Inspired by the ABIM Foundation’s Choosing Wisely® campaign, the “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A 67-year-old woman with a history of hypertension and osteoarthritis was hospitalized for fever, flank pain, and dysuria with pyuria on urinalysis. She was diagnosed with acute pyelonephritis and started ceftriaxone, ondansetron for nausea, and oxycodone for pain. On hospital day two, she developed acute confusion that waxed and waned in severity throughout the day. On examination, she appeared mildly agitated, inattentive, and was noted to pick at her linens and garment. She was oriented to person only and had a nonfocal neurologic examination. Her nurse reported no recent falls or trauma. As part of the patient’s evaluation, her attending physician ordered a head computed tomography (CT) scan.

Delirium is commonly diagnosed in hospitalized patients. It has a prevalence of 29%-64% and is associated with longer lengths of stay, higher mortality, and costs of over $164 billion per year in the United States.¹ While a number of practice guidelines have been created to help guide delirium diagnosis and management, there is not a clear consensus on when neuroimaging should be performed during the evaluation.^2-4 It should also be noted that numerous guidelines for delirium management exist, with variable quality and a heavy reliance on expert opinion.⁵ Perhaps due to this lack of consensus, neuroimaging is performed in 33% to 67% of hospitalized patients with delirium.^6,7

Delirium is known to be associated with intracranial processes. For example, delirium occurs in 13% to 48% of patients with acute stroke⁸ and conversely 7% of patients with new confusion evaluated in emergency departments or inpatient settings were found to have an acute stroke.⁹ The inclusion of neuroimaging as part of a delirium evaluation is supported in certain circumstances, such as in patients with recent falls, focal neurologic signs (including papilledema), systemic anticoagulation,² or increased risk of intracranial processes such as metastatic malignancy.⁴

A number of studies have evaluated the diagnostic yield of neuroimaging in hospitalized patients with delirium (Table).^6,7,10,11 Two studies included patients with delirium that developed after hospitalization^10,11 and two included patients with delirium at admission.^6,7

Theisen-Toupal et al. conducted a retrospective study of 220 hospitalized general medical patients who underwent head CT scans for an indication of delirium, altered mental status, confusion, encephalopathy, somnolence or unresponsiveness.¹⁰ Patients were excluded if they had a history of falls, head trauma, or new neurologic deficits in the preceding two weeks or if the admitting diagnosis was stroke or cerebral hemorrhage. Additionally, the authors limited patients to those who developed delirium 24 hours or more after admission. There were 6/220 (2.7%) patients identified with an acute intracranial process. Of these six patients, three were receiving anticoagulation. An additional 4/220 (1.8%) head CT scans were identified as equivocal, prompting further neuroimaging, which ultimately showed chronic findings.

Vijayakrishnan et al. performed a retrospective review of 400 hospitalized patients who underwent inpatient CT scans, then limited to those with new delirium.¹¹ They identified 36 patients, of which four (11%) had acute findings on CT: one case each of acute hemorrhage, subdural hematoma, brain metastases, and septic emboli. The authors state “all the four patients had preimaging clinical symptoms and signs, which warranted imaging as per guidelines suggested by the British Geriatrics Society and the Australian and New Zealand Society for Geriatric Medicine,” though they do not provide further details. The strength of this paper is that it isolated patients who developed delirium while hospitalized; however, conclusions were limited by the small sample size.

Lai et al.’s case-control study evaluated 300 consecutive patients admitted to a delirium unit over 18 months.⁶ Of these 300 patients, 200 (67%) had CT performed; 29/200 (14.5%) had intracranial findings on CT that explained their delirium, including 13 ischemic strokes, seven subdural hemorrhages, nine intracerebral hemorrhages, and three additional ischemic strokes that evolved on follow-up imaging but were not present on the initial scans. The authors performed univariate and multivariate analyses to identify risk factors for an intracranial cause of delirium. Only 3/29 patients with a positive scan did not have one of three main risk factors the authors identified: a fall in the preceding two weeks, new neurologic findings, or sudden deterioration of consciousness. It should be noted that authors did not define “deterioration of consciousness” and that all patients had confusion on admission to the unit, rather than developing during hospitalization.

Hijazi et al. conducted a retrospective cohort study over a 20-month period of 1,653 patients with delirium at the time of admission or during their hospitalization. Patients with delirium due to drug or medication withdrawal or “psychiatric reasons” were excluded. Overall, 538 (32.5%) patients underwent CT, MRI or both, and 78 (14.5%) patients had a positive finding on neuroimaging. This study’s 14.5 % overall yield matches that of Lai et al. Unfortunately, the study included all patients with delirium and did not report the rates of fall, neurologic deficits, and/or use of anticoagulation among those with positive neuroimaging. This limits the generalizability of the findings to a cohort of patients without intracranial pathology risk factors.

The reported yield of neuroimaging for hospitalized patients with delirium ranged from 2.7% to 14.5% across studies. However, in studies taking into account specific patient risk factors; the reported yields in patients without focal neurologic findings, new decline in mental status, systemic anticoagulation, or recent falls were 0%,¹¹ 1.4%,¹⁰ and 1.5%.⁶ While a rate of 1.5% may appear high for a serious outcome such as stroke or intracranial bleeding, it is comparable to rates reported for missed major cardiac events in clinical algorithms for evaluating chest pain.¹² It should also be noted that neuroimaging is imperfect for acute stroke, and thus the positive or negative predictive value may be poor in the setting of low prevalence. For example, for detection of any acute stroke, the sensitivity/specificity of MRI and CT are 83%/97% and 26%/98% respectively.¹³

Neuroimaging is expensive and has risks. The average charge for a head CT is approximately $1,400 at academic institutions.¹⁴ Moreover, computed tomography exposes patients to significant radiation and up to 2% of malignancies in the United States may be attributable to prior tomography exposure.¹⁵ Additionally, there are non-negligible rates of incidental findings during neuroimaging, 1% for CT¹⁶ and 2.7%-13.7% for MRI,^17,18 which may result in further evaluation or treatment that causes significant patient anxiety. Obtaining neuroimaging on delirious patients can be time consuming and labor intensive, which could delay care to other patients. Additionally, sedating medications are often administered to agitated patients prior to imaging, which risk worsening delirium. Ordering neuroimaging for all patients with acute delirium, therefore, exposes the large majority to unnecessary costs and potential harms.

The diagnostic yield of head CT in the evaluation of delirium is significantly higher in patients with specific risk factors. Lai et al. found adjusted odds ratios for abnormal CT of 18.2 in patients with new focal deficits, 5.6 with a fall in the preceding two weeks and 4.6 in patients with deterioration in consciousness. Patients with systemic anticoagulation had higher unadjusted, (OR 2.4) though not adjusted odds of having an abnormal CT.⁶ Thiesen-Toupal et al. excluded patients with recent falls or neurologic deficits but reported that three out of six delirious patients with abnormal neuroimaging were anticoagulated.¹⁰ Vijayakrishnan et al. found that all four delirious patients with intracranial findings met guideline criteria for neuroimaging.¹¹ Thus, current recommendations for neuroimaging in delirious patients with falls, focal neurologic deficits, or systemic anticoagulation are appropriate. In situations when a provider lacks an accurate history and is unable to determine if risk factors are present (for example a confused patient found sitting on the floor next to the bed), it may also be reasonable to consider neuroimaging.

Data are limited, but some authors advocate for neuroimaging in cases of delirium that do not improve with treatment.⁶ Additionally, it may be reasonable to consider neuroimaging in delirium patients with predispositions to embolic or metastatic intracranial processes such as endovascular infections and certain malignancies.⁴

Hospitalized patients with acute confusion should be assessed for delirium with a validated instrument such as the Confusion Assessment Method (CAM).^19,20 The original CAM included several components: acute change in mental status with a fluctuating course and inattention, plus either disorganized thinking and/or altered level of consciousness. Multiple delirium assessment tools have been created and validated, all of which include inattention as a required feature. A recent hospital-based study using a two item bedside test asking the patient to name the day of the week and list the months of the year backwards detected delirium with a sensitivity of 93% and specificity of 64%.²¹ Once the diagnosis of delirium is established, evaluation should begin with a careful history and physical examination focused on the identification of risk factors such as physical restraints, indwelling urinary catheters, and drugs known to precipitate delirium, particularly those with withdrawal potential, anticholinergic properties, and sedative-hypnotic agents.^22-24 Delirium may be the first harbinger of serious medical illness and specific testing should be guided by clinical suspicion. In general, a thorough physical examination should look for focal neurologic deficits, hypoxia, signs of infection, and other inflammatory or painful processes that could precipitate delirium.²⁵ Targeted laboratory evaluation may include a basic metabolic panel to identify electrolyte (including calcium) and metabolic derangements, complete blood count, and urinalysis if infection is suspected.

• Use a validated instrument such as CAM to evaluate hospitalized patients who develop altered mental status.
• Delirious patients should undergo a thorough history including a review of medications, physical exam, and targeted laboratory testing aimed at identifying common risk factors and precipitants of delirium that should be addressed.
• Perform neuroimaging if there is a history of fall or head trauma in the preceding two weeks, any new focal abnormalities on neurologic exam or if the patient is receiving systemic anticoagulation.
• It may be reasonable to consider neuroimaging for patients with an atypical course of delirium, such as a sudden decline in the level of consciousness, persistence despite addressing identified factors, or if there is a high degree of suspicion for embolic or metastatic processes.

Performing neuroimaging in undifferentiated patients who develop delirium while hospitalized has a low diagnostic yield, is costly, and is potentially harmful. Neuroimaging should be reserved for those with identified risk factors for intracranial pathology. For the patient described in the initial vignette with no risk factors for intracranial cause, neuroimaging would be unlikely to contribute to her care. To change provider beliefs and behaviors regarding neuroimaging, prospective studies evaluating guideline implementation are needed. However, based on the current evidence, neuroimaging should be reserved for those with identified risk factors.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by e-mailing TWDFNR@hospitalmedicine.org.

Disclosures

The authors have no conflicts of interest relevant to this article to disclose.

Inspired by the ABIM Foundation’s Choosing Wisely® campaign, the “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A 67-year-old woman with a history of hypertension and osteoarthritis was hospitalized for fever, flank pain, and dysuria with pyuria on urinalysis. She was diagnosed with acute pyelonephritis and started ceftriaxone, ondansetron for nausea, and oxycodone for pain. On hospital day two, she developed acute confusion that waxed and waned in severity throughout the day. On examination, she appeared mildly agitated, inattentive, and was noted to pick at her linens and garment. She was oriented to person only and had a nonfocal neurologic examination. Her nurse reported no recent falls or trauma. As part of the patient’s evaluation, her attending physician ordered a head computed tomography (CT) scan.

Delirium is commonly diagnosed in hospitalized patients. It has a prevalence of 29%-64% and is associated with longer lengths of stay, higher mortality, and costs of over $164 billion per year in the United States.¹ While a number of practice guidelines have been created to help guide delirium diagnosis and management, there is not a clear consensus on when neuroimaging should be performed during the evaluation.^2-4 It should also be noted that numerous guidelines for delirium management exist, with variable quality and a heavy reliance on expert opinion.⁵ Perhaps due to this lack of consensus, neuroimaging is performed in 33% to 67% of hospitalized patients with delirium.^6,7

Delirium is known to be associated with intracranial processes. For example, delirium occurs in 13% to 48% of patients with acute stroke⁸ and conversely 7% of patients with new confusion evaluated in emergency departments or inpatient settings were found to have an acute stroke.⁹ The inclusion of neuroimaging as part of a delirium evaluation is supported in certain circumstances, such as in patients with recent falls, focal neurologic signs (including papilledema), systemic anticoagulation,² or increased risk of intracranial processes such as metastatic malignancy.⁴

A number of studies have evaluated the diagnostic yield of neuroimaging in hospitalized patients with delirium (Table).^6,7,10,11 Two studies included patients with delirium that developed after hospitalization^10,11 and two included patients with delirium at admission.^6,7

Theisen-Toupal et al. conducted a retrospective study of 220 hospitalized general medical patients who underwent head CT scans for an indication of delirium, altered mental status, confusion, encephalopathy, somnolence or unresponsiveness.¹⁰ Patients were excluded if they had a history of falls, head trauma, or new neurologic deficits in the preceding two weeks or if the admitting diagnosis was stroke or cerebral hemorrhage. Additionally, the authors limited patients to those who developed delirium 24 hours or more after admission. There were 6/220 (2.7%) patients identified with an acute intracranial process. Of these six patients, three were receiving anticoagulation. An additional 4/220 (1.8%) head CT scans were identified as equivocal, prompting further neuroimaging, which ultimately showed chronic findings.

