It was late 2011. We were a practice of around 20 physicians, and just starting to integrate advanced practice providers into our practice. Our average daily census was about 100 patients and slightly more than 50% of our services were resident services.

My boss, colleague, friend, and mentor – Charles “Chuck” Sargent, MD, and I were on service together early one Saturday morning; Chuck gets a phone call that one of our colleagues was ill. With just 10 physicians working and 10 off, it was an ordeal for Chuck to call all 10 colleagues. Unlike most times, no one could come to moonlight that day. In the end Chuck and I took care of our colleague’s patients.

Yes, it was an exhausting few days, but illness and family needs do not come announced. Now, close to a decade later, we are a practice of 70 physicians and 16 advanced practice providers, our average daily census is about 270 patients, and we have two backup physicians every day – known as Jeopardy-1 and Jeopardy-2. Paternity leave, maternity leave, minor illness, minor trauma, surgery, and family needs are common for our practice. We considered it a good year when we utilized our Jeopardy-1 and Jeopardy-2 for 10% and 1% respectively; and for the past year with a lot of needs, we employed Jeopardy-1 and Jeopardy-2 for 25% and 10%, respectively.

Dr. Chadha is interim division chief in the division of hospital medicine at the University of Kentucky HealthCare in Lexington. He actively leads efforts of recruiting, scheduling, practice analysis, and operation of the group. He is a first-time member of the SHM Practice Analysis Committee. Ms. Babb is administrative support associate in the division of hospital medicine at University of Kentucky HealthCare.

It was late 2011. We were a practice of around 20 physicians, and just starting to integrate advanced practice providers into our practice. Our average daily census was about 100 patients and slightly more than 50% of our services were resident services.

My boss, colleague, friend, and mentor – Charles “Chuck” Sargent, MD, and I were on service together early one Saturday morning; Chuck gets a phone call that one of our colleagues was ill. With just 10 physicians working and 10 off, it was an ordeal for Chuck to call all 10 colleagues. Unlike most times, no one could come to moonlight that day. In the end Chuck and I took care of our colleague’s patients.

Yes, it was an exhausting few days, but illness and family needs do not come announced. Now, close to a decade later, we are a practice of 70 physicians and 16 advanced practice providers, our average daily census is about 270 patients, and we have two backup physicians every day – known as Jeopardy-1 and Jeopardy-2. Paternity leave, maternity leave, minor illness, minor trauma, surgery, and family needs are common for our practice. We considered it a good year when we utilized our Jeopardy-1 and Jeopardy-2 for 10% and 1% respectively; and for the past year with a lot of needs, we employed Jeopardy-1 and Jeopardy-2 for 25% and 10%, respectively.

Dr. Chadha is interim division chief in the division of hospital medicine at the University of Kentucky HealthCare in Lexington. He actively leads efforts of recruiting, scheduling, practice analysis, and operation of the group. He is a first-time member of the SHM Practice Analysis Committee. Ms. Babb is administrative support associate in the division of hospital medicine at University of Kentucky HealthCare.

It was late 2011. We were a practice of around 20 physicians, and just starting to integrate advanced practice providers into our practice. Our average daily census was about 100 patients and slightly more than 50% of our services were resident services.

My boss, colleague, friend, and mentor – Charles “Chuck” Sargent, MD, and I were on service together early one Saturday morning; Chuck gets a phone call that one of our colleagues was ill. With just 10 physicians working and 10 off, it was an ordeal for Chuck to call all 10 colleagues. Unlike most times, no one could come to moonlight that day. In the end Chuck and I took care of our colleague’s patients.

Yes, it was an exhausting few days, but illness and family needs do not come announced. Now, close to a decade later, we are a practice of 70 physicians and 16 advanced practice providers, our average daily census is about 270 patients, and we have two backup physicians every day – known as Jeopardy-1 and Jeopardy-2. Paternity leave, maternity leave, minor illness, minor trauma, surgery, and family needs are common for our practice. We considered it a good year when we utilized our Jeopardy-1 and Jeopardy-2 for 10% and 1% respectively; and for the past year with a lot of needs, we employed Jeopardy-1 and Jeopardy-2 for 25% and 10%, respectively.

Dr. Chadha is interim division chief in the division of hospital medicine at the University of Kentucky HealthCare in Lexington. He actively leads efforts of recruiting, scheduling, practice analysis, and operation of the group. He is a first-time member of the SHM Practice Analysis Committee. Ms. Babb is administrative support associate in the division of hospital medicine at University of Kentucky HealthCare.

Lung cancer is the leading cause of cancer death in the US, with 154 050 deaths in 2018.¹ There have been many attempts to reduce mortality of the disease through early diagnosis with use of computed tomography (CT). The National Lung Cancer Screening trial showed that screening high-risk populations with low-dose CT (LDCT) can reduce mortality.² However, implementing LDCT screening in the clinical setting has proven challenging, as illustrated by the VA Lung Cancer Screening Demonstration Project (LCSDP).³ A lung cancer diagnosis typically comprises several steps that require different medical specialties; this can lead to delays. In the LCSDP, the mean time to diagnosis was 137 days.³ There are no federal standards for timeliness of lung cancer diagnosis.

The nonprofit RAND Corporation is the only American research organization that has published guidelines specifying acceptable intervals for the diagnosis and treatment of lung cancer. In Quality of Care for Oncologic Conditions and HIV, RAND Corporation researchers propose management quality indicators: lung cancer diagnosis within 2 months of an abnormal radiologic study and treatment within 6 weeks of diagnosis.⁴ The Swedish Lung Cancer Study⁵ and the Canadian Strategy for Cancer Control⁶ both recommended a standard of about 30 days—half the time recommended by the RAND Corporation.

Bukhari and colleagues at the Dayton US Department of Veterans Affairs (VA) Medical Center (VAMC) conducted a quality improvement study that examined lung cancer diagnosis and management.7 They found the time (SD) from abnormal chest imaging to diagnosis was 35.5 (31.6) days. Of those veterans who received a lung cancer diagnosis, 89.2% had the diagnosis made within the 60 days recommended by the RAND Corporation. Although these results surpass those of the LCSDP, they can be exceeded.

Beyond the potential emotional distress of awaiting the final diagnosis of a lung lesion, a delay in diagnosis and treatment may adversely affect outcomes. LDCT screening has been shown to reduce mortality, which implies a link between survival and time to intervention. There is no published evidence that time to diagnosis in advanced stage lung cancer affects outcome. The National Cancer Database (NCDB) contains informtion on about 70% of the cancers diagnosed each year in the US.8 An analysis of 4984 patients with stage IA squamous cell lung cancer undergoing lobectomy from NCDB showed that earlier surgery was associated with an absolute decrease in 5-year mortality of 5% to 8%. 9 Hence, at least in early-stage disease, reduced time from initial suspect imaging to definitive treatment may improve survival.

A system that coordinates the requisite diagnostic steps and avoids delays should provide a significant improvement in patient care. The results of such an approach that utilized nurse navigators has been previously published. 10 Here, we present the results of a dedicated VA referral clinic with priority access to pulmonary consultation and procedures in place that are designed to expedite the diagnosis of potential lung cancer.

Methods

The John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas institutional review board approved this study, which was performed in accordance with the Declaration of Helsinki. Requirement for informed consent was waived, and patient confidentiality was maintained throughout.

We have developed a plan of care specifically to facilitate diagnosis and treatment of the large number of veterans referred to the JLMMVH Diagnostic Clinic for abnormal results of chest imaging. The clinic has priority access to same-day imaging and subspecialty consultation services. In the clinic, medical students and residents perform evaluations and a registered nurse (RN) manager coordinates care.

A Diagnostic Clinic consult for abnormal thoracic imaging immediately triggers an e-consult to an interventional pulmonologist (Figure). The RN manager and pulmonologist perform a joint review of records/imaging prior to scheduling, and the pulmonologist triages the patient. Triage options include follow-up imaging, bronchoscopy with endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and CT-guided biopsy.

The RN manager then schedules a clinic visit that includes a medical evaluation by clinic staff and any indicated procedures on the same day. The interventional pulmonologist performs EBUS, EUS with the convex curvilinear bronchoscope, or both combined as indicated for diagnosis and staging. All procedures are performed in the JLMMVH bronchoscopy suite with standard conscious sedation using midazolam and fentanyl. Any other relevant procedures, such as pleural tap, also are performed at time of procedure. The pulmonologist and an attending pathologist interpret biopsies obtained in the bronchoscopy suite.

We performed a retrospective chart review of patients diagnosed with primary lung cancer through referral to the JLMMVH Diagnostic Clinic. The primary outcome was time from initial suspect chest imaging to cancer diagnosis. The study population consisted of patients referred for abnormal thoracic imaging between January 1, 2013 and December 31, 2016 and subsequently diagnosed with a primary lung cancer.

Subjects were excluded if (1) the patient was referred from outside our care network and a delay of > 10 days occurred between initial lesion imaging and referral; (2) the patient did not show up for appointments or chose to delay evaluation following referral; (3) biopsy demonstrated a nonlung primary cancer; and (4) serious intercurrent illness interrupted the diagnostic plan. In some cases, the radiologist or consulting pulmonologist had judged the lung lesion too small for immediate biopsy and recommended repeat imaging at a later date.

Patients were included in the study if the follow- up imaging led to a lung cancer diagnosis. However, because the interval between the initial imaging and the follow-up imaging in these patients did not represent a systems delay problem, the date of the scheduled follow-up abnormal imaging, which resulted in initiation of a potential cancer evaluation, served as the index suspect imaging date for this study.

Patient electronic medical records were reviewed and the following data were abstracted: date of the abnormal imaging that led to referral and time from abnormal chest X-ray to chest CT scan if applicable; date of referral and date of clinic visit; date of biopsy; date of lung cancer diagnosis; method of obtaining diagnostic specimen; lung cancer type and stage; type and date of treatment initiation or decision for supportive care only; and decision to seek further evaluation or care outside of our system.

All patients diagnosed with lung cancer during the study period were reviewed for inclusion, hence no required sample-size estimate was calculated. All outcomes were assessed as calendar days. The primary outcome was the time from the index suspect chest imaging study to the date of diagnosis of lung cancer. Prior to the initiation of our study, we chose this more stringent 30-day recommendation of the Canadian6 and Swedish5 studies as the comparator for our primary outcome, although data with respect to the 60-day Rand Corporation guidelines also are reported.⁴

Statistical Methods

The mean time to lung cancer diagnosis in our cohort was compared with this 30-day standard using a 2-sided Mann–Whitney U test. Normality of data distribution was determined using the Kolmogorov–Smirnov test. For statistical significance testing a P value of .05 was used. Statistical calculations were performed using R statistical software version 3.2.4. Secondary outcomes consisted of time from diagnosis to treatment; proportion of subjects diagnosed within 60 days; time from initial clinic visit to biopsy; and time from biopsy to diagnosis.

Results

Overall, 222 patients were diagnosed with a malignant lung lesion, of which 63 were excluded from analysis: 22 cancelled or did not appear for appointments, declined further evaluation, or completed evaluation outside of our network; 13 had the diagnosis made prior to Diagnostic Clinic visit; 13 proved to have a nonlung primary tumor presenting in the lung or mediastinal nodes; 12 were delayed > 10 days in referral from an outside network; and 3 had an intervening serious acute medical problem forcing delay in the diagnostic process.

Of the 159 included subjects, 154 (96.9%) were male, and the mean (SD) age was 67.6 (8.1) years. For 76 subjects, the abnormal chest X-ray and subsequent chest CT scan were performed the same day or the lung lesion had initially been noted on a CT scan. For 54 subjects, there was a delay of ≥ 1 week in obtaining a chest CT scan. The mean (SD) time from placement of the Diagnostic Clinic consultation by the primary care provider (PCP) or other provider and the initial Diagnostic Clinic visit was 6.3 (4.4) days. The mean (SD) time from suspect imaging to diagnosis (primary outcome) was 22.6(16.6) days.

The distribution of this outcome was nonnormal (Kolmogorov-Smirnov test P < .01). When compared with the standard of 30 days, the primary outcome of 22.6 days was significantly shorter (2-sided Mann–Whitney U test P < .01). Three-quarters (76.1%) of subjects were diagnosed within 30 days and 95.0% of subjects were diagnosed within 60 days of the initial imaging. For the 8 subjects diagnosed after 60 days, contributing factors included PCP delay in Diagnostic Clinic consultation, initial negative biopsy, delay in performance of chest CT scan prior to consultation, and outsourcing of positron emission tomography (PET) scans.

Overall, 57 (35.8%) of the subjects underwent biopsy on the day of their Diagnostic Clinic visit: 14 underwent CT-guided biopsy and 43 underwent EBUS/EUS. Within 2 days of the initial visit 106 subjects (66.7%) had undergone biopsy. The mean (SD) time from initial Diagnostic Clinic visit to biopsy was 6.3 (9.5) days. The mean (SD) interval was 1.8 (3.0) days for EBUS/ EUS and 11.3 (11.7) days for CT-guided biopsy. The mean (SD) interval from biopsy to diagnosis was 3.2 (6.2) days with 64 cases (40.3%) diagnosed the day of biopsy.

Excluding subjects whose treatment was delayed by patient choice or intercurrent illness, and those who left the VA system to seek treatment elsewhere (n = 21), 24 opted for palliative care, 5 died before treatment could be initiated, and 109 underwent treatment for their tumors (Table). The mean times (SD) from diagnosis to treatment were: chemotherapy alone 34.7 (25.3) days; chemoradiation 37.0 (22.8) days; surgery 44.3 (24.4) days; radiation therapy alone 47.9 (26.0) days. With respect to the RAND Corporation recommended diagnosis to treatment time, 60.9% of chemotherapy alone, 61.5% of chemoradiation, 66.7% of surgery, and 45.0% of radiation therapy alone treatments were initiated within the 6-week window.

Discussion

This retrospective case study demonstrates the effectiveness of a dedicated diagnostic clinic with priority EBUS/EUS access in diagnosing lung cancer within the VA system. Although there is no universally accepted quality standard for comparison, the RAND Corporation recommendation of 60 days from abnormal imaging to diagnosis and the Dayton VAMC published mean of 35.5 days are guideposts; however, the results from the Dayton VAMC may have been affected negatively by some subjects undergoing serial imaging for asymptomatic nodules. We chose a more stringent standard of 30 days as recommended by Swedish and Canadian task forces.

When diagnosing lung cancer, the overriding purpose of the Diagnostic Clinic is to minimize system delays. The method is to have as simple a task as possible for the PCP or other provider who identifies a lung nodule or mass and submits a single consultation request to the Diagnostic Clinic. Once this consultation is placed, the clinic RN manager oversees all further steps required for diagnosis and referral for treatment. The key factor in achieving a mean diagnosis time of 22.6 days is the cooperation between the RN manager and the interventional pulmonologist. When a consultation is received, the RN manager and pulmonologist review the data together and schedule the initial clinic visit; the goal is same-day biopsy, which is achieved in more than one-third of cases. Not all patients with a chest image suspected for lung cancer had it ordered by their PCP. For this reason, a Diagnostic Clinic consultation is available to all health care providers in our system. Many patients reach the clinic after the discovery of a suspect chest X-ray during an emergency department visit, a regularly scheduled subspecialty appointment, or during a preoperative evaluation.

The mean time from initial visit to biopsy was 1.8 days for EBUS/EUS compared with an interval of 11.3 days for CT-guided biopsy. This difference reflects the pulmonologist’s involvement in initial scheduling of Diagnostic Clinic patients. The ability of the pulmonologist to provide an accurate assessment of sample adequacy and a preliminary diagnosis at bedside, with concurrent confirmation by a staff pathologist, permitted the Diagnostic Clinic to inform 40.3% of patients of the finding of malignancy on the day of biopsy. A published comparison of the onsite review of biopsy material showed our pulmonologist and staff pathologists to be equally accurate in their interpretations.¹¹

Sources of Delays

While this study documents the shortest intervals from suspect imaging to diagnosis reported to date, it also identifies sources of system delay in diagnosing lung cancer that JLMMVH could further optimize. The first is the time from initial abnormal chest X-ray imaging to performance of the chest CT scan. On occasion, the index lung lesion is identified unexpectedly on an outpatient or emergency department chest CT scan. With greater use of LDCT lung cancer screening, the initial detection of suspect lesions by CT scanning will increase in the future. However, the PCP most often investigates a patient complaint with a standard chest X-ray that reveals a suspect nodule or mass. When ordered by the PCP as an outpatient test, scheduling of the follow-up chest CT scan is not given priority. More than a third of subjects experienced a delay ≥ 1 week in obtaining a chest CT scan ordered by the PCP; for 29 subjects the delay was ≥ 3weeks. At JLMMVH, the Diagnostic Clinic is given priority in scheduling CT scans. Hence, for suspect lung lesions, the chest CT scan, if not already obtained, is generally performed on the morning of the clinic visit. Educating the PCP to refer the patient immediately to the Diagnostic Clinic rather than waiting to obtain an outpatient chest CT scan may remove this source of unnecessary delay.

Scheduling a CT-guided fine needle aspiration of a lung lesion is another source of system delay. When the chest CT scan is available at the time of the Diagnostic Clinic referral, the clinic visit is scheduled for the earliest day a required CT-guided biopsy can be performed. However, the mean time of 11.3 days from initial Diagnostic Clinic visit to CT-guided biopsy is indicative of the backlog faced by the interventional radiologists.

Although infrequent, PET scans that are required before biopsy can lead to substantial delays. PET scans are performed at our university affiliate, and the joint VA-university lung tumor board sometimes generates requests for such scans prior to tissue diagnosis, yet another source of delay.

The time from referral receipt to the Diagnostic Clinic visit averaged 6.3 days. This delay usually was determined by the availability of the CT-guided biopsy or the dedicated interventional pulmonologist. Although other interventional pulmonologists at JLMMVH may perform the requisite diagnostic procedures, they are not always available for immediate review of imaging studies of referred patients nor can their schedules flexibly accommodate the number of patients seen in our clinic for evaluation.

