives Mr. D literature on pulmonary nodules and contact information for the provider team. A PET scan shows negative uptake. Mr. D and his physician discuss CT surveillance and nonsurgical biopsy. He opts for CT surveillance. The next CT is scheduled for 3 months.

Solid nodules ≤8 mm

Management of these lesions generally follows the consensus-based guidelines that were first published by the Fleischner Society and subsequently endorsed by the ACCP.¹ The 2 main determinants that guide management of nodules ≤8 mm are the patient’s risk factors for cancer and nodule size (ALGORITHM 2).¹ The Fleischner guidelines pertain only to patients older than age 35 with no current extra pulmonary malignancy or unexplained fevers. The ACCP guidelines, although similar, do not include these limitations. Patient risk factors include history of smoking, older age, and a history of malignancy.¹

Patients with no risk factors for malignancy. The frequency of surveillance CT is determined by the size of the nodule. Nodules ≤4 mm do not need to be followed. For nodules >4 mm to 6 mm, a repeat CT in 12 months is recommended with no follow-up if stable. For nodules >6 to <8 mm, repeat CT is recommended at 6 to 12 months, and again between 18 and 24 months if unchanged.¹Patients with one or more risk factors for malignancy. Nodules ≤4 mm should be reevaluated at 12 months in patients with one or more risk factors; no additional follow-up is needed if unchanged. For nodules >4 mm to 6 mm, CT should be repeated between 6 and 12 months and again between 18 and 24 months. Nodules >6 mm to <8 mm should be followed initially between 3 to 6 months, then between 9 and 12 months and again at 24 months if unchanged.¹

Subsolid nodules have a high prevalence of premalignant and malignant disease.

Subsolid nodules require a different approach

Subsolid nodules have a high prevalence of premalignant and malignant disease (adenocarcinoma in situ, minimally invasive adenocarcinoma, and adenocarcinoma). Studies have reported subsolid nodule malignancy rates ranging from 20% to 75%.^11-15 This wide range may be a function of different nodule sizes or rates of biopsy. The prevalence increases even further in nodules with a part solid component.

These factors, plus challenges in measuring serial growth on CT and the uncertain prognosis of untreated premalignant disease, make it necessary to have separate guidelines for managing subsolid nodules. The Fleischner Society, National Comprehensive Cancer Network, and the American College of Radiology (LungRads) each have differing recommendations on the frequency of follow-up for different-sized subsolid nodules. Newer studies favor a more conservative approach.¹⁶ Here we describe the current ACCP guidelines for managing subsolid nodules (ALGORITHM 3).¹

GGNs. In an individual with a pure GGN ≤5 mm in diameter, no further evaluation is recommended. In an individual with a pure GGN >5 mm in diameter, annual surveillance with chest CT for at least 3 years is recommended.¹

Part solid nodules. In an individual with a part solid nodule ≤8 mm, conduct CT surveillance at 3, 12, and 24 months and then annually for an additional one to 3 years. In a patient with a part solid nodule >8 mm to 15 mm, repeat chest CT at 3 months followed by a PET scan, nonsurgical biopsy, and/or surgical resection if the nodule persists. A patient with a part solid nodule >15 mm should undergo a PET scan, nonsurgical biopsy, and/or surgical resection.

CASE 2 › Ms. G is seen in the office by her FP, and they discuss management options. A repeat CT is done in 3 months and shows a persistent, unchanged nodule. Ms. G opts for a transthoracic biopsy, which reveals adenocarcinoma. Following a PET scan, which shows no evidence of metastasis, curative surgical wedge resection is done.

Multiple subsolid nodules. In a patient who has a dominant nodule and one or more additional nodules, each nodule should be evaluated individually, according to recommendations from the Fleischner Society (the ACCP currently does not have guidelines for managing multiple subsolid nodules). An individual with multiple GGNs that all measure ≤5 mm should receive CT exams at 2 and 4 years.¹³ A patient with multiple GGNs that include at least one nodule >5 mm but no dominant nodule should undergo follow-up CT at 3 months and annual CT surveillance for at least 3 years.¹³

CORRESPONDENCE
Samina Yunus, MD, MPH, Cleveland Clinic, Family Medicine, 551 East Washington Street, Chagrin Falls, OH 44022; [email protected].

CASE 1 › George D is a 67-year-old patient who has never smoked and who has no history of malignancy. An x-ray of his ribs performed after a fall shows a 13-mm solitary nodule in his right upper lung.

CASE 2 › Cathy B is a healthy 80-year-old with no history of smoking. During a trip to the emergency department for chest pain, she had a computed tomography (CT) scan of her chest. While the chest pain was subsequently attributed to gastroesophageal reflux, the CT revealed a 9-mm part solid nodule that was 75% solid.

How should the physicians caring for each of these patients proceed with their care?

The widespread use of sensitive imaging techniques often leads to the incidental discovery of unrelated—but possibly significant—pulmonary findings. Pulmonary nodules are incidentally discovered on an estimated 0.09% to 0.2% of all chest x-rays, 13% of all chest CT angiograms,¹ 31% of all cardiac CTs performed for coronary calcium scoring,² and up to 50% of thin-section chest CT scans.¹

The widespread implementation of the US Preventive Services Task Force recommendations on lung cancer screening has further expanded the number of patients in whom asymptomatic pulmonary nodules will be detected. As a result, family physicians (FPs) will frequently encounter this challenging clinical dilemma and will need to:

• assess the patient’s risk profile
• address the patient’s concerns about malignancy while eliciting his or her preference for management
• minimize the risks of surveillance testing
• minimize patient distress while ensuring compliance with a follow-up that may extend up to 4 years
• determine when it’s appropriate to refer the patient to a pulmonologist and/or pulmonary nodule clinic or registry.

Taking these steps, however, can be challenging. In interviews, 15 primary care clinicians who care for patients with pulmonary nodules expressed concerns about limitations in time, knowledge, and resources, as well as a fear about such patients “falling through the cracks.”³ Familiarity with current evidence-based guidelines such as those from the American College of Chest Physicians (ACCP) and knowledge of emerging data on the management of various types of nodules are imperative.

To that end, this review will fill in the information gaps and provide guidance on how best to communicate what is known about a particular type of nodule with the patient who has one. (See “What to say to improve joint decision-making.”^4-7) But first, a word about terminology.

Solid vs subsolid pulmonary nodules

Solid pulmonary nodules. Traditionally, the term “solitary pulmonary nodule” has been used to describe a single, well-circumscribed, radiographic opacity that measures up to 3 cm in diameter and is completely surrounded by aerated lung.^1,8 The term “solitary” is now less useful because increasingly sensitive imaging techniques often reveal more than one nodule. In the absence of evidence of features that strongly suggest a benign etiology, these are now commonly referred to as indeterminate solid nodules.

If a solid nodule shows evidence of malignant growth on serial imaging, nonsurgical biopsy or surgical resection is recommended.

Subsolid nodules are pulmonary nodules that have unique characteristics and require separate guidelines for management. Subsolid nodules include pure ground glass nodules (GGNs) and part solid nodules. GGNs are focal nodular areas of increased lung attenuation through which normal parenchymal structures such as airways, vessels, and interlobular septa can be visualized.^1,8 Part solid nodules have a solid component. They are usually, but not necessarily, >50% ground glass in appearance.

Lung masses. Focal pulmonary lesions >3 cm in diameter are called lung masses and are presumed to be malignant (bronchogenic carcinoma) unless proven otherwise.^1,8

The specific approach to evaluating and monitoring a pulmonary nodule varies depending on whether the nodule is solid or subsolid and other factors, including the nodule’s size.

Monitoring solid nodules

Monitoring of an indeterminate solid nodule is largely determined by the patient’s risk profile and the characteristics of the identified nodule.¹ Independent patient predictors of malignancy include older age, smoking status, and history of prior malignancy (>5 years ago). Less established predictors are the presence of moderate or severe obstructive lung disease and exposure to particulate or sulfur oxide-related pollution.⁹

Patients who have an indeterminate nodule identified on chest x-ray should undergo a chest CT scan, preferably with thin sections through the nodule to help characterize it.¹ Nodule characteristics that can help predict a patient’s risk of malignancy include the size (>8 mm confers higher risk), malignant rate of growth, edge characteristics (spiculation or irregular edges), thickness of the wall of a cavitary pulmonary nodule (≥16 mm has a likelihood ratio [LR] 37.97 of malignancy), and the location of the nodule (upper or middle lobe [LR=1.2 to 1.6]). ¹⁰ A lack of growth over 2 years and a benign pattern of calcification eliminate the need for further evaluation.

Validated tools to help guide decision-making. Although many physicians estimate pretest probability of malignancy intuitively, validated tools are readily available and can help in clinical decision-making.¹¹ One such tool is the Mayo model, which is available at http://reference.medscape.com/calculator/solitary-pulmonary-nodule-risk. This model takes into account the patient’s age, smoking status, history of cancer, and characteristics of the nodule.

Solid nodules >8 mm to 3 cm

For a patient with a solid nodule >8 mm to 3 cm, ACCP guidelines suggest that physicians estimate the pretest probability of malignancy qualitatively using their clinical judgment and/or quantitatively by using a validated model, such as the Mayo model described above.

Based on the patient’s probability of malignancy, management options include continued CT surveillance, positron emission tomography (PET) imaging, CT-guided needle lung biopsy, bronchoscopy with biopsy, or surgical wedge resection (ALGORITHM 1).¹

CT surveillance is recommended for individuals:

• with very low (<5%) probability of malignancy
• with low to moderate (5% to 30%) or moderate to high (31% to 65%) probability of malignancy with negative functional imaging (PET)
• with high probability of malignancy (>65%) when needle biopsy is nondiagnostic and the lesion is not hypermetabolic on PET scan.

Surveillance is also recommended when a fully informed patient prefers nonaggressive management. The intervals for serial CT in this population are at 3 to 6 months, 9 to 12 months, and 18 to 24 months.

In an individual with a solid indeterminate nodule with a high probability of malignancy (>65%), functional imaging should not be performed to characterize the nodule. It may, however, be performed for staging.

Time for biopsy or resection? If a nodule shows evidence of malignant growth on serial imaging, nonsurgical biopsy (CT scan-guided transthoracic needle biopsy, bronchoscopy guided by fluoroscopy, endobronchial ultrasound, electromagnetic navigation bronchoscopy, or virtual bronchoscopy navigation) or surgical resection is recommended.

Nonsurgical biopsy is also recommended when the patient’s pretest probability and imaging test results are discordant, when a benign diagnosis requires specific medical treatment, or if a fully informed patient desires proof of diagnosis prior to surgery.

Thoracoscopy with wedge resection is the gold standard for diagnosis of a malignant nodule. It is recommended:

• when the clinical probability of malignancy is high (>65%)
• when the nodule is intensely hypermetabolic by PET scan or positive by other functional imaging tests
• when nonsurgical biopsy is suggestive of malignancy
• when a fully informed patient prefers a definitive diagnostic procedure.

CASE 1 › The FP contacts Mr. D and advises that he get a chest CT to better characterize his pulmonary nodule. A thin-slice CT of the lung reveals that the 13-mm solid nodule in the right upper lobe has spiculated margins. According to the Mayo risk calculator, Mr. D is at moderate risk of malignancy (32.5%). Mr. D and his physician discuss the findings and possible management options, and Mr. D opts to have a PET scan. The FP gives Mr. D literature on pulmonary nodules and contact information for the provider team. A PET scan shows negative uptake. Mr. D and his physician discuss CT surveillance and nonsurgical biopsy. He opts for CT surveillance. The next CT is scheduled for 3 months.

Solid nodules ≤8 mm

Management of these lesions generally follows the consensus-based guidelines that were first published by the Fleischner Society and subsequently endorsed by the ACCP.¹ The 2 main determinants that guide management of nodules ≤8 mm are the patient’s risk factors for cancer and nodule size (ALGORITHM 2).¹ The Fleischner guidelines pertain only to patients older than age 35 with no current extra pulmonary malignancy or unexplained fevers. The ACCP guidelines, although similar, do not include these limitations. Patient risk factors include history of smoking, older age, and a history of malignancy.¹

Patients with no risk factors for malignancy. The frequency of surveillance CT is determined by the size of the nodule. Nodules ≤4 mm do not need to be followed. For nodules >4 mm to 6 mm, a repeat CT in 12 months is recommended with no follow-up if stable. For nodules >6 to <8 mm, repeat CT is recommended at 6 to 12 months, and again between 18 and 24 months if unchanged.¹Patients with one or more risk factors for malignancy. Nodules ≤4 mm should be reevaluated at 12 months in patients with one or more risk factors; no additional follow-up is needed if unchanged. For nodules >4 mm to 6 mm, CT should be repeated between 6 and 12 months and again between 18 and 24 months. Nodules >6 mm to <8 mm should be followed initially between 3 to 6 months, then between 9 and 12 months and again at 24 months if unchanged.¹

Subsolid nodules have a high prevalence of premalignant and malignant disease.

Subsolid nodules require a different approach

Subsolid nodules have a high prevalence of premalignant and malignant disease (adenocarcinoma in situ, minimally invasive adenocarcinoma, and adenocarcinoma). Studies have reported subsolid nodule malignancy rates ranging from 20% to 75%.^11-15 This wide range may be a function of different nodule sizes or rates of biopsy. The prevalence increases even further in nodules with a part solid component.

These factors, plus challenges in measuring serial growth on CT and the uncertain prognosis of untreated premalignant disease, make it necessary to have separate guidelines for managing subsolid nodules. The Fleischner Society, National Comprehensive Cancer Network, and the American College of Radiology (LungRads) each have differing recommendations on the frequency of follow-up for different-sized subsolid nodules. Newer studies favor a more conservative approach.¹⁶ Here we describe the current ACCP guidelines for managing subsolid nodules (ALGORITHM 3).¹

GGNs. In an individual with a pure GGN ≤5 mm in diameter, no further evaluation is recommended. In an individual with a pure GGN >5 mm in diameter, annual surveillance with chest CT for at least 3 years is recommended.¹

Part solid nodules. In an individual with a part solid nodule ≤8 mm, conduct CT surveillance at 3, 12, and 24 months and then annually for an additional one to 3 years. In a patient with a part solid nodule >8 mm to 15 mm, repeat chest CT at 3 months followed by a PET scan, nonsurgical biopsy, and/or surgical resection if the nodule persists. A patient with a part solid nodule >15 mm should undergo a PET scan, nonsurgical biopsy, and/or surgical resection.