Vijayakrishnan et al. performed a retrospective review of 400 hospitalized patients who underwent inpatient CT scans, then limited to those with new delirium.¹¹ They identified 36 patients, of which four (11%) had acute findings on CT: one case each of acute hemorrhage, subdural hematoma, brain metastases, and septic emboli. The authors state “all the four patients had preimaging clinical symptoms and signs, which warranted imaging as per guidelines suggested by the British Geriatrics Society and the Australian and New Zealand Society for Geriatric Medicine,” though they do not provide further details. The strength of this paper is that it isolated patients who developed delirium while hospitalized; however, conclusions were limited by the small sample size.

Lai et al.’s case-control study evaluated 300 consecutive patients admitted to a delirium unit over 18 months.⁶ Of these 300 patients, 200 (67%) had CT performed; 29/200 (14.5%) had intracranial findings on CT that explained their delirium, including 13 ischemic strokes, seven subdural hemorrhages, nine intracerebral hemorrhages, and three additional ischemic strokes that evolved on follow-up imaging but were not present on the initial scans. The authors performed univariate and multivariate analyses to identify risk factors for an intracranial cause of delirium. Only 3/29 patients with a positive scan did not have one of three main risk factors the authors identified: a fall in the preceding two weeks, new neurologic findings, or sudden deterioration of consciousness. It should be noted that authors did not define “deterioration of consciousness” and that all patients had confusion on admission to the unit, rather than developing during hospitalization.

Hijazi et al. conducted a retrospective cohort study over a 20-month period of 1,653 patients with delirium at the time of admission or during their hospitalization. Patients with delirium due to drug or medication withdrawal or “psychiatric reasons” were excluded. Overall, 538 (32.5%) patients underwent CT, MRI or both, and 78 (14.5%) patients had a positive finding on neuroimaging. This study’s 14.5 % overall yield matches that of Lai et al. Unfortunately, the study included all patients with delirium and did not report the rates of fall, neurologic deficits, and/or use of anticoagulation among those with positive neuroimaging. This limits the generalizability of the findings to a cohort of patients without intracranial pathology risk factors.

The reported yield of neuroimaging for hospitalized patients with delirium ranged from 2.7% to 14.5% across studies. However, in studies taking into account specific patient risk factors; the reported yields in patients without focal neurologic findings, new decline in mental status, systemic anticoagulation, or recent falls were 0%,¹¹ 1.4%,¹⁰ and 1.5%.⁶ While a rate of 1.5% may appear high for a serious outcome such as stroke or intracranial bleeding, it is comparable to rates reported for missed major cardiac events in clinical algorithms for evaluating chest pain.¹² It should also be noted that neuroimaging is imperfect for acute stroke, and thus the positive or negative predictive value may be poor in the setting of low prevalence. For example, for detection of any acute stroke, the sensitivity/specificity of MRI and CT are 83%/97% and 26%/98% respectively.¹³

Neuroimaging is expensive and has risks. The average charge for a head CT is approximately $1,400 at academic institutions.¹⁴ Moreover, computed tomography exposes patients to significant radiation and up to 2% of malignancies in the United States may be attributable to prior tomography exposure.¹⁵ Additionally, there are non-negligible rates of incidental findings during neuroimaging, 1% for CT¹⁶ and 2.7%-13.7% for MRI,^17,18 which may result in further evaluation or treatment that causes significant patient anxiety. Obtaining neuroimaging on delirious patients can be time consuming and labor intensive, which could delay care to other patients. Additionally, sedating medications are often administered to agitated patients prior to imaging, which risk worsening delirium. Ordering neuroimaging for all patients with acute delirium, therefore, exposes the large majority to unnecessary costs and potential harms.

The diagnostic yield of head CT in the evaluation of delirium is significantly higher in patients with specific risk factors. Lai et al. found adjusted odds ratios for abnormal CT of 18.2 in patients with new focal deficits, 5.6 with a fall in the preceding two weeks and 4.6 in patients with deterioration in consciousness. Patients with systemic anticoagulation had higher unadjusted, (OR 2.4) though not adjusted odds of having an abnormal CT.⁶ Thiesen-Toupal et al. excluded patients with recent falls or neurologic deficits but reported that three out of six delirious patients with abnormal neuroimaging were anticoagulated.¹⁰ Vijayakrishnan et al. found that all four delirious patients with intracranial findings met guideline criteria for neuroimaging.¹¹ Thus, current recommendations for neuroimaging in delirious patients with falls, focal neurologic deficits, or systemic anticoagulation are appropriate. In situations when a provider lacks an accurate history and is unable to determine if risk factors are present (for example a confused patient found sitting on the floor next to the bed), it may also be reasonable to consider neuroimaging.

Data are limited, but some authors advocate for neuroimaging in cases of delirium that do not improve with treatment.⁶ Additionally, it may be reasonable to consider neuroimaging in delirium patients with predispositions to embolic or metastatic intracranial processes such as endovascular infections and certain malignancies.⁴

Hospitalized patients with acute confusion should be assessed for delirium with a validated instrument such as the Confusion Assessment Method (CAM).^19,20 The original CAM included several components: acute change in mental status with a fluctuating course and inattention, plus either disorganized thinking and/or altered level of consciousness. Multiple delirium assessment tools have been created and validated, all of which include inattention as a required feature. A recent hospital-based study using a two item bedside test asking the patient to name the day of the week and list the months of the year backwards detected delirium with a sensitivity of 93% and specificity of 64%.²¹ Once the diagnosis of delirium is established, evaluation should begin with a careful history and physical examination focused on the identification of risk factors such as physical restraints, indwelling urinary catheters, and drugs known to precipitate delirium, particularly those with withdrawal potential, anticholinergic properties, and sedative-hypnotic agents.^22-24 Delirium may be the first harbinger of serious medical illness and specific testing should be guided by clinical suspicion. In general, a thorough physical examination should look for focal neurologic deficits, hypoxia, signs of infection, and other inflammatory or painful processes that could precipitate delirium.²⁵ Targeted laboratory evaluation may include a basic metabolic panel to identify electrolyte (including calcium) and metabolic derangements, complete blood count, and urinalysis if infection is suspected.

• Use a validated instrument such as CAM to evaluate hospitalized patients who develop altered mental status.
• Delirious patients should undergo a thorough history including a review of medications, physical exam, and targeted laboratory testing aimed at identifying common risk factors and precipitants of delirium that should be addressed.
• Perform neuroimaging if there is a history of fall or head trauma in the preceding two weeks, any new focal abnormalities on neurologic exam or if the patient is receiving systemic anticoagulation.
• It may be reasonable to consider neuroimaging for patients with an atypical course of delirium, such as a sudden decline in the level of consciousness, persistence despite addressing identified factors, or if there is a high degree of suspicion for embolic or metastatic processes.

Performing neuroimaging in undifferentiated patients who develop delirium while hospitalized has a low diagnostic yield, is costly, and is potentially harmful. Neuroimaging should be reserved for those with identified risk factors for intracranial pathology. For the patient described in the initial vignette with no risk factors for intracranial cause, neuroimaging would be unlikely to contribute to her care. To change provider beliefs and behaviors regarding neuroimaging, prospective studies evaluating guideline implementation are needed. However, based on the current evidence, neuroimaging should be reserved for those with identified risk factors.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by e-mailing TWDFNR@hospitalmedicine.org.

Disclosures

The authors have no conflicts of interest relevant to this article to disclose.

Inspired by the ABIM Foundation’s Choosing Wisely® campaign, the “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A 67-year-old woman with a history of hypertension and osteoarthritis was hospitalized for fever, flank pain, and dysuria with pyuria on urinalysis. She was diagnosed with acute pyelonephritis and started ceftriaxone, ondansetron for nausea, and oxycodone for pain. On hospital day two, she developed acute confusion that waxed and waned in severity throughout the day. On examination, she appeared mildly agitated, inattentive, and was noted to pick at her linens and garment. She was oriented to person only and had a nonfocal neurologic examination. Her nurse reported no recent falls or trauma. As part of the patient’s evaluation, her attending physician ordered a head computed tomography (CT) scan.

Delirium is commonly diagnosed in hospitalized patients. It has a prevalence of 29%-64% and is associated with longer lengths of stay, higher mortality, and costs of over $164 billion per year in the United States.¹ While a number of practice guidelines have been created to help guide delirium diagnosis and management, there is not a clear consensus on when neuroimaging should be performed during the evaluation.^2-4 It should also be noted that numerous guidelines for delirium management exist, with variable quality and a heavy reliance on expert opinion.⁵ Perhaps due to this lack of consensus, neuroimaging is performed in 33% to 67% of hospitalized patients with delirium.^6,7

Delirium is known to be associated with intracranial processes. For example, delirium occurs in 13% to 48% of patients with acute stroke⁸ and conversely 7% of patients with new confusion evaluated in emergency departments or inpatient settings were found to have an acute stroke.⁹ The inclusion of neuroimaging as part of a delirium evaluation is supported in certain circumstances, such as in patients with recent falls, focal neurologic signs (including papilledema), systemic anticoagulation,² or increased risk of intracranial processes such as metastatic malignancy.⁴

A number of studies have evaluated the diagnostic yield of neuroimaging in hospitalized patients with delirium (Table).^6,7,10,11 Two studies included patients with delirium that developed after hospitalization^10,11 and two included patients with delirium at admission.^6,7

Theisen-Toupal et al. conducted a retrospective study of 220 hospitalized general medical patients who underwent head CT scans for an indication of delirium, altered mental status, confusion, encephalopathy, somnolence or unresponsiveness.¹⁰ Patients were excluded if they had a history of falls, head trauma, or new neurologic deficits in the preceding two weeks or if the admitting diagnosis was stroke or cerebral hemorrhage. Additionally, the authors limited patients to those who developed delirium 24 hours or more after admission. There were 6/220 (2.7%) patients identified with an acute intracranial process. Of these six patients, three were receiving anticoagulation. An additional 4/220 (1.8%) head CT scans were identified as equivocal, prompting further neuroimaging, which ultimately showed chronic findings.

Vijayakrishnan et al. performed a retrospective review of 400 hospitalized patients who underwent inpatient CT scans, then limited to those with new delirium.¹¹ They identified 36 patients, of which four (11%) had acute findings on CT: one case each of acute hemorrhage, subdural hematoma, brain metastases, and septic emboli. The authors state “all the four patients had preimaging clinical symptoms and signs, which warranted imaging as per guidelines suggested by the British Geriatrics Society and the Australian and New Zealand Society for Geriatric Medicine,” though they do not provide further details. The strength of this paper is that it isolated patients who developed delirium while hospitalized; however, conclusions were limited by the small sample size.

Lai et al.’s case-control study evaluated 300 consecutive patients admitted to a delirium unit over 18 months.⁶ Of these 300 patients, 200 (67%) had CT performed; 29/200 (14.5%) had intracranial findings on CT that explained their delirium, including 13 ischemic strokes, seven subdural hemorrhages, nine intracerebral hemorrhages, and three additional ischemic strokes that evolved on follow-up imaging but were not present on the initial scans. The authors performed univariate and multivariate analyses to identify risk factors for an intracranial cause of delirium. Only 3/29 patients with a positive scan did not have one of three main risk factors the authors identified: a fall in the preceding two weeks, new neurologic findings, or sudden deterioration of consciousness. It should be noted that authors did not define “deterioration of consciousness” and that all patients had confusion on admission to the unit, rather than developing during hospitalization.