Lung Cancer Diagnosis

Prompt diagnosis in the setting of a worrisome chest X-ray may help decrease patient anxiety, but does the clinic improve lung cancer treatment outcomes? Such improvement has been demonstrated only in stage IA squamous cell lung cancer.⁹ Of our study population, 37.7% had squamous cell carcinoma, and 85.5% had non-small cell lung cancer. Of those with non-small cell lung cancer, 28.9% had a clinical stage I tumor. Stage I squamous cell carcinoma, the type of tumor most likely to benefit from early diagnosis and treatment, was diagnosed in 11.3% of patients. With the increased application of LDCT screening, the proportion of veterans identified with early stage lung cancer may rise. The Providence VAMC in Rhode Island reported its results from instituting LDCT screening.¹² Prior to screening, 28% of patients diagnosed with lung cancer had a stage I tumor. Following the introduction of LDCT screening, 49% diagnosed by LDCT screening had a stage I tumor. Nearly a third of their patients diagnosed with lung cancer through LDCT screening had squamous cell tumor histology. Thus, we can anticipate an increasing number of veterans with early stage lung cancer who would benefit from timely diagnosis.

The JLMMVH is a referral center for the entire state of Arkansas. Quite a few of its referred patients come from a long distance, which may require overnight housing and other related travel expenses. Apart from any potential outcome benefit, the efficiencies of the system described herein include the minimization of extra trips, an inconvenience and cost to both patient and JLMMVH.

Although the primary task of the clinic is diagnosis, we also seek to facilitate timely treatment. Our lack of an on-site PET scanner and radiation therapy, resources present on-site at the Dayton VAMC, contribute to longer therapy wait times. The shortest mean wait time at JLMMVH is for chemotherapy alone (34.7 days), in part because the JLMMVH oncologists, performing initial consultations 2 to 3 times weekly in the Diagnostic Clinic, are more readily available than are our thoracic surgeons or radiation therapists. Yet overall, JLMMVH patients often face delay from the time of lung cancer diagnosis to initiation of treatment.

The Connecticut Veterans Affairs Healthcare System has published the results of changes in lung cancer management associated with a nurse navigator system.10 Prior to creating the position of cancer care coordinator, filled by an advanced practice RNs, the mean time from clinical suspicion of lung cancer to treatment was 117 days. After 4 years of such care navigation, this waiting time had decreased to 52.4 days. Associated with this dramatic improvement in overall waiting time were decreases in the turnaround time required for performance of CT and PET scans. With respect to this big picture view of lung cancer care, our Diagnostic Clinic serves as a model for the initial step of diagnosis. Coordination and streamlining of the various steps from diagnosis to definitive therapy shall require a more system-wide effort involving all the key players in cancer care.

Conclusion

We have developed a care pathway based in a dedicated diagnostic clinic and have been able to document the shortest interval from abnormality to diagnosis of lung cancer reported in the literature to date. Efficient functioning of this clinic is dependent upon the close cooperation between a full-time RN clinic manager and an interventional pulmonologist experienced in lung cancer management and able to interpret cytologic samples at the time of biopsy. Shortening the delay between diagnosis and definitive therapy remains a challenge and may benefit from the oncology nurse navigator model previously described within the VA system. ¹⁰

Lung cancer is the leading cause of cancer death in the US, with 154 050 deaths in 2018.¹ There have been many attempts to reduce mortality of the disease through early diagnosis with use of computed tomography (CT). The National Lung Cancer Screening trial showed that screening high-risk populations with low-dose CT (LDCT) can reduce mortality.² However, implementing LDCT screening in the clinical setting has proven challenging, as illustrated by the VA Lung Cancer Screening Demonstration Project (LCSDP).³ A lung cancer diagnosis typically comprises several steps that require different medical specialties; this can lead to delays. In the LCSDP, the mean time to diagnosis was 137 days.³ There are no federal standards for timeliness of lung cancer diagnosis.

The nonprofit RAND Corporation is the only American research organization that has published guidelines specifying acceptable intervals for the diagnosis and treatment of lung cancer. In Quality of Care for Oncologic Conditions and HIV, RAND Corporation researchers propose management quality indicators: lung cancer diagnosis within 2 months of an abnormal radiologic study and treatment within 6 weeks of diagnosis.⁴ The Swedish Lung Cancer Study⁵ and the Canadian Strategy for Cancer Control⁶ both recommended a standard of about 30 days—half the time recommended by the RAND Corporation.

Bukhari and colleagues at the Dayton US Department of Veterans Affairs (VA) Medical Center (VAMC) conducted a quality improvement study that examined lung cancer diagnosis and management.7 They found the time (SD) from abnormal chest imaging to diagnosis was 35.5 (31.6) days. Of those veterans who received a lung cancer diagnosis, 89.2% had the diagnosis made within the 60 days recommended by the RAND Corporation. Although these results surpass those of the LCSDP, they can be exceeded.

Beyond the potential emotional distress of awaiting the final diagnosis of a lung lesion, a delay in diagnosis and treatment may adversely affect outcomes. LDCT screening has been shown to reduce mortality, which implies a link between survival and time to intervention. There is no published evidence that time to diagnosis in advanced stage lung cancer affects outcome. The National Cancer Database (NCDB) contains informtion on about 70% of the cancers diagnosed each year in the US.8 An analysis of 4984 patients with stage IA squamous cell lung cancer undergoing lobectomy from NCDB showed that earlier surgery was associated with an absolute decrease in 5-year mortality of 5% to 8%. 9 Hence, at least in early-stage disease, reduced time from initial suspect imaging to definitive treatment may improve survival.

A system that coordinates the requisite diagnostic steps and avoids delays should provide a significant improvement in patient care. The results of such an approach that utilized nurse navigators has been previously published. 10 Here, we present the results of a dedicated VA referral clinic with priority access to pulmonary consultation and procedures in place that are designed to expedite the diagnosis of potential lung cancer.

Methods

The John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas institutional review board approved this study, which was performed in accordance with the Declaration of Helsinki. Requirement for informed consent was waived, and patient confidentiality was maintained throughout.

We have developed a plan of care specifically to facilitate diagnosis and treatment of the large number of veterans referred to the JLMMVH Diagnostic Clinic for abnormal results of chest imaging. The clinic has priority access to same-day imaging and subspecialty consultation services. In the clinic, medical students and residents perform evaluations and a registered nurse (RN) manager coordinates care.

A Diagnostic Clinic consult for abnormal thoracic imaging immediately triggers an e-consult to an interventional pulmonologist (Figure). The RN manager and pulmonologist perform a joint review of records/imaging prior to scheduling, and the pulmonologist triages the patient. Triage options include follow-up imaging, bronchoscopy with endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and CT-guided biopsy.

The RN manager then schedules a clinic visit that includes a medical evaluation by clinic staff and any indicated procedures on the same day. The interventional pulmonologist performs EBUS, EUS with the convex curvilinear bronchoscope, or both combined as indicated for diagnosis and staging. All procedures are performed in the JLMMVH bronchoscopy suite with standard conscious sedation using midazolam and fentanyl. Any other relevant procedures, such as pleural tap, also are performed at time of procedure. The pulmonologist and an attending pathologist interpret biopsies obtained in the bronchoscopy suite.

We performed a retrospective chart review of patients diagnosed with primary lung cancer through referral to the JLMMVH Diagnostic Clinic. The primary outcome was time from initial suspect chest imaging to cancer diagnosis. The study population consisted of patients referred for abnormal thoracic imaging between January 1, 2013 and December 31, 2016 and subsequently diagnosed with a primary lung cancer.

Subjects were excluded if (1) the patient was referred from outside our care network and a delay of > 10 days occurred between initial lesion imaging and referral; (2) the patient did not show up for appointments or chose to delay evaluation following referral; (3) biopsy demonstrated a nonlung primary cancer; and (4) serious intercurrent illness interrupted the diagnostic plan. In some cases, the radiologist or consulting pulmonologist had judged the lung lesion too small for immediate biopsy and recommended repeat imaging at a later date.

Patients were included in the study if the follow- up imaging led to a lung cancer diagnosis. However, because the interval between the initial imaging and the follow-up imaging in these patients did not represent a systems delay problem, the date of the scheduled follow-up abnormal imaging, which resulted in initiation of a potential cancer evaluation, served as the index suspect imaging date for this study.

Patient electronic medical records were reviewed and the following data were abstracted: date of the abnormal imaging that led to referral and time from abnormal chest X-ray to chest CT scan if applicable; date of referral and date of clinic visit; date of biopsy; date of lung cancer diagnosis; method of obtaining diagnostic specimen; lung cancer type and stage; type and date of treatment initiation or decision for supportive care only; and decision to seek further evaluation or care outside of our system.

All patients diagnosed with lung cancer during the study period were reviewed for inclusion, hence no required sample-size estimate was calculated. All outcomes were assessed as calendar days. The primary outcome was the time from the index suspect chest imaging study to the date of diagnosis of lung cancer. Prior to the initiation of our study, we chose this more stringent 30-day recommendation of the Canadian6 and Swedish5 studies as the comparator for our primary outcome, although data with respect to the 60-day Rand Corporation guidelines also are reported.⁴

Statistical Methods

The mean time to lung cancer diagnosis in our cohort was compared with this 30-day standard using a 2-sided Mann–Whitney U test. Normality of data distribution was determined using the Kolmogorov–Smirnov test. For statistical significance testing a P value of .05 was used. Statistical calculations were performed using R statistical software version 3.2.4. Secondary outcomes consisted of time from diagnosis to treatment; proportion of subjects diagnosed within 60 days; time from initial clinic visit to biopsy; and time from biopsy to diagnosis.

Results

Overall, 222 patients were diagnosed with a malignant lung lesion, of which 63 were excluded from analysis: 22 cancelled or did not appear for appointments, declined further evaluation, or completed evaluation outside of our network; 13 had the diagnosis made prior to Diagnostic Clinic visit; 13 proved to have a nonlung primary tumor presenting in the lung or mediastinal nodes; 12 were delayed > 10 days in referral from an outside network; and 3 had an intervening serious acute medical problem forcing delay in the diagnostic process.

Of the 159 included subjects, 154 (96.9%) were male, and the mean (SD) age was 67.6 (8.1) years. For 76 subjects, the abnormal chest X-ray and subsequent chest CT scan were performed the same day or the lung lesion had initially been noted on a CT scan. For 54 subjects, there was a delay of ≥ 1 week in obtaining a chest CT scan. The mean (SD) time from placement of the Diagnostic Clinic consultation by the primary care provider (PCP) or other provider and the initial Diagnostic Clinic visit was 6.3 (4.4) days. The mean (SD) time from suspect imaging to diagnosis (primary outcome) was 22.6(16.6) days.

The distribution of this outcome was nonnormal (Kolmogorov-Smirnov test P < .01). When compared with the standard of 30 days, the primary outcome of 22.6 days was significantly shorter (2-sided Mann–Whitney U test P < .01). Three-quarters (76.1%) of subjects were diagnosed within 30 days and 95.0% of subjects were diagnosed within 60 days of the initial imaging. For the 8 subjects diagnosed after 60 days, contributing factors included PCP delay in Diagnostic Clinic consultation, initial negative biopsy, delay in performance of chest CT scan prior to consultation, and outsourcing of positron emission tomography (PET) scans.

Overall, 57 (35.8%) of the subjects underwent biopsy on the day of their Diagnostic Clinic visit: 14 underwent CT-guided biopsy and 43 underwent EBUS/EUS. Within 2 days of the initial visit 106 subjects (66.7%) had undergone biopsy. The mean (SD) time from initial Diagnostic Clinic visit to biopsy was 6.3 (9.5) days. The mean (SD) interval was 1.8 (3.0) days for EBUS/ EUS and 11.3 (11.7) days for CT-guided biopsy. The mean (SD) interval from biopsy to diagnosis was 3.2 (6.2) days with 64 cases (40.3%) diagnosed the day of biopsy.

Excluding subjects whose treatment was delayed by patient choice or intercurrent illness, and those who left the VA system to seek treatment elsewhere (n = 21), 24 opted for palliative care, 5 died before treatment could be initiated, and 109 underwent treatment for their tumors (Table). The mean times (SD) from diagnosis to treatment were: chemotherapy alone 34.7 (25.3) days; chemoradiation 37.0 (22.8) days; surgery 44.3 (24.4) days; radiation therapy alone 47.9 (26.0) days. With respect to the RAND Corporation recommended diagnosis to treatment time, 60.9% of chemotherapy alone, 61.5% of chemoradiation, 66.7% of surgery, and 45.0% of radiation therapy alone treatments were initiated within the 6-week window.

Discussion

This retrospective case study demonstrates the effectiveness of a dedicated diagnostic clinic with priority EBUS/EUS access in diagnosing lung cancer within the VA system. Although there is no universally accepted quality standard for comparison, the RAND Corporation recommendation of 60 days from abnormal imaging to diagnosis and the Dayton VAMC published mean of 35.5 days are guideposts; however, the results from the Dayton VAMC may have been affected negatively by some subjects undergoing serial imaging for asymptomatic nodules. We chose a more stringent standard of 30 days as recommended by Swedish and Canadian task forces.

When diagnosing lung cancer, the overriding purpose of the Diagnostic Clinic is to minimize system delays. The method is to have as simple a task as possible for the PCP or other provider who identifies a lung nodule or mass and submits a single consultation request to the Diagnostic Clinic. Once this consultation is placed, the clinic RN manager oversees all further steps required for diagnosis and referral for treatment. The key factor in achieving a mean diagnosis time of 22.6 days is the cooperation between the RN manager and the interventional pulmonologist. When a consultation is received, the RN manager and pulmonologist review the data together and schedule the initial clinic visit; the goal is same-day biopsy, which is achieved in more than one-third of cases. Not all patients with a chest image suspected for lung cancer had it ordered by their PCP. For this reason, a Diagnostic Clinic consultation is available to all health care providers in our system. Many patients reach the clinic after the discovery of a suspect chest X-ray during an emergency department visit, a regularly scheduled subspecialty appointment, or during a preoperative evaluation.

The mean time from initial visit to biopsy was 1.8 days for EBUS/EUS compared with an interval of 11.3 days for CT-guided biopsy. This difference reflects the pulmonologist’s involvement in initial scheduling of Diagnostic Clinic patients. The ability of the pulmonologist to provide an accurate assessment of sample adequacy and a preliminary diagnosis at bedside, with concurrent confirmation by a staff pathologist, permitted the Diagnostic Clinic to inform 40.3% of patients of the finding of malignancy on the day of biopsy. A published comparison of the onsite review of biopsy material showed our pulmonologist and staff pathologists to be equally accurate in their interpretations.¹¹

Sources of Delays

While this study documents the shortest intervals from suspect imaging to diagnosis reported to date, it also identifies sources of system delay in diagnosing lung cancer that JLMMVH could further optimize. The first is the time from initial abnormal chest X-ray imaging to performance of the chest CT scan. On occasion, the index lung lesion is identified unexpectedly on an outpatient or emergency department chest CT scan. With greater use of LDCT lung cancer screening, the initial detection of suspect lesions by CT scanning will increase in the future. However, the PCP most often investigates a patient complaint with a standard chest X-ray that reveals a suspect nodule or mass. When ordered by the PCP as an outpatient test, scheduling of the follow-up chest CT scan is not given priority. More than a third of subjects experienced a delay ≥ 1 week in obtaining a chest CT scan ordered by the PCP; for 29 subjects the delay was ≥ 3weeks. At JLMMVH, the Diagnostic Clinic is given priority in scheduling CT scans. Hence, for suspect lung lesions, the chest CT scan, if not already obtained, is generally performed on the morning of the clinic visit. Educating the PCP to refer the patient immediately to the Diagnostic Clinic rather than waiting to obtain an outpatient chest CT scan may remove this source of unnecessary delay.

Scheduling a CT-guided fine needle aspiration of a lung lesion is another source of system delay. When the chest CT scan is available at the time of the Diagnostic Clinic referral, the clinic visit is scheduled for the earliest day a required CT-guided biopsy can be performed. However, the mean time of 11.3 days from initial Diagnostic Clinic visit to CT-guided biopsy is indicative of the backlog faced by the interventional radiologists.

Although infrequent, PET scans that are required before biopsy can lead to substantial delays. PET scans are performed at our university affiliate, and the joint VA-university lung tumor board sometimes generates requests for such scans prior to tissue diagnosis, yet another source of delay.

The time from referral receipt to the Diagnostic Clinic visit averaged 6.3 days. This delay usually was determined by the availability of the CT-guided biopsy or the dedicated interventional pulmonologist. Although other interventional pulmonologists at JLMMVH may perform the requisite diagnostic procedures, they are not always available for immediate review of imaging studies of referred patients nor can their schedules flexibly accommodate the number of patients seen in our clinic for evaluation.

Lung Cancer Diagnosis

Prompt diagnosis in the setting of a worrisome chest X-ray may help decrease patient anxiety, but does the clinic improve lung cancer treatment outcomes? Such improvement has been demonstrated only in stage IA squamous cell lung cancer.⁹ Of our study population, 37.7% had squamous cell carcinoma, and 85.5% had non-small cell lung cancer. Of those with non-small cell lung cancer, 28.9% had a clinical stage I tumor. Stage I squamous cell carcinoma, the type of tumor most likely to benefit from early diagnosis and treatment, was diagnosed in 11.3% of patients. With the increased application of LDCT screening, the proportion of veterans identified with early stage lung cancer may rise. The Providence VAMC in Rhode Island reported its results from instituting LDCT screening.¹² Prior to screening, 28% of patients diagnosed with lung cancer had a stage I tumor. Following the introduction of LDCT screening, 49% diagnosed by LDCT screening had a stage I tumor. Nearly a third of their patients diagnosed with lung cancer through LDCT screening had squamous cell tumor histology. Thus, we can anticipate an increasing number of veterans with early stage lung cancer who would benefit from timely diagnosis.

The JLMMVH is a referral center for the entire state of Arkansas. Quite a few of its referred patients come from a long distance, which may require overnight housing and other related travel expenses. Apart from any potential outcome benefit, the efficiencies of the system described herein include the minimization of extra trips, an inconvenience and cost to both patient and JLMMVH.

Although the primary task of the clinic is diagnosis, we also seek to facilitate timely treatment. Our lack of an on-site PET scanner and radiation therapy, resources present on-site at the Dayton VAMC, contribute to longer therapy wait times. The shortest mean wait time at JLMMVH is for chemotherapy alone (34.7 days), in part because the JLMMVH oncologists, performing initial consultations 2 to 3 times weekly in the Diagnostic Clinic, are more readily available than are our thoracic surgeons or radiation therapists. Yet overall, JLMMVH patients often face delay from the time of lung cancer diagnosis to initiation of treatment.