CASE 2 › Ms. G is seen in the office by her FP, and they discuss management options. A repeat CT is done in 3 months and shows a persistent, unchanged nodule. Ms. G opts for a transthoracic biopsy, which reveals adenocarcinoma. Following a PET scan, which shows no evidence of metastasis, curative surgical wedge resection is done.

Multiple subsolid nodules. In a patient who has a dominant nodule and one or more additional nodules, each nodule should be evaluated individually, according to recommendations from the Fleischner Society (the ACCP currently does not have guidelines for managing multiple subsolid nodules). An individual with multiple GGNs that all measure ≤5 mm should receive CT exams at 2 and 4 years.¹³ A patient with multiple GGNs that include at least one nodule >5 mm but no dominant nodule should undergo follow-up CT at 3 months and annual CT surveillance for at least 3 years.¹³

CORRESPONDENCE
Samina Yunus, MD, MPH, Cleveland Clinic, Family Medicine, 551 East Washington Street, Chagrin Falls, OH 44022; [email protected].

ANSWER
The radiograph shows diffuse osteopenia and spondylosis. Of note is a moderate to severe compression deformity of the T8 vertebral body. However, by plain radiograph, it is age indeterminate as to its acuity. For definitive diagnosis, MRI without contrast is required to assess for marrow edema, which then suggests an acute fracture.

This patient was admitted for further workup. MRI was ultimately obtained and revealed marrow edema within that vertebral body. She was treated with a rigid custom-made brace.

ANSWER
The radiograph shows diffuse osteopenia and spondylosis. Of note is a moderate to severe compression deformity of the T8 vertebral body. However, by plain radiograph, it is age indeterminate as to its acuity. For definitive diagnosis, MRI without contrast is required to assess for marrow edema, which then suggests an acute fracture.

This patient was admitted for further workup. MRI was ultimately obtained and revealed marrow edema within that vertebral body. She was treated with a rigid custom-made brace.

ANSWER
The radiograph shows diffuse osteopenia and spondylosis. Of note is a moderate to severe compression deformity of the T8 vertebral body. However, by plain radiograph, it is age indeterminate as to its acuity. For definitive diagnosis, MRI without contrast is required to assess for marrow edema, which then suggests an acute fracture.

This patient was admitted for further workup. MRI was ultimately obtained and revealed marrow edema within that vertebral body. She was treated with a rigid custom-made brace.

ANSWER
The correct answer is to obtain a biopsy (choice “d”), the results of which would likely dictate rational and effective treatment. The other choices are largely empirical and not based on available evidence.

DISCUSSION
In this case, the biopsy (with samples from the arm rash as well as from the ears) showed unequivocal evidence of connective tissue disease—almost certainly lupus.

Systemic lupus erythematosus (SLE) has protean manifestations because it can affect so many different organs in so many different ways. Reduced to its simplest elements, lupus is an autoimmune process that results in a form of vasculitis that can affect any perfused tissue.

In terms of the skin, the visible manifestations of lupus are numerous and not always obvious. Sun is a known exacerbating factor, as this case demonstrated quite well: The patient’s rash was pronounced on sun-exposed skin but spared covered skin. When this was brought to her attention, the patient recalled a baby-sitting job earlier in the year (summer) that had required her to spend time outdoors. She also acknowledged that her smoking habit often took her into the backyard, where she would stand in the sun.

That being said, neither the arm rash nor the ear changes are “typical” of lupus (although the latter did include patulous follicular orifices, enlarged pores often seen focally with lupus). The effect is simply the result of the patient’s normal dark skin color; on a white person, the discoloration would have been pink or red.

Although these changes were suspicious for lupus, it was necessary to establish the diagnosis by biopsy—especially since the patient was already being treated for the disease. With that accomplished, the patient was sent back to her rheumatologist, who indicated he would probably treat her with a biologic, plus or minus methotrexate.

ANSWER
The correct answer is to obtain a biopsy (choice “d”), the results of which would likely dictate rational and effective treatment. The other choices are largely empirical and not based on available evidence.

DISCUSSION
In this case, the biopsy (with samples from the arm rash as well as from the ears) showed unequivocal evidence of connective tissue disease—almost certainly lupus.

Systemic lupus erythematosus (SLE) has protean manifestations because it can affect so many different organs in so many different ways. Reduced to its simplest elements, lupus is an autoimmune process that results in a form of vasculitis that can affect any perfused tissue.

In terms of the skin, the visible manifestations of lupus are numerous and not always obvious. Sun is a known exacerbating factor, as this case demonstrated quite well: The patient’s rash was pronounced on sun-exposed skin but spared covered skin. When this was brought to her attention, the patient recalled a baby-sitting job earlier in the year (summer) that had required her to spend time outdoors. She also acknowledged that her smoking habit often took her into the backyard, where she would stand in the sun.

That being said, neither the arm rash nor the ear changes are “typical” of lupus (although the latter did include patulous follicular orifices, enlarged pores often seen focally with lupus). The effect is simply the result of the patient’s normal dark skin color; on a white person, the discoloration would have been pink or red.

Although these changes were suspicious for lupus, it was necessary to establish the diagnosis by biopsy—especially since the patient was already being treated for the disease. With that accomplished, the patient was sent back to her rheumatologist, who indicated he would probably treat her with a biologic, plus or minus methotrexate.

ANSWER
The correct answer is to obtain a biopsy (choice “d”), the results of which would likely dictate rational and effective treatment. The other choices are largely empirical and not based on available evidence.

DISCUSSION
In this case, the biopsy (with samples from the arm rash as well as from the ears) showed unequivocal evidence of connective tissue disease—almost certainly lupus.

Systemic lupus erythematosus (SLE) has protean manifestations because it can affect so many different organs in so many different ways. Reduced to its simplest elements, lupus is an autoimmune process that results in a form of vasculitis that can affect any perfused tissue.

In terms of the skin, the visible manifestations of lupus are numerous and not always obvious. Sun is a known exacerbating factor, as this case demonstrated quite well: The patient’s rash was pronounced on sun-exposed skin but spared covered skin. When this was brought to her attention, the patient recalled a baby-sitting job earlier in the year (summer) that had required her to spend time outdoors. She also acknowledged that her smoking habit often took her into the backyard, where she would stand in the sun.

That being said, neither the arm rash nor the ear changes are “typical” of lupus (although the latter did include patulous follicular orifices, enlarged pores often seen focally with lupus). The effect is simply the result of the patient’s normal dark skin color; on a white person, the discoloration would have been pink or red.

Although these changes were suspicious for lupus, it was necessary to establish the diagnosis by biopsy—especially since the patient was already being treated for the disease. With that accomplished, the patient was sent back to her rheumatologist, who indicated he would probably treat her with a biologic, plus or minus methotrexate.

We are all exposed to initiatives from multiple stakeholders telling us to order fewer tests. Many of these efforts to control costs and improve efficiency and quality of care are directed at populations of patients and are broad concepts: provide screening only to those most likely to benefit (eg, don’t screen for prostate cancer in men with a lifespan < 10 years); avoid procedures that provided limited benefit in controlled trials (eg, limit routine arthroscopic treatment of knee osteoarthritis); and avoid reflexive practices unlikely to improve patient outcomes (eg, eliminate routine preoperative testing before elective procedures in otherwise healthy patients).

Whether system-based changes will be implemented and have an impact remains to be determined. But I sense that with all the attention being focused on population management and healthcare practices, including an emphasis on documenting and coding our encounters with patients, whether substantive or simply digital housekeeping, we are increasingly distracted from the patient in front of us and are spending less time reviewing the principles underlying the diagnoses we make and the tests we order—just as we are taking less time to perform relevant physical examinations.¹ The latter may mostly relate to time pressures. The former, I believe, is a product of both time pressures and a false sense of confidence in our knowledge of seemingly commonplace laboratory tests.

As I lecture, work with trainees, and reflect on my own patients, I realize that we are slowly but progressively minimizing the importance of a working knowledge of the basic foundations of clinical practice—perhaps because facts can always be looked up. I am not referring to knowledge of arcane biochemical pathways, eponymous references, or the latest recommended treatment of inclusion body myositis. I am thinking instead of the value of regularly refreshing our knowledge of laboratory tests and diagnoses we frequently encounter.

Having access to multiple clinical databases literally in our pockets is likely bolstering a false sense of confidence in our knowledge. The National Library of Medicine may be only a tap on a smart phone away, but accessing it regularly is a different thing. Attending conferences and reading educational journals help to keep our broad-based knowledge of internal medicine refreshed, but time pressures may significantly limit our ability to regularly pursue these activities.

In this issue of the Journal, Drs. Moghadam-Kia et al discuss their approach to asymptomatic elevations in creatine kinase (CK). Although no longer included in the most commonly used lab panels, CK measurement is often ordered in patients taking statins, even if they have no relevant muscle-related symptoms. Thus, evaluating a patient with an asymptomatic elevated CK level is not rare. The authors delve into the clinically relevant test characteristics, and their important caveats about interpreting elevated CK levels are germane not only to the asymptomatic patient, but also to the patient being evaluated for myalgia or weakness. This latter situation is one I frequently face in both the hospital and the outpatient clinic. I am often asked to consult on patients who have incompletely defined symptoms and elevated CK.

As discussed in the article, the laboratory definition of “normal” must first be considered. Laboratory test results must always be interpreted in the clinical context. An isolated elevation in parathyroid hormone cannot be interpreted without knowing the patient’s vitamin D level. Nor can “normal” low-density lipoprotein or serum urate levels be interpreted properly without knowing if the patient is accumulating excess cholesterol or urate deposits. As we order and interpret test results, we must consider the biology of the substance being measured as well as the test characteristics; too often, we react to abnormal laboratory results with an incomplete understanding of these aspects.

Moghadam-Kia et al do not dwell on the organ involvement causing CK elevations, but specificity is another very important aspect when clinically interpreting the results of a CK test. Many patients with muscle damage or inflammation have elevations in serum aspartate aminotransferase and alanine aminotransferase levels (the ratio of elevation depends on the time course of the muscle damage and on the relative clearance rate of the two enzymes). Without knowing that the CK is elevated, one might assume that an aminotransferase elevation reflects hepatitis. I have seen several patients with elevated aminotransferases and complaints of weakness and fatigue who were subjected to liver biopsy before it was recognized that the source of the enzyme elevation (“liver function test changes”) was muscle (or hemolysis). Frequently unrecognized is that aldolase, which has a cell distribution similar to that of lactate dehydrogenase, does not have the relative specificity of localization to muscle that CK has. CK is quite useful in distinguishing myocyte from hepatocyte damage.

This paper presents a wonderful reminder of the value of updating and reviewing what we know about tests that we order, even if we feel comfortable when ordering them. Before initiating a cascade of additional tests and consultations to explore the cause of an abnormal test result, a little time spent reviewing its basic characteristics and biology may pay dividends.

As 2015 comes to a close, we at the Journal share with you our sincere wishes for personal satisfaction and a globally more peaceful 2016.

We are all exposed to initiatives from multiple stakeholders telling us to order fewer tests. Many of these efforts to control costs and improve efficiency and quality of care are directed at populations of patients and are broad concepts: provide screening only to those most likely to benefit (eg, don’t screen for prostate cancer in men with a lifespan < 10 years); avoid procedures that provided limited benefit in controlled trials (eg, limit routine arthroscopic treatment of knee osteoarthritis); and avoid reflexive practices unlikely to improve patient outcomes (eg, eliminate routine preoperative testing before elective procedures in otherwise healthy patients).

Whether system-based changes will be implemented and have an impact remains to be determined. But I sense that with all the attention being focused on population management and healthcare practices, including an emphasis on documenting and coding our encounters with patients, whether substantive or simply digital housekeeping, we are increasingly distracted from the patient in front of us and are spending less time reviewing the principles underlying the diagnoses we make and the tests we order—just as we are taking less time to perform relevant physical examinations.¹ The latter may mostly relate to time pressures. The former, I believe, is a product of both time pressures and a false sense of confidence in our knowledge of seemingly commonplace laboratory tests.

As I lecture, work with trainees, and reflect on my own patients, I realize that we are slowly but progressively minimizing the importance of a working knowledge of the basic foundations of clinical practice—perhaps because facts can always be looked up. I am not referring to knowledge of arcane biochemical pathways, eponymous references, or the latest recommended treatment of inclusion body myositis. I am thinking instead of the value of regularly refreshing our knowledge of laboratory tests and diagnoses we frequently encounter.

Having access to multiple clinical databases literally in our pockets is likely bolstering a false sense of confidence in our knowledge. The National Library of Medicine may be only a tap on a smart phone away, but accessing it regularly is a different thing. Attending conferences and reading educational journals help to keep our broad-based knowledge of internal medicine refreshed, but time pressures may significantly limit our ability to regularly pursue these activities.

In this issue of the Journal, Drs. Moghadam-Kia et al discuss their approach to asymptomatic elevations in creatine kinase (CK). Although no longer included in the most commonly used lab panels, CK measurement is often ordered in patients taking statins, even if they have no relevant muscle-related symptoms. Thus, evaluating a patient with an asymptomatic elevated CK level is not rare. The authors delve into the clinically relevant test characteristics, and their important caveats about interpreting elevated CK levels are germane not only to the asymptomatic patient, but also to the patient being evaluated for myalgia or weakness. This latter situation is one I frequently face in both the hospital and the outpatient clinic. I am often asked to consult on patients who have incompletely defined symptoms and elevated CK.

As discussed in the article, the laboratory definition of “normal” must first be considered. Laboratory test results must always be interpreted in the clinical context. An isolated elevation in parathyroid hormone cannot be interpreted without knowing the patient’s vitamin D level. Nor can “normal” low-density lipoprotein or serum urate levels be interpreted properly without knowing if the patient is accumulating excess cholesterol or urate deposits. As we order and interpret test results, we must consider the biology of the substance being measured as well as the test characteristics; too often, we react to abnormal laboratory results with an incomplete understanding of these aspects.