Hijazi et al. conducted a retrospective cohort study over a 20-month period of 1,653 patients with delirium at the time of admission or during their hospitalization. Patients with delirium due to drug or medication withdrawal or “psychiatric reasons” were excluded. Overall, 538 (32.5%) patients underwent CT, MRI or both, and 78 (14.5%) patients had a positive finding on neuroimaging. This study’s 14.5 % overall yield matches that of Lai et al. Unfortunately, the study included all patients with delirium and did not report the rates of fall, neurologic deficits, and/or use of anticoagulation among those with positive neuroimaging. This limits the generalizability of the findings to a cohort of patients without intracranial pathology risk factors.

The reported yield of neuroimaging for hospitalized patients with delirium ranged from 2.7% to 14.5% across studies. However, in studies taking into account specific patient risk factors; the reported yields in patients without focal neurologic findings, new decline in mental status, systemic anticoagulation, or recent falls were 0%,¹¹ 1.4%,¹⁰ and 1.5%.⁶ While a rate of 1.5% may appear high for a serious outcome such as stroke or intracranial bleeding, it is comparable to rates reported for missed major cardiac events in clinical algorithms for evaluating chest pain.¹² It should also be noted that neuroimaging is imperfect for acute stroke, and thus the positive or negative predictive value may be poor in the setting of low prevalence. For example, for detection of any acute stroke, the sensitivity/specificity of MRI and CT are 83%/97% and 26%/98% respectively.¹³

Neuroimaging is expensive and has risks. The average charge for a head CT is approximately $1,400 at academic institutions.¹⁴ Moreover, computed tomography exposes patients to significant radiation and up to 2% of malignancies in the United States may be attributable to prior tomography exposure.¹⁵ Additionally, there are non-negligible rates of incidental findings during neuroimaging, 1% for CT¹⁶ and 2.7%-13.7% for MRI,^17,18 which may result in further evaluation or treatment that causes significant patient anxiety. Obtaining neuroimaging on delirious patients can be time consuming and labor intensive, which could delay care to other patients. Additionally, sedating medications are often administered to agitated patients prior to imaging, which risk worsening delirium. Ordering neuroimaging for all patients with acute delirium, therefore, exposes the large majority to unnecessary costs and potential harms.

The diagnostic yield of head CT in the evaluation of delirium is significantly higher in patients with specific risk factors. Lai et al. found adjusted odds ratios for abnormal CT of 18.2 in patients with new focal deficits, 5.6 with a fall in the preceding two weeks and 4.6 in patients with deterioration in consciousness. Patients with systemic anticoagulation had higher unadjusted, (OR 2.4) though not adjusted odds of having an abnormal CT.⁶ Thiesen-Toupal et al. excluded patients with recent falls or neurologic deficits but reported that three out of six delirious patients with abnormal neuroimaging were anticoagulated.¹⁰ Vijayakrishnan et al. found that all four delirious patients with intracranial findings met guideline criteria for neuroimaging.¹¹ Thus, current recommendations for neuroimaging in delirious patients with falls, focal neurologic deficits, or systemic anticoagulation are appropriate. In situations when a provider lacks an accurate history and is unable to determine if risk factors are present (for example a confused patient found sitting on the floor next to the bed), it may also be reasonable to consider neuroimaging.

Data are limited, but some authors advocate for neuroimaging in cases of delirium that do not improve with treatment.⁶ Additionally, it may be reasonable to consider neuroimaging in delirium patients with predispositions to embolic or metastatic intracranial processes such as endovascular infections and certain malignancies.⁴

Hospitalized patients with acute confusion should be assessed for delirium with a validated instrument such as the Confusion Assessment Method (CAM).^19,20 The original CAM included several components: acute change in mental status with a fluctuating course and inattention, plus either disorganized thinking and/or altered level of consciousness. Multiple delirium assessment tools have been created and validated, all of which include inattention as a required feature. A recent hospital-based study using a two item bedside test asking the patient to name the day of the week and list the months of the year backwards detected delirium with a sensitivity of 93% and specificity of 64%.²¹ Once the diagnosis of delirium is established, evaluation should begin with a careful history and physical examination focused on the identification of risk factors such as physical restraints, indwelling urinary catheters, and drugs known to precipitate delirium, particularly those with withdrawal potential, anticholinergic properties, and sedative-hypnotic agents.^22-24 Delirium may be the first harbinger of serious medical illness and specific testing should be guided by clinical suspicion. In general, a thorough physical examination should look for focal neurologic deficits, hypoxia, signs of infection, and other inflammatory or painful processes that could precipitate delirium.²⁵ Targeted laboratory evaluation may include a basic metabolic panel to identify electrolyte (including calcium) and metabolic derangements, complete blood count, and urinalysis if infection is suspected.

• Use a validated instrument such as CAM to evaluate hospitalized patients who develop altered mental status.
• Delirious patients should undergo a thorough history including a review of medications, physical exam, and targeted laboratory testing aimed at identifying common risk factors and precipitants of delirium that should be addressed.
• Perform neuroimaging if there is a history of fall or head trauma in the preceding two weeks, any new focal abnormalities on neurologic exam or if the patient is receiving systemic anticoagulation.
• It may be reasonable to consider neuroimaging for patients with an atypical course of delirium, such as a sudden decline in the level of consciousness, persistence despite addressing identified factors, or if there is a high degree of suspicion for embolic or metastatic processes.

Performing neuroimaging in undifferentiated patients who develop delirium while hospitalized has a low diagnostic yield, is costly, and is potentially harmful. Neuroimaging should be reserved for those with identified risk factors for intracranial pathology. For the patient described in the initial vignette with no risk factors for intracranial cause, neuroimaging would be unlikely to contribute to her care. To change provider beliefs and behaviors regarding neuroimaging, prospective studies evaluating guideline implementation are needed. However, based on the current evidence, neuroimaging should be reserved for those with identified risk factors.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by e-mailing TWDFNR@hospitalmedicine.org.

Disclosures

The authors have no conflicts of interest relevant to this article to disclose.

A 46-year-old man presented to the emergency room in the postmonsoon month of September with a seven-day history of high fevers as well as a four-day history of a dry cough, dyspnea, and progressive rash. The patient reported no chest pain, hemoptysis, chest tightness, palpitations, wheezing, orthopnea, paroxysmal nocturnal dyspnea, or leg swelling. He lived and sought healthcare in Delhi, India.

Fever followed by a progressive but as yet uncharacterized rash and pulmonary symptoms in a middle-aged man suggests a host of possibilities. While it is tempting to ascribe his symptoms to an infectious process, especially a “tropical” infection based on his residence in Delhi, the location may simply represent a red herring. Potential infections can be divided into those endemic to the Indian subcontinent, and those encountered more globally. The former include diseases such as measles and dengue, while the latter include entities such as Mycoplasma pneumonia, varicella, and acute human immunodeficiency virus (HIV) infection. Noninfectious categories of diseases that should be considered include drug reactions and rheumatologic processes. Several rheumatologic diseases, including granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and systemic lupus erythematosus (SLE) may present with fever, rash, and pulmonary symptomatology.

A history of the patient’s exposures, both environmental and pharmaceutical, should be obtained. More information regarding his immunization history, rash characteristics (distribution and nature of the lesions), and other salient exam findings such as organomegaly and joint abnormalities will be helpful.

Fever reached a maximum of 103° Fahrenheit and was associated with chills but not rigors. There were several fever spikes daily, relieved completely with antipyretics. The patient’s dyspnea was predominantly noted on exertion, nonpleuritic, not temporally related to cough, and progressively worsening over three days. The skin lesions were first noticed on his trunk and were described as reddish, flat, and pinpoint size. However, the rash spread to the face and extremities sparing the palms and soles. There was no bleeding, nausea, vomiting, abdominal pain, change in bowel habits, dysuria, headache, photophobia, neck stiffness, or joint pain.

The patient reported no significant past medical history, took no medications, and had no recent travel outside of Delhi, India in the past year. He was married and monogamous. He had no pets nor did he report any contact with animals. He did not use tobacco, alcohol, or illicit substances. He did not remember being bitten by an insect. He worked as a software engineer. There was no history of similar illness in the patient’s family or at his workplace. He had no history of recent blood transfusion or immunization (including MMR and Tdap).

Several noninfectious and inflammatory conditions can explain his symptoms. Eosinophilic granulomatosis with polyangiitis is considerably less likely in the absence of asthma, and vasculitic processes, in general, are less likely given the nongravity dependent nature of the rash. SLE and sarcoidosis are possible causes of a systemic inflammatory illness presenting acutely with fever, rash, and pulmonary symptoms.

The patient’s expanded history makes several infections less likely. Although much of the presentation is consistent with measles, the initial appearance of the truncal rash is atypical, and there is no mention of coryza or conjunctivitis. Likewise, the description of the exanthem is not suggestive of varicella, and dengue and chikungunya are much less likely in the absence of a headache and arthralgias. Other infections including leptospirosis and scrub typhus are possible, and both might be contracted in greater Delhi. Typhoid is another infectious syndrome endemic to the Indian subcontinent that should be considered. The presence of rash involving the face and extremities would be highly atypical, however; and the presence of dyspnea and the absence of a headache argue against typhoid. Acute HIV infection and Mycoplasma pneumonia remain possible diagnoses. Toxic shock syndrome is possible, but a faster and fulminant course would be expected.

On physical examination, the temperature was 103° Fahrenheit, heart rate was 120 beats per minute and regular, respiratory rate was 24 breaths per minute, blood pressure was 100/60 mm Hg, and resting oxygen saturation was 93% while breathing ambient air. He appeared uncomfortable. Jugular venous pulse was elevated at 10 cm H₂O. Mild icterus was present, but there was neither conjunctival congestion nor subconjunctival hemorrhage. S1 and S2 heart sounds were loud, but there were no murmurs. Chest auscultation revealed bilateral basal coarse crackles. The abdominal right upper quadrant was mildly tender to palpation, and the liver edge was palpable 2 cm below the subcostal margin. There was neither splenomegaly nor peripheral lymphadenopathy. Kernig and Brudzinski signs were negative, and there were no focal neurological deficits. A generalized, nonpalpable, maculopapular and petechial rash was present on the face, extremities, and trunk.

The patient’s presentation must now incorporate the additional findings of bibasilar chest crackles, maculopapular/petechial rash, icterus, modest hypoxia, and hepatomegaly. Some of the noninfectious entities already mentioned (SLE and sarcoidosis) remain possible explanations. Hemophagocytic lymphohistiocytosis (HLH) may also explain most of the patient’s presenting signs and symptoms, and several other infectious diseases account for his presentation. Scrub typhus (or a more uncommon rickettsia disease, Indian tick typhus), leptospirosis, and perhaps infective endocarditis seem most likely to provide a unifying diagnosis for the symptoms mentioned above. Leptospirosis presents in a minority of instances as a severe illness known as Weil disease, characterized by several of this patient’s findings including icterus, kidney injury, and pulmonary symptoms. However, the rash is relatively uncommon in leptospirosis and when present, is usually more localized. The patient’s rash as described is not typically expected in infective endocarditis, although high-grade Staphylococcus aureus bacteremia will occasionally present with a diffuse rash that may be confused with that of meningococcemia. The etiology of the patient’s elevated jugular venous pressure is not readily apparent, with the cardiac examination making acute valvular insufficiency much less likely. Myocarditis, however, is possible in the setting of several of the diseases listed above, including leptospirosis, scrub typhus, SLE, and dengue.

In addition to basic laboratory studies and a chest radiograph, multiple sets of blood cultures should be obtained, along with a transthoracic echocardiogram and a ferritin level. The evidence to support leptospirosis and scrub typhus is strong enough to justify empiric use of doxycycline once the blood cultures are obtained, especially given the difficulty in definitively diagnosing these diseases in a timely fashion.