The Connecticut Veterans Affairs Healthcare System has published the results of changes in lung cancer management associated with a nurse navigator system.10 Prior to creating the position of cancer care coordinator, filled by an advanced practice RNs, the mean time from clinical suspicion of lung cancer to treatment was 117 days. After 4 years of such care navigation, this waiting time had decreased to 52.4 days. Associated with this dramatic improvement in overall waiting time were decreases in the turnaround time required for performance of CT and PET scans. With respect to this big picture view of lung cancer care, our Diagnostic Clinic serves as a model for the initial step of diagnosis. Coordination and streamlining of the various steps from diagnosis to definitive therapy shall require a more system-wide effort involving all the key players in cancer care.

Conclusion

We have developed a care pathway based in a dedicated diagnostic clinic and have been able to document the shortest interval from abnormality to diagnosis of lung cancer reported in the literature to date. Efficient functioning of this clinic is dependent upon the close cooperation between a full-time RN clinic manager and an interventional pulmonologist experienced in lung cancer management and able to interpret cytologic samples at the time of biopsy. Shortening the delay between diagnosis and definitive therapy remains a challenge and may benefit from the oncology nurse navigator model previously described within the VA system. ¹⁰

Lung cancer is the leading cause of cancer death in the US, with 154 050 deaths in 2018.¹ There have been many attempts to reduce mortality of the disease through early diagnosis with use of computed tomography (CT). The National Lung Cancer Screening trial showed that screening high-risk populations with low-dose CT (LDCT) can reduce mortality.² However, implementing LDCT screening in the clinical setting has proven challenging, as illustrated by the VA Lung Cancer Screening Demonstration Project (LCSDP).³ A lung cancer diagnosis typically comprises several steps that require different medical specialties; this can lead to delays. In the LCSDP, the mean time to diagnosis was 137 days.³ There are no federal standards for timeliness of lung cancer diagnosis.

The nonprofit RAND Corporation is the only American research organization that has published guidelines specifying acceptable intervals for the diagnosis and treatment of lung cancer. In Quality of Care for Oncologic Conditions and HIV, RAND Corporation researchers propose management quality indicators: lung cancer diagnosis within 2 months of an abnormal radiologic study and treatment within 6 weeks of diagnosis.⁴ The Swedish Lung Cancer Study⁵ and the Canadian Strategy for Cancer Control⁶ both recommended a standard of about 30 days—half the time recommended by the RAND Corporation.

Bukhari and colleagues at the Dayton US Department of Veterans Affairs (VA) Medical Center (VAMC) conducted a quality improvement study that examined lung cancer diagnosis and management.7 They found the time (SD) from abnormal chest imaging to diagnosis was 35.5 (31.6) days. Of those veterans who received a lung cancer diagnosis, 89.2% had the diagnosis made within the 60 days recommended by the RAND Corporation. Although these results surpass those of the LCSDP, they can be exceeded.

Beyond the potential emotional distress of awaiting the final diagnosis of a lung lesion, a delay in diagnosis and treatment may adversely affect outcomes. LDCT screening has been shown to reduce mortality, which implies a link between survival and time to intervention. There is no published evidence that time to diagnosis in advanced stage lung cancer affects outcome. The National Cancer Database (NCDB) contains informtion on about 70% of the cancers diagnosed each year in the US.8 An analysis of 4984 patients with stage IA squamous cell lung cancer undergoing lobectomy from NCDB showed that earlier surgery was associated with an absolute decrease in 5-year mortality of 5% to 8%. 9 Hence, at least in early-stage disease, reduced time from initial suspect imaging to definitive treatment may improve survival.

A system that coordinates the requisite diagnostic steps and avoids delays should provide a significant improvement in patient care. The results of such an approach that utilized nurse navigators has been previously published. 10 Here, we present the results of a dedicated VA referral clinic with priority access to pulmonary consultation and procedures in place that are designed to expedite the diagnosis of potential lung cancer.

Methods

The John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas institutional review board approved this study, which was performed in accordance with the Declaration of Helsinki. Requirement for informed consent was waived, and patient confidentiality was maintained throughout.

We have developed a plan of care specifically to facilitate diagnosis and treatment of the large number of veterans referred to the JLMMVH Diagnostic Clinic for abnormal results of chest imaging. The clinic has priority access to same-day imaging and subspecialty consultation services. In the clinic, medical students and residents perform evaluations and a registered nurse (RN) manager coordinates care.

A Diagnostic Clinic consult for abnormal thoracic imaging immediately triggers an e-consult to an interventional pulmonologist (Figure). The RN manager and pulmonologist perform a joint review of records/imaging prior to scheduling, and the pulmonologist triages the patient. Triage options include follow-up imaging, bronchoscopy with endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and CT-guided biopsy.

The RN manager then schedules a clinic visit that includes a medical evaluation by clinic staff and any indicated procedures on the same day. The interventional pulmonologist performs EBUS, EUS with the convex curvilinear bronchoscope, or both combined as indicated for diagnosis and staging. All procedures are performed in the JLMMVH bronchoscopy suite with standard conscious sedation using midazolam and fentanyl. Any other relevant procedures, such as pleural tap, also are performed at time of procedure. The pulmonologist and an attending pathologist interpret biopsies obtained in the bronchoscopy suite.

We performed a retrospective chart review of patients diagnosed with primary lung cancer through referral to the JLMMVH Diagnostic Clinic. The primary outcome was time from initial suspect chest imaging to cancer diagnosis. The study population consisted of patients referred for abnormal thoracic imaging between January 1, 2013 and December 31, 2016 and subsequently diagnosed with a primary lung cancer.

Subjects were excluded if (1) the patient was referred from outside our care network and a delay of > 10 days occurred between initial lesion imaging and referral; (2) the patient did not show up for appointments or chose to delay evaluation following referral; (3) biopsy demonstrated a nonlung primary cancer; and (4) serious intercurrent illness interrupted the diagnostic plan. In some cases, the radiologist or consulting pulmonologist had judged the lung lesion too small for immediate biopsy and recommended repeat imaging at a later date.

Patients were included in the study if the follow- up imaging led to a lung cancer diagnosis. However, because the interval between the initial imaging and the follow-up imaging in these patients did not represent a systems delay problem, the date of the scheduled follow-up abnormal imaging, which resulted in initiation of a potential cancer evaluation, served as the index suspect imaging date for this study.

Patient electronic medical records were reviewed and the following data were abstracted: date of the abnormal imaging that led to referral and time from abnormal chest X-ray to chest CT scan if applicable; date of referral and date of clinic visit; date of biopsy; date of lung cancer diagnosis; method of obtaining diagnostic specimen; lung cancer type and stage; type and date of treatment initiation or decision for supportive care only; and decision to seek further evaluation or care outside of our system.

All patients diagnosed with lung cancer during the study period were reviewed for inclusion, hence no required sample-size estimate was calculated. All outcomes were assessed as calendar days. The primary outcome was the time from the index suspect chest imaging study to the date of diagnosis of lung cancer. Prior to the initiation of our study, we chose this more stringent 30-day recommendation of the Canadian6 and Swedish5 studies as the comparator for our primary outcome, although data with respect to the 60-day Rand Corporation guidelines also are reported.⁴

Statistical Methods

The mean time to lung cancer diagnosis in our cohort was compared with this 30-day standard using a 2-sided Mann–Whitney U test. Normality of data distribution was determined using the Kolmogorov–Smirnov test. For statistical significance testing a P value of .05 was used. Statistical calculations were performed using R statistical software version 3.2.4. Secondary outcomes consisted of time from diagnosis to treatment; proportion of subjects diagnosed within 60 days; time from initial clinic visit to biopsy; and time from biopsy to diagnosis.

Results

Overall, 222 patients were diagnosed with a malignant lung lesion, of which 63 were excluded from analysis: 22 cancelled or did not appear for appointments, declined further evaluation, or completed evaluation outside of our network; 13 had the diagnosis made prior to Diagnostic Clinic visit; 13 proved to have a nonlung primary tumor presenting in the lung or mediastinal nodes; 12 were delayed > 10 days in referral from an outside network; and 3 had an intervening serious acute medical problem forcing delay in the diagnostic process.

Of the 159 included subjects, 154 (96.9%) were male, and the mean (SD) age was 67.6 (8.1) years. For 76 subjects, the abnormal chest X-ray and subsequent chest CT scan were performed the same day or the lung lesion had initially been noted on a CT scan. For 54 subjects, there was a delay of ≥ 1 week in obtaining a chest CT scan. The mean (SD) time from placement of the Diagnostic Clinic consultation by the primary care provider (PCP) or other provider and the initial Diagnostic Clinic visit was 6.3 (4.4) days. The mean (SD) time from suspect imaging to diagnosis (primary outcome) was 22.6(16.6) days.

The distribution of this outcome was nonnormal (Kolmogorov-Smirnov test P < .01). When compared with the standard of 30 days, the primary outcome of 22.6 days was significantly shorter (2-sided Mann–Whitney U test P < .01). Three-quarters (76.1%) of subjects were diagnosed within 30 days and 95.0% of subjects were diagnosed within 60 days of the initial imaging. For the 8 subjects diagnosed after 60 days, contributing factors included PCP delay in Diagnostic Clinic consultation, initial negative biopsy, delay in performance of chest CT scan prior to consultation, and outsourcing of positron emission tomography (PET) scans.

Overall, 57 (35.8%) of the subjects underwent biopsy on the day of their Diagnostic Clinic visit: 14 underwent CT-guided biopsy and 43 underwent EBUS/EUS. Within 2 days of the initial visit 106 subjects (66.7%) had undergone biopsy. The mean (SD) time from initial Diagnostic Clinic visit to biopsy was 6.3 (9.5) days. The mean (SD) interval was 1.8 (3.0) days for EBUS/ EUS and 11.3 (11.7) days for CT-guided biopsy. The mean (SD) interval from biopsy to diagnosis was 3.2 (6.2) days with 64 cases (40.3%) diagnosed the day of biopsy.

Excluding subjects whose treatment was delayed by patient choice or intercurrent illness, and those who left the VA system to seek treatment elsewhere (n = 21), 24 opted for palliative care, 5 died before treatment could be initiated, and 109 underwent treatment for their tumors (Table). The mean times (SD) from diagnosis to treatment were: chemotherapy alone 34.7 (25.3) days; chemoradiation 37.0 (22.8) days; surgery 44.3 (24.4) days; radiation therapy alone 47.9 (26.0) days. With respect to the RAND Corporation recommended diagnosis to treatment time, 60.9% of chemotherapy alone, 61.5% of chemoradiation, 66.7% of surgery, and 45.0% of radiation therapy alone treatments were initiated within the 6-week window.

Discussion

This retrospective case study demonstrates the effectiveness of a dedicated diagnostic clinic with priority EBUS/EUS access in diagnosing lung cancer within the VA system. Although there is no universally accepted quality standard for comparison, the RAND Corporation recommendation of 60 days from abnormal imaging to diagnosis and the Dayton VAMC published mean of 35.5 days are guideposts; however, the results from the Dayton VAMC may have been affected negatively by some subjects undergoing serial imaging for asymptomatic nodules. We chose a more stringent standard of 30 days as recommended by Swedish and Canadian task forces.

When diagnosing lung cancer, the overriding purpose of the Diagnostic Clinic is to minimize system delays. The method is to have as simple a task as possible for the PCP or other provider who identifies a lung nodule or mass and submits a single consultation request to the Diagnostic Clinic. Once this consultation is placed, the clinic RN manager oversees all further steps required for diagnosis and referral for treatment. The key factor in achieving a mean diagnosis time of 22.6 days is the cooperation between the RN manager and the interventional pulmonologist. When a consultation is received, the RN manager and pulmonologist review the data together and schedule the initial clinic visit; the goal is same-day biopsy, which is achieved in more than one-third of cases. Not all patients with a chest image suspected for lung cancer had it ordered by their PCP. For this reason, a Diagnostic Clinic consultation is available to all health care providers in our system. Many patients reach the clinic after the discovery of a suspect chest X-ray during an emergency department visit, a regularly scheduled subspecialty appointment, or during a preoperative evaluation.

The mean time from initial visit to biopsy was 1.8 days for EBUS/EUS compared with an interval of 11.3 days for CT-guided biopsy. This difference reflects the pulmonologist’s involvement in initial scheduling of Diagnostic Clinic patients. The ability of the pulmonologist to provide an accurate assessment of sample adequacy and a preliminary diagnosis at bedside, with concurrent confirmation by a staff pathologist, permitted the Diagnostic Clinic to inform 40.3% of patients of the finding of malignancy on the day of biopsy. A published comparison of the onsite review of biopsy material showed our pulmonologist and staff pathologists to be equally accurate in their interpretations.¹¹

Sources of Delays

While this study documents the shortest intervals from suspect imaging to diagnosis reported to date, it also identifies sources of system delay in diagnosing lung cancer that JLMMVH could further optimize. The first is the time from initial abnormal chest X-ray imaging to performance of the chest CT scan. On occasion, the index lung lesion is identified unexpectedly on an outpatient or emergency department chest CT scan. With greater use of LDCT lung cancer screening, the initial detection of suspect lesions by CT scanning will increase in the future. However, the PCP most often investigates a patient complaint with a standard chest X-ray that reveals a suspect nodule or mass. When ordered by the PCP as an outpatient test, scheduling of the follow-up chest CT scan is not given priority. More than a third of subjects experienced a delay ≥ 1 week in obtaining a chest CT scan ordered by the PCP; for 29 subjects the delay was ≥ 3weeks. At JLMMVH, the Diagnostic Clinic is given priority in scheduling CT scans. Hence, for suspect lung lesions, the chest CT scan, if not already obtained, is generally performed on the morning of the clinic visit. Educating the PCP to refer the patient immediately to the Diagnostic Clinic rather than waiting to obtain an outpatient chest CT scan may remove this source of unnecessary delay.

Scheduling a CT-guided fine needle aspiration of a lung lesion is another source of system delay. When the chest CT scan is available at the time of the Diagnostic Clinic referral, the clinic visit is scheduled for the earliest day a required CT-guided biopsy can be performed. However, the mean time of 11.3 days from initial Diagnostic Clinic visit to CT-guided biopsy is indicative of the backlog faced by the interventional radiologists.

Although infrequent, PET scans that are required before biopsy can lead to substantial delays. PET scans are performed at our university affiliate, and the joint VA-university lung tumor board sometimes generates requests for such scans prior to tissue diagnosis, yet another source of delay.

The time from referral receipt to the Diagnostic Clinic visit averaged 6.3 days. This delay usually was determined by the availability of the CT-guided biopsy or the dedicated interventional pulmonologist. Although other interventional pulmonologists at JLMMVH may perform the requisite diagnostic procedures, they are not always available for immediate review of imaging studies of referred patients nor can their schedules flexibly accommodate the number of patients seen in our clinic for evaluation.

Lung Cancer Diagnosis

Prompt diagnosis in the setting of a worrisome chest X-ray may help decrease patient anxiety, but does the clinic improve lung cancer treatment outcomes? Such improvement has been demonstrated only in stage IA squamous cell lung cancer.⁹ Of our study population, 37.7% had squamous cell carcinoma, and 85.5% had non-small cell lung cancer. Of those with non-small cell lung cancer, 28.9% had a clinical stage I tumor. Stage I squamous cell carcinoma, the type of tumor most likely to benefit from early diagnosis and treatment, was diagnosed in 11.3% of patients. With the increased application of LDCT screening, the proportion of veterans identified with early stage lung cancer may rise. The Providence VAMC in Rhode Island reported its results from instituting LDCT screening.¹² Prior to screening, 28% of patients diagnosed with lung cancer had a stage I tumor. Following the introduction of LDCT screening, 49% diagnosed by LDCT screening had a stage I tumor. Nearly a third of their patients diagnosed with lung cancer through LDCT screening had squamous cell tumor histology. Thus, we can anticipate an increasing number of veterans with early stage lung cancer who would benefit from timely diagnosis.

The JLMMVH is a referral center for the entire state of Arkansas. Quite a few of its referred patients come from a long distance, which may require overnight housing and other related travel expenses. Apart from any potential outcome benefit, the efficiencies of the system described herein include the minimization of extra trips, an inconvenience and cost to both patient and JLMMVH.

Although the primary task of the clinic is diagnosis, we also seek to facilitate timely treatment. Our lack of an on-site PET scanner and radiation therapy, resources present on-site at the Dayton VAMC, contribute to longer therapy wait times. The shortest mean wait time at JLMMVH is for chemotherapy alone (34.7 days), in part because the JLMMVH oncologists, performing initial consultations 2 to 3 times weekly in the Diagnostic Clinic, are more readily available than are our thoracic surgeons or radiation therapists. Yet overall, JLMMVH patients often face delay from the time of lung cancer diagnosis to initiation of treatment.

The Connecticut Veterans Affairs Healthcare System has published the results of changes in lung cancer management associated with a nurse navigator system.10 Prior to creating the position of cancer care coordinator, filled by an advanced practice RNs, the mean time from clinical suspicion of lung cancer to treatment was 117 days. After 4 years of such care navigation, this waiting time had decreased to 52.4 days. Associated with this dramatic improvement in overall waiting time were decreases in the turnaround time required for performance of CT and PET scans. With respect to this big picture view of lung cancer care, our Diagnostic Clinic serves as a model for the initial step of diagnosis. Coordination and streamlining of the various steps from diagnosis to definitive therapy shall require a more system-wide effort involving all the key players in cancer care.