Moghadam-Kia et al do not dwell on the organ involvement causing CK elevations, but specificity is another very important aspect when clinically interpreting the results of a CK test. Many patients with muscle damage or inflammation have elevations in serum aspartate aminotransferase and alanine aminotransferase levels (the ratio of elevation depends on the time course of the muscle damage and on the relative clearance rate of the two enzymes). Without knowing that the CK is elevated, one might assume that an aminotransferase elevation reflects hepatitis. I have seen several patients with elevated aminotransferases and complaints of weakness and fatigue who were subjected to liver biopsy before it was recognized that the source of the enzyme elevation (“liver function test changes”) was muscle (or hemolysis). Frequently unrecognized is that aldolase, which has a cell distribution similar to that of lactate dehydrogenase, does not have the relative specificity of localization to muscle that CK has. CK is quite useful in distinguishing myocyte from hepatocyte damage.

This paper presents a wonderful reminder of the value of updating and reviewing what we know about tests that we order, even if we feel comfortable when ordering them. Before initiating a cascade of additional tests and consultations to explore the cause of an abnormal test result, a little time spent reviewing its basic characteristics and biology may pay dividends.

As 2015 comes to a close, we at the Journal share with you our sincere wishes for personal satisfaction and a globally more peaceful 2016.

We are all exposed to initiatives from multiple stakeholders telling us to order fewer tests. Many of these efforts to control costs and improve efficiency and quality of care are directed at populations of patients and are broad concepts: provide screening only to those most likely to benefit (eg, don’t screen for prostate cancer in men with a lifespan < 10 years); avoid procedures that provided limited benefit in controlled trials (eg, limit routine arthroscopic treatment of knee osteoarthritis); and avoid reflexive practices unlikely to improve patient outcomes (eg, eliminate routine preoperative testing before elective procedures in otherwise healthy patients).

Whether system-based changes will be implemented and have an impact remains to be determined. But I sense that with all the attention being focused on population management and healthcare practices, including an emphasis on documenting and coding our encounters with patients, whether substantive or simply digital housekeeping, we are increasingly distracted from the patient in front of us and are spending less time reviewing the principles underlying the diagnoses we make and the tests we order—just as we are taking less time to perform relevant physical examinations.¹ The latter may mostly relate to time pressures. The former, I believe, is a product of both time pressures and a false sense of confidence in our knowledge of seemingly commonplace laboratory tests.

As I lecture, work with trainees, and reflect on my own patients, I realize that we are slowly but progressively minimizing the importance of a working knowledge of the basic foundations of clinical practice—perhaps because facts can always be looked up. I am not referring to knowledge of arcane biochemical pathways, eponymous references, or the latest recommended treatment of inclusion body myositis. I am thinking instead of the value of regularly refreshing our knowledge of laboratory tests and diagnoses we frequently encounter.

Having access to multiple clinical databases literally in our pockets is likely bolstering a false sense of confidence in our knowledge. The National Library of Medicine may be only a tap on a smart phone away, but accessing it regularly is a different thing. Attending conferences and reading educational journals help to keep our broad-based knowledge of internal medicine refreshed, but time pressures may significantly limit our ability to regularly pursue these activities.

In this issue of the Journal, Drs. Moghadam-Kia et al discuss their approach to asymptomatic elevations in creatine kinase (CK). Although no longer included in the most commonly used lab panels, CK measurement is often ordered in patients taking statins, even if they have no relevant muscle-related symptoms. Thus, evaluating a patient with an asymptomatic elevated CK level is not rare. The authors delve into the clinically relevant test characteristics, and their important caveats about interpreting elevated CK levels are germane not only to the asymptomatic patient, but also to the patient being evaluated for myalgia or weakness. This latter situation is one I frequently face in both the hospital and the outpatient clinic. I am often asked to consult on patients who have incompletely defined symptoms and elevated CK.

As discussed in the article, the laboratory definition of “normal” must first be considered. Laboratory test results must always be interpreted in the clinical context. An isolated elevation in parathyroid hormone cannot be interpreted without knowing the patient’s vitamin D level. Nor can “normal” low-density lipoprotein or serum urate levels be interpreted properly without knowing if the patient is accumulating excess cholesterol or urate deposits. As we order and interpret test results, we must consider the biology of the substance being measured as well as the test characteristics; too often, we react to abnormal laboratory results with an incomplete understanding of these aspects.

Moghadam-Kia et al do not dwell on the organ involvement causing CK elevations, but specificity is another very important aspect when clinically interpreting the results of a CK test. Many patients with muscle damage or inflammation have elevations in serum aspartate aminotransferase and alanine aminotransferase levels (the ratio of elevation depends on the time course of the muscle damage and on the relative clearance rate of the two enzymes). Without knowing that the CK is elevated, one might assume that an aminotransferase elevation reflects hepatitis. I have seen several patients with elevated aminotransferases and complaints of weakness and fatigue who were subjected to liver biopsy before it was recognized that the source of the enzyme elevation (“liver function test changes”) was muscle (or hemolysis). Frequently unrecognized is that aldolase, which has a cell distribution similar to that of lactate dehydrogenase, does not have the relative specificity of localization to muscle that CK has. CK is quite useful in distinguishing myocyte from hepatocyte damage.

This paper presents a wonderful reminder of the value of updating and reviewing what we know about tests that we order, even if we feel comfortable when ordering them. Before initiating a cascade of additional tests and consultations to explore the cause of an abnormal test result, a little time spent reviewing its basic characteristics and biology may pay dividends.

As 2015 comes to a close, we at the Journal share with you our sincere wishes for personal satisfaction and a globally more peaceful 2016.

Patients who have risk factors for obstructive sleep apnea (OSA) or who report symptoms of OSA should be screened for it, first with a complete sleep history and standardized questionnaire, and then by objective testing if indicated. The gold standard test for OSA is polysomnography performed overnight in a sleep laboratory. Home testing is an option in certain instances.

Common risk factors include obesity, resistant hypertension, retrognathia, large neck circumference (> 17 inches in men, > 16 inches in women), and history of stroke, atrial fibrillation, nocturnal arrhythmias, heart failure, and pulmonary hypertension. Screening is also recommended for any patient who is found on physical examination to have upper-airway narrowing or who reports symptoms such as loud snoring, observed episodes of apnea, gasping or choking at night, unrefreshing sleep, morning headaches, unexplained fatigue, and excessive tiredness during the day.

The American Academy of Sleep Medicine suggests three opportunities to screen for OSA¹:

• At routine health maintenance visits
• If the patient reports clinical symptoms of OSA
• If the patient has risk factors.

A DISMAL STATISTIC

The prevalence of OSA in the United States is high, estimated to be 2% in women and 4% in men in the middle-aged work force,² and even more in blacks, Asians, and older adults.³ Yet only 10% of people with OSA are diagnosed⁴—a dismal statistic considering the association of OSA with resistant hypertension⁵ and with a greater risk of stroke,⁶ cardiovascular disease, and death.⁷

CONSEQUENCES OF UNTREATED OSA

Untreated OSA is associated with a number of conditions⁷:

• Hypertension. OSA is one of the most common conditions associated with resistant hypertension. Patients with severe OSA and resistant hypertension who comply with continuous positive airway pressure (CPAP) treatment have significant reductions in blood pressure.
• Coronary artery disease. OSA is twice as common in people with coronary artery disease as in those with no coronary artery disease. In patients with coronary artery disease and OSA, CPAP may reduce the rate of nonfatal and fatal cardiovascular events.
• Heart failure. OSA is common in patients with systolic dysfunction (11% to 37%). OSA also has been detected in more than 50% of patients with heart failure with preserved systolic function. CPAP treatment can improve ejection fraction in patients with systolic dysfunction.
• Arrythmias. Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy have been reported to be significantly more common in people with OSA.⁸ If the underlying cardiac conduction system is normal and there is no significant thyroid dysfunction, bradyarrhythmias and heart block may be treated effectively with CPAP.⁷ Treatment of OSA may decrease the incidence and severity of ventricular arrhythmias.⁷
• Sudden cardiac death. OSA was independently associated with sudden cardiac death in a longitudinal study.⁹
• Stroke. The Sleep Heart Health Study⁶ showed that OSA is 30% more common in patients who developed ischemic stroke. Long-term CPAP treatment in moderate to severe OSA and ischemic stroke is associated with a reduction in the mortality rate.¹⁰
• Diabetes. The Sleep Heart Health Study showed that OSA is independently associated with glucose intolerance and insulin resistance and may lead to type 2 diabetes mellitus.¹¹

A QUESTIONNAIRE HELPS IDENTIFY WHO NEEDS TESTING

If you suspect OSA, consider administering a sleep disorder questionnaire such as the Berlin,¹² the Epworth Sleepiness Scale, or the STOP-Bang questionnaire (Table 1). The STOP-Bang questionnaire is an easy-to-use tool that expands on the STOP questionnaire (snoring, tiredness, observed apnea, high blood pressure) with the addition of body mass index, age, neck size, and gender. The Berlin questionnaire has been validated in the primary care setting.¹² The STOP-Bang questionnaire has been validated in preoperative settings¹³ but not in the primary care setting (although it has been commonly used in primary care).

WHICH TEST TO ORDER?

If the score on the questionnaire indicates a moderate or high risk of OSA, the patient should undergo objective testing with polysomnography or, in certain instances, home testing.¹ Polysomnography is the gold standard. Home testing costs less and is easier to arrange, but the American Academy of Sleep Medicine recommends it as an alternative to polysomnography, in conjunction with a comprehensive sleep evaluation, only in the following situations¹⁴:

• If the patient has a high pretest probability of moderate to severe OSA
• If immobility or critical illness makes polysomnography unfeasible
• If direct monitoring of the response to non-CPAP treatments for sleep apnea is needed.

Home testing for OSA should not be used in the following situations:

• If the patient has significant morbidity such as moderate to severe pulmonary disease, neuromuscular disease, or congestive heart failure
• In evaluating a patient suspected of having comorbid sleep disorders such as central sleep apnea, periodic limb movement disorder, insomnia, parasomnias, circadian rhythm disorder, or narcolepsy
• In screening of asymptomatic patients.

Home testing has important drawbacks. It may underestimate the severity of sleep apnea. The rate of false-negative results may be as high as 17%. If the home test was thought to be technically inadequate or the results were inconsistent with those that were expected—ie, if the patient has a high pretest probability of OSA based on risk factors or symptoms but negative results on home testing—then the patient should undergo polysomnography.¹⁴

DIAGNOSIS

The diagnosis of OSA is confirmed if the number of apnea events per hour (ie, the apnea-hypopnea index) on polysomnography or home testing is more than 15, regardless of symptoms, or more than 5 in a patient who reports OSA symptoms. An apnea-hypopnea index of 5 to 14 indicates mild OSA, 15 to 30 indicates moderate OSA, and greater than 30 indicates severe OSA.

BENEFITS OF TREATMENT

Treatment of OSA with CPAP reduces the 10-year risk of fatal and nonfatal motor vehicle accidents by 52%, the 10-year expected number of myocardial infarctions by 49%, and the 10-year risk of stroke by 31%.⁷ It has also been found to be cost-effective, for men and women of all ages with moderate to severe OSA.¹⁵

Patients who have risk factors for obstructive sleep apnea (OSA) or who report symptoms of OSA should be screened for it, first with a complete sleep history and standardized questionnaire, and then by objective testing if indicated. The gold standard test for OSA is polysomnography performed overnight in a sleep laboratory. Home testing is an option in certain instances.

Common risk factors include obesity, resistant hypertension, retrognathia, large neck circumference (> 17 inches in men, > 16 inches in women), and history of stroke, atrial fibrillation, nocturnal arrhythmias, heart failure, and pulmonary hypertension. Screening is also recommended for any patient who is found on physical examination to have upper-airway narrowing or who reports symptoms such as loud snoring, observed episodes of apnea, gasping or choking at night, unrefreshing sleep, morning headaches, unexplained fatigue, and excessive tiredness during the day.

The American Academy of Sleep Medicine suggests three opportunities to screen for OSA¹:

• At routine health maintenance visits
• If the patient reports clinical symptoms of OSA
• If the patient has risk factors.

A DISMAL STATISTIC

The prevalence of OSA in the United States is high, estimated to be 2% in women and 4% in men in the middle-aged work force,² and even more in blacks, Asians, and older adults.³ Yet only 10% of people with OSA are diagnosed⁴—a dismal statistic considering the association of OSA with resistant hypertension⁵ and with a greater risk of stroke,⁶ cardiovascular disease, and death.⁷

CONSEQUENCES OF UNTREATED OSA

Untreated OSA is associated with a number of conditions⁷:

• Hypertension. OSA is one of the most common conditions associated with resistant hypertension. Patients with severe OSA and resistant hypertension who comply with continuous positive airway pressure (CPAP) treatment have significant reductions in blood pressure.
• Coronary artery disease. OSA is twice as common in people with coronary artery disease as in those with no coronary artery disease. In patients with coronary artery disease and OSA, CPAP may reduce the rate of nonfatal and fatal cardiovascular events.
• Heart failure. OSA is common in patients with systolic dysfunction (11% to 37%). OSA also has been detected in more than 50% of patients with heart failure with preserved systolic function. CPAP treatment can improve ejection fraction in patients with systolic dysfunction.
• Arrythmias. Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy have been reported to be significantly more common in people with OSA.⁸ If the underlying cardiac conduction system is normal and there is no significant thyroid dysfunction, bradyarrhythmias and heart block may be treated effectively with CPAP.⁷ Treatment of OSA may decrease the incidence and severity of ventricular arrhythmias.⁷
• Sudden cardiac death. OSA was independently associated with sudden cardiac death in a longitudinal study.⁹
• Stroke. The Sleep Heart Health Study⁶ showed that OSA is 30% more common in patients who developed ischemic stroke. Long-term CPAP treatment in moderate to severe OSA and ischemic stroke is associated with a reduction in the mortality rate.¹⁰
• Diabetes. The Sleep Heart Health Study showed that OSA is independently associated with glucose intolerance and insulin resistance and may lead to type 2 diabetes mellitus.¹¹

A QUESTIONNAIRE HELPS IDENTIFY WHO NEEDS TESTING

If you suspect OSA, consider administering a sleep disorder questionnaire such as the Berlin,¹² the Epworth Sleepiness Scale, or the STOP-Bang questionnaire (Table 1). The STOP-Bang questionnaire is an easy-to-use tool that expands on the STOP questionnaire (snoring, tiredness, observed apnea, high blood pressure) with the addition of body mass index, age, neck size, and gender. The Berlin questionnaire has been validated in the primary care setting.¹² The STOP-Bang questionnaire has been validated in preoperative settings¹³ but not in the primary care setting (although it has been commonly used in primary care).