Laboratory analysis revealed a total leukocyte count of 13,600/uL (85% neutrophils), hemoglobin 10 g/dL, and platelet count 35,000/uL. Absolute eosinophil count was 136/uL. Serum chemistry showed sodium of 145 meq/L, potassium 4.1 meq/L, blood urea nitrogen 80 mg/dL, creatinine 1.6 mg/dL, aspartate transaminase (AST) 44 U/L (normal, 0-40), alanine transaminase (ALT) 81 U/L (normal, 0-40), direct bilirubin 3 mg/dL, and indirect bilirubin 3 mg/dL. Lactate dehydrogenase, alkaline phosphatase, albumin, and coagulation studies were normal. Erythrocyte sedimentation rate (ESR) was 42 mm (normal, 0-25) and highly sensitive C-reactive protein was 42 mg/L (normal, 0-10). Arterial blood gas on ambient air revealed a pH of 7.52, PaCO2 24 mm Hg, PaO2 55 mm Hg, and bicarbonate 20 meq/L. Urinalysis was normal. Blood cultures were obtained. Electrocardiogram (ECG) showed regular narrow complex tachycardia with incomplete left bundle branch block. Old ECGs were not available for comparison. Chest radiograph showed bilateral air space opacities with evidence of vein cephalization. Abdominal and pelvis ultrasonography showed pericholecystic fluid and mild hepatomegaly, but no free fluid, pleural effusion, or evidence of cholecystitis. Point of care immunochromatographic rapid malarial antigen detection test (detects Plasmodium falciparum, Plasmodium vivax, Plasmodium malaria, and Plasmodium ovale) was negative.

Most of the findings described are commonly observed in both scrub typhus and leptospirosis, including cytopenias, parenchymal infiltrates, hepatomegaly, elevated transaminases and bilirubin, cardiac involvement, fever, and rash. The rash described is more consistent with scrub typhus than with leptospirosis. The absence of a headache and joint findings argue modestly against these diagnoses. Likewise, HLH provides an adequate explanation for most of the patient’s symptoms, signs, and test results. These include fever, lung involvement, rash, hepatomegaly, elevated bilirubin, and cytopenias; however, leukocytosis and cardiac involvement are less characteristic. SLE also provides a satisfactory explanation for much of the symptoms, although the rash characteristics, normal urinalysis, and leukocytosis make this diagnosis less likely.

Additional testing that should be performed includes serum antinuclear antibody (ANA) and ferritin, since the latter may be markedly elevated in the setting of HLH. Bone marrow aspirate and biopsy should be performed looking specifically for evidence of hemophagocytosis. Finally, a transthoracic echocardiogram (TTE) should be performed to assess evidence of myocardial dysfunction as it may alter the therapeutic approach, although the results will be unlikely to differentiate between the preceding considerations.

Troponin I was negative, but N-terminal probrain natriuretic peptide was elevated at 20,000 pg/mL (normal, 0-900). D-dimer was negative. TTE showed left ventricular ejection fraction (LVEF) of 35% with global left ventricular hypokinesis. On three separate examinations, the peripheral blood smear did not show malarial parasites, atypical lymphocytes, or schistocytes. Three sets of blood cultures, testing for bacteria and fungi, were sterile. A throat culture was sterile. Widal test, as well as Leptospira and Mycoplasma serologies, were negative. Serology for Legionella pneumophila was positive, but the urinary antigen testing was negative. Antibodies to HIV 1 and 2 and anti-hepatitis C virus (HCV) antibody were negative. Dengue IgM ELISA (qualitative) returned positive.

Despite the absence of arthralgias, myalgias, headache, and retro-orbital pain, a positive dengue IgM ELISA supports acute dengue infection, provided the patient did not experience an unexplained febrile illness in the previous months. Most of his presentation may be explained by dengue, including fever, rash, liver abnormalities, myocardial dysfunction, and thrombocytopenia. The bilateral airspace opacities seen on chest radiograph also fit reasonably provided these actually reflect pulmonary edema. Leukocytosis (as opposed to leukopenia) is highly unexpected in dengue, but its presence could be an outlier.

If dengue does indeed explain the entire presentation, defervescence should have occurred by the time the blood cultures and serologic studies returned. Also, by that time, the patient would be expected to demonstrate evidence of improvement, barring the appearance of the serious complications of dengue hemorrhagic fever/dengue shock syndrome. Should fever persist and signs of recovery fail to materialize, the possibility of a superimposed process will need to be considered. Of note, the sensitivity of Leptospira serology early in the course of illness is low, and leptospirosis is thus not yet excluded.

A presumptive diagnosis of severe dengue fever was made, based on evidence of pulmonary edema and sepsis. The patient was managed conservatively with oral fluid restriction, low dose of diuretics, and supplemental oxygenation. The patient was also given levofloxacin for possible legionellosis. Despite these therapies, the patient had no improvement in 24 hours. His tachypnea increased, and his measured PaO2 to FIO2 (P:F) ratio decreased to 230 from 285 on admission. This prompted the initiation of BiPAP at 10 cm H2O inspiration PAP and 5 cm H2O expiration PAP. However, he did not tolerate BiPAP, and his P:F ratio decreased to below 200.

The patient was transferred to the intensive care unit and underwent elective intubation with mechanical ventilation. Axial and coronal computed tomography of the thorax (Figure 1A and 1B, respectively) showed extensive ground-glass opacities and consolidation sparing the nondependent portions of the lungs. On physical inspection, a round, well-defined, painless black lesion surrounded by erythema was noticed in the right axilla (Figure 2). The rest of the examination findings were unchanged.

The discovery of eschar in the axilla provides a “pivot point” in determining the cause of the patient’s illness. This finding appears to point, with high specificity, toward rickettsia as the explanation of the patient’s disease, and this is most likely to be scrub typhus. The report of a positive dengue IgM may represent concurrent infection or may simply reflect a recent infection in an area that is highly endemic for dengue. Although most of the patient’s clinical presentation could be attributed to dengue, multiple features including the leukocytosis, myocarditis, and elevated bilirubin are more likely to be seen in scrub typhus. In any event, dengue cannot satisfactorily explain the eschar.

No mention has been made to the initiation of doxycycline thus far; this agent needs to be started promptly. Polymerase chain reaction (PCR) testing for scrub typhus should be ordered if available; if not, acute and convalescent serology may be obtained.

Given the finding of axillary eschar, the patient was diagnosed with scrub typhus. Doxycycline 100 mg by nasogastric tube twice a day was initiated. The patient began to show marked symptomatic improvement. His P:F ratio improved, and he was successfully weaned off and extubated after 24 hours. Postextubation, he was kept on BiPAP for 12 hours. He was transferred out of the ICU and monitored for 72 hours. With therapy, his cytopenias, liver and renal function, and ECG normalized. Indirect immunofluorescence assay for scrub typhus returned positive at a dilution of > 1:512. PCR assay targeting the 56 kDa region of Orientia tsutsugamushi was also positive. Repeated TTE showed an LVEF of 65%. He was subsequently discharged with oral doxycycline and a plan to complete a course of 14 days on an outpatient basis. The final diagnosis was scrub typhus with myocarditis leading to acutely decompensated heart failure with reduced ejection fraction.

Scrub typhus is a mite-borne tropical infection caused by the gram-negative intracellular parasite Orientia tsutsugamushi from the Rickettsiaceae family that is known to occur in certain parts of Asia and Australia. Although this entity is well known in the Sub Himalayan belt and southern part of India, very few cases have been described in Delhi, the capital state in North India. Scrub typhus, like most other tropical infections, is found most often during the postmonsoon season.^1,2

Patients with scrub typhus present with fever in addition to a variety of nonspecific symptoms and findings. These often manifest within 10 days of being bitten by a mite. Malaise, headache, myalgias, lymphadenopathy, and maculopapular or petechial rash are common. If present, the rash manifests on the 3^rd to 5^th day of fever.³ Disseminated vasculitis due to scrub typhus can frequently result in multiorgan system involvement. Pulmonary involvement often leads to acute respiratory distress syndrome (ARDS) with an incidence of 8%-10%.^1,4 Acute kidney injury, mostly mild and nonoliguric, has been reported in up to 2/3 cases.^4-6 The cardiac myocyte is a known target cell affected by scrub typhus, and therefore patients commonly present with myocarditis.⁷ Liver involvement in scrub typhus is evident through elevated liver enzymes and can occur without other clinical evidence of the illness.^4,6,8,9 As in dengue, patients often develop thrombocytopenia, but normal hemoglobin in scrub typhus differentiates it from dengue.^6,8

Given the nonspecific presentation, it can be challenging to diagnose and treat scrub typhus. The gold standard for diagnosis is the detection of IgM antibodies to Orientia tsutsugamushi using an indirect immunofluorescence assay (IFA). For patients from endemic regions, it may be necessary to show a four-fold increase in titers two weeks apart to distinguish from background immunity. Presence of the characteristic eschar, as discussed below, is highly suggestive of scrub typhus. The treatment of choice is doxycycline or azithromycin for seven days.^10,11 Early initiation of doxycycline when considering either scrub typhus or leptospirosis is appropriate and may be life-saving.

Medical decision making is fraught with uncertainty, and physicians must use their experience, evidence base, and cognitive heuristics wisely to care for patients effectively. For this patient, the region of Delhi experiences massive outbreaks of dengue every year during the time the patient presented to the hospital, whereas rickettsia infections are relatively uncommon. The clinical presentation was conceivably consistent with either dengue or scrub typhus, though somewhat more suggestive of the latter. Once the serological diagnosis of recent or concomitant dengue was obtained, however, scrub typhus was considered even less. The team called upon Occam’s razor or the heuristic that the simplest and most unifying explanation for any given problem is the one most likely to be correct and that other, less satisfactory explanations (in this case, scrub typhus) are “shaven off.” The patient was managed conservatively for dengue. Only when his condition worsened did the team recognize this conflicting information without dismissing it, consider alternative possibilities, and reexamined the patient.

An eschar can be an important clue in the diagnosis of scrub typhus, though it is not often obvious. The presence of this necrotic skin lesion with black crust is highly suggestive of scrub typhus, and in the right clinical context, it is virtually diagnostic. However, it is uncommon (9.5%-45%) in most of the studies from the Indian subcontinent (ie, high specificity but low sensitivity).^1,12 An eschar is often found in obscure locations such as the axillae or groin, areas that may easily be missed or overlooked. Eschars may be seen in a variety of other infectious diseases, including rickettsia pox, Rocky Mountain spotted fever, other members of the spotted fever group, tularemia, and cutaneous anthrax. Given this patient’s lack of improvement, repeated examination revealed an eschar in the right axilla, a finding that was either missed or still evolving at the time of presentation.

This case illustrates the challenges in interpreting the significance of multiple positive serological tests in the context of an undifferentiated clinical syndrome. Possible reasons for a positive dengue serology could have been persistent antibodies from a previous infection, recent asymptomatic infection, concurrent infection, or cross-reactivity with flaviviruses such as West Nile Virus or Japanese Encephalitis.¹³ The patient also had positive IgM antibodies against Legionella pneumophila, but the urinary antigen was negative. In view of a negative antigen test, low specificity of the serologic test, low incidence of legionellosis in the Indian subcontinent, and absence of therapeutic response to a trial of fluoroquinolones, the diagnosis of legionellosis was considered unlikely in this patient.

With rapid advancements in technology, the importance of history taking and physical examination is at risk of being overshadowed. Approximately 80% of correct diagnoses in medicine can arrive through history and physical examination alone.^14,15 In this case, Occam’s razor combined with multiple serological tests was relied on to create the likely list of diagnoses. However, recognition of the limitations of these heuristics and tests proved critical. The life-saving diagnosis was only made when the clinicians returned to basics, looked in every nook and cranny, and found the eschar on physical examination.

• In patients living in endemic areas who present with an acute febrile illness, the differential diagnosis should include “tropical” infections such as dengue, chikungunya, enteric fever, leptospirosis, malaria, and scrub typhus.
• Serology is commonly employed for diagnosis of tropical infections, which may be misleading. These tests can be falsely positive from past asymptomatic infection or cross reactivity between antibodies, or falsely negative, as in the first few days of infection.
• Presence of eschar is a very useful clue in the diagnosis of scrub typhus, but this finding can be missed since it is often found in obscure locations. A thorough clinical history and physical examination are paramount.