Conclusion

We have developed a care pathway based in a dedicated diagnostic clinic and have been able to document the shortest interval from abnormality to diagnosis of lung cancer reported in the literature to date. Efficient functioning of this clinic is dependent upon the close cooperation between a full-time RN clinic manager and an interventional pulmonologist experienced in lung cancer management and able to interpret cytologic samples at the time of biopsy. Shortening the delay between diagnosis and definitive therapy remains a challenge and may benefit from the oncology nurse navigator model previously described within the VA system. ¹⁰

Pustular psoriasis of pregnancy (PPP) is a rare but potentially serious dermatosis of pregnancy. Left untreated, PPP can be fatal for both the mother and the fetus.^1,2 Contrary to many other pregnancy dermatoses, which are typically limited to the skin, systemic signs and symptoms often accompany PPP, including fatigue, fever, diarrhea, delirium, elevated markers of inflammation such as an increased erythrocyte sedimentation rate, and increased white blood cell counts.^1,3,4 Progression of the rash to erythroderma with subsequent dangerous fluid and electrolyte imbalances, loss of thermoregulation in the skin, and the risk for secondary infection and sepsis can occur in severe cases.^1,5 

Increasing evidence suggests that PPP is likely a variant of generalized pustular psoriasis (GPP), which can be vulnerable to a variety of triggers, including metabolic disturbances, systemic steroid withdrawals, and pregnancy; however, classification of the disease as either a variant of disease or a distinct disease state remains controversial.^1,6 Early recognition and prompt treatment are critically important given the potential for fetal and maternal morbidity and mortality that is associated with PPP.^1,6,7 

Clinical Presentation

Most cases of PPP involve presentation in the early part of the third trimester of pregnancy; postpartum PPP has been reported but is exceedingly rare.¹ Typically, lesions develop in the skin folds and spread centrifugally.^2,6 The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet usually are spared; occasionally, involvement of oral and esophageal mucosae is seen. Biopsy findings usually comprise spongiform pustules with neutrophil invasion into the epidermis. Characteristic laboratory findings include electrolyte derangements with elevated erythrocyte sedimentation rate and leukocytosis.^2,8 

As was seen in the case presentation, PPP largely resolves following childbirth; however, there is a significant risk for recurrence in subsequent pregnancies, which may be more severe and present earlier.^1,6 Menstrual cycle changes and the use of oral contraceptives, particularly those containing progesterone, also have been associated with PPP flares.^1,6 Although its pathophysiology is not entirely understood, the development of PPP is believed to be associated with the hormonal changes that occur in the third trimester, in particular elevated progesterone levels.⁶ 

Treatment

Oral corticosteroids remain the mainstay of treatment for PPP.⁶ Lower dosages ranging from 15 to 30 mg daily can be used for mild cases.¹ More severe cases usually are treated with an initial trial of prednisone or prednisolone with dosages ranging from 30 mg daily to as high as 60 to 80 mg daily. Higher doses should be used with caution, however, as they may result in reduced fetal reactivity on fetal monitoring.^1,9 Treatment at least throughout the remainder of a patient’s pregnancy usually is required, with subsequent gradual tapering of the medication.¹ 
 

Although it was once reserved for severe or refractory PPP, in 2012, a task force from the National Psoriasis Foundation categorized cyclosporine as an appropriate first-line therapy for PPP.¹⁰ Published case reports have documented the successful treatment of PPP with cyclosporine in cases that did not respond to systemic steroids.^6,11 

Several case reports have documented the safe use of anti–tumor necrosis factors (TNFs), primarily infliximab, for PPP.¹² Infliximab and other TNF-α antibodies are pregnancy category B, but limited controlled human data exist regarding their safety in pregnancy.¹

Finally, the addition of narrowband UVB light therapy to oral corticosteroids also has been proposed as a safe treatment of refractory disease.^6,13 Unlike psoralen plus UVA, which is usually reserved for postpartum use, narrowband UVB light therapy has been shown to be safe for use during pregnancy.¹ 

Future Directions

Genetic and pathogenesis studies have described involvement of IL-1 and IL-36 cytokines in GPP.¹ These interleukins are important in neutrophil chemotaxis leading to pustule formation.  In addition, as in other psoriasis variants, TNF-α and IL-17α are important. Such findings may help to pave the way for the development of future therapies for both GPP and PPP. 
 

Bottom Line

Clinicians should have a high index of suspicion for PPP in pregnant women who present with widespread cutaneous eruptions. Presently, oral corticosteroids paired with close involvement of obstetric care remains the cornerstone of treatment for PPP. As the case report illustrates, effective diagnosis, treatment, and monitoring are essential for safe outcomes for both mother and baby.
 

Pustular psoriasis of pregnancy (PPP) is a rare but potentially serious dermatosis of pregnancy. Left untreated, PPP can be fatal for both the mother and the fetus.^1,2 Contrary to many other pregnancy dermatoses, which are typically limited to the skin, systemic signs and symptoms often accompany PPP, including fatigue, fever, diarrhea, delirium, elevated markers of inflammation such as an increased erythrocyte sedimentation rate, and increased white blood cell counts.^1,3,4 Progression of the rash to erythroderma with subsequent dangerous fluid and electrolyte imbalances, loss of thermoregulation in the skin, and the risk for secondary infection and sepsis can occur in severe cases.^1,5 

Increasing evidence suggests that PPP is likely a variant of generalized pustular psoriasis (GPP), which can be vulnerable to a variety of triggers, including metabolic disturbances, systemic steroid withdrawals, and pregnancy; however, classification of the disease as either a variant of disease or a distinct disease state remains controversial.^1,6 Early recognition and prompt treatment are critically important given the potential for fetal and maternal morbidity and mortality that is associated with PPP.^1,6,7 

Clinical Presentation

Most cases of PPP involve presentation in the early part of the third trimester of pregnancy; postpartum PPP has been reported but is exceedingly rare.¹ Typically, lesions develop in the skin folds and spread centrifugally.^2,6 The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet usually are spared; occasionally, involvement of oral and esophageal mucosae is seen. Biopsy findings usually comprise spongiform pustules with neutrophil invasion into the epidermis. Characteristic laboratory findings include electrolyte derangements with elevated erythrocyte sedimentation rate and leukocytosis.^2,8 

As was seen in the case presentation, PPP largely resolves following childbirth; however, there is a significant risk for recurrence in subsequent pregnancies, which may be more severe and present earlier.^1,6 Menstrual cycle changes and the use of oral contraceptives, particularly those containing progesterone, also have been associated with PPP flares.^1,6 Although its pathophysiology is not entirely understood, the development of PPP is believed to be associated with the hormonal changes that occur in the third trimester, in particular elevated progesterone levels.⁶ 

Treatment

Oral corticosteroids remain the mainstay of treatment for PPP.⁶ Lower dosages ranging from 15 to 30 mg daily can be used for mild cases.¹ More severe cases usually are treated with an initial trial of prednisone or prednisolone with dosages ranging from 30 mg daily to as high as 60 to 80 mg daily. Higher doses should be used with caution, however, as they may result in reduced fetal reactivity on fetal monitoring.^1,9 Treatment at least throughout the remainder of a patient’s pregnancy usually is required, with subsequent gradual tapering of the medication.¹ 
 

Although it was once reserved for severe or refractory PPP, in 2012, a task force from the National Psoriasis Foundation categorized cyclosporine as an appropriate first-line therapy for PPP.¹⁰ Published case reports have documented the successful treatment of PPP with cyclosporine in cases that did not respond to systemic steroids.^6,11 

Several case reports have documented the safe use of anti–tumor necrosis factors (TNFs), primarily infliximab, for PPP.¹² Infliximab and other TNF-α antibodies are pregnancy category B, but limited controlled human data exist regarding their safety in pregnancy.¹

Finally, the addition of narrowband UVB light therapy to oral corticosteroids also has been proposed as a safe treatment of refractory disease.^6,13 Unlike psoralen plus UVA, which is usually reserved for postpartum use, narrowband UVB light therapy has been shown to be safe for use during pregnancy.¹ 

Future Directions

Genetic and pathogenesis studies have described involvement of IL-1 and IL-36 cytokines in GPP.¹ These interleukins are important in neutrophil chemotaxis leading to pustule formation.  In addition, as in other psoriasis variants, TNF-α and IL-17α are important. Such findings may help to pave the way for the development of future therapies for both GPP and PPP. 
 

Bottom Line

Clinicians should have a high index of suspicion for PPP in pregnant women who present with widespread cutaneous eruptions. Presently, oral corticosteroids paired with close involvement of obstetric care remains the cornerstone of treatment for PPP. As the case report illustrates, effective diagnosis, treatment, and monitoring are essential for safe outcomes for both mother and baby.
 

Pustular psoriasis of pregnancy (PPP) is a rare but potentially serious dermatosis of pregnancy. Left untreated, PPP can be fatal for both the mother and the fetus.^1,2 Contrary to many other pregnancy dermatoses, which are typically limited to the skin, systemic signs and symptoms often accompany PPP, including fatigue, fever, diarrhea, delirium, elevated markers of inflammation such as an increased erythrocyte sedimentation rate, and increased white blood cell counts.^1,3,4 Progression of the rash to erythroderma with subsequent dangerous fluid and electrolyte imbalances, loss of thermoregulation in the skin, and the risk for secondary infection and sepsis can occur in severe cases.^1,5 

Increasing evidence suggests that PPP is likely a variant of generalized pustular psoriasis (GPP), which can be vulnerable to a variety of triggers, including metabolic disturbances, systemic steroid withdrawals, and pregnancy; however, classification of the disease as either a variant of disease or a distinct disease state remains controversial.^1,6 Early recognition and prompt treatment are critically important given the potential for fetal and maternal morbidity and mortality that is associated with PPP.^1,6,7 

Clinical Presentation

Most cases of PPP involve presentation in the early part of the third trimester of pregnancy; postpartum PPP has been reported but is exceedingly rare.¹ Typically, lesions develop in the skin folds and spread centrifugally.^2,6 The lesions usually begin as erythematous plaques with a pustular ring with a central erosion. The face, palms, and soles of the feet usually are spared; occasionally, involvement of oral and esophageal mucosae is seen. Biopsy findings usually comprise spongiform pustules with neutrophil invasion into the epidermis. Characteristic laboratory findings include electrolyte derangements with elevated erythrocyte sedimentation rate and leukocytosis.^2,8 

As was seen in the case presentation, PPP largely resolves following childbirth; however, there is a significant risk for recurrence in subsequent pregnancies, which may be more severe and present earlier.^1,6 Menstrual cycle changes and the use of oral contraceptives, particularly those containing progesterone, also have been associated with PPP flares.^1,6 Although its pathophysiology is not entirely understood, the development of PPP is believed to be associated with the hormonal changes that occur in the third trimester, in particular elevated progesterone levels.⁶ 

Treatment

Oral corticosteroids remain the mainstay of treatment for PPP.⁶ Lower dosages ranging from 15 to 30 mg daily can be used for mild cases.¹ More severe cases usually are treated with an initial trial of prednisone or prednisolone with dosages ranging from 30 mg daily to as high as 60 to 80 mg daily. Higher doses should be used with caution, however, as they may result in reduced fetal reactivity on fetal monitoring.^1,9 Treatment at least throughout the remainder of a patient’s pregnancy usually is required, with subsequent gradual tapering of the medication.¹ 
 

Although it was once reserved for severe or refractory PPP, in 2012, a task force from the National Psoriasis Foundation categorized cyclosporine as an appropriate first-line therapy for PPP.¹⁰ Published case reports have documented the successful treatment of PPP with cyclosporine in cases that did not respond to systemic steroids.^6,11 

Several case reports have documented the safe use of anti–tumor necrosis factors (TNFs), primarily infliximab, for PPP.¹² Infliximab and other TNF-α antibodies are pregnancy category B, but limited controlled human data exist regarding their safety in pregnancy.¹

Finally, the addition of narrowband UVB light therapy to oral corticosteroids also has been proposed as a safe treatment of refractory disease.^6,13 Unlike psoralen plus UVA, which is usually reserved for postpartum use, narrowband UVB light therapy has been shown to be safe for use during pregnancy.¹ 

Future Directions

Genetic and pathogenesis studies have described involvement of IL-1 and IL-36 cytokines in GPP.¹ These interleukins are important in neutrophil chemotaxis leading to pustule formation.  In addition, as in other psoriasis variants, TNF-α and IL-17α are important. Such findings may help to pave the way for the development of future therapies for both GPP and PPP. 
 

Bottom Line

Clinicians should have a high index of suspicion for PPP in pregnant women who present with widespread cutaneous eruptions. Presently, oral corticosteroids paired with close involvement of obstetric care remains the cornerstone of treatment for PPP. As the case report illustrates, effective diagnosis, treatment, and monitoring are essential for safe outcomes for both mother and baby.
 

Real-world electronic health record data on tumor progression appears to be a good surrogate for overall survival, a finding that could help to improve estimates of benefit for complex cancer therapy regimens for use in both clinical trials and treatment planning, investigators say.

A study of electronic health record (EHR) data on more than 30,000 patients with non–small cell lung cancer (NSCLC) showed that real-world data on progression-free survival (PFS) showed a high degree of correlation with overall survival (OS), reported Sandra D. Griffith, PhD, of Flatiron Health, New York, and colleagues.

“As survival rates have improved and more than one therapy line has become typical, OS has become an inadequate metric for ascertaining the benefit of some cancer treatment interventions. Intermediate endpoints are essential for evaluating treatment benefits in real-world contexts. This study presents a scalable, feasible, and replicable approach to yield an EHR-generated progression variable ready for incorporation into large, contemporary real-world analyses,” they wrote in JCO Clinical Cancer Informatics.

The investigators studied retrospectively whether it would be feasible on a large scale to extract clinically relevant endpoints from an EHR-derived database that relies on technology-assisted abstraction of data from patient charts.

Their cohort included 30,276 patients diagnosed with advanced NSCLC from January 2011 through February 2018 who had two or more visits documented on EHR and who had been started on one or more lines of systemic therapy. Of this group, 16,606 had one or more documented tumor progression events, and 11,366 either died, discontinued therapy, or started on a new therapy.

The investigators found that among 20,000 evaluable patients, correlation of real-word PFS with OS was moderately high (Spearman’s P = .076), although for 11,902 patients with a progression event who died the correlation of EHR data with actual OS was somewhat lower (Spearman’s P = .069).

The strength of the correlations was verified in an duplicate random sample reviewed by independent abstractors.

The median time to abstract data on disease progression from individual electronic health records was 18 minutes.

“More work is needed to document how real-world progression under different treatments relates to treatment effects observed in clinical trials; understand the impact of different imaging and assessment cadences—for example, informative censoring; and clarify the relationship between real-world progression and other endpoints, such as real-world tumor response. Similar work is also needed in other tumor types,” Dr. Griffiths and colleagues wrote.

The study was supported by Flatiron Health, a subsidiary of Roche. Dr. Griffith and multiple co-authors are employees and stockholders of Flatiron Health and/or Roche.

SOURCE: Griffith SD et al. JCO Clinical Informatics. 2019 Aug 12. doi: 10.1200/CCI.19.00013.

Real-world electronic health record data on tumor progression appears to be a good surrogate for overall survival, a finding that could help to improve estimates of benefit for complex cancer therapy regimens for use in both clinical trials and treatment planning, investigators say.

A study of electronic health record (EHR) data on more than 30,000 patients with non–small cell lung cancer (NSCLC) showed that real-world data on progression-free survival (PFS) showed a high degree of correlation with overall survival (OS), reported Sandra D. Griffith, PhD, of Flatiron Health, New York, and colleagues.

“As survival rates have improved and more than one therapy line has become typical, OS has become an inadequate metric for ascertaining the benefit of some cancer treatment interventions. Intermediate endpoints are essential for evaluating treatment benefits in real-world contexts. This study presents a scalable, feasible, and replicable approach to yield an EHR-generated progression variable ready for incorporation into large, contemporary real-world analyses,” they wrote in JCO Clinical Cancer Informatics.

The investigators studied retrospectively whether it would be feasible on a large scale to extract clinically relevant endpoints from an EHR-derived database that relies on technology-assisted abstraction of data from patient charts.

Their cohort included 30,276 patients diagnosed with advanced NSCLC from January 2011 through February 2018 who had two or more visits documented on EHR and who had been started on one or more lines of systemic therapy. Of this group, 16,606 had one or more documented tumor progression events, and 11,366 either died, discontinued therapy, or started on a new therapy.

The investigators found that among 20,000 evaluable patients, correlation of real-word PFS with OS was moderately high (Spearman’s P = .076), although for 11,902 patients with a progression event who died the correlation of EHR data with actual OS was somewhat lower (Spearman’s P = .069).

The strength of the correlations was verified in an duplicate random sample reviewed by independent abstractors.

The median time to abstract data on disease progression from individual electronic health records was 18 minutes.

“More work is needed to document how real-world progression under different treatments relates to treatment effects observed in clinical trials; understand the impact of different imaging and assessment cadences—for example, informative censoring; and clarify the relationship between real-world progression and other endpoints, such as real-world tumor response. Similar work is also needed in other tumor types,” Dr. Griffiths and colleagues wrote.

The study was supported by Flatiron Health, a subsidiary of Roche. Dr. Griffith and multiple co-authors are employees and stockholders of Flatiron Health and/or Roche.

SOURCE: Griffith SD et al. JCO Clinical Informatics. 2019 Aug 12. doi: 10.1200/CCI.19.00013.

Real-world electronic health record data on tumor progression appears to be a good surrogate for overall survival, a finding that could help to improve estimates of benefit for complex cancer therapy regimens for use in both clinical trials and treatment planning, investigators say.

A study of electronic health record (EHR) data on more than 30,000 patients with non–small cell lung cancer (NSCLC) showed that real-world data on progression-free survival (PFS) showed a high degree of correlation with overall survival (OS), reported Sandra D. Griffith, PhD, of Flatiron Health, New York, and colleagues.

“As survival rates have improved and more than one therapy line has become typical, OS has become an inadequate metric for ascertaining the benefit of some cancer treatment interventions. Intermediate endpoints are essential for evaluating treatment benefits in real-world contexts. This study presents a scalable, feasible, and replicable approach to yield an EHR-generated progression variable ready for incorporation into large, contemporary real-world analyses,” they wrote in JCO Clinical Cancer Informatics.

The investigators studied retrospectively whether it would be feasible on a large scale to extract clinically relevant endpoints from an EHR-derived database that relies on technology-assisted abstraction of data from patient charts.

Their cohort included 30,276 patients diagnosed with advanced NSCLC from January 2011 through February 2018 who had two or more visits documented on EHR and who had been started on one or more lines of systemic therapy. Of this group, 16,606 had one or more documented tumor progression events, and 11,366 either died, discontinued therapy, or started on a new therapy.