WHICH TEST TO ORDER?

If the score on the questionnaire indicates a moderate or high risk of OSA, the patient should undergo objective testing with polysomnography or, in certain instances, home testing.¹ Polysomnography is the gold standard. Home testing costs less and is easier to arrange, but the American Academy of Sleep Medicine recommends it as an alternative to polysomnography, in conjunction with a comprehensive sleep evaluation, only in the following situations¹⁴:

• If the patient has a high pretest probability of moderate to severe OSA
• If immobility or critical illness makes polysomnography unfeasible
• If direct monitoring of the response to non-CPAP treatments for sleep apnea is needed.

Home testing for OSA should not be used in the following situations:

• If the patient has significant morbidity such as moderate to severe pulmonary disease, neuromuscular disease, or congestive heart failure
• In evaluating a patient suspected of having comorbid sleep disorders such as central sleep apnea, periodic limb movement disorder, insomnia, parasomnias, circadian rhythm disorder, or narcolepsy
• In screening of asymptomatic patients.

Home testing has important drawbacks. It may underestimate the severity of sleep apnea. The rate of false-negative results may be as high as 17%. If the home test was thought to be technically inadequate or the results were inconsistent with those that were expected—ie, if the patient has a high pretest probability of OSA based on risk factors or symptoms but negative results on home testing—then the patient should undergo polysomnography.¹⁴

DIAGNOSIS

The diagnosis of OSA is confirmed if the number of apnea events per hour (ie, the apnea-hypopnea index) on polysomnography or home testing is more than 15, regardless of symptoms, or more than 5 in a patient who reports OSA symptoms. An apnea-hypopnea index of 5 to 14 indicates mild OSA, 15 to 30 indicates moderate OSA, and greater than 30 indicates severe OSA.

BENEFITS OF TREATMENT

Treatment of OSA with CPAP reduces the 10-year risk of fatal and nonfatal motor vehicle accidents by 52%, the 10-year expected number of myocardial infarctions by 49%, and the 10-year risk of stroke by 31%.⁷ It has also been found to be cost-effective, for men and women of all ages with moderate to severe OSA.¹⁵

Patients who have risk factors for obstructive sleep apnea (OSA) or who report symptoms of OSA should be screened for it, first with a complete sleep history and standardized questionnaire, and then by objective testing if indicated. The gold standard test for OSA is polysomnography performed overnight in a sleep laboratory. Home testing is an option in certain instances.

Common risk factors include obesity, resistant hypertension, retrognathia, large neck circumference (> 17 inches in men, > 16 inches in women), and history of stroke, atrial fibrillation, nocturnal arrhythmias, heart failure, and pulmonary hypertension. Screening is also recommended for any patient who is found on physical examination to have upper-airway narrowing or who reports symptoms such as loud snoring, observed episodes of apnea, gasping or choking at night, unrefreshing sleep, morning headaches, unexplained fatigue, and excessive tiredness during the day.

The American Academy of Sleep Medicine suggests three opportunities to screen for OSA¹:

• At routine health maintenance visits
• If the patient reports clinical symptoms of OSA
• If the patient has risk factors.

A DISMAL STATISTIC

The prevalence of OSA in the United States is high, estimated to be 2% in women and 4% in men in the middle-aged work force,² and even more in blacks, Asians, and older adults.³ Yet only 10% of people with OSA are diagnosed⁴—a dismal statistic considering the association of OSA with resistant hypertension⁵ and with a greater risk of stroke,⁶ cardiovascular disease, and death.⁷

CONSEQUENCES OF UNTREATED OSA

Untreated OSA is associated with a number of conditions⁷:

• Hypertension. OSA is one of the most common conditions associated with resistant hypertension. Patients with severe OSA and resistant hypertension who comply with continuous positive airway pressure (CPAP) treatment have significant reductions in blood pressure.
• Coronary artery disease. OSA is twice as common in people with coronary artery disease as in those with no coronary artery disease. In patients with coronary artery disease and OSA, CPAP may reduce the rate of nonfatal and fatal cardiovascular events.
• Heart failure. OSA is common in patients with systolic dysfunction (11% to 37%). OSA also has been detected in more than 50% of patients with heart failure with preserved systolic function. CPAP treatment can improve ejection fraction in patients with systolic dysfunction.
• Arrythmias. Atrial fibrillation, nonsustained ventricular tachycardia, and complex ventricular ectopy have been reported to be significantly more common in people with OSA.⁸ If the underlying cardiac conduction system is normal and there is no significant thyroid dysfunction, bradyarrhythmias and heart block may be treated effectively with CPAP.⁷ Treatment of OSA may decrease the incidence and severity of ventricular arrhythmias.⁷
• Sudden cardiac death. OSA was independently associated with sudden cardiac death in a longitudinal study.⁹
• Stroke. The Sleep Heart Health Study⁶ showed that OSA is 30% more common in patients who developed ischemic stroke. Long-term CPAP treatment in moderate to severe OSA and ischemic stroke is associated with a reduction in the mortality rate.¹⁰
• Diabetes. The Sleep Heart Health Study showed that OSA is independently associated with glucose intolerance and insulin resistance and may lead to type 2 diabetes mellitus.¹¹

A QUESTIONNAIRE HELPS IDENTIFY WHO NEEDS TESTING

If you suspect OSA, consider administering a sleep disorder questionnaire such as the Berlin,¹² the Epworth Sleepiness Scale, or the STOP-Bang questionnaire (Table 1). The STOP-Bang questionnaire is an easy-to-use tool that expands on the STOP questionnaire (snoring, tiredness, observed apnea, high blood pressure) with the addition of body mass index, age, neck size, and gender. The Berlin questionnaire has been validated in the primary care setting.¹² The STOP-Bang questionnaire has been validated in preoperative settings¹³ but not in the primary care setting (although it has been commonly used in primary care).

WHICH TEST TO ORDER?

If the score on the questionnaire indicates a moderate or high risk of OSA, the patient should undergo objective testing with polysomnography or, in certain instances, home testing.¹ Polysomnography is the gold standard. Home testing costs less and is easier to arrange, but the American Academy of Sleep Medicine recommends it as an alternative to polysomnography, in conjunction with a comprehensive sleep evaluation, only in the following situations¹⁴:

• If the patient has a high pretest probability of moderate to severe OSA
• If immobility or critical illness makes polysomnography unfeasible
• If direct monitoring of the response to non-CPAP treatments for sleep apnea is needed.

Home testing for OSA should not be used in the following situations:

• If the patient has significant morbidity such as moderate to severe pulmonary disease, neuromuscular disease, or congestive heart failure
• In evaluating a patient suspected of having comorbid sleep disorders such as central sleep apnea, periodic limb movement disorder, insomnia, parasomnias, circadian rhythm disorder, or narcolepsy
• In screening of asymptomatic patients.

Home testing has important drawbacks. It may underestimate the severity of sleep apnea. The rate of false-negative results may be as high as 17%. If the home test was thought to be technically inadequate or the results were inconsistent with those that were expected—ie, if the patient has a high pretest probability of OSA based on risk factors or symptoms but negative results on home testing—then the patient should undergo polysomnography.¹⁴

DIAGNOSIS

The diagnosis of OSA is confirmed if the number of apnea events per hour (ie, the apnea-hypopnea index) on polysomnography or home testing is more than 15, regardless of symptoms, or more than 5 in a patient who reports OSA symptoms. An apnea-hypopnea index of 5 to 14 indicates mild OSA, 15 to 30 indicates moderate OSA, and greater than 30 indicates severe OSA.

BENEFITS OF TREATMENT

Treatment of OSA with CPAP reduces the 10-year risk of fatal and nonfatal motor vehicle accidents by 52%, the 10-year expected number of myocardial infarctions by 49%, and the 10-year risk of stroke by 31%.⁷ It has also been found to be cost-effective, for men and women of all ages with moderate to severe OSA.¹⁵

A 25-year-old man is evaluated for angioedema (swelling of lips and tongue) after eating paella at a Spanish restaurant. He has no history of allergies, but he says he had never eaten such a large variety of seafood before, especially shellfish.

He suspects that he is allergic to shellfish and asks the attending physician to order blood tests for seafood allergies, as he heard from a friend that blood tests are superior to other types of tests for allergy. The physician requests a serum immunoglobulin E (IgE) food panel test for this patient.

SERUM ALLERGEN-SPECIFIC IgE TESTING

Many methods of testing for allergy are available, including the skin-prick test, double-blind and single-blind placebo-controlled food challenges, open food challenges, inhalant challenges, drug challenges, and serum IgE tests. In clinical practice, these tests are often used in combination because when used individually, few of them are both highly sensitive and specific (Table 1).^1–6

Skin-prick testing is generally the method of choice for the preliminary evaluation of IgE-mediated allergies because it is more sensitive and requires less time to get a result.¹ But it is not the preferred test if the patient is at risk of a systemic reaction or has widespread dermatitis, nor is it useful if the patient is taking drugs that suppress the histamine response, such as antihistamines or tricyclic antidepressants.⁶ Moreover, skin-prick testing is more invasive and time-consuming than serum IgE testing.

Serum IgE testing is an attractive alternative, and it is more convenient because it requires only a single blood draw and poses a lower risk of adverse effects.

NOT A RELIABLE DIAGNOSTIC TOOL

As serum IgE testing has gained popularity, researchers have tried to improve its diagnostic power (ie, maximize its sensitivity and specificity) by determining the best cutoff values for IgE against specific antigens. Unfortunately, these values are difficult to determine because of confounding factors such as the lack of a reference standard, population diversity, patient atopy, and the overwhelming number of allergens that must be examined.

In addition, some researchers have used positive and negative predictive values to evaluate diagnostic cutoffs for serum antigen-specific IgE values. But these are not the most suitable performance measure to evaluate because they depend on disease prevalence and population characteristics.

Despite these efforts, results are still conflicting, and serum antigen-specific IgE testing is not a reliable diagnostic tool.

In an effort to gain insight from the available research data, we evaluated the clinical usefulness of 89 antigen-specific IgE tests, using an approach of summing their sensitivity and specificity. Previously, Wians⁷ proposed that a test is likely to be clinically useful if the sum of its sensitivity and specificity is equal to or greater than 170. Figure 1 shows the 89 tests, grouped into categories, and their summed sensitivities and specificities. The dashed line indicates a cutoff of 170; any bar that touches or crosses that line indicates that the test may be clinically useful, according to Wians.⁷

Only 7 of the 89 tests (cow, buckwheat, hazelnut, latex, Alternaria alternata, honey bee venom, and Johnson grass) satisfied this criterion. This suggests that a significant number of serum antigen-specific IgE tests perform suboptimally, and we are left with the question of why they are so commonly ordered.

Inappropriate use can lead to false-positive results, a situation in which patients may be subjected to unnecessary food avoidance that can result in nutritional deficiencies and decreased quality of life. It can also lead to false-negative results, when life-threatening diagnoses are missed and further excessive downstream testing is required—all leading; to negative outcomes for both patients and healthcare providers.

CHOOSING WISELY

The Choosing Wisely campaign in the United States has partnered with the American Academy of Allergy, Asthma, and Immunology to advocate against indiscriminate IgE testing in evaluating allergy.⁸ Allergy diagnosis and evaluation should be based on a combination of clinical history and judicious ordering of specific IgE tests, whether through skin or blood testing. Ordering of serum allergen-specific IgE tests for food allergies should be consistent with a clinical history of potential IgE-mediated food allergy⁸ and not food intolerance (Table 2).^4,5

Some jurisdictions in Canada have followed suit by restricting the number of serum IgE tests each physician is allowed to order per patient, to encourage more responsible ordering and to lower the number of potential false-positive results, which can lead to increased downstream costs as well as unnecessary patient worry and lifestyle modification.

CLINICAL BOTTOM LINE

Ordering diagnostic tests that have little clinical utility has long-term detrimental effects on both patient safety and healthcare sustainability.

In the case of the 25-year-old evaluated for shellfish allergy, the clinician should first explain that the swelling of the lips and tongue (angioedema) does suggest an IgE-mediated allergic reaction and not a non–IgE-mediated allergic reaction or a food intolerance. Non–IgE-mediated food allergies and food intolerances are marked by symptoms relating mainly to nonimmune aspects of the digestive system, whereas IgE-mediated food allergies affect the immune system and can involve a multitude of organs, including the skin and the respiratory and digestive systems (Table 2).

However, clinicians should avoid indiscriminately ordering food allergen IgE panels and instead should focus on foods likely to be the culprits based on the clinical history.⁹ Indiscriminate testing can lead to false-positive results and unnecessary food avoidance.

Since the patient developed symptoms of angioedema when he was exposed to his allergen, he may be apprehensive about a skin- prick test and the possibility of being subjected to the same discomfort. Therefore, in this situation, it may be best to perform serum IgE tests, but on a few targeted seafoods rather than the food panel the physician had ordered. A patient can be sensitized to an allergen (possess IgE antibodies) but not experience symptoms when exposed to it (ie, have tolerance).⁵ Also, false-negative results may occur, so a negative serum allergen-specific IgE test should likewise be interpreted in light of the pretest probability of allergy to a specific antigen.

If the history and the results of testing are not clear and congruent, the patient should be referred to an allergist for diagnosis or for management. The allergist can provide management techniques and periodic assessment as to the progression and resolution of the allergy. Table 2 highlights symptoms that differentiate an IgE-mediated from a non–IgE-mediated food allergy.^10,11 Table 1 presents clinical indications and suggested diagnostic methods to the five most common allergen groups and the diagnostically invalid tests.^1–6

The bottom line is that we must consider the poor performance of serum allergen-specific IgE tests when diagnosing and treating suspected type I allergies and avoid ordering food allergen IgE panels whenever possible.