Disclosures

The authors do not report any conflict of interest.

A 46-year-old man presented to the emergency room in the postmonsoon month of September with a seven-day history of high fevers as well as a four-day history of a dry cough, dyspnea, and progressive rash. The patient reported no chest pain, hemoptysis, chest tightness, palpitations, wheezing, orthopnea, paroxysmal nocturnal dyspnea, or leg swelling. He lived and sought healthcare in Delhi, India.

Fever followed by a progressive but as yet uncharacterized rash and pulmonary symptoms in a middle-aged man suggests a host of possibilities. While it is tempting to ascribe his symptoms to an infectious process, especially a “tropical” infection based on his residence in Delhi, the location may simply represent a red herring. Potential infections can be divided into those endemic to the Indian subcontinent, and those encountered more globally. The former include diseases such as measles and dengue, while the latter include entities such as Mycoplasma pneumonia, varicella, and acute human immunodeficiency virus (HIV) infection. Noninfectious categories of diseases that should be considered include drug reactions and rheumatologic processes. Several rheumatologic diseases, including granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and systemic lupus erythematosus (SLE) may present with fever, rash, and pulmonary symptomatology.

A history of the patient’s exposures, both environmental and pharmaceutical, should be obtained. More information regarding his immunization history, rash characteristics (distribution and nature of the lesions), and other salient exam findings such as organomegaly and joint abnormalities will be helpful.

Fever reached a maximum of 103° Fahrenheit and was associated with chills but not rigors. There were several fever spikes daily, relieved completely with antipyretics. The patient’s dyspnea was predominantly noted on exertion, nonpleuritic, not temporally related to cough, and progressively worsening over three days. The skin lesions were first noticed on his trunk and were described as reddish, flat, and pinpoint size. However, the rash spread to the face and extremities sparing the palms and soles. There was no bleeding, nausea, vomiting, abdominal pain, change in bowel habits, dysuria, headache, photophobia, neck stiffness, or joint pain.

The patient reported no significant past medical history, took no medications, and had no recent travel outside of Delhi, India in the past year. He was married and monogamous. He had no pets nor did he report any contact with animals. He did not use tobacco, alcohol, or illicit substances. He did not remember being bitten by an insect. He worked as a software engineer. There was no history of similar illness in the patient’s family or at his workplace. He had no history of recent blood transfusion or immunization (including MMR and Tdap).

Several noninfectious and inflammatory conditions can explain his symptoms. Eosinophilic granulomatosis with polyangiitis is considerably less likely in the absence of asthma, and vasculitic processes, in general, are less likely given the nongravity dependent nature of the rash. SLE and sarcoidosis are possible causes of a systemic inflammatory illness presenting acutely with fever, rash, and pulmonary symptoms.

The patient’s expanded history makes several infections less likely. Although much of the presentation is consistent with measles, the initial appearance of the truncal rash is atypical, and there is no mention of coryza or conjunctivitis. Likewise, the description of the exanthem is not suggestive of varicella, and dengue and chikungunya are much less likely in the absence of a headache and arthralgias. Other infections including leptospirosis and scrub typhus are possible, and both might be contracted in greater Delhi. Typhoid is another infectious syndrome endemic to the Indian subcontinent that should be considered. The presence of rash involving the face and extremities would be highly atypical, however; and the presence of dyspnea and the absence of a headache argue against typhoid. Acute HIV infection and Mycoplasma pneumonia remain possible diagnoses. Toxic shock syndrome is possible, but a faster and fulminant course would be expected.

On physical examination, the temperature was 103° Fahrenheit, heart rate was 120 beats per minute and regular, respiratory rate was 24 breaths per minute, blood pressure was 100/60 mm Hg, and resting oxygen saturation was 93% while breathing ambient air. He appeared uncomfortable. Jugular venous pulse was elevated at 10 cm H₂O. Mild icterus was present, but there was neither conjunctival congestion nor subconjunctival hemorrhage. S1 and S2 heart sounds were loud, but there were no murmurs. Chest auscultation revealed bilateral basal coarse crackles. The abdominal right upper quadrant was mildly tender to palpation, and the liver edge was palpable 2 cm below the subcostal margin. There was neither splenomegaly nor peripheral lymphadenopathy. Kernig and Brudzinski signs were negative, and there were no focal neurological deficits. A generalized, nonpalpable, maculopapular and petechial rash was present on the face, extremities, and trunk.

The patient’s presentation must now incorporate the additional findings of bibasilar chest crackles, maculopapular/petechial rash, icterus, modest hypoxia, and hepatomegaly. Some of the noninfectious entities already mentioned (SLE and sarcoidosis) remain possible explanations. Hemophagocytic lymphohistiocytosis (HLH) may also explain most of the patient’s presenting signs and symptoms, and several other infectious diseases account for his presentation. Scrub typhus (or a more uncommon rickettsia disease, Indian tick typhus), leptospirosis, and perhaps infective endocarditis seem most likely to provide a unifying diagnosis for the symptoms mentioned above. Leptospirosis presents in a minority of instances as a severe illness known as Weil disease, characterized by several of this patient’s findings including icterus, kidney injury, and pulmonary symptoms. However, the rash is relatively uncommon in leptospirosis and when present, is usually more localized. The patient’s rash as described is not typically expected in infective endocarditis, although high-grade Staphylococcus aureus bacteremia will occasionally present with a diffuse rash that may be confused with that of meningococcemia. The etiology of the patient’s elevated jugular venous pressure is not readily apparent, with the cardiac examination making acute valvular insufficiency much less likely. Myocarditis, however, is possible in the setting of several of the diseases listed above, including leptospirosis, scrub typhus, SLE, and dengue.

In addition to basic laboratory studies and a chest radiograph, multiple sets of blood cultures should be obtained, along with a transthoracic echocardiogram and a ferritin level. The evidence to support leptospirosis and scrub typhus is strong enough to justify empiric use of doxycycline once the blood cultures are obtained, especially given the difficulty in definitively diagnosing these diseases in a timely fashion.

Laboratory analysis revealed a total leukocyte count of 13,600/uL (85% neutrophils), hemoglobin 10 g/dL, and platelet count 35,000/uL. Absolute eosinophil count was 136/uL. Serum chemistry showed sodium of 145 meq/L, potassium 4.1 meq/L, blood urea nitrogen 80 mg/dL, creatinine 1.6 mg/dL, aspartate transaminase (AST) 44 U/L (normal, 0-40), alanine transaminase (ALT) 81 U/L (normal, 0-40), direct bilirubin 3 mg/dL, and indirect bilirubin 3 mg/dL. Lactate dehydrogenase, alkaline phosphatase, albumin, and coagulation studies were normal. Erythrocyte sedimentation rate (ESR) was 42 mm (normal, 0-25) and highly sensitive C-reactive protein was 42 mg/L (normal, 0-10). Arterial blood gas on ambient air revealed a pH of 7.52, PaCO2 24 mm Hg, PaO2 55 mm Hg, and bicarbonate 20 meq/L. Urinalysis was normal. Blood cultures were obtained. Electrocardiogram (ECG) showed regular narrow complex tachycardia with incomplete left bundle branch block. Old ECGs were not available for comparison. Chest radiograph showed bilateral air space opacities with evidence of vein cephalization. Abdominal and pelvis ultrasonography showed pericholecystic fluid and mild hepatomegaly, but no free fluid, pleural effusion, or evidence of cholecystitis. Point of care immunochromatographic rapid malarial antigen detection test (detects Plasmodium falciparum, Plasmodium vivax, Plasmodium malaria, and Plasmodium ovale) was negative.

Most of the findings described are commonly observed in both scrub typhus and leptospirosis, including cytopenias, parenchymal infiltrates, hepatomegaly, elevated transaminases and bilirubin, cardiac involvement, fever, and rash. The rash described is more consistent with scrub typhus than with leptospirosis. The absence of a headache and joint findings argue modestly against these diagnoses. Likewise, HLH provides an adequate explanation for most of the patient’s symptoms, signs, and test results. These include fever, lung involvement, rash, hepatomegaly, elevated bilirubin, and cytopenias; however, leukocytosis and cardiac involvement are less characteristic. SLE also provides a satisfactory explanation for much of the symptoms, although the rash characteristics, normal urinalysis, and leukocytosis make this diagnosis less likely.

Additional testing that should be performed includes serum antinuclear antibody (ANA) and ferritin, since the latter may be markedly elevated in the setting of HLH. Bone marrow aspirate and biopsy should be performed looking specifically for evidence of hemophagocytosis. Finally, a transthoracic echocardiogram (TTE) should be performed to assess evidence of myocardial dysfunction as it may alter the therapeutic approach, although the results will be unlikely to differentiate between the preceding considerations.

Troponin I was negative, but N-terminal probrain natriuretic peptide was elevated at 20,000 pg/mL (normal, 0-900). D-dimer was negative. TTE showed left ventricular ejection fraction (LVEF) of 35% with global left ventricular hypokinesis. On three separate examinations, the peripheral blood smear did not show malarial parasites, atypical lymphocytes, or schistocytes. Three sets of blood cultures, testing for bacteria and fungi, were sterile. A throat culture was sterile. Widal test, as well as Leptospira and Mycoplasma serologies, were negative. Serology for Legionella pneumophila was positive, but the urinary antigen testing was negative. Antibodies to HIV 1 and 2 and anti-hepatitis C virus (HCV) antibody were negative. Dengue IgM ELISA (qualitative) returned positive.

Despite the absence of arthralgias, myalgias, headache, and retro-orbital pain, a positive dengue IgM ELISA supports acute dengue infection, provided the patient did not experience an unexplained febrile illness in the previous months. Most of his presentation may be explained by dengue, including fever, rash, liver abnormalities, myocardial dysfunction, and thrombocytopenia. The bilateral airspace opacities seen on chest radiograph also fit reasonably provided these actually reflect pulmonary edema. Leukocytosis (as opposed to leukopenia) is highly unexpected in dengue, but its presence could be an outlier.

If dengue does indeed explain the entire presentation, defervescence should have occurred by the time the blood cultures and serologic studies returned. Also, by that time, the patient would be expected to demonstrate evidence of improvement, barring the appearance of the serious complications of dengue hemorrhagic fever/dengue shock syndrome. Should fever persist and signs of recovery fail to materialize, the possibility of a superimposed process will need to be considered. Of note, the sensitivity of Leptospira serology early in the course of illness is low, and leptospirosis is thus not yet excluded.

A presumptive diagnosis of severe dengue fever was made, based on evidence of pulmonary edema and sepsis. The patient was managed conservatively with oral fluid restriction, low dose of diuretics, and supplemental oxygenation. The patient was also given levofloxacin for possible legionellosis. Despite these therapies, the patient had no improvement in 24 hours. His tachypnea increased, and his measured PaO2 to FIO2 (P:F) ratio decreased to 230 from 285 on admission. This prompted the initiation of BiPAP at 10 cm H2O inspiration PAP and 5 cm H2O expiration PAP. However, he did not tolerate BiPAP, and his P:F ratio decreased to below 200.

The patient was transferred to the intensive care unit and underwent elective intubation with mechanical ventilation. Axial and coronal computed tomography of the thorax (Figure 1A and 1B, respectively) showed extensive ground-glass opacities and consolidation sparing the nondependent portions of the lungs. On physical inspection, a round, well-defined, painless black lesion surrounded by erythema was noticed in the right axilla (Figure 2). The rest of the examination findings were unchanged.

The discovery of eschar in the axilla provides a “pivot point” in determining the cause of the patient’s illness. This finding appears to point, with high specificity, toward rickettsia as the explanation of the patient’s disease, and this is most likely to be scrub typhus. The report of a positive dengue IgM may represent concurrent infection or may simply reflect a recent infection in an area that is highly endemic for dengue. Although most of the patient’s clinical presentation could be attributed to dengue, multiple features including the leukocytosis, myocarditis, and elevated bilirubin are more likely to be seen in scrub typhus. In any event, dengue cannot satisfactorily explain the eschar.