The investigators found that among 20,000 evaluable patients, correlation of real-word PFS with OS was moderately high (Spearman’s P = .076), although for 11,902 patients with a progression event who died the correlation of EHR data with actual OS was somewhat lower (Spearman’s P = .069).

The strength of the correlations was verified in an duplicate random sample reviewed by independent abstractors.

The median time to abstract data on disease progression from individual electronic health records was 18 minutes.

“More work is needed to document how real-world progression under different treatments relates to treatment effects observed in clinical trials; understand the impact of different imaging and assessment cadences—for example, informative censoring; and clarify the relationship between real-world progression and other endpoints, such as real-world tumor response. Similar work is also needed in other tumor types,” Dr. Griffiths and colleagues wrote.

The study was supported by Flatiron Health, a subsidiary of Roche. Dr. Griffith and multiple co-authors are employees and stockholders of Flatiron Health and/or Roche.

SOURCE: Griffith SD et al. JCO Clinical Informatics. 2019 Aug 12. doi: 10.1200/CCI.19.00013.

ANSWER

The radiograph shows 3 abnormalities:

(1) The endotracheal tube is in the right mainstem bronchus—a finding that in part leads to

(2) A whiteout of the left lung; the latter is due partly to collapse and atelectasis and partly to a possible pneumothorax.

(3) There is evidence of free air under the left hemidiaphragm, which is concerning for an intra-abdominal injury, such as a perforated viscus.

The patient’s endotracheal tube was partially withdrawn, and a left chest tube was placed. Subsequent CT of the abdomen confirmed the finding of free air. She was then taken to the operating room for an emergent laparotomy.

ANSWER

The radiograph shows 3 abnormalities:

(1) The endotracheal tube is in the right mainstem bronchus—a finding that in part leads to

(2) A whiteout of the left lung; the latter is due partly to collapse and atelectasis and partly to a possible pneumothorax.

(3) There is evidence of free air under the left hemidiaphragm, which is concerning for an intra-abdominal injury, such as a perforated viscus.

The patient’s endotracheal tube was partially withdrawn, and a left chest tube was placed. Subsequent CT of the abdomen confirmed the finding of free air. She was then taken to the operating room for an emergent laparotomy.

ANSWER

The radiograph shows 3 abnormalities:

(1) The endotracheal tube is in the right mainstem bronchus—a finding that in part leads to

(2) A whiteout of the left lung; the latter is due partly to collapse and atelectasis and partly to a possible pneumothorax.

(3) There is evidence of free air under the left hemidiaphragm, which is concerning for an intra-abdominal injury, such as a perforated viscus.

The patient’s endotracheal tube was partially withdrawn, and a left chest tube was placed. Subsequent CT of the abdomen confirmed the finding of free air. She was then taken to the operating room for an emergent laparotomy.

An 88-year-old man with hypertension, chronic obstructive pulmonary disease, and atrial fibrillation presents with severe cerebral palsy and is diagnosed with a non–ST-elevation MI. He is found to have 90% left anterior descending artery occlusion and receives a drug-eluting stent. His current medications include warfarin, tiotropium, amlodipine, aspirin, and lisinopril. What anticoagulant therapy should he receive?

A) Clopidogrel, warfarin, and aspirin

B) Clopidogrel and aspirin

C) Clopidogrel and warfarin

D) Warfarin

E) Warfarin and aspirin

This issue comes up frequently with our patients with atrial fibrillation who are on anticoagulation, then have a coronary event and have a stent placed. What is the best approach to anticoagulation? I think for this patient adding clopidogrel, continuing warfarin, and stopping aspirin would be the best of the options presented.

Elderly patients have a higher risk of bleeding. They also have a greater chance of accumulating cardiovascular disease (atrial fibrillation, cardiac allograft vasculopathy, and valvular disease) that requires anticoagulation. Dewilde et al. studied the difference in bleeding risk in patients who were on oral anticoagulants who then underwent a percutaneous coronary intervention.¹ Patients were assigned clopidogrel alone or clopidogrel plus aspirin in addition to their oral anticoagulant (warfarin). There was a significant increase in all-cause mortality in the patients who received clopidogrel plus aspirin (P = .027), and no significant difference in cardiac mortality between the two groups. There was a much higher risk of bleeding (44.4%) in the patients receiving triple therapy, compared with the double-therapy group (19.4%; P less than .0001).

In a large meta-analysis of over 7,000 patients by D’Ascenzo et al., there was no difference in thrombotic risk between double and triple therapy, and lower bleeding risk in patients who received double therapy.²

In a recently published article, Lopes et al. looked at the benefits and risks of antithrombotic therapy after acute coronary syndrome or percutaneous coronary intervention in patients with atrial fibrillation.³ The study included 4,614 patients, all of whom received a P2Y12 inhibitor. In addition, they received either apixaban or warfarin, and either aspirin or placebo. The patients who received apixaban had a lower risk of bleeding than those receiving warfarin (P less than .001), and those receiving aspirin had a higher risk than those receiving placebo (hazard ratio, 1.89; P less than .001). Patients using the combination of apixaban plus placebo had the lowest event rate per 100 years (16.8), followed by warfarin plus placebo (26.7), then apixaban plus aspirin (33.6), with warfarin plus aspirin having the highest event rate (49.1). The conclusion for the study was that regimens with apixaban without aspirin had less bleeding and hospitalizations without increased ischemic events, compared with regimens of warfarin with or without aspirin.

I think it is best to avoid aspirin in patients who are anticoagulated with warfarin, and likely this extends to Xa inhibitors as well.

Pearl: Avoid using triple anticoagulant therapy by eliminating aspirin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Dewilde WJ et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: An open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15.

2. D’Ascenzo F et al. Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2015 May 1;115(9):1185-93.

3. Lopes RD et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-24.

An 88-year-old man with hypertension, chronic obstructive pulmonary disease, and atrial fibrillation presents with severe cerebral palsy and is diagnosed with a non–ST-elevation MI. He is found to have 90% left anterior descending artery occlusion and receives a drug-eluting stent. His current medications include warfarin, tiotropium, amlodipine, aspirin, and lisinopril. What anticoagulant therapy should he receive?

A) Clopidogrel, warfarin, and aspirin

B) Clopidogrel and aspirin

C) Clopidogrel and warfarin

D) Warfarin

E) Warfarin and aspirin

This issue comes up frequently with our patients with atrial fibrillation who are on anticoagulation, then have a coronary event and have a stent placed. What is the best approach to anticoagulation? I think for this patient adding clopidogrel, continuing warfarin, and stopping aspirin would be the best of the options presented.

Elderly patients have a higher risk of bleeding. They also have a greater chance of accumulating cardiovascular disease (atrial fibrillation, cardiac allograft vasculopathy, and valvular disease) that requires anticoagulation. Dewilde et al. studied the difference in bleeding risk in patients who were on oral anticoagulants who then underwent a percutaneous coronary intervention.¹ Patients were assigned clopidogrel alone or clopidogrel plus aspirin in addition to their oral anticoagulant (warfarin). There was a significant increase in all-cause mortality in the patients who received clopidogrel plus aspirin (P = .027), and no significant difference in cardiac mortality between the two groups. There was a much higher risk of bleeding (44.4%) in the patients receiving triple therapy, compared with the double-therapy group (19.4%; P less than .0001).

In a large meta-analysis of over 7,000 patients by D’Ascenzo et al., there was no difference in thrombotic risk between double and triple therapy, and lower bleeding risk in patients who received double therapy.²

In a recently published article, Lopes et al. looked at the benefits and risks of antithrombotic therapy after acute coronary syndrome or percutaneous coronary intervention in patients with atrial fibrillation.³ The study included 4,614 patients, all of whom received a P2Y12 inhibitor. In addition, they received either apixaban or warfarin, and either aspirin or placebo. The patients who received apixaban had a lower risk of bleeding than those receiving warfarin (P less than .001), and those receiving aspirin had a higher risk than those receiving placebo (hazard ratio, 1.89; P less than .001). Patients using the combination of apixaban plus placebo had the lowest event rate per 100 years (16.8), followed by warfarin plus placebo (26.7), then apixaban plus aspirin (33.6), with warfarin plus aspirin having the highest event rate (49.1). The conclusion for the study was that regimens with apixaban without aspirin had less bleeding and hospitalizations without increased ischemic events, compared with regimens of warfarin with or without aspirin.

I think it is best to avoid aspirin in patients who are anticoagulated with warfarin, and likely this extends to Xa inhibitors as well.

Pearl: Avoid using triple anticoagulant therapy by eliminating aspirin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Dewilde WJ et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: An open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15.

2. D’Ascenzo F et al. Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2015 May 1;115(9):1185-93.

3. Lopes RD et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-24.

An 88-year-old man with hypertension, chronic obstructive pulmonary disease, and atrial fibrillation presents with severe cerebral palsy and is diagnosed with a non–ST-elevation MI. He is found to have 90% left anterior descending artery occlusion and receives a drug-eluting stent. His current medications include warfarin, tiotropium, amlodipine, aspirin, and lisinopril. What anticoagulant therapy should he receive?

A) Clopidogrel, warfarin, and aspirin

B) Clopidogrel and aspirin

C) Clopidogrel and warfarin

D) Warfarin

E) Warfarin and aspirin

This issue comes up frequently with our patients with atrial fibrillation who are on anticoagulation, then have a coronary event and have a stent placed. What is the best approach to anticoagulation? I think for this patient adding clopidogrel, continuing warfarin, and stopping aspirin would be the best of the options presented.

Elderly patients have a higher risk of bleeding. They also have a greater chance of accumulating cardiovascular disease (atrial fibrillation, cardiac allograft vasculopathy, and valvular disease) that requires anticoagulation. Dewilde et al. studied the difference in bleeding risk in patients who were on oral anticoagulants who then underwent a percutaneous coronary intervention.¹ Patients were assigned clopidogrel alone or clopidogrel plus aspirin in addition to their oral anticoagulant (warfarin). There was a significant increase in all-cause mortality in the patients who received clopidogrel plus aspirin (P = .027), and no significant difference in cardiac mortality between the two groups. There was a much higher risk of bleeding (44.4%) in the patients receiving triple therapy, compared with the double-therapy group (19.4%; P less than .0001).

In a large meta-analysis of over 7,000 patients by D’Ascenzo et al., there was no difference in thrombotic risk between double and triple therapy, and lower bleeding risk in patients who received double therapy.²

In a recently published article, Lopes et al. looked at the benefits and risks of antithrombotic therapy after acute coronary syndrome or percutaneous coronary intervention in patients with atrial fibrillation.³ The study included 4,614 patients, all of whom received a P2Y12 inhibitor. In addition, they received either apixaban or warfarin, and either aspirin or placebo. The patients who received apixaban had a lower risk of bleeding than those receiving warfarin (P less than .001), and those receiving aspirin had a higher risk than those receiving placebo (hazard ratio, 1.89; P less than .001). Patients using the combination of apixaban plus placebo had the lowest event rate per 100 years (16.8), followed by warfarin plus placebo (26.7), then apixaban plus aspirin (33.6), with warfarin plus aspirin having the highest event rate (49.1). The conclusion for the study was that regimens with apixaban without aspirin had less bleeding and hospitalizations without increased ischemic events, compared with regimens of warfarin with or without aspirin.

I think it is best to avoid aspirin in patients who are anticoagulated with warfarin, and likely this extends to Xa inhibitors as well.

Pearl: Avoid using triple anticoagulant therapy by eliminating aspirin.

Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the University of Washington. Contact Dr. Paauw at [email protected].

References

1. Dewilde WJ et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: An open-label, randomised, controlled trial. Lancet. 2013 Mar 30;381(9872):1107-15.

2. D’Ascenzo F et al. Meta-analysis of randomized controlled trials and adjusted observational results of use of clopidogrel, aspirin, and oral anticoagulants in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2015 May 1;115(9):1185-93.

3. Lopes RD et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-24.

LJUBLJANA, SLOVENIA – A point-of-care presepsin measurement in the emergency department displayed powerful accuracy for early rule-out of invasive bacterial infection in infants less than 3 months old presenting with fever without a source, based on results of a phase 3 multicenter Italian study.

Bruce Jancin/MDedge News

“P-SEP [presepsin] is a promising new biomarker. P-SEP accuracy for invasive bacterial infection is comparable to procalcitonin, even though P-SEP, like procalcitonin, is probably not accurate enough to be used as a stand-alone marker to rule-in an invasive bacterial infection,” Luca Pierantoni, MD, said in presenting the preliminary study results at the annual meeting of the European Society for Paediatric Infectious Diseases.

The presepsin test is a rapid point-of-care test well-suited for the ED setting, with a cost equal to that of point-of-care procalcitonin.

Presepsin is a form of soluble CD14 that is released from the surface of macrophages, monocytes, and neutrophils when these immune cells are stimulated by pathogens. “We think it may be a reliable diagnostic and prognostic marker of sepsis in adults and neonates,” explained Dr. Pierantoni of the University of Bologna, Italy.

Indeed, studies in adults suggest presepsin has better sensitivity and specificity than other biomarkers for early diagnosis of sepsis, and that it provides useful information on severity and prognosis as well. But, Dr. Pierantoni and his coworkers wondered, how does it perform in febrile young infants?

The Italian study was designed to address an unmet need: Fever accounts for about one-third of ED visits in infants up to age 3 months, 20% of whom are initially categorized as having fever without source. Yet ultimately 10%-20% of those youngsters having fever without source are found to have an invasive bacterial infection – that is, sepsis or meningitis – or a severe bacterial infection such as pneumonia, a urinary tract infection, or an infected umbilical cord. The sooner these infants can be identified and appropriately treated, the better.

The study enrolled 284 children less than 3 months old who had fever without cause of a mean 10.5 hours duration and presented to the emergency departments of six Italian medical centers. Children were eligible for the study regardless of whether they appeared toxic or well. Presepsin, procalcitonin, and C-reactive protein levels were immediately measured in all participants. Ultimately, 5.6% of subjects were diagnosed with an invasive bacterial infection, and another 21.2% had a severe bacterial infection.

Using a cutoff value of 449 pg/mL, P-SEP had good diagnostic accuracy for invasive bacterial infection, with an area under the receiver operating characteristics curve of 0.81, essentially the same as the 0.82 value for procalcitonin. P-SEP had a sensitivity and specificity of 87% and 75%, respectively, placing it in the same ballpark as the 82% and 86% values for procalcitonin. The strong point for P-SEP was its 99% negative predictive value, as compared to 91% for procalcitonin. The positive predictive values were 17% for P-SEP and 20% for procalcitonin.

In response to an audience question, Dr. Pierantoni speculated that the best use for P-SEP in the setting of fever of unknown origin may be in combination with procalcitonin rather than as a replacement for it. The research team is now in the process of analyzing their study data to see if that is indeed the case.

He reported having no financial conflicts regarding his study, conducted free of commercial support.

[email protected]

LJUBLJANA, SLOVENIA – A point-of-care presepsin measurement in the emergency department displayed powerful accuracy for early rule-out of invasive bacterial infection in infants less than 3 months old presenting with fever without a source, based on results of a phase 3 multicenter Italian study.

Bruce Jancin/MDedge News

“P-SEP [presepsin] is a promising new biomarker. P-SEP accuracy for invasive bacterial infection is comparable to procalcitonin, even though P-SEP, like procalcitonin, is probably not accurate enough to be used as a stand-alone marker to rule-in an invasive bacterial infection,” Luca Pierantoni, MD, said in presenting the preliminary study results at the annual meeting of the European Society for Paediatric Infectious Diseases.

The presepsin test is a rapid point-of-care test well-suited for the ED setting, with a cost equal to that of point-of-care procalcitonin.

Presepsin is a form of soluble CD14 that is released from the surface of macrophages, monocytes, and neutrophils when these immune cells are stimulated by pathogens. “We think it may be a reliable diagnostic and prognostic marker of sepsis in adults and neonates,” explained Dr. Pierantoni of the University of Bologna, Italy.

Indeed, studies in adults suggest presepsin has better sensitivity and specificity than other biomarkers for early diagnosis of sepsis, and that it provides useful information on severity and prognosis as well. But, Dr. Pierantoni and his coworkers wondered, how does it perform in febrile young infants?

The Italian study was designed to address an unmet need: Fever accounts for about one-third of ED visits in infants up to age 3 months, 20% of whom are initially categorized as having fever without source. Yet ultimately 10%-20% of those youngsters having fever without source are found to have an invasive bacterial infection – that is, sepsis or meningitis – or a severe bacterial infection such as pneumonia, a urinary tract infection, or an infected umbilical cord. The sooner these infants can be identified and appropriately treated, the better.

The study enrolled 284 children less than 3 months old who had fever without cause of a mean 10.5 hours duration and presented to the emergency departments of six Italian medical centers. Children were eligible for the study regardless of whether they appeared toxic or well. Presepsin, procalcitonin, and C-reactive protein levels were immediately measured in all participants. Ultimately, 5.6% of subjects were diagnosed with an invasive bacterial infection, and another 21.2% had a severe bacterial infection.

Using a cutoff value of 449 pg/mL, P-SEP had good diagnostic accuracy for invasive bacterial infection, with an area under the receiver operating characteristics curve of 0.81, essentially the same as the 0.82 value for procalcitonin. P-SEP had a sensitivity and specificity of 87% and 75%, respectively, placing it in the same ballpark as the 82% and 86% values for procalcitonin. The strong point for P-SEP was its 99% negative predictive value, as compared to 91% for procalcitonin. The positive predictive values were 17% for P-SEP and 20% for procalcitonin.

In response to an audience question, Dr. Pierantoni speculated that the best use for P-SEP in the setting of fever of unknown origin may be in combination with procalcitonin rather than as a replacement for it. The research team is now in the process of analyzing their study data to see if that is indeed the case.

He reported having no financial conflicts regarding his study, conducted free of commercial support.

[email protected]

LJUBLJANA, SLOVENIA – A point-of-care presepsin measurement in the emergency department displayed powerful accuracy for early rule-out of invasive bacterial infection in infants less than 3 months old presenting with fever without a source, based on results of a phase 3 multicenter Italian study.

Bruce Jancin/MDedge News

“P-SEP [presepsin] is a promising new biomarker. P-SEP accuracy for invasive bacterial infection is comparable to procalcitonin, even though P-SEP, like procalcitonin, is probably not accurate enough to be used as a stand-alone marker to rule-in an invasive bacterial infection,” Luca Pierantoni, MD, said in presenting the preliminary study results at the annual meeting of the European Society for Paediatric Infectious Diseases.