A 25-year-old man is evaluated for angioedema (swelling of lips and tongue) after eating paella at a Spanish restaurant. He has no history of allergies, but he says he had never eaten such a large variety of seafood before, especially shellfish.

He suspects that he is allergic to shellfish and asks the attending physician to order blood tests for seafood allergies, as he heard from a friend that blood tests are superior to other types of tests for allergy. The physician requests a serum immunoglobulin E (IgE) food panel test for this patient.

SERUM ALLERGEN-SPECIFIC IgE TESTING

Many methods of testing for allergy are available, including the skin-prick test, double-blind and single-blind placebo-controlled food challenges, open food challenges, inhalant challenges, drug challenges, and serum IgE tests. In clinical practice, these tests are often used in combination because when used individually, few of them are both highly sensitive and specific (Table 1).^1–6

Skin-prick testing is generally the method of choice for the preliminary evaluation of IgE-mediated allergies because it is more sensitive and requires less time to get a result.¹ But it is not the preferred test if the patient is at risk of a systemic reaction or has widespread dermatitis, nor is it useful if the patient is taking drugs that suppress the histamine response, such as antihistamines or tricyclic antidepressants.⁶ Moreover, skin-prick testing is more invasive and time-consuming than serum IgE testing.

Serum IgE testing is an attractive alternative, and it is more convenient because it requires only a single blood draw and poses a lower risk of adverse effects.

NOT A RELIABLE DIAGNOSTIC TOOL

As serum IgE testing has gained popularity, researchers have tried to improve its diagnostic power (ie, maximize its sensitivity and specificity) by determining the best cutoff values for IgE against specific antigens. Unfortunately, these values are difficult to determine because of confounding factors such as the lack of a reference standard, population diversity, patient atopy, and the overwhelming number of allergens that must be examined.

In addition, some researchers have used positive and negative predictive values to evaluate diagnostic cutoffs for serum antigen-specific IgE values. But these are not the most suitable performance measure to evaluate because they depend on disease prevalence and population characteristics.

Despite these efforts, results are still conflicting, and serum antigen-specific IgE testing is not a reliable diagnostic tool.

In an effort to gain insight from the available research data, we evaluated the clinical usefulness of 89 antigen-specific IgE tests, using an approach of summing their sensitivity and specificity. Previously, Wians⁷ proposed that a test is likely to be clinically useful if the sum of its sensitivity and specificity is equal to or greater than 170. Figure 1 shows the 89 tests, grouped into categories, and their summed sensitivities and specificities. The dashed line indicates a cutoff of 170; any bar that touches or crosses that line indicates that the test may be clinically useful, according to Wians.⁷

Only 7 of the 89 tests (cow, buckwheat, hazelnut, latex, Alternaria alternata, honey bee venom, and Johnson grass) satisfied this criterion. This suggests that a significant number of serum antigen-specific IgE tests perform suboptimally, and we are left with the question of why they are so commonly ordered.

Inappropriate use can lead to false-positive results, a situation in which patients may be subjected to unnecessary food avoidance that can result in nutritional deficiencies and decreased quality of life. It can also lead to false-negative results, when life-threatening diagnoses are missed and further excessive downstream testing is required—all leading; to negative outcomes for both patients and healthcare providers.

CHOOSING WISELY

The Choosing Wisely campaign in the United States has partnered with the American Academy of Allergy, Asthma, and Immunology to advocate against indiscriminate IgE testing in evaluating allergy.⁸ Allergy diagnosis and evaluation should be based on a combination of clinical history and judicious ordering of specific IgE tests, whether through skin or blood testing. Ordering of serum allergen-specific IgE tests for food allergies should be consistent with a clinical history of potential IgE-mediated food allergy⁸ and not food intolerance (Table 2).^4,5

Some jurisdictions in Canada have followed suit by restricting the number of serum IgE tests each physician is allowed to order per patient, to encourage more responsible ordering and to lower the number of potential false-positive results, which can lead to increased downstream costs as well as unnecessary patient worry and lifestyle modification.

CLINICAL BOTTOM LINE

Ordering diagnostic tests that have little clinical utility has long-term detrimental effects on both patient safety and healthcare sustainability.

In the case of the 25-year-old evaluated for shellfish allergy, the clinician should first explain that the swelling of the lips and tongue (angioedema) does suggest an IgE-mediated allergic reaction and not a non–IgE-mediated allergic reaction or a food intolerance. Non–IgE-mediated food allergies and food intolerances are marked by symptoms relating mainly to nonimmune aspects of the digestive system, whereas IgE-mediated food allergies affect the immune system and can involve a multitude of organs, including the skin and the respiratory and digestive systems (Table 2).

However, clinicians should avoid indiscriminately ordering food allergen IgE panels and instead should focus on foods likely to be the culprits based on the clinical history.⁹ Indiscriminate testing can lead to false-positive results and unnecessary food avoidance.

Since the patient developed symptoms of angioedema when he was exposed to his allergen, he may be apprehensive about a skin- prick test and the possibility of being subjected to the same discomfort. Therefore, in this situation, it may be best to perform serum IgE tests, but on a few targeted seafoods rather than the food panel the physician had ordered. A patient can be sensitized to an allergen (possess IgE antibodies) but not experience symptoms when exposed to it (ie, have tolerance).⁵ Also, false-negative results may occur, so a negative serum allergen-specific IgE test should likewise be interpreted in light of the pretest probability of allergy to a specific antigen.

If the history and the results of testing are not clear and congruent, the patient should be referred to an allergist for diagnosis or for management. The allergist can provide management techniques and periodic assessment as to the progression and resolution of the allergy. Table 2 highlights symptoms that differentiate an IgE-mediated from a non–IgE-mediated food allergy.^10,11 Table 1 presents clinical indications and suggested diagnostic methods to the five most common allergen groups and the diagnostically invalid tests.^1–6

The bottom line is that we must consider the poor performance of serum allergen-specific IgE tests when diagnosing and treating suspected type I allergies and avoid ordering food allergen IgE panels whenever possible.

A 25-year-old man is evaluated for angioedema (swelling of lips and tongue) after eating paella at a Spanish restaurant. He has no history of allergies, but he says he had never eaten such a large variety of seafood before, especially shellfish.

He suspects that he is allergic to shellfish and asks the attending physician to order blood tests for seafood allergies, as he heard from a friend that blood tests are superior to other types of tests for allergy. The physician requests a serum immunoglobulin E (IgE) food panel test for this patient.

SERUM ALLERGEN-SPECIFIC IgE TESTING

Many methods of testing for allergy are available, including the skin-prick test, double-blind and single-blind placebo-controlled food challenges, open food challenges, inhalant challenges, drug challenges, and serum IgE tests. In clinical practice, these tests are often used in combination because when used individually, few of them are both highly sensitive and specific (Table 1).^1–6

Skin-prick testing is generally the method of choice for the preliminary evaluation of IgE-mediated allergies because it is more sensitive and requires less time to get a result.¹ But it is not the preferred test if the patient is at risk of a systemic reaction or has widespread dermatitis, nor is it useful if the patient is taking drugs that suppress the histamine response, such as antihistamines or tricyclic antidepressants.⁶ Moreover, skin-prick testing is more invasive and time-consuming than serum IgE testing.

Serum IgE testing is an attractive alternative, and it is more convenient because it requires only a single blood draw and poses a lower risk of adverse effects.

NOT A RELIABLE DIAGNOSTIC TOOL

As serum IgE testing has gained popularity, researchers have tried to improve its diagnostic power (ie, maximize its sensitivity and specificity) by determining the best cutoff values for IgE against specific antigens. Unfortunately, these values are difficult to determine because of confounding factors such as the lack of a reference standard, population diversity, patient atopy, and the overwhelming number of allergens that must be examined.

In addition, some researchers have used positive and negative predictive values to evaluate diagnostic cutoffs for serum antigen-specific IgE values. But these are not the most suitable performance measure to evaluate because they depend on disease prevalence and population characteristics.

Despite these efforts, results are still conflicting, and serum antigen-specific IgE testing is not a reliable diagnostic tool.

In an effort to gain insight from the available research data, we evaluated the clinical usefulness of 89 antigen-specific IgE tests, using an approach of summing their sensitivity and specificity. Previously, Wians⁷ proposed that a test is likely to be clinically useful if the sum of its sensitivity and specificity is equal to or greater than 170. Figure 1 shows the 89 tests, grouped into categories, and their summed sensitivities and specificities. The dashed line indicates a cutoff of 170; any bar that touches or crosses that line indicates that the test may be clinically useful, according to Wians.⁷

Only 7 of the 89 tests (cow, buckwheat, hazelnut, latex, Alternaria alternata, honey bee venom, and Johnson grass) satisfied this criterion. This suggests that a significant number of serum antigen-specific IgE tests perform suboptimally, and we are left with the question of why they are so commonly ordered.

Inappropriate use can lead to false-positive results, a situation in which patients may be subjected to unnecessary food avoidance that can result in nutritional deficiencies and decreased quality of life. It can also lead to false-negative results, when life-threatening diagnoses are missed and further excessive downstream testing is required—all leading; to negative outcomes for both patients and healthcare providers.

CHOOSING WISELY

The Choosing Wisely campaign in the United States has partnered with the American Academy of Allergy, Asthma, and Immunology to advocate against indiscriminate IgE testing in evaluating allergy.⁸ Allergy diagnosis and evaluation should be based on a combination of clinical history and judicious ordering of specific IgE tests, whether through skin or blood testing. Ordering of serum allergen-specific IgE tests for food allergies should be consistent with a clinical history of potential IgE-mediated food allergy⁸ and not food intolerance (Table 2).^4,5

Some jurisdictions in Canada have followed suit by restricting the number of serum IgE tests each physician is allowed to order per patient, to encourage more responsible ordering and to lower the number of potential false-positive results, which can lead to increased downstream costs as well as unnecessary patient worry and lifestyle modification.

CLINICAL BOTTOM LINE

Ordering diagnostic tests that have little clinical utility has long-term detrimental effects on both patient safety and healthcare sustainability.

In the case of the 25-year-old evaluated for shellfish allergy, the clinician should first explain that the swelling of the lips and tongue (angioedema) does suggest an IgE-mediated allergic reaction and not a non–IgE-mediated allergic reaction or a food intolerance. Non–IgE-mediated food allergies and food intolerances are marked by symptoms relating mainly to nonimmune aspects of the digestive system, whereas IgE-mediated food allergies affect the immune system and can involve a multitude of organs, including the skin and the respiratory and digestive systems (Table 2).

However, clinicians should avoid indiscriminately ordering food allergen IgE panels and instead should focus on foods likely to be the culprits based on the clinical history.⁹ Indiscriminate testing can lead to false-positive results and unnecessary food avoidance.

Since the patient developed symptoms of angioedema when he was exposed to his allergen, he may be apprehensive about a skin- prick test and the possibility of being subjected to the same discomfort. Therefore, in this situation, it may be best to perform serum IgE tests, but on a few targeted seafoods rather than the food panel the physician had ordered. A patient can be sensitized to an allergen (possess IgE antibodies) but not experience symptoms when exposed to it (ie, have tolerance).⁵ Also, false-negative results may occur, so a negative serum allergen-specific IgE test should likewise be interpreted in light of the pretest probability of allergy to a specific antigen.

If the history and the results of testing are not clear and congruent, the patient should be referred to an allergist for diagnosis or for management. The allergist can provide management techniques and periodic assessment as to the progression and resolution of the allergy. Table 2 highlights symptoms that differentiate an IgE-mediated from a non–IgE-mediated food allergy.^10,11 Table 1 presents clinical indications and suggested diagnostic methods to the five most common allergen groups and the diagnostically invalid tests.^1–6

The bottom line is that we must consider the poor performance of serum allergen-specific IgE tests when diagnosing and treating suspected type I allergies and avoid ordering food allergen IgE panels whenever possible.

Primary care physicians are playing a bigger role in evaluating the incidental finding of interstitial lung diseases since the recent publication of guidelines recommending computed tomography (CT) to screen for lung cancer.

In August 2011, the National Cancer Institute published its findings from the National Lung Screening Trial, which demonstrated a 20% reduction in mortality from lung cancer in patients at high risk screened with low-dose CT.¹ Based on these results, the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommended annual screening for lung cancer with low-dose CT in adults ages 55 to 74 who have a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years.² In December 2013, the US Preventive Services Task Force published similar guidelines but increased the age range to include high-risk patients ages 55 to 80.³

Bach et al⁴ estimated that, in 2010 in the United States, 8.6 million people met the criteria used in the National Lung Screening Trial for low-dose CT screening. These are the same criteria as in the multisociety recommendations cited above.² With such large numbers of patients eligible for CT screening, internists and other primary care physicians are undoubtedly encountering the incidental discovery of nonmalignant pulmonary diseases such as interstitial lung disease.

This article reviews the radiographic characteristics of the most common interstitial lung diseases the internist may encounter on screening CT in long-term smokers.

Referral to a specialist has been associated with lower rates of morbidity and death,⁵ and a diagnosis of interstitial lung disease should be confirmed by a pulmonologist and a radiologist specializing in differentiating the subtypes. But the primary care physician now plays a critical role in recognizing the need for further evaluation.

HOW COMMON IS INTERSTITIAL LUNG DISEASE IN SMOKERS?

Several studies have published data on the prevalence of interstitial lung disease in patients undergoing low-dose CT for lung cancer screening.

A trial at Mayo Clinic in current and former smokers identified “diffuse lung disease” in 9 (0.9%) of 1,049 participants.⁶

A trial in Ireland identified idiopathic pulmonary fibrosis in 6 (1.3%) of 449 current smokers who underwent low-dose CT screening for lung cancer.⁷

Sverzellati et al⁸ evaluated 692 participants in the Multicentric Italian Lung Detection CT screening study and reported a respiratory bronchiolitis pattern in 109 (15.7%), a usual interstitial pneumonia pattern in 2 (0.3%), and other patterns of chronic interstitial pneumonia in 26 (3.8%).