No mention has been made to the initiation of doxycycline thus far; this agent needs to be started promptly. Polymerase chain reaction (PCR) testing for scrub typhus should be ordered if available; if not, acute and convalescent serology may be obtained.

Given the finding of axillary eschar, the patient was diagnosed with scrub typhus. Doxycycline 100 mg by nasogastric tube twice a day was initiated. The patient began to show marked symptomatic improvement. His P:F ratio improved, and he was successfully weaned off and extubated after 24 hours. Postextubation, he was kept on BiPAP for 12 hours. He was transferred out of the ICU and monitored for 72 hours. With therapy, his cytopenias, liver and renal function, and ECG normalized. Indirect immunofluorescence assay for scrub typhus returned positive at a dilution of > 1:512. PCR assay targeting the 56 kDa region of Orientia tsutsugamushi was also positive. Repeated TTE showed an LVEF of 65%. He was subsequently discharged with oral doxycycline and a plan to complete a course of 14 days on an outpatient basis. The final diagnosis was scrub typhus with myocarditis leading to acutely decompensated heart failure with reduced ejection fraction.

Scrub typhus is a mite-borne tropical infection caused by the gram-negative intracellular parasite Orientia tsutsugamushi from the Rickettsiaceae family that is known to occur in certain parts of Asia and Australia. Although this entity is well known in the Sub Himalayan belt and southern part of India, very few cases have been described in Delhi, the capital state in North India. Scrub typhus, like most other tropical infections, is found most often during the postmonsoon season.^1,2

Patients with scrub typhus present with fever in addition to a variety of nonspecific symptoms and findings. These often manifest within 10 days of being bitten by a mite. Malaise, headache, myalgias, lymphadenopathy, and maculopapular or petechial rash are common. If present, the rash manifests on the 3^rd to 5^th day of fever.³ Disseminated vasculitis due to scrub typhus can frequently result in multiorgan system involvement. Pulmonary involvement often leads to acute respiratory distress syndrome (ARDS) with an incidence of 8%-10%.^1,4 Acute kidney injury, mostly mild and nonoliguric, has been reported in up to 2/3 cases.^4-6 The cardiac myocyte is a known target cell affected by scrub typhus, and therefore patients commonly present with myocarditis.⁷ Liver involvement in scrub typhus is evident through elevated liver enzymes and can occur without other clinical evidence of the illness.^4,6,8,9 As in dengue, patients often develop thrombocytopenia, but normal hemoglobin in scrub typhus differentiates it from dengue.^6,8

Given the nonspecific presentation, it can be challenging to diagnose and treat scrub typhus. The gold standard for diagnosis is the detection of IgM antibodies to Orientia tsutsugamushi using an indirect immunofluorescence assay (IFA). For patients from endemic regions, it may be necessary to show a four-fold increase in titers two weeks apart to distinguish from background immunity. Presence of the characteristic eschar, as discussed below, is highly suggestive of scrub typhus. The treatment of choice is doxycycline or azithromycin for seven days.^10,11 Early initiation of doxycycline when considering either scrub typhus or leptospirosis is appropriate and may be life-saving.

Medical decision making is fraught with uncertainty, and physicians must use their experience, evidence base, and cognitive heuristics wisely to care for patients effectively. For this patient, the region of Delhi experiences massive outbreaks of dengue every year during the time the patient presented to the hospital, whereas rickettsia infections are relatively uncommon. The clinical presentation was conceivably consistent with either dengue or scrub typhus, though somewhat more suggestive of the latter. Once the serological diagnosis of recent or concomitant dengue was obtained, however, scrub typhus was considered even less. The team called upon Occam’s razor or the heuristic that the simplest and most unifying explanation for any given problem is the one most likely to be correct and that other, less satisfactory explanations (in this case, scrub typhus) are “shaven off.” The patient was managed conservatively for dengue. Only when his condition worsened did the team recognize this conflicting information without dismissing it, consider alternative possibilities, and reexamined the patient.

An eschar can be an important clue in the diagnosis of scrub typhus, though it is not often obvious. The presence of this necrotic skin lesion with black crust is highly suggestive of scrub typhus, and in the right clinical context, it is virtually diagnostic. However, it is uncommon (9.5%-45%) in most of the studies from the Indian subcontinent (ie, high specificity but low sensitivity).^1,12 An eschar is often found in obscure locations such as the axillae or groin, areas that may easily be missed or overlooked. Eschars may be seen in a variety of other infectious diseases, including rickettsia pox, Rocky Mountain spotted fever, other members of the spotted fever group, tularemia, and cutaneous anthrax. Given this patient’s lack of improvement, repeated examination revealed an eschar in the right axilla, a finding that was either missed or still evolving at the time of presentation.

This case illustrates the challenges in interpreting the significance of multiple positive serological tests in the context of an undifferentiated clinical syndrome. Possible reasons for a positive dengue serology could have been persistent antibodies from a previous infection, recent asymptomatic infection, concurrent infection, or cross-reactivity with flaviviruses such as West Nile Virus or Japanese Encephalitis.¹³ The patient also had positive IgM antibodies against Legionella pneumophila, but the urinary antigen was negative. In view of a negative antigen test, low specificity of the serologic test, low incidence of legionellosis in the Indian subcontinent, and absence of therapeutic response to a trial of fluoroquinolones, the diagnosis of legionellosis was considered unlikely in this patient.

With rapid advancements in technology, the importance of history taking and physical examination is at risk of being overshadowed. Approximately 80% of correct diagnoses in medicine can arrive through history and physical examination alone.^14,15 In this case, Occam’s razor combined with multiple serological tests was relied on to create the likely list of diagnoses. However, recognition of the limitations of these heuristics and tests proved critical. The life-saving diagnosis was only made when the clinicians returned to basics, looked in every nook and cranny, and found the eschar on physical examination.

• In patients living in endemic areas who present with an acute febrile illness, the differential diagnosis should include “tropical” infections such as dengue, chikungunya, enteric fever, leptospirosis, malaria, and scrub typhus.
• Serology is commonly employed for diagnosis of tropical infections, which may be misleading. These tests can be falsely positive from past asymptomatic infection or cross reactivity between antibodies, or falsely negative, as in the first few days of infection.
• Presence of eschar is a very useful clue in the diagnosis of scrub typhus, but this finding can be missed since it is often found in obscure locations. A thorough clinical history and physical examination are paramount.

Disclosures

The authors do not report any conflict of interest.

A 46-year-old man presented to the emergency room in the postmonsoon month of September with a seven-day history of high fevers as well as a four-day history of a dry cough, dyspnea, and progressive rash. The patient reported no chest pain, hemoptysis, chest tightness, palpitations, wheezing, orthopnea, paroxysmal nocturnal dyspnea, or leg swelling. He lived and sought healthcare in Delhi, India.

Fever followed by a progressive but as yet uncharacterized rash and pulmonary symptoms in a middle-aged man suggests a host of possibilities. While it is tempting to ascribe his symptoms to an infectious process, especially a “tropical” infection based on his residence in Delhi, the location may simply represent a red herring. Potential infections can be divided into those endemic to the Indian subcontinent, and those encountered more globally. The former include diseases such as measles and dengue, while the latter include entities such as Mycoplasma pneumonia, varicella, and acute human immunodeficiency virus (HIV) infection. Noninfectious categories of diseases that should be considered include drug reactions and rheumatologic processes. Several rheumatologic diseases, including granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and systemic lupus erythematosus (SLE) may present with fever, rash, and pulmonary symptomatology.

A history of the patient’s exposures, both environmental and pharmaceutical, should be obtained. More information regarding his immunization history, rash characteristics (distribution and nature of the lesions), and other salient exam findings such as organomegaly and joint abnormalities will be helpful.

Fever reached a maximum of 103° Fahrenheit and was associated with chills but not rigors. There were several fever spikes daily, relieved completely with antipyretics. The patient’s dyspnea was predominantly noted on exertion, nonpleuritic, not temporally related to cough, and progressively worsening over three days. The skin lesions were first noticed on his trunk and were described as reddish, flat, and pinpoint size. However, the rash spread to the face and extremities sparing the palms and soles. There was no bleeding, nausea, vomiting, abdominal pain, change in bowel habits, dysuria, headache, photophobia, neck stiffness, or joint pain.

The patient reported no significant past medical history, took no medications, and had no recent travel outside of Delhi, India in the past year. He was married and monogamous. He had no pets nor did he report any contact with animals. He did not use tobacco, alcohol, or illicit substances. He did not remember being bitten by an insect. He worked as a software engineer. There was no history of similar illness in the patient’s family or at his workplace. He had no history of recent blood transfusion or immunization (including MMR and Tdap).

Several noninfectious and inflammatory conditions can explain his symptoms. Eosinophilic granulomatosis with polyangiitis is considerably less likely in the absence of asthma, and vasculitic processes, in general, are less likely given the nongravity dependent nature of the rash. SLE and sarcoidosis are possible causes of a systemic inflammatory illness presenting acutely with fever, rash, and pulmonary symptoms.

The patient’s expanded history makes several infections less likely. Although much of the presentation is consistent with measles, the initial appearance of the truncal rash is atypical, and there is no mention of coryza or conjunctivitis. Likewise, the description of the exanthem is not suggestive of varicella, and dengue and chikungunya are much less likely in the absence of a headache and arthralgias. Other infections including leptospirosis and scrub typhus are possible, and both might be contracted in greater Delhi. Typhoid is another infectious syndrome endemic to the Indian subcontinent that should be considered. The presence of rash involving the face and extremities would be highly atypical, however; and the presence of dyspnea and the absence of a headache argue against typhoid. Acute HIV infection and Mycoplasma pneumonia remain possible diagnoses. Toxic shock syndrome is possible, but a faster and fulminant course would be expected.

On physical examination, the temperature was 103° Fahrenheit, heart rate was 120 beats per minute and regular, respiratory rate was 24 breaths per minute, blood pressure was 100/60 mm Hg, and resting oxygen saturation was 93% while breathing ambient air. He appeared uncomfortable. Jugular venous pulse was elevated at 10 cm H₂O. Mild icterus was present, but there was neither conjunctival congestion nor subconjunctival hemorrhage. S1 and S2 heart sounds were loud, but there were no murmurs. Chest auscultation revealed bilateral basal coarse crackles. The abdominal right upper quadrant was mildly tender to palpation, and the liver edge was palpable 2 cm below the subcostal margin. There was neither splenomegaly nor peripheral lymphadenopathy. Kernig and Brudzinski signs were negative, and there were no focal neurological deficits. A generalized, nonpalpable, maculopapular and petechial rash was present on the face, extremities, and trunk.

The patient’s presentation must now incorporate the additional findings of bibasilar chest crackles, maculopapular/petechial rash, icterus, modest hypoxia, and hepatomegaly. Some of the noninfectious entities already mentioned (SLE and sarcoidosis) remain possible explanations. Hemophagocytic lymphohistiocytosis (HLH) may also explain most of the patient’s presenting signs and symptoms, and several other infectious diseases account for his presentation. Scrub typhus (or a more uncommon rickettsia disease, Indian tick typhus), leptospirosis, and perhaps infective endocarditis seem most likely to provide a unifying diagnosis for the symptoms mentioned above. Leptospirosis presents in a minority of instances as a severe illness known as Weil disease, characterized by several of this patient’s findings including icterus, kidney injury, and pulmonary symptoms. However, the rash is relatively uncommon in leptospirosis and when present, is usually more localized. The patient’s rash as described is not typically expected in infective endocarditis, although high-grade Staphylococcus aureus bacteremia will occasionally present with a diffuse rash that may be confused with that of meningococcemia. The etiology of the patient’s elevated jugular venous pressure is not readily apparent, with the cardiac examination making acute valvular insufficiency much less likely. Myocarditis, however, is possible in the setting of several of the diseases listed above, including leptospirosis, scrub typhus, SLE, and dengue.

In addition to basic laboratory studies and a chest radiograph, multiple sets of blood cultures should be obtained, along with a transthoracic echocardiogram and a ferritin level. The evidence to support leptospirosis and scrub typhus is strong enough to justify empiric use of doxycycline once the blood cultures are obtained, especially given the difficulty in definitively diagnosing these diseases in a timely fashion.