The presepsin test is a rapid point-of-care test well-suited for the ED setting, with a cost equal to that of point-of-care procalcitonin.

Presepsin is a form of soluble CD14 that is released from the surface of macrophages, monocytes, and neutrophils when these immune cells are stimulated by pathogens. “We think it may be a reliable diagnostic and prognostic marker of sepsis in adults and neonates,” explained Dr. Pierantoni of the University of Bologna, Italy.

Indeed, studies in adults suggest presepsin has better sensitivity and specificity than other biomarkers for early diagnosis of sepsis, and that it provides useful information on severity and prognosis as well. But, Dr. Pierantoni and his coworkers wondered, how does it perform in febrile young infants?

The Italian study was designed to address an unmet need: Fever accounts for about one-third of ED visits in infants up to age 3 months, 20% of whom are initially categorized as having fever without source. Yet ultimately 10%-20% of those youngsters having fever without source are found to have an invasive bacterial infection – that is, sepsis or meningitis – or a severe bacterial infection such as pneumonia, a urinary tract infection, or an infected umbilical cord. The sooner these infants can be identified and appropriately treated, the better.

The study enrolled 284 children less than 3 months old who had fever without cause of a mean 10.5 hours duration and presented to the emergency departments of six Italian medical centers. Children were eligible for the study regardless of whether they appeared toxic or well. Presepsin, procalcitonin, and C-reactive protein levels were immediately measured in all participants. Ultimately, 5.6% of subjects were diagnosed with an invasive bacterial infection, and another 21.2% had a severe bacterial infection.

Using a cutoff value of 449 pg/mL, P-SEP had good diagnostic accuracy for invasive bacterial infection, with an area under the receiver operating characteristics curve of 0.81, essentially the same as the 0.82 value for procalcitonin. P-SEP had a sensitivity and specificity of 87% and 75%, respectively, placing it in the same ballpark as the 82% and 86% values for procalcitonin. The strong point for P-SEP was its 99% negative predictive value, as compared to 91% for procalcitonin. The positive predictive values were 17% for P-SEP and 20% for procalcitonin.

In response to an audience question, Dr. Pierantoni speculated that the best use for P-SEP in the setting of fever of unknown origin may be in combination with procalcitonin rather than as a replacement for it. The research team is now in the process of analyzing their study data to see if that is indeed the case.

He reported having no financial conflicts regarding his study, conducted free of commercial support.

[email protected]

Fresher blood products are not necessarily better for patients with beta thalassemia, according to a pair of experts.

Red blood cell units stored less than 2 weeks are ideal, but older units are acceptable, and phenotype matching should take priority over unit age, advised Ashutosh Lal, MD, and Elliott Vichinsky, MD, both of UCSF Benioff Children’s Hospital Oakland (Calif.). They discussed these and other recommendations for transfusing patients with thalassemia during a webinar hosted by the Centers for Disease Control and Prevention.

Indications for transfusion

Dr. Lal said patients with beta thalassemia major should be transfused if their hemoglobin is less than 7 g/dL on two occasions 2 weeks apart at baseline, or if their hemoglobin is greater than 7 g/dL and they have symptoms of anemia.

Patients with hemoglobin E beta thalassemia major should be transfused only if they have symptoms of anemia.

“The rationale is that, in beta thalassemia major, it is well established that, once the hemoglobin levels fall below 7 g/dL in young children, there is going to be massive bone marrow expansion, and there will be severe symptoms from anemia,” Dr. Lal said. “But the relationship of hemoglobin with symptoms in E beta thalassemia is less precise.”

The symptoms that should prompt transfusion include slowed growth, skeletal facial changes, splenomegaly, symptomatic or moderate to severe extramedullary hematopoiesis, cerebrovascular events, venous thromboembolism, pulmonary hypertension, osteoporotic fracture, and impaired quality of life in adults.

Dr. Lal said physicians should consider a 6-month trial of transfusions if the indication is unclear. He also noted that red cell antigen genotyping should be performed in all patients who may need transfusions.

Blood products

Dr. Lal said beta thalassemia patients should receive packed red blood cells that are leukoreduced prior to storage. The storage solution can be citrate-phosphate-dextrose solution with adenine (hematocrit 75%) or additive solution (hematocrit 60%).

“It’s important to note that the hematocrit of the two is quite different, and that needs to be inculcated into the decisions on how much volume to transfuse to younger children,” Dr. Lal said.

He noted that units should not be irradiated, as this damages the red cell membrane. And patients with severe allergic reactions should receive washed red blood cells because washing units removes residual donor plasma proteins.

Finally, units should be less than 2 weeks old if possible. Dr. Lal said using fresh units increases the survival of red blood cells post transfusion. However, he and Dr. Vichinsky both stressed that older units are acceptable, and phenotype matching is more important than the age of the unit.

Phenotype matching

Beta thalassemia patients who do not have preexisting alloantibodies or have transient autoantibodies should be matched to Rh and Kell, according to Dr. Lal.

Patients with preexisting alloantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and the specific alloantibody. Patients with persistent autoantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and any alloantibody.

Patients who start transfusions after 5 years of age should be matched to Rh, Kell, Duffy, Kidd, and S. Pregnant patients should be matched to Rh, Kell, Duffy, Kidd, and S, and units should be cytomegalovirus negative.

How to transfuse

Dr. Lal said the pretransfusion hemoglobin target is 10 g/dL, with a range of 9.5-10.5 g/dL in beta thalassemia major and a range of 9.0-10.5 g/dL for E beta thalassemia. A target of 10 g/dL is adequate for most individuals, Dr. Lal said, but he recommends individualization of hemoglobin target for patients with E beta thalassemia.

In general, patients should be transfused every 3 weeks, although 4 weeks is acceptable in younger children and those with hemoglobin E beta thalassemia.

As for the volume of a transfusion, children should receive 4 mL per kg of body weight, per gram increase in hemoglobin desired. Partial units can be used to avoid undertransfusion.

For adults, in general, those with pretransfusion hemoglobin less than 10 g/dL should receive three units, and those with pretransfusion hemoglobin of 10 g/dL or greater should receive two units.

The hemoglobin threshold should be adjusted based on fatigue or bone pain, Dr. Lal said. He also noted that patients with intact spleens have higher transfusion needs.

The rate of transfusion should be 5 mL/kg/hour in children and 200-300 mL/hour in adults, based on tolerance. Patients with impaired cardiac function should receive a reduced blood volume at a reduced rate.

Non–transfusion dependent thalassemia

Dr. Vichinsky discussed recommendations for non–transfusion dependent thalassemia (NTDT), noting that these patients may need transient transfusions to prevent morbidity.

Hemoglobin should not be the sole determinant of transfusion need in NTDT patients, he said. Their well-being – activity level, growth, and skeletal changes – is more important than hemoglobin levels. However, patients with hemoglobin levels less than 7 g/dL often have severe morbidity, and those with levels of 10 g/dL or greater are usually protected from severe morbidity.

Indications for transfusion in NTDT patients include:
 

• Growth failure.
• Hematopoietic tumors.
• Pulmonary hypertension.
• Silent brain infarcts.
• Skin ulcers.
• Severe bone pain.
• Poor quality of life.
• Frequent hemolytic crises.
• Marked and enlarging spleen.
• Failure of secondary sex development.
• Cosmetic and facial changes.
• Pregnancy.

“There is a risk to transfusing this population,” Dr. Vichinsky said. “They’re older, and when you transfuse them, they can get iron overloaded.”

He added that splenectomized NTDT patients have a high risk of alloimmunization, and the transfusion duration should be serially reevaluated in NTDT patients.

Alpha thalassemia major

For alpha thalassemia major, Dr. Vichinsky discussed the importance of prevention, screening, and fetal therapy. He said couples with a fetus at risk of alpha thalassemia major should be identified early and offered, in addition to termination, the option of early fetal transfusion.

Dr. Vichinsky recommended prenatal testing and monitoring of at-risk pregnancies with ultrasound. If the fetus requires a transfusion, monitoring hemoglobin Barts and hemoglobin A is necessary.

A fetus that requires a transfusion should receive packed red blood cells that are cytomegalovirus negative, are less than 7 days old, have been irradiated, have a hemoglobin mass greater than 75%, and have been optimally cross matched with the mother first.

“These babies appear, with serial transfusions, to survive and have a relatively normal neonatal period,” Dr. Vichinsky said.

He added, however, that postnatal management of alpha thalassemia major involves an aggressive transfusion protocol. These patients should be transfused to a higher hemoglobin level than patients with beta thalassemia – roughly 12 g/dL versus 10 g/dL.

These and Dr. Lal’s recommendations are based on information in the Standards of Care Guidelines for Thalassemia – Oakland 2011, the Thalassemia International Federation Guidelines – 2014, the Thalassemia Management Checklists: United States – 2018, the Thalassemia Western Consortium Consensus: US – 2019, and the International Collaboration for Transfusion Medicine Guidelines – 2019.

Dr. Lal and Dr. Vichinsky did not disclose any conflicts of interest.

[email protected]

Fresher blood products are not necessarily better for patients with beta thalassemia, according to a pair of experts.

Red blood cell units stored less than 2 weeks are ideal, but older units are acceptable, and phenotype matching should take priority over unit age, advised Ashutosh Lal, MD, and Elliott Vichinsky, MD, both of UCSF Benioff Children’s Hospital Oakland (Calif.). They discussed these and other recommendations for transfusing patients with thalassemia during a webinar hosted by the Centers for Disease Control and Prevention.

Indications for transfusion

Dr. Lal said patients with beta thalassemia major should be transfused if their hemoglobin is less than 7 g/dL on two occasions 2 weeks apart at baseline, or if their hemoglobin is greater than 7 g/dL and they have symptoms of anemia.

Patients with hemoglobin E beta thalassemia major should be transfused only if they have symptoms of anemia.

“The rationale is that, in beta thalassemia major, it is well established that, once the hemoglobin levels fall below 7 g/dL in young children, there is going to be massive bone marrow expansion, and there will be severe symptoms from anemia,” Dr. Lal said. “But the relationship of hemoglobin with symptoms in E beta thalassemia is less precise.”

The symptoms that should prompt transfusion include slowed growth, skeletal facial changes, splenomegaly, symptomatic or moderate to severe extramedullary hematopoiesis, cerebrovascular events, venous thromboembolism, pulmonary hypertension, osteoporotic fracture, and impaired quality of life in adults.

Dr. Lal said physicians should consider a 6-month trial of transfusions if the indication is unclear. He also noted that red cell antigen genotyping should be performed in all patients who may need transfusions.

Blood products

Dr. Lal said beta thalassemia patients should receive packed red blood cells that are leukoreduced prior to storage. The storage solution can be citrate-phosphate-dextrose solution with adenine (hematocrit 75%) or additive solution (hematocrit 60%).

“It’s important to note that the hematocrit of the two is quite different, and that needs to be inculcated into the decisions on how much volume to transfuse to younger children,” Dr. Lal said.

He noted that units should not be irradiated, as this damages the red cell membrane. And patients with severe allergic reactions should receive washed red blood cells because washing units removes residual donor plasma proteins.

Finally, units should be less than 2 weeks old if possible. Dr. Lal said using fresh units increases the survival of red blood cells post transfusion. However, he and Dr. Vichinsky both stressed that older units are acceptable, and phenotype matching is more important than the age of the unit.

Phenotype matching

Beta thalassemia patients who do not have preexisting alloantibodies or have transient autoantibodies should be matched to Rh and Kell, according to Dr. Lal.

Patients with preexisting alloantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and the specific alloantibody. Patients with persistent autoantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and any alloantibody.

Patients who start transfusions after 5 years of age should be matched to Rh, Kell, Duffy, Kidd, and S. Pregnant patients should be matched to Rh, Kell, Duffy, Kidd, and S, and units should be cytomegalovirus negative.

How to transfuse

Dr. Lal said the pretransfusion hemoglobin target is 10 g/dL, with a range of 9.5-10.5 g/dL in beta thalassemia major and a range of 9.0-10.5 g/dL for E beta thalassemia. A target of 10 g/dL is adequate for most individuals, Dr. Lal said, but he recommends individualization of hemoglobin target for patients with E beta thalassemia.

In general, patients should be transfused every 3 weeks, although 4 weeks is acceptable in younger children and those with hemoglobin E beta thalassemia.

As for the volume of a transfusion, children should receive 4 mL per kg of body weight, per gram increase in hemoglobin desired. Partial units can be used to avoid undertransfusion.

For adults, in general, those with pretransfusion hemoglobin less than 10 g/dL should receive three units, and those with pretransfusion hemoglobin of 10 g/dL or greater should receive two units.

The hemoglobin threshold should be adjusted based on fatigue or bone pain, Dr. Lal said. He also noted that patients with intact spleens have higher transfusion needs.

The rate of transfusion should be 5 mL/kg/hour in children and 200-300 mL/hour in adults, based on tolerance. Patients with impaired cardiac function should receive a reduced blood volume at a reduced rate.

Non–transfusion dependent thalassemia

Dr. Vichinsky discussed recommendations for non–transfusion dependent thalassemia (NTDT), noting that these patients may need transient transfusions to prevent morbidity.

Hemoglobin should not be the sole determinant of transfusion need in NTDT patients, he said. Their well-being – activity level, growth, and skeletal changes – is more important than hemoglobin levels. However, patients with hemoglobin levels less than 7 g/dL often have severe morbidity, and those with levels of 10 g/dL or greater are usually protected from severe morbidity.

Indications for transfusion in NTDT patients include:
 

• Growth failure.
• Hematopoietic tumors.
• Pulmonary hypertension.
• Silent brain infarcts.
• Skin ulcers.
• Severe bone pain.
• Poor quality of life.
• Frequent hemolytic crises.
• Marked and enlarging spleen.
• Failure of secondary sex development.
• Cosmetic and facial changes.
• Pregnancy.

“There is a risk to transfusing this population,” Dr. Vichinsky said. “They’re older, and when you transfuse them, they can get iron overloaded.”

He added that splenectomized NTDT patients have a high risk of alloimmunization, and the transfusion duration should be serially reevaluated in NTDT patients.

Alpha thalassemia major

For alpha thalassemia major, Dr. Vichinsky discussed the importance of prevention, screening, and fetal therapy. He said couples with a fetus at risk of alpha thalassemia major should be identified early and offered, in addition to termination, the option of early fetal transfusion.

Dr. Vichinsky recommended prenatal testing and monitoring of at-risk pregnancies with ultrasound. If the fetus requires a transfusion, monitoring hemoglobin Barts and hemoglobin A is necessary.

A fetus that requires a transfusion should receive packed red blood cells that are cytomegalovirus negative, are less than 7 days old, have been irradiated, have a hemoglobin mass greater than 75%, and have been optimally cross matched with the mother first.

“These babies appear, with serial transfusions, to survive and have a relatively normal neonatal period,” Dr. Vichinsky said.

He added, however, that postnatal management of alpha thalassemia major involves an aggressive transfusion protocol. These patients should be transfused to a higher hemoglobin level than patients with beta thalassemia – roughly 12 g/dL versus 10 g/dL.

These and Dr. Lal’s recommendations are based on information in the Standards of Care Guidelines for Thalassemia – Oakland 2011, the Thalassemia International Federation Guidelines – 2014, the Thalassemia Management Checklists: United States – 2018, the Thalassemia Western Consortium Consensus: US – 2019, and the International Collaboration for Transfusion Medicine Guidelines – 2019.

Dr. Lal and Dr. Vichinsky did not disclose any conflicts of interest.

[email protected]

Fresher blood products are not necessarily better for patients with beta thalassemia, according to a pair of experts.

Red blood cell units stored less than 2 weeks are ideal, but older units are acceptable, and phenotype matching should take priority over unit age, advised Ashutosh Lal, MD, and Elliott Vichinsky, MD, both of UCSF Benioff Children’s Hospital Oakland (Calif.). They discussed these and other recommendations for transfusing patients with thalassemia during a webinar hosted by the Centers for Disease Control and Prevention.

Indications for transfusion

Dr. Lal said patients with beta thalassemia major should be transfused if their hemoglobin is less than 7 g/dL on two occasions 2 weeks apart at baseline, or if their hemoglobin is greater than 7 g/dL and they have symptoms of anemia.

Patients with hemoglobin E beta thalassemia major should be transfused only if they have symptoms of anemia.

“The rationale is that, in beta thalassemia major, it is well established that, once the hemoglobin levels fall below 7 g/dL in young children, there is going to be massive bone marrow expansion, and there will be severe symptoms from anemia,” Dr. Lal said. “But the relationship of hemoglobin with symptoms in E beta thalassemia is less precise.”

The symptoms that should prompt transfusion include slowed growth, skeletal facial changes, splenomegaly, symptomatic or moderate to severe extramedullary hematopoiesis, cerebrovascular events, venous thromboembolism, pulmonary hypertension, osteoporotic fracture, and impaired quality of life in adults.

Dr. Lal said physicians should consider a 6-month trial of transfusions if the indication is unclear. He also noted that red cell antigen genotyping should be performed in all patients who may need transfusions.

Blood products

Dr. Lal said beta thalassemia patients should receive packed red blood cells that are leukoreduced prior to storage. The storage solution can be citrate-phosphate-dextrose solution with adenine (hematocrit 75%) or additive solution (hematocrit 60%).

“It’s important to note that the hematocrit of the two is quite different, and that needs to be inculcated into the decisions on how much volume to transfuse to younger children,” Dr. Lal said.

He noted that units should not be irradiated, as this damages the red cell membrane. And patients with severe allergic reactions should receive washed red blood cells because washing units removes residual donor plasma proteins.

Finally, units should be less than 2 weeks old if possible. Dr. Lal said using fresh units increases the survival of red blood cells post transfusion. However, he and Dr. Vichinsky both stressed that older units are acceptable, and phenotype matching is more important than the age of the unit.

Phenotype matching

Beta thalassemia patients who do not have preexisting alloantibodies or have transient autoantibodies should be matched to Rh and Kell, according to Dr. Lal.

Patients with preexisting alloantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and the specific alloantibody. Patients with persistent autoantibodies should be matched to Rh, Kell, Duffy, Kidd, S, and any alloantibody.