The National Lung Screening Trial reported that the frequency of “clinically significant” incidental findings (including pulmonary fibrosis) in all participants was 7.5%.¹ A retrospective analysis of 884 participants at a single site in this trial identified interstitial lung abnormalities in 86 participants (9.7%).⁹ These abnormalities were further categorized as nonfibrotic in 52 (5.9%) of 884, fibrotic in 19 (2.1%) of 884, and mixed fibrotic and nonfibrotic in 15 (1.7%) of 884.

Follow-up CT at 2 years in this trial demonstrated improvement in 50% and progression in 11% of patients who had nonfibrotic abnormalities, while fibrotic abnormalities improved in no cases and progressed in 37%. Interstitial lung abnormalities were more common in those who currently smoked and in those with more pack-years of cigarette smoking.⁹

In sum, these trials suggest that low-dose CT screening for lung cancer can detect the most common forms of interstitial lung disease in this at-risk population and can characterize them as fibrotic or nonfibrotic, a distinction important for prognosis and subsequent management.

NONFIBROTIC VS FIBROTIC DISEASE

It is important to distinguish between nonfibrotic and fibrotic interstitial lung disease, as fibrotic disease carries a worse prognosis and is treated differently.

Features of nonfibrotic interstitial lung disease:

• Ground-glass opacities
• Nodules
• Mosaic attenuation or consolidation.

Features of fibrotic interstitial lung disease:

• Combination of ground-glass opacities and reticulation
• Reticulation by itself
• Traction bronchiectasis
• Honeycombing
• Loss of lung volume.

NONFIBROTIC INTERSTITIAL LUNG DISEASES

Given the strong likelihood that a patient undergoing screening CT is either a current or former smoker, physicians may encounter, in addition to emphysema and lung cancer, the following smoking-related interstitial lung diseases, which are primarily nonfibrotic and which frequently coexist (Table 1):

• Respiratory bronchiolitis
• Respiratory bronchiolitis-interstitial lung disease
• Desquamative interstitial pneumonia
• Pulmonary Langerhans cell histiocytosis.

Respiratory bronchiolitis

Respiratory bronchiolitis occurs mostly in smokers and does not necessarily lead to respiratory symptoms in all patients.¹⁰ It cannot always be identified radiographically but occasionally appears as predominantly upper-lobe, patchy ground-glass opacities or ill-defined centrilobular nodules without evidence of fibrosis (Figure 1).

Respiratory bronchiolitis-interstitial lung disease

In rare cases, respiratory bronchiolitis leads to peribronchial fibrosis invading the alveolar walls, which is then classified as respiratory bronchiolitis-interstitial lung disease.¹¹ The CT findings in respiratory bronchiolitis-interstitial lung disease are upper-lobe-predominant centrilobular ground-glass nodules, patchy ground-glass opacities, and bronchial wall thickening (Figure 2).¹⁰ Occasionally, mild reticulation is noted without honeycombing. Mild air trapping can be seen in the lower lobes, with centrilobular emphysema in the upper lobes.¹²

The only successful therapy for respiratory bronchiolitis and respiratory bronchiolitis-interstitial lung disease is smoking cessation. Finding either of these diseases should prompt aggressive counseling by the internist and consideration of referral to a specialist in interstitial lung disease.

Desquamative interstitial pneumonia

Although pathologically different from respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia has a similar clinical and radiographic presentation. Because their features significantly overlap, they are considered a pathomorphologic continuum, representing degrees of severity of the same disease process caused by prolonged tobacco inhalation.^10,13

Widespread ground-glass opacities are the predominant CT finding. These are bilateral and symmetric in distribution in 86%, basal and peripheral in 60%, patchy in 20%, and diffuse in 20% (Figure 3).¹⁴ Other frequent findings are mild reticulation with traction bronchiectasis and coexistent emphysema (Figure 4).¹⁵ The small peripheral cystic spaces noted in this disease most likely represent dilated bronchioles and alveolar ducts rather than honeycombing.¹⁶

No additional treatment beyond elimination of smoking has been proven effective for desquamative interstitial pneumonia, and patients who manage to quit smoking generally have a favorable prognosis.^17,18

Pulmonary Langerhans cell histiocytosis

The combination of upper-lobe-predominant cysts and nodules in a young heavy smoker are diagnostic of pulmonary Langerhans cell histiocytosis. The cysts are bizarrely shaped, thin- or thick-walled, and nonuniform in size (Figure 5). The irregular cavitary nodules are centrilobular. The disease characteristically spares the costophrenic angles.

Spontaneous pneumothorax is the initial clinical presentation in 15% of patients.¹⁶ In the early stages of the disease (nodule-predominant disease without cysts), infection and metastatic disease need to be excluded (Figure 6). In the later stages, the cysts become coalescent, making the distinction between this disease and “burned-out” lymphangioleiomyomatosis or severe emphysema extremely difficult (Figure 7).¹⁷ Smoking cessation and corticosteroids are the mainstay of medical therapy for pulmonary Langerhans cell histiocytosis, and about 50% of patients who quit smoking and receive corticosteroids demonstrate partial or complete clearing of the radiographic abnormalities and symptoms (Figure 8).

FIBROTIC INTERSTITIAL LUNG DISEASES

If CT identifies a diffuse fibrotic pattern, the two most common possibilities (Table 2) are:

• Nonspecific interstitial pneumonia
• Usual interstitial pneumonia.

As noted above, these carry a worse prognosis than the nonfibrotic interstitial lung diseases.

Nonspecific interstitial pneumonia

While most frequently idiopathic, the nonspecific interstitial pneumonia pattern can often be seen in connective tissue diseases. It has also been associated with chronic hypersensitivity pneumonitis, drug toxicity, and slowly resolving diffuse alveolar damage.¹⁹ Although it is not the only pathologic pattern in interstitial lung disease associated with connective tissue disease, it is the most common pattern in systemic sclerosis, systemic lupus erythematosus, dermatomyositis-polymyositis, and mixed connective tissue disease.²⁰

The parenchymal changes are typically subpleural and symmetric in distribution (Figure 9). In about one-third of cases, there is a peribronchovascular distribution of the abnormalities (Figure 10).

Ground-glass opacities are the dominant imaging findings, seen in 80% of cases.¹⁸ In advanced disease (also referred to as fibrotic nonspecific interstitial pneumonia), patients have accompanying fine or coarse reticular opacities, traction bronchiectasis, and consolidation (Figure 11). Honeycombing is seen in 1% to 5% of patients.²¹

The most specific sign of nonspecific interstitial pneumonia is sparing of the immediate subpleural lung, apparent in 30% to 50% of patients (Figure 12).²² Subpleural sparing with a peribronchovascular distribution of abnormalities, absence of lobular areas with decreased attenuation, and lack of honeycombing are imaging features that increase the diagnostic confidence of nonspecific interstitial pneumonia (Table 3).²³ Clinically, compared with those who have usual interstitial pneumonia (see below), patients are younger and more of them are female. These patients also present with extrapulmonary manifestations such as joint involvement, rash, and Raynaud phenomenon. Therefore, these associated symptoms on presentation can help distinguish nonspecific interstitial pneumonia or usual interstitial pneumonia related to connective tissue disease from the idiopathic forms.

The first step in managing nonspecific interstitial pneumonia is to remove all potential exposure to inhaled substances or to drugs. Although immunosuppressive therapy has never been studied in a randomized controlled trial in this disease, numerous reports suggest that patients may respond to prednisone and to steroid-sparing immunosuppressants.²⁴

In several studies, survival rates in nonspecific interstitial pneumonia were significantly greater than in usual interstitial pneumonia independent of the treatment strategy. In long-term follow-up of patients with idiopathic nonspecific interstitial pneumonia treated with immunosuppressive therapy, two-thirds remained stable or improved.^25–27

Although most connective tissue diseases cause a lung pattern of nonspecific interstitial pneumonia, some (eg, rheumatoid arthritis) may present with a pattern of usual interstitial pneumonia. In these cases and in those of advanced fibrotic nonspecific interstitial pneumonia, the prognosis is worse, as the disease is less responsive to immunosuppressive therapy.²⁰

Usual interstitial pneumonia

Usual interstitial pneumonia is the most severe form of lung fibrosis. Most cases are idio­pathic and are termed idiopathic pulmonary fibrosis. Other causes of the usual interstitial pneumonia pattern include domestic and occupational environmental exposures, connective tissue disease, and drug toxicity.²⁸ An epidemiologic association between smoking and usual interstitial pneumonia is well documented.²⁸

Idiopathic pulmonary fibrosis typically affects men ages 50 to 70. Because its risk factors coincide with those of lung cancer, there is a high likelihood of detecting idiopathic pulmonary fibrosis early in this screening population. It has an especially poor prognosis, with a mean survival of 2 to 5 years from the time of diagnosis.¹⁸

The distribution of disease in usual interstitial pneumonia is characteristically subpleural and basal. CT features include coarse subpleural reticulation and honeycombing combined with traction bronchiectasis or bronchiolectasis and architectural distortion (Figure 13).¹⁸ Honeycombing is the most specific and key diagnostic CT finding for establishing a definitive diagnosis of usual interstitial pneumonia.²⁹ However, ground-glass opacities are present in most patients, typically in the region of interstitial fibrosis, and are always less extensive than the reticulation.³⁰ The findings demonstrate morphologic heterogeneity, with areas of fibrosis adjacent to areas of normal lung (Figure 14).

In addition to the aforementioned imaging features, the 2011 American Thoracic Society and European Respiratory Society joint guidelines for the CT diagnosis of usual interstitial pneumonia patterns require the absence of atypical features that suggest an alternative diagnosis, including those seen in nonspecific interstitial pneumonia, such as an upper, midlung, or peribronchovascular distribution and extensive ground-glass attenuation.²⁸ Mild mediastinal lymphadenopathy (usually < 1.5 cm in the short axis) is common in usual interstitial pneumonia.³¹

Because other chronic interstitial pneumonias that may resemble usual interstitial pneumonia have a more favorable course and may respond to immunosuppressive therapy, establishing an early and accurate diagnosis is of the utmost importance.⁵ Additionally, the emergence of possible new therapies for idiopathic pulmonary fibrosis makes early referral to a specialist paramount in these cases. Recent studies have demonstrated significant slowing of the progression of disease in idiopathic pulmonary fibrosis with both pirfenidone and nintedanib.^32,33

DIAGNOSIS AND MANAGEMENT

The diagnosis of these nonfibrotic and fibrotic lung diseases is complex. In all cases in which interstitial lung disease is detected on screening CT for lung cancer, the internist should strongly consider further evaluation with dedicated high-resolution CT and early referral to a specialist (Figure 15).

Because smoking cessation is the only recommended treatment for nonfibrotic smoking-related interstitial lung diseases, particular emphasis on smoking cessation counseling is essential.

Referral for bronchoscopy with transbronchial lung biopsy is generally not helpful in the diagnosis of the interstitial lung diseases discussed in this article unless there is a need to rule out infection or neoplasm.³⁴ Referral for surgical lung biopsy may be indicated in some cases of suspected pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, or usual interstitial pneumonia if the diagnosis is uncertain (Tables 1 and 2).³⁵

The American Thoracic Society/European Respiratory Society guidelines suggest a multidisciplinary team approach that includes a pathologist, radiologist, and clinician.³⁵ This approach more readily determines the correct diagnosis and relies less on invasive methods such as surgical biopsy and more on noninvasive methods such as radiology and clinical history. Overall, this will promote earlier access to appropriate therapies, clinical trial enrollment, and in more severe cases, lung transplant.

Currently, 23% of all lung transplants worldwide are performed in patients with idiopathic pulmonary fibrosis. Other forms of pulmonary fibrosis account for 3% to 4% of lung transplants performed.³⁶

Evidence suggests that early referral reduces rates of morbidity and death in these patients. The results of a single-center study³⁷ of patients with idiopathic pulmonary fibrosis demonstrated that a longer delay from the onset of symptoms to evaluation by a specialist at a tertiary care referral center was associated with a higher rate of death from this disease independent of disease severity. Those with the longest delay in referral had a multivariable-adjusted death rate 3.4 times higher than those with the shortest delay.^5,37

In summary, with implementation of the new lung cancer screening guidelines, primary care physicians are more often encountering the incidental finding of interstitial lung disease in their patients. Prompt diagnosis of interstitial lung disease helps ensure that patients receive appropriate care and early consideration for clinical trials and lung transplant.

Primary care physicians play a critical role in the initial identification of key characteristics of the interstitial abnormality—namely, whether the pattern is nonfibrotic or fibrotic—and in the correlation of the history and physical findings to expedite the diagnosis. Subsequently, ordering high-resolution CT for more detailed characterization and prompt referral to a specialist in interstitial lung disease allow for a more rapid and accurate diagnosis, specialized therapy, and supportive care.

Primary care physicians are playing a bigger role in evaluating the incidental finding of interstitial lung diseases since the recent publication of guidelines recommending computed tomography (CT) to screen for lung cancer.

In August 2011, the National Cancer Institute published its findings from the National Lung Screening Trial, which demonstrated a 20% reduction in mortality from lung cancer in patients at high risk screened with low-dose CT.¹ Based on these results, the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommended annual screening for lung cancer with low-dose CT in adults ages 55 to 74 who have a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years.² In December 2013, the US Preventive Services Task Force published similar guidelines but increased the age range to include high-risk patients ages 55 to 80.³

Bach et al⁴ estimated that, in 2010 in the United States, 8.6 million people met the criteria used in the National Lung Screening Trial for low-dose CT screening. These are the same criteria as in the multisociety recommendations cited above.² With such large numbers of patients eligible for CT screening, internists and other primary care physicians are undoubtedly encountering the incidental discovery of nonmalignant pulmonary diseases such as interstitial lung disease.

This article reviews the radiographic characteristics of the most common interstitial lung diseases the internist may encounter on screening CT in long-term smokers.

Referral to a specialist has been associated with lower rates of morbidity and death,⁵ and a diagnosis of interstitial lung disease should be confirmed by a pulmonologist and a radiologist specializing in differentiating the subtypes. But the primary care physician now plays a critical role in recognizing the need for further evaluation.

HOW COMMON IS INTERSTITIAL LUNG DISEASE IN SMOKERS?

Several studies have published data on the prevalence of interstitial lung disease in patients undergoing low-dose CT for lung cancer screening.