Laboratory analysis revealed a total leukocyte count of 13,600/uL (85% neutrophils), hemoglobin 10 g/dL, and platelet count 35,000/uL. Absolute eosinophil count was 136/uL. Serum chemistry showed sodium of 145 meq/L, potassium 4.1 meq/L, blood urea nitrogen 80 mg/dL, creatinine 1.6 mg/dL, aspartate transaminase (AST) 44 U/L (normal, 0-40), alanine transaminase (ALT) 81 U/L (normal, 0-40), direct bilirubin 3 mg/dL, and indirect bilirubin 3 mg/dL. Lactate dehydrogenase, alkaline phosphatase, albumin, and coagulation studies were normal. Erythrocyte sedimentation rate (ESR) was 42 mm (normal, 0-25) and highly sensitive C-reactive protein was 42 mg/L (normal, 0-10). Arterial blood gas on ambient air revealed a pH of 7.52, PaCO2 24 mm Hg, PaO2 55 mm Hg, and bicarbonate 20 meq/L. Urinalysis was normal. Blood cultures were obtained. Electrocardiogram (ECG) showed regular narrow complex tachycardia with incomplete left bundle branch block. Old ECGs were not available for comparison. Chest radiograph showed bilateral air space opacities with evidence of vein cephalization. Abdominal and pelvis ultrasonography showed pericholecystic fluid and mild hepatomegaly, but no free fluid, pleural effusion, or evidence of cholecystitis. Point of care immunochromatographic rapid malarial antigen detection test (detects Plasmodium falciparum, Plasmodium vivax, Plasmodium malaria, and Plasmodium ovale) was negative.

Most of the findings described are commonly observed in both scrub typhus and leptospirosis, including cytopenias, parenchymal infiltrates, hepatomegaly, elevated transaminases and bilirubin, cardiac involvement, fever, and rash. The rash described is more consistent with scrub typhus than with leptospirosis. The absence of a headache and joint findings argue modestly against these diagnoses. Likewise, HLH provides an adequate explanation for most of the patient’s symptoms, signs, and test results. These include fever, lung involvement, rash, hepatomegaly, elevated bilirubin, and cytopenias; however, leukocytosis and cardiac involvement are less characteristic. SLE also provides a satisfactory explanation for much of the symptoms, although the rash characteristics, normal urinalysis, and leukocytosis make this diagnosis less likely.

Additional testing that should be performed includes serum antinuclear antibody (ANA) and ferritin, since the latter may be markedly elevated in the setting of HLH. Bone marrow aspirate and biopsy should be performed looking specifically for evidence of hemophagocytosis. Finally, a transthoracic echocardiogram (TTE) should be performed to assess evidence of myocardial dysfunction as it may alter the therapeutic approach, although the results will be unlikely to differentiate between the preceding considerations.

Troponin I was negative, but N-terminal probrain natriuretic peptide was elevated at 20,000 pg/mL (normal, 0-900). D-dimer was negative. TTE showed left ventricular ejection fraction (LVEF) of 35% with global left ventricular hypokinesis. On three separate examinations, the peripheral blood smear did not show malarial parasites, atypical lymphocytes, or schistocytes. Three sets of blood cultures, testing for bacteria and fungi, were sterile. A throat culture was sterile. Widal test, as well as Leptospira and Mycoplasma serologies, were negative. Serology for Legionella pneumophila was positive, but the urinary antigen testing was negative. Antibodies to HIV 1 and 2 and anti-hepatitis C virus (HCV) antibody were negative. Dengue IgM ELISA (qualitative) returned positive.

Despite the absence of arthralgias, myalgias, headache, and retro-orbital pain, a positive dengue IgM ELISA supports acute dengue infection, provided the patient did not experience an unexplained febrile illness in the previous months. Most of his presentation may be explained by dengue, including fever, rash, liver abnormalities, myocardial dysfunction, and thrombocytopenia. The bilateral airspace opacities seen on chest radiograph also fit reasonably provided these actually reflect pulmonary edema. Leukocytosis (as opposed to leukopenia) is highly unexpected in dengue, but its presence could be an outlier.

If dengue does indeed explain the entire presentation, defervescence should have occurred by the time the blood cultures and serologic studies returned. Also, by that time, the patient would be expected to demonstrate evidence of improvement, barring the appearance of the serious complications of dengue hemorrhagic fever/dengue shock syndrome. Should fever persist and signs of recovery fail to materialize, the possibility of a superimposed process will need to be considered. Of note, the sensitivity of Leptospira serology early in the course of illness is low, and leptospirosis is thus not yet excluded.

A presumptive diagnosis of severe dengue fever was made, based on evidence of pulmonary edema and sepsis. The patient was managed conservatively with oral fluid restriction, low dose of diuretics, and supplemental oxygenation. The patient was also given levofloxacin for possible legionellosis. Despite these therapies, the patient had no improvement in 24 hours. His tachypnea increased, and his measured PaO2 to FIO2 (P:F) ratio decreased to 230 from 285 on admission. This prompted the initiation of BiPAP at 10 cm H2O inspiration PAP and 5 cm H2O expiration PAP. However, he did not tolerate BiPAP, and his P:F ratio decreased to below 200.

The patient was transferred to the intensive care unit and underwent elective intubation with mechanical ventilation. Axial and coronal computed tomography of the thorax (Figure 1A and 1B, respectively) showed extensive ground-glass opacities and consolidation sparing the nondependent portions of the lungs. On physical inspection, a round, well-defined, painless black lesion surrounded by erythema was noticed in the right axilla (Figure 2). The rest of the examination findings were unchanged.

The discovery of eschar in the axilla provides a “pivot point” in determining the cause of the patient’s illness. This finding appears to point, with high specificity, toward rickettsia as the explanation of the patient’s disease, and this is most likely to be scrub typhus. The report of a positive dengue IgM may represent concurrent infection or may simply reflect a recent infection in an area that is highly endemic for dengue. Although most of the patient’s clinical presentation could be attributed to dengue, multiple features including the leukocytosis, myocarditis, and elevated bilirubin are more likely to be seen in scrub typhus. In any event, dengue cannot satisfactorily explain the eschar.

No mention has been made to the initiation of doxycycline thus far; this agent needs to be started promptly. Polymerase chain reaction (PCR) testing for scrub typhus should be ordered if available; if not, acute and convalescent serology may be obtained.

Given the finding of axillary eschar, the patient was diagnosed with scrub typhus. Doxycycline 100 mg by nasogastric tube twice a day was initiated. The patient began to show marked symptomatic improvement. His P:F ratio improved, and he was successfully weaned off and extubated after 24 hours. Postextubation, he was kept on BiPAP for 12 hours. He was transferred out of the ICU and monitored for 72 hours. With therapy, his cytopenias, liver and renal function, and ECG normalized. Indirect immunofluorescence assay for scrub typhus returned positive at a dilution of > 1:512. PCR assay targeting the 56 kDa region of Orientia tsutsugamushi was also positive. Repeated TTE showed an LVEF of 65%. He was subsequently discharged with oral doxycycline and a plan to complete a course of 14 days on an outpatient basis. The final diagnosis was scrub typhus with myocarditis leading to acutely decompensated heart failure with reduced ejection fraction.

Scrub typhus is a mite-borne tropical infection caused by the gram-negative intracellular parasite Orientia tsutsugamushi from the Rickettsiaceae family that is known to occur in certain parts of Asia and Australia. Although this entity is well known in the Sub Himalayan belt and southern part of India, very few cases have been described in Delhi, the capital state in North India. Scrub typhus, like most other tropical infections, is found most often during the postmonsoon season.^1,2

Patients with scrub typhus present with fever in addition to a variety of nonspecific symptoms and findings. These often manifest within 10 days of being bitten by a mite. Malaise, headache, myalgias, lymphadenopathy, and maculopapular or petechial rash are common. If present, the rash manifests on the 3^rd to 5^th day of fever.³ Disseminated vasculitis due to scrub typhus can frequently result in multiorgan system involvement. Pulmonary involvement often leads to acute respiratory distress syndrome (ARDS) with an incidence of 8%-10%.^1,4 Acute kidney injury, mostly mild and nonoliguric, has been reported in up to 2/3 cases.^4-6 The cardiac myocyte is a known target cell affected by scrub typhus, and therefore patients commonly present with myocarditis.⁷ Liver involvement in scrub typhus is evident through elevated liver enzymes and can occur without other clinical evidence of the illness.^4,6,8,9 As in dengue, patients often develop thrombocytopenia, but normal hemoglobin in scrub typhus differentiates it from dengue.^6,8

Given the nonspecific presentation, it can be challenging to diagnose and treat scrub typhus. The gold standard for diagnosis is the detection of IgM antibodies to Orientia tsutsugamushi using an indirect immunofluorescence assay (IFA). For patients from endemic regions, it may be necessary to show a four-fold increase in titers two weeks apart to distinguish from background immunity. Presence of the characteristic eschar, as discussed below, is highly suggestive of scrub typhus. The treatment of choice is doxycycline or azithromycin for seven days.^10,11 Early initiation of doxycycline when considering either scrub typhus or leptospirosis is appropriate and may be life-saving.

Medical decision making is fraught with uncertainty, and physicians must use their experience, evidence base, and cognitive heuristics wisely to care for patients effectively. For this patient, the region of Delhi experiences massive outbreaks of dengue every year during the time the patient presented to the hospital, whereas rickettsia infections are relatively uncommon. The clinical presentation was conceivably consistent with either dengue or scrub typhus, though somewhat more suggestive of the latter. Once the serological diagnosis of recent or concomitant dengue was obtained, however, scrub typhus was considered even less. The team called upon Occam’s razor or the heuristic that the simplest and most unifying explanation for any given problem is the one most likely to be correct and that other, less satisfactory explanations (in this case, scrub typhus) are “shaven off.” The patient was managed conservatively for dengue. Only when his condition worsened did the team recognize this conflicting information without dismissing it, consider alternative possibilities, and reexamined the patient.

An eschar can be an important clue in the diagnosis of scrub typhus, though it is not often obvious. The presence of this necrotic skin lesion with black crust is highly suggestive of scrub typhus, and in the right clinical context, it is virtually diagnostic. However, it is uncommon (9.5%-45%) in most of the studies from the Indian subcontinent (ie, high specificity but low sensitivity).^1,12 An eschar is often found in obscure locations such as the axillae or groin, areas that may easily be missed or overlooked. Eschars may be seen in a variety of other infectious diseases, including rickettsia pox, Rocky Mountain spotted fever, other members of the spotted fever group, tularemia, and cutaneous anthrax. Given this patient’s lack of improvement, repeated examination revealed an eschar in the right axilla, a finding that was either missed or still evolving at the time of presentation.

This case illustrates the challenges in interpreting the significance of multiple positive serological tests in the context of an undifferentiated clinical syndrome. Possible reasons for a positive dengue serology could have been persistent antibodies from a previous infection, recent asymptomatic infection, concurrent infection, or cross-reactivity with flaviviruses such as West Nile Virus or Japanese Encephalitis.¹³ The patient also had positive IgM antibodies against Legionella pneumophila, but the urinary antigen was negative. In view of a negative antigen test, low specificity of the serologic test, low incidence of legionellosis in the Indian subcontinent, and absence of therapeutic response to a trial of fluoroquinolones, the diagnosis of legionellosis was considered unlikely in this patient.

With rapid advancements in technology, the importance of history taking and physical examination is at risk of being overshadowed. Approximately 80% of correct diagnoses in medicine can arrive through history and physical examination alone.^14,15 In this case, Occam’s razor combined with multiple serological tests was relied on to create the likely list of diagnoses. However, recognition of the limitations of these heuristics and tests proved critical. The life-saving diagnosis was only made when the clinicians returned to basics, looked in every nook and cranny, and found the eschar on physical examination.