Patients who start transfusions after 5 years of age should be matched to Rh, Kell, Duffy, Kidd, and S. Pregnant patients should be matched to Rh, Kell, Duffy, Kidd, and S, and units should be cytomegalovirus negative.

How to transfuse

Dr. Lal said the pretransfusion hemoglobin target is 10 g/dL, with a range of 9.5-10.5 g/dL in beta thalassemia major and a range of 9.0-10.5 g/dL for E beta thalassemia. A target of 10 g/dL is adequate for most individuals, Dr. Lal said, but he recommends individualization of hemoglobin target for patients with E beta thalassemia.

In general, patients should be transfused every 3 weeks, although 4 weeks is acceptable in younger children and those with hemoglobin E beta thalassemia.

As for the volume of a transfusion, children should receive 4 mL per kg of body weight, per gram increase in hemoglobin desired. Partial units can be used to avoid undertransfusion.

For adults, in general, those with pretransfusion hemoglobin less than 10 g/dL should receive three units, and those with pretransfusion hemoglobin of 10 g/dL or greater should receive two units.

The hemoglobin threshold should be adjusted based on fatigue or bone pain, Dr. Lal said. He also noted that patients with intact spleens have higher transfusion needs.

The rate of transfusion should be 5 mL/kg/hour in children and 200-300 mL/hour in adults, based on tolerance. Patients with impaired cardiac function should receive a reduced blood volume at a reduced rate.

Non–transfusion dependent thalassemia

Dr. Vichinsky discussed recommendations for non–transfusion dependent thalassemia (NTDT), noting that these patients may need transient transfusions to prevent morbidity.

Hemoglobin should not be the sole determinant of transfusion need in NTDT patients, he said. Their well-being – activity level, growth, and skeletal changes – is more important than hemoglobin levels. However, patients with hemoglobin levels less than 7 g/dL often have severe morbidity, and those with levels of 10 g/dL or greater are usually protected from severe morbidity.

Indications for transfusion in NTDT patients include:
 

• Growth failure.
• Hematopoietic tumors.
• Pulmonary hypertension.
• Silent brain infarcts.
• Skin ulcers.
• Severe bone pain.
• Poor quality of life.
• Frequent hemolytic crises.
• Marked and enlarging spleen.
• Failure of secondary sex development.
• Cosmetic and facial changes.
• Pregnancy.

“There is a risk to transfusing this population,” Dr. Vichinsky said. “They’re older, and when you transfuse them, they can get iron overloaded.”

He added that splenectomized NTDT patients have a high risk of alloimmunization, and the transfusion duration should be serially reevaluated in NTDT patients.

Alpha thalassemia major

For alpha thalassemia major, Dr. Vichinsky discussed the importance of prevention, screening, and fetal therapy. He said couples with a fetus at risk of alpha thalassemia major should be identified early and offered, in addition to termination, the option of early fetal transfusion.

Dr. Vichinsky recommended prenatal testing and monitoring of at-risk pregnancies with ultrasound. If the fetus requires a transfusion, monitoring hemoglobin Barts and hemoglobin A is necessary.

A fetus that requires a transfusion should receive packed red blood cells that are cytomegalovirus negative, are less than 7 days old, have been irradiated, have a hemoglobin mass greater than 75%, and have been optimally cross matched with the mother first.

“These babies appear, with serial transfusions, to survive and have a relatively normal neonatal period,” Dr. Vichinsky said.

He added, however, that postnatal management of alpha thalassemia major involves an aggressive transfusion protocol. These patients should be transfused to a higher hemoglobin level than patients with beta thalassemia – roughly 12 g/dL versus 10 g/dL.

These and Dr. Lal’s recommendations are based on information in the Standards of Care Guidelines for Thalassemia – Oakland 2011, the Thalassemia International Federation Guidelines – 2014, the Thalassemia Management Checklists: United States – 2018, the Thalassemia Western Consortium Consensus: US – 2019, and the International Collaboration for Transfusion Medicine Guidelines – 2019.

Dr. Lal and Dr. Vichinsky did not disclose any conflicts of interest.

[email protected]

It has been 40 years since the first reported case of IgE-mediated natural rubber latex allergy, which was soon followed by a global epidemic of allergic and anaphylactic reactions.^1,2 Resolution came through insightful work in the 1990s that led to the removal of cornstarch powder and a switch to nonpowdered latex and synthetic examination gloves.² Also discovered during this period was the cross-reactivity of many patients to latex and various fruits. This column will briefly discuss the latex/fruit allergy syndrome, which should be considered in patients who are sensitive to various skincare products.

tookapic/Pixabay

Research substantiates reports

Blanco et al. conducted a prospective study in their outpatient clinic in 25 patients diagnosed with latex allergy, published in 1994.They used a clinical questionnaire, skin-prick tests, skin test with a latex extract, and identification of total and specific IgE to help ascertain clinical characteristics and cross-reactivity. Of the 23 women and 2 men in the study (mean age 33, plus or minus 9 years), 9 (36%) experienced latex-induced reactions characterized by systemic anaphylaxis. In 13 patients (52%), 42 food allergies were identified, and 23 included systemic anaphylaxis. Avocado (9), chestnut (9), banana (7), kiwi (5), and papaya (3) were the most common foods to cause hypersensitivities. The researchers concluded that their small study supported the reality of a “latex-fruit syndrome.”³

Another study aimed to characterize the cross-reactivity of latex and foods and evaluate clinical significance. Beezhold et al. examined 47 patients allergic to latex and 46 nonallergic controls. The investigators found immunologic reactivity to foods to be prevalent (33 latex-allergic patients and seven controls), with 27% of food skin-prick tests positive in the latex-allergic group. In addition, clinical symptoms were linked to 27% of positive skin-prick tests. Among the 17 patients who displayed clinical allergies to at least one food, 14 showed local sensitivity reactions, with anaphylaxis noted in 11. Avocado (53%), potato (40%), banana (38%), tomato (28%), chestnut (28%), and kiwi (17%) were the foods most frequently cited for provoking a skin test reaction. The authors observed extensive cross-reactivity between latex sensitivity and particular foods, with potatoes and tomatoes reported for the first time.⁴

In 1997, Brehler et al. studied serum samples from 136 patients whose immediate hypersensitivity to latex proteins was clinically observable and documented. The samples were assessed for IgE antibodies against several fruits, with fruit-specific IgE antibodies recorded in 69.1%. Radioallergosorbent (RAST) -inhibition tests yielded the recognition of cross-reacting IgE antibodies in latex and multiple fruit allergens: avocado, banana, chestnut, fig, kiwi, mango, melon, papaya, passion fruit, peach, pineapple, and tomato. The investigators recorded 112 intolerance reactions and noted that 42.5% of their patients reported allergic symptoms after consuming these fruits. Fruit-specific IgE antibodies were detected in only 32.1% of these patients, suggesting to the researchers that serologic tests were suboptimal in forecasting food hypersensitivities in patients who are allergic to latex.⁵

Cross-reactivity with banana

Mäkinen-Kiljunen studied 47 patients to investigate banana allergy in patients with latex allergy in 1994, measuring latex-, banana-, and pollen-specific (birch, timothy, and mugwort) IgE. Thirty-one patients were also given skin-prick tests with banana and were queried about reactions after consuming bananas. Of the 47 sera samples, latex RAST results were positive in 31 and banana RAST results in 26. RAST results from latex and banana were correlated (25 of the 31 latex RAST-positive samples were also banana RAST-positive), but not with pollen. Sixteen of the 31 patients who ate banana reported symptoms, and 11 of the 31 patients given the banana skin-prick test showed positive results. The author confirmed the cross-reactivity of IgE antibodies for latex and banana, identifying for the first time a structurally similar antigen/allergen as at least one antigen from banana fused with an antigen from latex in crossed-line immunoelectrophoresis.⁶

In 1998, Mikkola et al. investigated whether proteins similar to hevein, a major natural rubber latex allergen, are present in banana and account for cross-reactivity between these botanicals. Immunoblotting revealed that 9 of 15 sera from latex-allergic patients with IgE to hevein also bound to 32- and 33-kd banana proteins. Studies using ELISA [enzyme-linked immunosorbent assay] showed that the common presentation of hypersensitivity to banana among patients allergic to latex could be attributed to cross-reacting IgE antibodies binding to epitopes in hevein and in the then-newly identified hevein-like endochitinase found in banana.⁷

Cross-reactivity with avocado

In response to reports of an association between allergy to natural rubber latex and avocado, Ahlroth et al. investigated cross-reactive proteins between natural rubber latex and avocado in 1995 by using skin-prick tests with fresh avocado on 11 patients and the sera of 18 patients with known latex allergy for IgE antibodies. Fourteen of the 18 sera were found to have IgE antibodies binding to 17 distinct avocado proteins, with multiple immunoblot experiments and skin-prick test results (positive in 7 of 11 patients) revealing marked immunologic cross-reactivity between latex and avocado.⁸

In 1998, Chen et al. set out to identify the cross-sensitizing allergen between latex and avocado, with hevein suspected. The researchers looked at sera samples from 118 health care workers allergic to latex and 78 patients with spina bifida who were allergic to latex. They noted a robust correlation between the prevalence of seropositive IgE antibodies to avocado in the presence of hevein-specific IgE antibodies in both groups. All members in the spina bifida group and 91 (73%) of the health care workers had positive IgE antibodies to hevein and high IgE values to avocado. Additional results supported the conclusion that sensitization to avocado in the majority of people allergic to latex is engendered by IgE-binding epitopes found in hevein.⁹

A year later, Diaz-Perales et al. considered the potential relevance of chitinases and complex glycans as factors in the then newly described latex/food syndrome, particularly in avocado, banana, and chestnuts. The investigators culled extracts from 20 various plant foods as well as latex. In immunoblot inhibition assays, the primary allergen and class I chitinase in avocado, Prs a 1, and the latex extract potently or completely blocked IgE binding by these constituents. Polyclonal antibodies to chitinases and sera from patients with latex/fruit allergy responded to reactive proteins of about 30-45 kd (putative class I chitinases) in chestnut, cherimoya, kiwi, mango, papaya, passion fruit, tomato, and wheat flour extracts. The glycans complex was deemed to be irrelevant in latex/fruit cross-reactivity, but the researchers found the putative class I chitinases to be notable players in the latex/fruit syndrome.¹⁰

According to Wagner and Breitender, anywhere from 30%-50% of people with known latex allergy also evince a related hypersensitivity or allergy to various plant-derived foods, with avocado, banana, chestnut, kiwi, peach, tomato, potato, and bell pepper among the foods most frequently linked to latex/fruit syndrome. They summarize that several plant defense proteins have been shown to be involved in the syndrome, with the most prominent, class I chitinases with an N-terminal hevein-like domain, having been found to cross-react with hevein (Hev b 6.02), a major IgE-binding allergen for individuals allergic to latex. A beta-1,3-glucanase, a key latex allergen, has also shown cross-reactivity with proteins of bell pepper, and another significant latex allergen, Hev b 7, a patatin-like protein, cross-reacts with its analogous protein in potato.¹¹

Conclusion

It is unknown whether latex allergy precedes or follows food allergy.11 The latex/food syndrome itself merits attention as a significant source of hypersensitivity to natural cosmeceutical ingredients. Dermatologists should be aware of the lengthy list of cross-reacting plant-derived products, particularly when it comes to reviewing topical product ingredients with susceptible or allergic patients. Latex-allergic patients may react to these natural ingredients in food or when topically applied to the skin.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

References

1. Nutter AF. Br J Dermatol 1979 Nov;101(5):597-8.

2. Kelly KJ et al. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5(5):1212-16.

3. Blanco C et al. Ann Allergy. 1994 Oct;73(4):309-14.

4. Beezhold DH et al. Clin Exp Allergy. 1996 Apr;26(4):416-22.

5. Brehler R et al. Allergy. 1997 Apr;52(4):404-10.

6. Mäkinen-Kiljunen S. J Allergy Clin Immunol. 1994 Jun;93(6):990-6.

7. Mikkola JH et al. J Allergy Clin Immunol. 1998 Dec;102(6 Pt 1):1005-12.

8. Ahlroth M et al. J Allergy Clin Immunol. 1995 Aug;96(2):167-73.

9. Chen Z et al. J Allergy Clin Immunol. 1998 Sep;102(3):476-81.

10. Diaz-Perales A et al. J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):681-7.

11. Wagner S et al. Biochem Soc Trans. 2002 Nov;30(Pt 6):935-40.

It has been 40 years since the first reported case of IgE-mediated natural rubber latex allergy, which was soon followed by a global epidemic of allergic and anaphylactic reactions.^1,2 Resolution came through insightful work in the 1990s that led to the removal of cornstarch powder and a switch to nonpowdered latex and synthetic examination gloves.² Also discovered during this period was the cross-reactivity of many patients to latex and various fruits. This column will briefly discuss the latex/fruit allergy syndrome, which should be considered in patients who are sensitive to various skincare products.

tookapic/Pixabay

Research substantiates reports

Blanco et al. conducted a prospective study in their outpatient clinic in 25 patients diagnosed with latex allergy, published in 1994.They used a clinical questionnaire, skin-prick tests, skin test with a latex extract, and identification of total and specific IgE to help ascertain clinical characteristics and cross-reactivity. Of the 23 women and 2 men in the study (mean age 33, plus or minus 9 years), 9 (36%) experienced latex-induced reactions characterized by systemic anaphylaxis. In 13 patients (52%), 42 food allergies were identified, and 23 included systemic anaphylaxis. Avocado (9), chestnut (9), banana (7), kiwi (5), and papaya (3) were the most common foods to cause hypersensitivities. The researchers concluded that their small study supported the reality of a “latex-fruit syndrome.”³

Another study aimed to characterize the cross-reactivity of latex and foods and evaluate clinical significance. Beezhold et al. examined 47 patients allergic to latex and 46 nonallergic controls. The investigators found immunologic reactivity to foods to be prevalent (33 latex-allergic patients and seven controls), with 27% of food skin-prick tests positive in the latex-allergic group. In addition, clinical symptoms were linked to 27% of positive skin-prick tests. Among the 17 patients who displayed clinical allergies to at least one food, 14 showed local sensitivity reactions, with anaphylaxis noted in 11. Avocado (53%), potato (40%), banana (38%), tomato (28%), chestnut (28%), and kiwi (17%) were the foods most frequently cited for provoking a skin test reaction. The authors observed extensive cross-reactivity between latex sensitivity and particular foods, with potatoes and tomatoes reported for the first time.⁴

In 1997, Brehler et al. studied serum samples from 136 patients whose immediate hypersensitivity to latex proteins was clinically observable and documented. The samples were assessed for IgE antibodies against several fruits, with fruit-specific IgE antibodies recorded in 69.1%. Radioallergosorbent (RAST) -inhibition tests yielded the recognition of cross-reacting IgE antibodies in latex and multiple fruit allergens: avocado, banana, chestnut, fig, kiwi, mango, melon, papaya, passion fruit, peach, pineapple, and tomato. The investigators recorded 112 intolerance reactions and noted that 42.5% of their patients reported allergic symptoms after consuming these fruits. Fruit-specific IgE antibodies were detected in only 32.1% of these patients, suggesting to the researchers that serologic tests were suboptimal in forecasting food hypersensitivities in patients who are allergic to latex.⁵

Cross-reactivity with banana

Mäkinen-Kiljunen studied 47 patients to investigate banana allergy in patients with latex allergy in 1994, measuring latex-, banana-, and pollen-specific (birch, timothy, and mugwort) IgE. Thirty-one patients were also given skin-prick tests with banana and were queried about reactions after consuming bananas. Of the 47 sera samples, latex RAST results were positive in 31 and banana RAST results in 26. RAST results from latex and banana were correlated (25 of the 31 latex RAST-positive samples were also banana RAST-positive), but not with pollen. Sixteen of the 31 patients who ate banana reported symptoms, and 11 of the 31 patients given the banana skin-prick test showed positive results. The author confirmed the cross-reactivity of IgE antibodies for latex and banana, identifying for the first time a structurally similar antigen/allergen as at least one antigen from banana fused with an antigen from latex in crossed-line immunoelectrophoresis.⁶

In 1998, Mikkola et al. investigated whether proteins similar to hevein, a major natural rubber latex allergen, are present in banana and account for cross-reactivity between these botanicals. Immunoblotting revealed that 9 of 15 sera from latex-allergic patients with IgE to hevein also bound to 32- and 33-kd banana proteins. Studies using ELISA [enzyme-linked immunosorbent assay] showed that the common presentation of hypersensitivity to banana among patients allergic to latex could be attributed to cross-reacting IgE antibodies binding to epitopes in hevein and in the then-newly identified hevein-like endochitinase found in banana.⁷

Cross-reactivity with avocado

In response to reports of an association between allergy to natural rubber latex and avocado, Ahlroth et al. investigated cross-reactive proteins between natural rubber latex and avocado in 1995 by using skin-prick tests with fresh avocado on 11 patients and the sera of 18 patients with known latex allergy for IgE antibodies. Fourteen of the 18 sera were found to have IgE antibodies binding to 17 distinct avocado proteins, with multiple immunoblot experiments and skin-prick test results (positive in 7 of 11 patients) revealing marked immunologic cross-reactivity between latex and avocado.⁸

In 1998, Chen et al. set out to identify the cross-sensitizing allergen between latex and avocado, with hevein suspected. The researchers looked at sera samples from 118 health care workers allergic to latex and 78 patients with spina bifida who were allergic to latex. They noted a robust correlation between the prevalence of seropositive IgE antibodies to avocado in the presence of hevein-specific IgE antibodies in both groups. All members in the spina bifida group and 91 (73%) of the health care workers had positive IgE antibodies to hevein and high IgE values to avocado. Additional results supported the conclusion that sensitization to avocado in the majority of people allergic to latex is engendered by IgE-binding epitopes found in hevein.⁹