A trial at Mayo Clinic in current and former smokers identified “diffuse lung disease” in 9 (0.9%) of 1,049 participants.⁶

A trial in Ireland identified idiopathic pulmonary fibrosis in 6 (1.3%) of 449 current smokers who underwent low-dose CT screening for lung cancer.⁷

Sverzellati et al⁸ evaluated 692 participants in the Multicentric Italian Lung Detection CT screening study and reported a respiratory bronchiolitis pattern in 109 (15.7%), a usual interstitial pneumonia pattern in 2 (0.3%), and other patterns of chronic interstitial pneumonia in 26 (3.8%).

The National Lung Screening Trial reported that the frequency of “clinically significant” incidental findings (including pulmonary fibrosis) in all participants was 7.5%.¹ A retrospective analysis of 884 participants at a single site in this trial identified interstitial lung abnormalities in 86 participants (9.7%).⁹ These abnormalities were further categorized as nonfibrotic in 52 (5.9%) of 884, fibrotic in 19 (2.1%) of 884, and mixed fibrotic and nonfibrotic in 15 (1.7%) of 884.

Follow-up CT at 2 years in this trial demonstrated improvement in 50% and progression in 11% of patients who had nonfibrotic abnormalities, while fibrotic abnormalities improved in no cases and progressed in 37%. Interstitial lung abnormalities were more common in those who currently smoked and in those with more pack-years of cigarette smoking.⁹

In sum, these trials suggest that low-dose CT screening for lung cancer can detect the most common forms of interstitial lung disease in this at-risk population and can characterize them as fibrotic or nonfibrotic, a distinction important for prognosis and subsequent management.

NONFIBROTIC VS FIBROTIC DISEASE

It is important to distinguish between nonfibrotic and fibrotic interstitial lung disease, as fibrotic disease carries a worse prognosis and is treated differently.

Features of nonfibrotic interstitial lung disease:

• Ground-glass opacities
• Nodules
• Mosaic attenuation or consolidation.

Features of fibrotic interstitial lung disease:

• Combination of ground-glass opacities and reticulation
• Reticulation by itself
• Traction bronchiectasis
• Honeycombing
• Loss of lung volume.

NONFIBROTIC INTERSTITIAL LUNG DISEASES

Given the strong likelihood that a patient undergoing screening CT is either a current or former smoker, physicians may encounter, in addition to emphysema and lung cancer, the following smoking-related interstitial lung diseases, which are primarily nonfibrotic and which frequently coexist (Table 1):

• Respiratory bronchiolitis
• Respiratory bronchiolitis-interstitial lung disease
• Desquamative interstitial pneumonia
• Pulmonary Langerhans cell histiocytosis.

Respiratory bronchiolitis

Respiratory bronchiolitis occurs mostly in smokers and does not necessarily lead to respiratory symptoms in all patients.¹⁰ It cannot always be identified radiographically but occasionally appears as predominantly upper-lobe, patchy ground-glass opacities or ill-defined centrilobular nodules without evidence of fibrosis (Figure 1).

Respiratory bronchiolitis-interstitial lung disease

In rare cases, respiratory bronchiolitis leads to peribronchial fibrosis invading the alveolar walls, which is then classified as respiratory bronchiolitis-interstitial lung disease.¹¹ The CT findings in respiratory bronchiolitis-interstitial lung disease are upper-lobe-predominant centrilobular ground-glass nodules, patchy ground-glass opacities, and bronchial wall thickening (Figure 2).¹⁰ Occasionally, mild reticulation is noted without honeycombing. Mild air trapping can be seen in the lower lobes, with centrilobular emphysema in the upper lobes.¹²

The only successful therapy for respiratory bronchiolitis and respiratory bronchiolitis-interstitial lung disease is smoking cessation. Finding either of these diseases should prompt aggressive counseling by the internist and consideration of referral to a specialist in interstitial lung disease.

Desquamative interstitial pneumonia

Although pathologically different from respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia has a similar clinical and radiographic presentation. Because their features significantly overlap, they are considered a pathomorphologic continuum, representing degrees of severity of the same disease process caused by prolonged tobacco inhalation.^10,13

Widespread ground-glass opacities are the predominant CT finding. These are bilateral and symmetric in distribution in 86%, basal and peripheral in 60%, patchy in 20%, and diffuse in 20% (Figure 3).¹⁴ Other frequent findings are mild reticulation with traction bronchiectasis and coexistent emphysema (Figure 4).¹⁵ The small peripheral cystic spaces noted in this disease most likely represent dilated bronchioles and alveolar ducts rather than honeycombing.¹⁶

No additional treatment beyond elimination of smoking has been proven effective for desquamative interstitial pneumonia, and patients who manage to quit smoking generally have a favorable prognosis.^17,18

Pulmonary Langerhans cell histiocytosis

The combination of upper-lobe-predominant cysts and nodules in a young heavy smoker are diagnostic of pulmonary Langerhans cell histiocytosis. The cysts are bizarrely shaped, thin- or thick-walled, and nonuniform in size (Figure 5). The irregular cavitary nodules are centrilobular. The disease characteristically spares the costophrenic angles.

Spontaneous pneumothorax is the initial clinical presentation in 15% of patients.¹⁶ In the early stages of the disease (nodule-predominant disease without cysts), infection and metastatic disease need to be excluded (Figure 6). In the later stages, the cysts become coalescent, making the distinction between this disease and “burned-out” lymphangioleiomyomatosis or severe emphysema extremely difficult (Figure 7).¹⁷ Smoking cessation and corticosteroids are the mainstay of medical therapy for pulmonary Langerhans cell histiocytosis, and about 50% of patients who quit smoking and receive corticosteroids demonstrate partial or complete clearing of the radiographic abnormalities and symptoms (Figure 8).

FIBROTIC INTERSTITIAL LUNG DISEASES

If CT identifies a diffuse fibrotic pattern, the two most common possibilities (Table 2) are:

• Nonspecific interstitial pneumonia
• Usual interstitial pneumonia.

As noted above, these carry a worse prognosis than the nonfibrotic interstitial lung diseases.

Nonspecific interstitial pneumonia

While most frequently idiopathic, the nonspecific interstitial pneumonia pattern can often be seen in connective tissue diseases. It has also been associated with chronic hypersensitivity pneumonitis, drug toxicity, and slowly resolving diffuse alveolar damage.¹⁹ Although it is not the only pathologic pattern in interstitial lung disease associated with connective tissue disease, it is the most common pattern in systemic sclerosis, systemic lupus erythematosus, dermatomyositis-polymyositis, and mixed connective tissue disease.²⁰

The parenchymal changes are typically subpleural and symmetric in distribution (Figure 9). In about one-third of cases, there is a peribronchovascular distribution of the abnormalities (Figure 10).

Ground-glass opacities are the dominant imaging findings, seen in 80% of cases.¹⁸ In advanced disease (also referred to as fibrotic nonspecific interstitial pneumonia), patients have accompanying fine or coarse reticular opacities, traction bronchiectasis, and consolidation (Figure 11). Honeycombing is seen in 1% to 5% of patients.²¹

The most specific sign of nonspecific interstitial pneumonia is sparing of the immediate subpleural lung, apparent in 30% to 50% of patients (Figure 12).²² Subpleural sparing with a peribronchovascular distribution of abnormalities, absence of lobular areas with decreased attenuation, and lack of honeycombing are imaging features that increase the diagnostic confidence of nonspecific interstitial pneumonia (Table 3).²³ Clinically, compared with those who have usual interstitial pneumonia (see below), patients are younger and more of them are female. These patients also present with extrapulmonary manifestations such as joint involvement, rash, and Raynaud phenomenon. Therefore, these associated symptoms on presentation can help distinguish nonspecific interstitial pneumonia or usual interstitial pneumonia related to connective tissue disease from the idiopathic forms.

The first step in managing nonspecific interstitial pneumonia is to remove all potential exposure to inhaled substances or to drugs. Although immunosuppressive therapy has never been studied in a randomized controlled trial in this disease, numerous reports suggest that patients may respond to prednisone and to steroid-sparing immunosuppressants.²⁴

In several studies, survival rates in nonspecific interstitial pneumonia were significantly greater than in usual interstitial pneumonia independent of the treatment strategy. In long-term follow-up of patients with idiopathic nonspecific interstitial pneumonia treated with immunosuppressive therapy, two-thirds remained stable or improved.^25–27

Although most connective tissue diseases cause a lung pattern of nonspecific interstitial pneumonia, some (eg, rheumatoid arthritis) may present with a pattern of usual interstitial pneumonia. In these cases and in those of advanced fibrotic nonspecific interstitial pneumonia, the prognosis is worse, as the disease is less responsive to immunosuppressive therapy.²⁰

Usual interstitial pneumonia

Usual interstitial pneumonia is the most severe form of lung fibrosis. Most cases are idio­pathic and are termed idiopathic pulmonary fibrosis. Other causes of the usual interstitial pneumonia pattern include domestic and occupational environmental exposures, connective tissue disease, and drug toxicity.²⁸ An epidemiologic association between smoking and usual interstitial pneumonia is well documented.²⁸

Idiopathic pulmonary fibrosis typically affects men ages 50 to 70. Because its risk factors coincide with those of lung cancer, there is a high likelihood of detecting idiopathic pulmonary fibrosis early in this screening population. It has an especially poor prognosis, with a mean survival of 2 to 5 years from the time of diagnosis.¹⁸

The distribution of disease in usual interstitial pneumonia is characteristically subpleural and basal. CT features include coarse subpleural reticulation and honeycombing combined with traction bronchiectasis or bronchiolectasis and architectural distortion (Figure 13).¹⁸ Honeycombing is the most specific and key diagnostic CT finding for establishing a definitive diagnosis of usual interstitial pneumonia.²⁹ However, ground-glass opacities are present in most patients, typically in the region of interstitial fibrosis, and are always less extensive than the reticulation.³⁰ The findings demonstrate morphologic heterogeneity, with areas of fibrosis adjacent to areas of normal lung (Figure 14).

In addition to the aforementioned imaging features, the 2011 American Thoracic Society and European Respiratory Society joint guidelines for the CT diagnosis of usual interstitial pneumonia patterns require the absence of atypical features that suggest an alternative diagnosis, including those seen in nonspecific interstitial pneumonia, such as an upper, midlung, or peribronchovascular distribution and extensive ground-glass attenuation.²⁸ Mild mediastinal lymphadenopathy (usually < 1.5 cm in the short axis) is common in usual interstitial pneumonia.³¹

Because other chronic interstitial pneumonias that may resemble usual interstitial pneumonia have a more favorable course and may respond to immunosuppressive therapy, establishing an early and accurate diagnosis is of the utmost importance.⁵ Additionally, the emergence of possible new therapies for idiopathic pulmonary fibrosis makes early referral to a specialist paramount in these cases. Recent studies have demonstrated significant slowing of the progression of disease in idiopathic pulmonary fibrosis with both pirfenidone and nintedanib.^32,33

DIAGNOSIS AND MANAGEMENT

The diagnosis of these nonfibrotic and fibrotic lung diseases is complex. In all cases in which interstitial lung disease is detected on screening CT for lung cancer, the internist should strongly consider further evaluation with dedicated high-resolution CT and early referral to a specialist (Figure 15).

Because smoking cessation is the only recommended treatment for nonfibrotic smoking-related interstitial lung diseases, particular emphasis on smoking cessation counseling is essential.

Referral for bronchoscopy with transbronchial lung biopsy is generally not helpful in the diagnosis of the interstitial lung diseases discussed in this article unless there is a need to rule out infection or neoplasm.³⁴ Referral for surgical lung biopsy may be indicated in some cases of suspected pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, or usual interstitial pneumonia if the diagnosis is uncertain (Tables 1 and 2).³⁵

The American Thoracic Society/European Respiratory Society guidelines suggest a multidisciplinary team approach that includes a pathologist, radiologist, and clinician.³⁵ This approach more readily determines the correct diagnosis and relies less on invasive methods such as surgical biopsy and more on noninvasive methods such as radiology and clinical history. Overall, this will promote earlier access to appropriate therapies, clinical trial enrollment, and in more severe cases, lung transplant.

Currently, 23% of all lung transplants worldwide are performed in patients with idiopathic pulmonary fibrosis. Other forms of pulmonary fibrosis account for 3% to 4% of lung transplants performed.³⁶

Evidence suggests that early referral reduces rates of morbidity and death in these patients. The results of a single-center study³⁷ of patients with idiopathic pulmonary fibrosis demonstrated that a longer delay from the onset of symptoms to evaluation by a specialist at a tertiary care referral center was associated with a higher rate of death from this disease independent of disease severity. Those with the longest delay in referral had a multivariable-adjusted death rate 3.4 times higher than those with the shortest delay.^5,37

In summary, with implementation of the new lung cancer screening guidelines, primary care physicians are more often encountering the incidental finding of interstitial lung disease in their patients. Prompt diagnosis of interstitial lung disease helps ensure that patients receive appropriate care and early consideration for clinical trials and lung transplant.

Primary care physicians play a critical role in the initial identification of key characteristics of the interstitial abnormality—namely, whether the pattern is nonfibrotic or fibrotic—and in the correlation of the history and physical findings to expedite the diagnosis. Subsequently, ordering high-resolution CT for more detailed characterization and prompt referral to a specialist in interstitial lung disease allow for a more rapid and accurate diagnosis, specialized therapy, and supportive care.

Primary care physicians are playing a bigger role in evaluating the incidental finding of interstitial lung diseases since the recent publication of guidelines recommending computed tomography (CT) to screen for lung cancer.

In August 2011, the National Cancer Institute published its findings from the National Lung Screening Trial, which demonstrated a 20% reduction in mortality from lung cancer in patients at high risk screened with low-dose CT.¹ Based on these results, the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network recommended annual screening for lung cancer with low-dose CT in adults ages 55 to 74 who have a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years.² In December 2013, the US Preventive Services Task Force published similar guidelines but increased the age range to include high-risk patients ages 55 to 80.³

Bach et al⁴ estimated that, in 2010 in the United States, 8.6 million people met the criteria used in the National Lung Screening Trial for low-dose CT screening. These are the same criteria as in the multisociety recommendations cited above.² With such large numbers of patients eligible for CT screening, internists and other primary care physicians are undoubtedly encountering the incidental discovery of nonmalignant pulmonary diseases such as interstitial lung disease.