A year later, Diaz-Perales et al. considered the potential relevance of chitinases and complex glycans as factors in the then newly described latex/food syndrome, particularly in avocado, banana, and chestnuts. The investigators culled extracts from 20 various plant foods as well as latex. In immunoblot inhibition assays, the primary allergen and class I chitinase in avocado, Prs a 1, and the latex extract potently or completely blocked IgE binding by these constituents. Polyclonal antibodies to chitinases and sera from patients with latex/fruit allergy responded to reactive proteins of about 30-45 kd (putative class I chitinases) in chestnut, cherimoya, kiwi, mango, papaya, passion fruit, tomato, and wheat flour extracts. The glycans complex was deemed to be irrelevant in latex/fruit cross-reactivity, but the researchers found the putative class I chitinases to be notable players in the latex/fruit syndrome.¹⁰

According to Wagner and Breitender, anywhere from 30%-50% of people with known latex allergy also evince a related hypersensitivity or allergy to various plant-derived foods, with avocado, banana, chestnut, kiwi, peach, tomato, potato, and bell pepper among the foods most frequently linked to latex/fruit syndrome. They summarize that several plant defense proteins have been shown to be involved in the syndrome, with the most prominent, class I chitinases with an N-terminal hevein-like domain, having been found to cross-react with hevein (Hev b 6.02), a major IgE-binding allergen for individuals allergic to latex. A beta-1,3-glucanase, a key latex allergen, has also shown cross-reactivity with proteins of bell pepper, and another significant latex allergen, Hev b 7, a patatin-like protein, cross-reacts with its analogous protein in potato.¹¹

Conclusion

It is unknown whether latex allergy precedes or follows food allergy.11 The latex/food syndrome itself merits attention as a significant source of hypersensitivity to natural cosmeceutical ingredients. Dermatologists should be aware of the lengthy list of cross-reacting plant-derived products, particularly when it comes to reviewing topical product ingredients with susceptible or allergic patients. Latex-allergic patients may react to these natural ingredients in food or when topically applied to the skin.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

References

1. Nutter AF. Br J Dermatol 1979 Nov;101(5):597-8.

2. Kelly KJ et al. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5(5):1212-16.

3. Blanco C et al. Ann Allergy. 1994 Oct;73(4):309-14.

4. Beezhold DH et al. Clin Exp Allergy. 1996 Apr;26(4):416-22.

5. Brehler R et al. Allergy. 1997 Apr;52(4):404-10.

6. Mäkinen-Kiljunen S. J Allergy Clin Immunol. 1994 Jun;93(6):990-6.

7. Mikkola JH et al. J Allergy Clin Immunol. 1998 Dec;102(6 Pt 1):1005-12.

8. Ahlroth M et al. J Allergy Clin Immunol. 1995 Aug;96(2):167-73.

9. Chen Z et al. J Allergy Clin Immunol. 1998 Sep;102(3):476-81.

10. Diaz-Perales A et al. J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):681-7.

11. Wagner S et al. Biochem Soc Trans. 2002 Nov;30(Pt 6):935-40.

It has been 40 years since the first reported case of IgE-mediated natural rubber latex allergy, which was soon followed by a global epidemic of allergic and anaphylactic reactions.^1,2 Resolution came through insightful work in the 1990s that led to the removal of cornstarch powder and a switch to nonpowdered latex and synthetic examination gloves.² Also discovered during this period was the cross-reactivity of many patients to latex and various fruits. This column will briefly discuss the latex/fruit allergy syndrome, which should be considered in patients who are sensitive to various skincare products.

tookapic/Pixabay

Research substantiates reports

Blanco et al. conducted a prospective study in their outpatient clinic in 25 patients diagnosed with latex allergy, published in 1994.They used a clinical questionnaire, skin-prick tests, skin test with a latex extract, and identification of total and specific IgE to help ascertain clinical characteristics and cross-reactivity. Of the 23 women and 2 men in the study (mean age 33, plus or minus 9 years), 9 (36%) experienced latex-induced reactions characterized by systemic anaphylaxis. In 13 patients (52%), 42 food allergies were identified, and 23 included systemic anaphylaxis. Avocado (9), chestnut (9), banana (7), kiwi (5), and papaya (3) were the most common foods to cause hypersensitivities. The researchers concluded that their small study supported the reality of a “latex-fruit syndrome.”³

Another study aimed to characterize the cross-reactivity of latex and foods and evaluate clinical significance. Beezhold et al. examined 47 patients allergic to latex and 46 nonallergic controls. The investigators found immunologic reactivity to foods to be prevalent (33 latex-allergic patients and seven controls), with 27% of food skin-prick tests positive in the latex-allergic group. In addition, clinical symptoms were linked to 27% of positive skin-prick tests. Among the 17 patients who displayed clinical allergies to at least one food, 14 showed local sensitivity reactions, with anaphylaxis noted in 11. Avocado (53%), potato (40%), banana (38%), tomato (28%), chestnut (28%), and kiwi (17%) were the foods most frequently cited for provoking a skin test reaction. The authors observed extensive cross-reactivity between latex sensitivity and particular foods, with potatoes and tomatoes reported for the first time.⁴

In 1997, Brehler et al. studied serum samples from 136 patients whose immediate hypersensitivity to latex proteins was clinically observable and documented. The samples were assessed for IgE antibodies against several fruits, with fruit-specific IgE antibodies recorded in 69.1%. Radioallergosorbent (RAST) -inhibition tests yielded the recognition of cross-reacting IgE antibodies in latex and multiple fruit allergens: avocado, banana, chestnut, fig, kiwi, mango, melon, papaya, passion fruit, peach, pineapple, and tomato. The investigators recorded 112 intolerance reactions and noted that 42.5% of their patients reported allergic symptoms after consuming these fruits. Fruit-specific IgE antibodies were detected in only 32.1% of these patients, suggesting to the researchers that serologic tests were suboptimal in forecasting food hypersensitivities in patients who are allergic to latex.⁵

Cross-reactivity with banana

Mäkinen-Kiljunen studied 47 patients to investigate banana allergy in patients with latex allergy in 1994, measuring latex-, banana-, and pollen-specific (birch, timothy, and mugwort) IgE. Thirty-one patients were also given skin-prick tests with banana and were queried about reactions after consuming bananas. Of the 47 sera samples, latex RAST results were positive in 31 and banana RAST results in 26. RAST results from latex and banana were correlated (25 of the 31 latex RAST-positive samples were also banana RAST-positive), but not with pollen. Sixteen of the 31 patients who ate banana reported symptoms, and 11 of the 31 patients given the banana skin-prick test showed positive results. The author confirmed the cross-reactivity of IgE antibodies for latex and banana, identifying for the first time a structurally similar antigen/allergen as at least one antigen from banana fused with an antigen from latex in crossed-line immunoelectrophoresis.⁶

In 1998, Mikkola et al. investigated whether proteins similar to hevein, a major natural rubber latex allergen, are present in banana and account for cross-reactivity between these botanicals. Immunoblotting revealed that 9 of 15 sera from latex-allergic patients with IgE to hevein also bound to 32- and 33-kd banana proteins. Studies using ELISA [enzyme-linked immunosorbent assay] showed that the common presentation of hypersensitivity to banana among patients allergic to latex could be attributed to cross-reacting IgE antibodies binding to epitopes in hevein and in the then-newly identified hevein-like endochitinase found in banana.⁷

Cross-reactivity with avocado

In response to reports of an association between allergy to natural rubber latex and avocado, Ahlroth et al. investigated cross-reactive proteins between natural rubber latex and avocado in 1995 by using skin-prick tests with fresh avocado on 11 patients and the sera of 18 patients with known latex allergy for IgE antibodies. Fourteen of the 18 sera were found to have IgE antibodies binding to 17 distinct avocado proteins, with multiple immunoblot experiments and skin-prick test results (positive in 7 of 11 patients) revealing marked immunologic cross-reactivity between latex and avocado.⁸

In 1998, Chen et al. set out to identify the cross-sensitizing allergen between latex and avocado, with hevein suspected. The researchers looked at sera samples from 118 health care workers allergic to latex and 78 patients with spina bifida who were allergic to latex. They noted a robust correlation between the prevalence of seropositive IgE antibodies to avocado in the presence of hevein-specific IgE antibodies in both groups. All members in the spina bifida group and 91 (73%) of the health care workers had positive IgE antibodies to hevein and high IgE values to avocado. Additional results supported the conclusion that sensitization to avocado in the majority of people allergic to latex is engendered by IgE-binding epitopes found in hevein.⁹

A year later, Diaz-Perales et al. considered the potential relevance of chitinases and complex glycans as factors in the then newly described latex/food syndrome, particularly in avocado, banana, and chestnuts. The investigators culled extracts from 20 various plant foods as well as latex. In immunoblot inhibition assays, the primary allergen and class I chitinase in avocado, Prs a 1, and the latex extract potently or completely blocked IgE binding by these constituents. Polyclonal antibodies to chitinases and sera from patients with latex/fruit allergy responded to reactive proteins of about 30-45 kd (putative class I chitinases) in chestnut, cherimoya, kiwi, mango, papaya, passion fruit, tomato, and wheat flour extracts. The glycans complex was deemed to be irrelevant in latex/fruit cross-reactivity, but the researchers found the putative class I chitinases to be notable players in the latex/fruit syndrome.¹⁰

According to Wagner and Breitender, anywhere from 30%-50% of people with known latex allergy also evince a related hypersensitivity or allergy to various plant-derived foods, with avocado, banana, chestnut, kiwi, peach, tomato, potato, and bell pepper among the foods most frequently linked to latex/fruit syndrome. They summarize that several plant defense proteins have been shown to be involved in the syndrome, with the most prominent, class I chitinases with an N-terminal hevein-like domain, having been found to cross-react with hevein (Hev b 6.02), a major IgE-binding allergen for individuals allergic to latex. A beta-1,3-glucanase, a key latex allergen, has also shown cross-reactivity with proteins of bell pepper, and another significant latex allergen, Hev b 7, a patatin-like protein, cross-reacts with its analogous protein in potato.¹¹

Conclusion

It is unknown whether latex allergy precedes or follows food allergy.11 The latex/food syndrome itself merits attention as a significant source of hypersensitivity to natural cosmeceutical ingredients. Dermatologists should be aware of the lengthy list of cross-reacting plant-derived products, particularly when it comes to reviewing topical product ingredients with susceptible or allergic patients. Latex-allergic patients may react to these natural ingredients in food or when topically applied to the skin.

Dr. Baumann is a private practice dermatologist, researcher, author, and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC. Write to her at [email protected].

References

1. Nutter AF. Br J Dermatol 1979 Nov;101(5):597-8.

2. Kelly KJ et al. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5(5):1212-16.

3. Blanco C et al. Ann Allergy. 1994 Oct;73(4):309-14.

4. Beezhold DH et al. Clin Exp Allergy. 1996 Apr;26(4):416-22.

5. Brehler R et al. Allergy. 1997 Apr;52(4):404-10.

6. Mäkinen-Kiljunen S. J Allergy Clin Immunol. 1994 Jun;93(6):990-6.

7. Mikkola JH et al. J Allergy Clin Immunol. 1998 Dec;102(6 Pt 1):1005-12.

8. Ahlroth M et al. J Allergy Clin Immunol. 1995 Aug;96(2):167-73.

9. Chen Z et al. J Allergy Clin Immunol. 1998 Sep;102(3):476-81.

10. Diaz-Perales A et al. J Allergy Clin Immunol. 1999 Sep;104(3 Pt 1):681-7.

11. Wagner S et al. Biochem Soc Trans. 2002 Nov;30(Pt 6):935-40.

The progression, not just age of onset, of Huntington’s disease can be predicted by a measurable genetic factor, researchers have learned.

Huntington’s, an inherited neurodegenerative disease that affects motor function and cognition, is caused by an expansion of the CAG trinucleotide sequence on the huntingtin gene. Scientists have previously linked younger age at onset to a higher number of CAG repeats on the gene, but the association between these and the rate of progression after onset was poorly understood.

In research published online August 12 in JAMA Neurology, investigators linked the rate of progression – which, like age at onset, is highly variable in Huntington’s – to CAG repeat length. CAG repeat length was strongly associated with distinct patterns of brain damage, as well as clinical measures of cognitive and motor decline.

For their research, Douglas R. Langbehn, MD, PhD, of the University of Iowa, Iowa City, and colleagues used data from two longitudinal observational studies in gene carriers for Huntington’s and nonrelated controls. The researchers looked at data from 443 participants (56% female; mean age, 44.4 years) who were followed for a mean of 4 years, with more than 2,000 study visits across the multisite cohort. Neuropsychiatric testing and brain imaging were conducted annually, using composite scoring systems of the investigators’ design. These composite scores sought to be more sensitive by combining results from several validated clinical and imaging tests.

Age and speed of decline in total functional capacity tracked with more CAG repeats, the researchers found. For example, in people with 40 CAG repeats, the estimated mean age of initial motor-cognitive score change was 42.46 years; for those with 45 repeats, 26.65 years, and for people with 50 CAG repeats, 18.49 years. Higher repeats were seen significantly associated with accelerated, nonlinear decline on both clinical and brain-volume measures, except gray matter volume, according to principal component analyses conducted on the data.

“We derived a single summary measure capturing the motor-cognitive phenotype and showed that the accelerating progression of the phenotype with aging is highly CAG repeat length dependent (i.e., those with higher CAG decline earlier and faster). Contrary to some previous assertions, this CAG dependence continues well past the onset of clinical illness,” Dr. Langbehn and colleagues wrote in their analysis. “By characterizing these CAG repeat length–dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline.”

Dr. Langbehn and colleagues acknowledged as a limitation of their study its likely exclusion of the sickest subjects because of the cohorts’ design. The CHDI Foundation funded the study. Of the 16 coauthors, 13 reported receiving funding from CHDI and/or from pharmaceutical manufacturers.

SOURCE: Langbehn et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2328

The progression, not just age of onset, of Huntington’s disease can be predicted by a measurable genetic factor, researchers have learned.

Huntington’s, an inherited neurodegenerative disease that affects motor function and cognition, is caused by an expansion of the CAG trinucleotide sequence on the huntingtin gene. Scientists have previously linked younger age at onset to a higher number of CAG repeats on the gene, but the association between these and the rate of progression after onset was poorly understood.

In research published online August 12 in JAMA Neurology, investigators linked the rate of progression – which, like age at onset, is highly variable in Huntington’s – to CAG repeat length. CAG repeat length was strongly associated with distinct patterns of brain damage, as well as clinical measures of cognitive and motor decline.

For their research, Douglas R. Langbehn, MD, PhD, of the University of Iowa, Iowa City, and colleagues used data from two longitudinal observational studies in gene carriers for Huntington’s and nonrelated controls. The researchers looked at data from 443 participants (56% female; mean age, 44.4 years) who were followed for a mean of 4 years, with more than 2,000 study visits across the multisite cohort. Neuropsychiatric testing and brain imaging were conducted annually, using composite scoring systems of the investigators’ design. These composite scores sought to be more sensitive by combining results from several validated clinical and imaging tests.

Age and speed of decline in total functional capacity tracked with more CAG repeats, the researchers found. For example, in people with 40 CAG repeats, the estimated mean age of initial motor-cognitive score change was 42.46 years; for those with 45 repeats, 26.65 years, and for people with 50 CAG repeats, 18.49 years. Higher repeats were seen significantly associated with accelerated, nonlinear decline on both clinical and brain-volume measures, except gray matter volume, according to principal component analyses conducted on the data.

“We derived a single summary measure capturing the motor-cognitive phenotype and showed that the accelerating progression of the phenotype with aging is highly CAG repeat length dependent (i.e., those with higher CAG decline earlier and faster). Contrary to some previous assertions, this CAG dependence continues well past the onset of clinical illness,” Dr. Langbehn and colleagues wrote in their analysis. “By characterizing these CAG repeat length–dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline.”

Dr. Langbehn and colleagues acknowledged as a limitation of their study its likely exclusion of the sickest subjects because of the cohorts’ design. The CHDI Foundation funded the study. Of the 16 coauthors, 13 reported receiving funding from CHDI and/or from pharmaceutical manufacturers.

SOURCE: Langbehn et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2328

The progression, not just age of onset, of Huntington’s disease can be predicted by a measurable genetic factor, researchers have learned.

Huntington’s, an inherited neurodegenerative disease that affects motor function and cognition, is caused by an expansion of the CAG trinucleotide sequence on the huntingtin gene. Scientists have previously linked younger age at onset to a higher number of CAG repeats on the gene, but the association between these and the rate of progression after onset was poorly understood.

In research published online August 12 in JAMA Neurology, investigators linked the rate of progression – which, like age at onset, is highly variable in Huntington’s – to CAG repeat length. CAG repeat length was strongly associated with distinct patterns of brain damage, as well as clinical measures of cognitive and motor decline.

For their research, Douglas R. Langbehn, MD, PhD, of the University of Iowa, Iowa City, and colleagues used data from two longitudinal observational studies in gene carriers for Huntington’s and nonrelated controls. The researchers looked at data from 443 participants (56% female; mean age, 44.4 years) who were followed for a mean of 4 years, with more than 2,000 study visits across the multisite cohort. Neuropsychiatric testing and brain imaging were conducted annually, using composite scoring systems of the investigators’ design. These composite scores sought to be more sensitive by combining results from several validated clinical and imaging tests.

Age and speed of decline in total functional capacity tracked with more CAG repeats, the researchers found. For example, in people with 40 CAG repeats, the estimated mean age of initial motor-cognitive score change was 42.46 years; for those with 45 repeats, 26.65 years, and for people with 50 CAG repeats, 18.49 years. Higher repeats were seen significantly associated with accelerated, nonlinear decline on both clinical and brain-volume measures, except gray matter volume, according to principal component analyses conducted on the data.

“We derived a single summary measure capturing the motor-cognitive phenotype and showed that the accelerating progression of the phenotype with aging is highly CAG repeat length dependent (i.e., those with higher CAG decline earlier and faster). Contrary to some previous assertions, this CAG dependence continues well past the onset of clinical illness,” Dr. Langbehn and colleagues wrote in their analysis. “By characterizing these CAG repeat length–dependent disease trajectories, we provide insights into disease progression that may guide future therapeutic approaches and identify the most appropriate intervention ages to prevent clinical decline.”

Dr. Langbehn and colleagues acknowledged as a limitation of their study its likely exclusion of the sickest subjects because of the cohorts’ design. The CHDI Foundation funded the study. Of the 16 coauthors, 13 reported receiving funding from CHDI and/or from pharmaceutical manufacturers.

SOURCE: Langbehn et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2328