This article reviews the radiographic characteristics of the most common interstitial lung diseases the internist may encounter on screening CT in long-term smokers.

Referral to a specialist has been associated with lower rates of morbidity and death,⁵ and a diagnosis of interstitial lung disease should be confirmed by a pulmonologist and a radiologist specializing in differentiating the subtypes. But the primary care physician now plays a critical role in recognizing the need for further evaluation.

HOW COMMON IS INTERSTITIAL LUNG DISEASE IN SMOKERS?

Several studies have published data on the prevalence of interstitial lung disease in patients undergoing low-dose CT for lung cancer screening.

A trial at Mayo Clinic in current and former smokers identified “diffuse lung disease” in 9 (0.9%) of 1,049 participants.⁶

A trial in Ireland identified idiopathic pulmonary fibrosis in 6 (1.3%) of 449 current smokers who underwent low-dose CT screening for lung cancer.⁷

Sverzellati et al⁸ evaluated 692 participants in the Multicentric Italian Lung Detection CT screening study and reported a respiratory bronchiolitis pattern in 109 (15.7%), a usual interstitial pneumonia pattern in 2 (0.3%), and other patterns of chronic interstitial pneumonia in 26 (3.8%).

The National Lung Screening Trial reported that the frequency of “clinically significant” incidental findings (including pulmonary fibrosis) in all participants was 7.5%.¹ A retrospective analysis of 884 participants at a single site in this trial identified interstitial lung abnormalities in 86 participants (9.7%).⁹ These abnormalities were further categorized as nonfibrotic in 52 (5.9%) of 884, fibrotic in 19 (2.1%) of 884, and mixed fibrotic and nonfibrotic in 15 (1.7%) of 884.

Follow-up CT at 2 years in this trial demonstrated improvement in 50% and progression in 11% of patients who had nonfibrotic abnormalities, while fibrotic abnormalities improved in no cases and progressed in 37%. Interstitial lung abnormalities were more common in those who currently smoked and in those with more pack-years of cigarette smoking.⁹

In sum, these trials suggest that low-dose CT screening for lung cancer can detect the most common forms of interstitial lung disease in this at-risk population and can characterize them as fibrotic or nonfibrotic, a distinction important for prognosis and subsequent management.

NONFIBROTIC VS FIBROTIC DISEASE

It is important to distinguish between nonfibrotic and fibrotic interstitial lung disease, as fibrotic disease carries a worse prognosis and is treated differently.

Features of nonfibrotic interstitial lung disease:

• Ground-glass opacities
• Nodules
• Mosaic attenuation or consolidation.

Features of fibrotic interstitial lung disease:

• Combination of ground-glass opacities and reticulation
• Reticulation by itself
• Traction bronchiectasis
• Honeycombing
• Loss of lung volume.

NONFIBROTIC INTERSTITIAL LUNG DISEASES

Given the strong likelihood that a patient undergoing screening CT is either a current or former smoker, physicians may encounter, in addition to emphysema and lung cancer, the following smoking-related interstitial lung diseases, which are primarily nonfibrotic and which frequently coexist (Table 1):

• Respiratory bronchiolitis
• Respiratory bronchiolitis-interstitial lung disease
• Desquamative interstitial pneumonia
• Pulmonary Langerhans cell histiocytosis.

Respiratory bronchiolitis

Respiratory bronchiolitis occurs mostly in smokers and does not necessarily lead to respiratory symptoms in all patients.¹⁰ It cannot always be identified radiographically but occasionally appears as predominantly upper-lobe, patchy ground-glass opacities or ill-defined centrilobular nodules without evidence of fibrosis (Figure 1).

Respiratory bronchiolitis-interstitial lung disease

In rare cases, respiratory bronchiolitis leads to peribronchial fibrosis invading the alveolar walls, which is then classified as respiratory bronchiolitis-interstitial lung disease.¹¹ The CT findings in respiratory bronchiolitis-interstitial lung disease are upper-lobe-predominant centrilobular ground-glass nodules, patchy ground-glass opacities, and bronchial wall thickening (Figure 2).¹⁰ Occasionally, mild reticulation is noted without honeycombing. Mild air trapping can be seen in the lower lobes, with centrilobular emphysema in the upper lobes.¹²

The only successful therapy for respiratory bronchiolitis and respiratory bronchiolitis-interstitial lung disease is smoking cessation. Finding either of these diseases should prompt aggressive counseling by the internist and consideration of referral to a specialist in interstitial lung disease.

Desquamative interstitial pneumonia

Although pathologically different from respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia has a similar clinical and radiographic presentation. Because their features significantly overlap, they are considered a pathomorphologic continuum, representing degrees of severity of the same disease process caused by prolonged tobacco inhalation.^10,13

Widespread ground-glass opacities are the predominant CT finding. These are bilateral and symmetric in distribution in 86%, basal and peripheral in 60%, patchy in 20%, and diffuse in 20% (Figure 3).¹⁴ Other frequent findings are mild reticulation with traction bronchiectasis and coexistent emphysema (Figure 4).¹⁵ The small peripheral cystic spaces noted in this disease most likely represent dilated bronchioles and alveolar ducts rather than honeycombing.¹⁶

No additional treatment beyond elimination of smoking has been proven effective for desquamative interstitial pneumonia, and patients who manage to quit smoking generally have a favorable prognosis.^17,18

Pulmonary Langerhans cell histiocytosis

The combination of upper-lobe-predominant cysts and nodules in a young heavy smoker are diagnostic of pulmonary Langerhans cell histiocytosis. The cysts are bizarrely shaped, thin- or thick-walled, and nonuniform in size (Figure 5). The irregular cavitary nodules are centrilobular. The disease characteristically spares the costophrenic angles.

Spontaneous pneumothorax is the initial clinical presentation in 15% of patients.¹⁶ In the early stages of the disease (nodule-predominant disease without cysts), infection and metastatic disease need to be excluded (Figure 6). In the later stages, the cysts become coalescent, making the distinction between this disease and “burned-out” lymphangioleiomyomatosis or severe emphysema extremely difficult (Figure 7).¹⁷ Smoking cessation and corticosteroids are the mainstay of medical therapy for pulmonary Langerhans cell histiocytosis, and about 50% of patients who quit smoking and receive corticosteroids demonstrate partial or complete clearing of the radiographic abnormalities and symptoms (Figure 8).

FIBROTIC INTERSTITIAL LUNG DISEASES

If CT identifies a diffuse fibrotic pattern, the two most common possibilities (Table 2) are:

• Nonspecific interstitial pneumonia
• Usual interstitial pneumonia.

As noted above, these carry a worse prognosis than the nonfibrotic interstitial lung diseases.

Nonspecific interstitial pneumonia

While most frequently idiopathic, the nonspecific interstitial pneumonia pattern can often be seen in connective tissue diseases. It has also been associated with chronic hypersensitivity pneumonitis, drug toxicity, and slowly resolving diffuse alveolar damage.¹⁹ Although it is not the only pathologic pattern in interstitial lung disease associated with connective tissue disease, it is the most common pattern in systemic sclerosis, systemic lupus erythematosus, dermatomyositis-polymyositis, and mixed connective tissue disease.²⁰

The parenchymal changes are typically subpleural and symmetric in distribution (Figure 9). In about one-third of cases, there is a peribronchovascular distribution of the abnormalities (Figure 10).

Ground-glass opacities are the dominant imaging findings, seen in 80% of cases.¹⁸ In advanced disease (also referred to as fibrotic nonspecific interstitial pneumonia), patients have accompanying fine or coarse reticular opacities, traction bronchiectasis, and consolidation (Figure 11). Honeycombing is seen in 1% to 5% of patients.²¹

The most specific sign of nonspecific interstitial pneumonia is sparing of the immediate subpleural lung, apparent in 30% to 50% of patients (Figure 12).²² Subpleural sparing with a peribronchovascular distribution of abnormalities, absence of lobular areas with decreased attenuation, and lack of honeycombing are imaging features that increase the diagnostic confidence of nonspecific interstitial pneumonia (Table 3).²³ Clinically, compared with those who have usual interstitial pneumonia (see below), patients are younger and more of them are female. These patients also present with extrapulmonary manifestations such as joint involvement, rash, and Raynaud phenomenon. Therefore, these associated symptoms on presentation can help distinguish nonspecific interstitial pneumonia or usual interstitial pneumonia related to connective tissue disease from the idiopathic forms.

The first step in managing nonspecific interstitial pneumonia is to remove all potential exposure to inhaled substances or to drugs. Although immunosuppressive therapy has never been studied in a randomized controlled trial in this disease, numerous reports suggest that patients may respond to prednisone and to steroid-sparing immunosuppressants.²⁴

In several studies, survival rates in nonspecific interstitial pneumonia were significantly greater than in usual interstitial pneumonia independent of the treatment strategy. In long-term follow-up of patients with idiopathic nonspecific interstitial pneumonia treated with immunosuppressive therapy, two-thirds remained stable or improved.^25–27

Although most connective tissue diseases cause a lung pattern of nonspecific interstitial pneumonia, some (eg, rheumatoid arthritis) may present with a pattern of usual interstitial pneumonia. In these cases and in those of advanced fibrotic nonspecific interstitial pneumonia, the prognosis is worse, as the disease is less responsive to immunosuppressive therapy.²⁰

Usual interstitial pneumonia

Usual interstitial pneumonia is the most severe form of lung fibrosis. Most cases are idio­pathic and are termed idiopathic pulmonary fibrosis. Other causes of the usual interstitial pneumonia pattern include domestic and occupational environmental exposures, connective tissue disease, and drug toxicity.²⁸ An epidemiologic association between smoking and usual interstitial pneumonia is well documented.²⁸

Idiopathic pulmonary fibrosis typically affects men ages 50 to 70. Because its risk factors coincide with those of lung cancer, there is a high likelihood of detecting idiopathic pulmonary fibrosis early in this screening population. It has an especially poor prognosis, with a mean survival of 2 to 5 years from the time of diagnosis.¹⁸

The distribution of disease in usual interstitial pneumonia is characteristically subpleural and basal. CT features include coarse subpleural reticulation and honeycombing combined with traction bronchiectasis or bronchiolectasis and architectural distortion (Figure 13).¹⁸ Honeycombing is the most specific and key diagnostic CT finding for establishing a definitive diagnosis of usual interstitial pneumonia.²⁹ However, ground-glass opacities are present in most patients, typically in the region of interstitial fibrosis, and are always less extensive than the reticulation.³⁰ The findings demonstrate morphologic heterogeneity, with areas of fibrosis adjacent to areas of normal lung (Figure 14).

In addition to the aforementioned imaging features, the 2011 American Thoracic Society and European Respiratory Society joint guidelines for the CT diagnosis of usual interstitial pneumonia patterns require the absence of atypical features that suggest an alternative diagnosis, including those seen in nonspecific interstitial pneumonia, such as an upper, midlung, or peribronchovascular distribution and extensive ground-glass attenuation.²⁸ Mild mediastinal lymphadenopathy (usually < 1.5 cm in the short axis) is common in usual interstitial pneumonia.³¹

Because other chronic interstitial pneumonias that may resemble usual interstitial pneumonia have a more favorable course and may respond to immunosuppressive therapy, establishing an early and accurate diagnosis is of the utmost importance.⁵ Additionally, the emergence of possible new therapies for idiopathic pulmonary fibrosis makes early referral to a specialist paramount in these cases. Recent studies have demonstrated significant slowing of the progression of disease in idiopathic pulmonary fibrosis with both pirfenidone and nintedanib.^32,33

DIAGNOSIS AND MANAGEMENT

The diagnosis of these nonfibrotic and fibrotic lung diseases is complex. In all cases in which interstitial lung disease is detected on screening CT for lung cancer, the internist should strongly consider further evaluation with dedicated high-resolution CT and early referral to a specialist (Figure 15).

Because smoking cessation is the only recommended treatment for nonfibrotic smoking-related interstitial lung diseases, particular emphasis on smoking cessation counseling is essential.

Referral for bronchoscopy with transbronchial lung biopsy is generally not helpful in the diagnosis of the interstitial lung diseases discussed in this article unless there is a need to rule out infection or neoplasm.³⁴ Referral for surgical lung biopsy may be indicated in some cases of suspected pulmonary Langerhans cell histiocytosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, or usual interstitial pneumonia if the diagnosis is uncertain (Tables 1 and 2).³⁵

The American Thoracic Society/European Respiratory Society guidelines suggest a multidisciplinary team approach that includes a pathologist, radiologist, and clinician.³⁵ This approach more readily determines the correct diagnosis and relies less on invasive methods such as surgical biopsy and more on noninvasive methods such as radiology and clinical history. Overall, this will promote earlier access to appropriate therapies, clinical trial enrollment, and in more severe cases, lung transplant.

Currently, 23% of all lung transplants worldwide are performed in patients with idiopathic pulmonary fibrosis. Other forms of pulmonary fibrosis account for 3% to 4% of lung transplants performed.³⁶

Evidence suggests that early referral reduces rates of morbidity and death in these patients. The results of a single-center study³⁷ of patients with idiopathic pulmonary fibrosis demonstrated that a longer delay from the onset of symptoms to evaluation by a specialist at a tertiary care referral center was associated with a higher rate of death from this disease independent of disease severity. Those with the longest delay in referral had a multivariable-adjusted death rate 3.4 times higher than those with the shortest delay.^5,37

In summary, with implementation of the new lung cancer screening guidelines, primary care physicians are more often encountering the incidental finding of interstitial lung disease in their patients. Prompt diagnosis of interstitial lung disease helps ensure that patients receive appropriate care and early consideration for clinical trials and lung transplant.

Primary care physicians play a critical role in the initial identification of key characteristics of the interstitial abnormality—namely, whether the pattern is nonfibrotic or fibrotic—and in the correlation of the history and physical findings to expedite the diagnosis. Subsequently, ordering high-resolution CT for more detailed characterization and prompt referral to a specialist in interstitial lung disease allow for a more rapid and accurate diagnosis, specialized therapy, and supportive care.