• In patients living in endemic areas who present with an acute febrile illness, the differential diagnosis should include “tropical” infections such as dengue, chikungunya, enteric fever, leptospirosis, malaria, and scrub typhus.
• Serology is commonly employed for diagnosis of tropical infections, which may be misleading. These tests can be falsely positive from past asymptomatic infection or cross reactivity between antibodies, or falsely negative, as in the first few days of infection.
• Presence of eschar is a very useful clue in the diagnosis of scrub typhus, but this finding can be missed since it is often found in obscure locations. A thorough clinical history and physical examination are paramount.

Disclosures

The authors do not report any conflict of interest.

Millions of patients use urinary collection devices. For men, both indwelling and condom-style urinary catheters (known as “external catheters”) are commonly used. National infection prevention guidelines recommend condom catheters as a preferred alternative to indwelling catheters for patients without urinary retention^1,2 to reduce the risk of catheter-associated urinary tract infection (UTI). Unfortunately, little outcome data comparing condom catheters with indwelling urethral catheters exists. We therefore assessed the incidence of infectious and noninfectious complications in condom catheter and indwelling urethral catheter users.

Study Overview

As part of a larger prospective, observational study,³ we compared complications in patients who received a condom catheter during hospitalization with those in patients who received an indwelling urethral catheter. Hospitalized patients with either a condom catheter or indwelling urethral catheter were identified at two Veterans Affairs (VA) medical centers and followed for 30 days after initial catheter placement. Patient-reported data were collected during in-person patient interviews at baseline (within three days of catheter placement), and by in-person or phone interviews at 14 days and 30 days postplacement (Supplementary Appendix A and B). Questions were primarily closed-ended, except for a final question inviting open comments. Information about the catheter and any reported complications was also collected from electronic medical record documentation for each patient. Institutional review board approval was received from both participating study sites.

Data Collection and Inclusion Criteria

Hospitalized patients who had a condom or indwelling urethral catheter placed were eligible to participate if they met the following criteria: (1) were hospitalized on an acute care unit; (2) had a new condom catheter or indwelling urethral catheter placed during this hospital stay that was not present on admission; (3) had a device in place for three days or less; (4) were at least 18 years old; and (5) were able to speak English. Patients were excluded if they: (1) did not have the capacity to give consent or participate in the interview/assessment process; (2) refused to provide written informed consent to participate; or (3) had previously participated in this project.

As the larger study was focused on indwelling urethral catheter users, participants with a condom catheter were recruited from only one facility, while those with an indwelling urethral catheter were recruited from both hospitals. Indwelling catheter patients that had a possible contraindication to condom catheter use (such as urinary retention or perioperative use for a surgical procedure) were excluded to make the groups comparable. Any indication for condom catheterization was permitted.

Information about catheter-related complications was collected from two sources: directly from patients and through medical record review. Patients were interviewed at baseline and approximately 14 days and 30 days after catheter placement. The follow-up assessments asked patients about their symptoms and experience over the previous two weeks. We also conducted a medical record review covering the 30 days after initial catheter placement.

Study Measures

A patient was considered to have an infectious complication in the medical record review if a medical professional documented a UTI (for condom catheter patients) or catheter-associated UTI (for indwelling urethral catheter patients) in the medical record. Patients who either reported being told they had a UTI or reported they had fever, chills, burning with urination, urinary frequency, urinary urgency, or other symptoms suggestive of an infection that required the patient to see a doctor were considered to have a self-reported infectious complication. Noninfectious complications included symptoms such as pain or discomfort, trauma, a sense of urgency or bladder spasms, blood in their urine, leaking urine after catheter removal, and difficulty with starting or stopping a urine stream. Secondary outcomes focused on patient perspectives about their devices, including sexual function.

Data Analysis

The primary outcome was the percentage of patients who experienced a complication related to a urinary catheter during the 30 days after the catheter was initially placed. Comparisons by group—condom versus indwelling catheter—were conducted using chi-square tests (Fisher’s exact test when necessary) for categorical variables and the Student’s t-test for continuous variables. All analyses were performed using SAS (Cary, North Carolina). All statistical tests were two-sided with alpha set to .05.

RESULTS

Of the 76 patients invited to participate after having a condom catheter placed, 49 consented (64.5%). Of those, 36 had sufficient data for inclusion in this analysis. The comparison group consisted of 44 patients with an indwelling urethral catheter. There were no statistically significant differences between the two groups in terms of age, race, or ethnicity (Table 1). There were statistically significant differences in patient-reported reasons for catheter placement, but these were due to the exclusion criteria used for indwelling urethral catheter patients.

Both patient-reported and clinician-reported (ie, recorded in the patient’s medical record) outcomes are described in Table 2. In total, 80.6% of condom catheter users reported experiencing at least one catheter-related complication during the month after initial catheter placement compared with 88.6% of indwelling catheter users (P = .32). A similar number of condom catheter patients and indwelling urethral catheter patients experienced an infectious complication according to both self-report data (8.3% condom, 6.8% indwelling; P = .99) and medical record review (11.1% condom, 6.8% indwelling; P = .69).

At least one noninfectious complication was identified in 77.8% of condom catheter patients (28 of 36) and 88.6% of indwelling urethral catheter patients (39 of 44) using combined self-report and medical record review data (P = .19); most of these were based on self-reported data. Significantly fewer condom catheter patients reported complications during placement (eg, pain, discomfort, bleeding, or other trauma) compared with those with indwelling catheters (13.9% vs 43.2%, P < .001). Pain, discomfort, bleeding, or other trauma during catheter removal were commonly reported by both condom catheter and indwelling urethral catheter patients (40.9% vs 42.1%, respectively; P = .99).

Patient-reported noninfectious complications were often not documented in the medical record: 75.0% of condom catheter patients and 86.4% of indwelling catheter patients reported complications, in comparison with the 25.0% of condom catheter patients and 27.3% of indwelling urethral catheter patients with noninfectious complications identified during medical record review.

 

 

DISCUSSION

Our study revealed three important findings. First, noninfectious complications greatly outnumbered infectious complications, regardless of the device type. Second, condom catheter users reported significantly less pain related to placement of their device compared with the indwelling urethral catheter group. Finally, many patients reported complications that were not documented in the medical record.

The only randomized trial comparing these devices enrolled 75 men hospitalized at a single VA medical center and found that using a condom catheter rather than an indwelling catheter in patients without urinary retention lowered the composite endpoint of bacteriuria, symptomatic UTI, or death.⁴ Additionally, patients in this trial reported that the condom catheter was significantly more comfortable (90% vs 58%; P = .02) and less painful (5% vs 36%; P = .02) than the indwelling catheter,⁴ supporting a previous study in hospitalized male Veterans.⁵

Importantly, we included patient-reported complications that may be of concern to patients but inconsistently documented in the medical record. Pain associated with removal of both condom catheters and indwelling urethral catheters was reported in over 40% in both groups but was not documented in the medical record. One patient with a condom catheter described removal this way: “It got stuck on my hair, so was hard to get off…” Condom catheters also posed some issues with staying in place as has been previously described.⁶ As one condom catheter user said: “When I was laying down it was okay, but every time I moved around…it would slide off.”

Recent efforts to reduce catheter-associated UTI,^7-9 which have focused on reducing the use of indwelling urethral catheters,^10,11 have been relatively successful. Clinical policy makers should consider similar efforts to address the noninfectious harms of both catheter types. Such efforts could include further decreasing any type of catheter use along with improved training of those placing such devices.¹² Substantial improvement will require a systematic approach to surveilling noninfectious complications of both types of urinary catheters.

Our study has several limitations. First, we conducted the study at two VA hospitals; therefore, the results may not be generalizable to a non-VA population. Second, we only included 80 patients because we recruited a limited number of condom catheter users. Third, although we tried to compare two similar groups of patients, it is possible that indwelling catheter patients had greater morbidity, which necessitated the use of an indwelling catheter instead of a condom catheter. Finally, we found a large discrepancy between what our patients reported and the information gained from a review of their medical records. While complications reported by the patient may not constitute a medically defined complication, due to the well-known phenomenon of poor documentation of catheter complications in general,¹³ we believe that what patients report is important for understanding the full scope of potential problems.

Limitations notwithstanding, we provide comparison data between condom and indwelling urethral catheters. Condom catheter users reported significantly less pain related to initial placement of their device compared with those using an indwelling urethral catheter. For both devices, patients experienced noninfectious complications much more commonly than infectious ones, underscoring the need to systematically address such complications, perhaps through a surveillance system that includes the patient’s perspective. The patient’s voice is important and necessary in view of the apparent underreporting of noninfectious harms in the medical record.

 

 

Acknowledgments

The authors thank the following individuals who assisted with data collection for the study: Laura Dillon, Jeanaya McKinley, Laura Peña, Jason Mann, Marylena Rouse, Kathy Swalwell, Suzanne Winter, Jane Wong, and Debbie Zawol.

Disclaimer

The funding sources played no role in the design, conducting, or evaluation of this study. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Department of Veterans Affairs.

Millions of patients use urinary collection devices. For men, both indwelling and condom-style urinary catheters (known as “external catheters”) are commonly used. National infection prevention guidelines recommend condom catheters as a preferred alternative to indwelling catheters for patients without urinary retention^1,2 to reduce the risk of catheter-associated urinary tract infection (UTI). Unfortunately, little outcome data comparing condom catheters with indwelling urethral catheters exists. We therefore assessed the incidence of infectious and noninfectious complications in condom catheter and indwelling urethral catheter users.

Study Overview

As part of a larger prospective, observational study,³ we compared complications in patients who received a condom catheter during hospitalization with those in patients who received an indwelling urethral catheter. Hospitalized patients with either a condom catheter or indwelling urethral catheter were identified at two Veterans Affairs (VA) medical centers and followed for 30 days after initial catheter placement. Patient-reported data were collected during in-person patient interviews at baseline (within three days of catheter placement), and by in-person or phone interviews at 14 days and 30 days postplacement (Supplementary Appendix A and B). Questions were primarily closed-ended, except for a final question inviting open comments. Information about the catheter and any reported complications was also collected from electronic medical record documentation for each patient. Institutional review board approval was received from both participating study sites.

Data Collection and Inclusion Criteria

Hospitalized patients who had a condom or indwelling urethral catheter placed were eligible to participate if they met the following criteria: (1) were hospitalized on an acute care unit; (2) had a new condom catheter or indwelling urethral catheter placed during this hospital stay that was not present on admission; (3) had a device in place for three days or less; (4) were at least 18 years old; and (5) were able to speak English. Patients were excluded if they: (1) did not have the capacity to give consent or participate in the interview/assessment process; (2) refused to provide written informed consent to participate; or (3) had previously participated in this project.

As the larger study was focused on indwelling urethral catheter users, participants with a condom catheter were recruited from only one facility, while those with an indwelling urethral catheter were recruited from both hospitals. Indwelling catheter patients that had a possible contraindication to condom catheter use (such as urinary retention or perioperative use for a surgical procedure) were excluded to make the groups comparable. Any indication for condom catheterization was permitted.

Information about catheter-related complications was collected from two sources: directly from patients and through medical record review. Patients were interviewed at baseline and approximately 14 days and 30 days after catheter placement. The follow-up assessments asked patients about their symptoms and experience over the previous two weeks. We also conducted a medical record review covering the 30 days after initial catheter placement.

Study Measures

A patient was considered to have an infectious complication in the medical record review if a medical professional documented a UTI (for condom catheter patients) or catheter-associated UTI (for indwelling urethral catheter patients) in the medical record. Patients who either reported being told they had a UTI or reported they had fever, chills, burning with urination, urinary frequency, urinary urgency, or other symptoms suggestive of an infection that required the patient to see a doctor were considered to have a self-reported infectious complication. Noninfectious complications included symptoms such as pain or discomfort, trauma, a sense of urgency or bladder spasms, blood in their urine, leaking urine after catheter removal, and difficulty with starting or stopping a urine stream. Secondary outcomes focused on patient perspectives about their devices, including sexual function.

Data Analysis

The primary outcome was the percentage of patients who experienced a complication related to a urinary catheter during the 30 days after the catheter was initially placed. Comparisons by group—condom versus indwelling catheter—were conducted using chi-square tests (Fisher’s exact test when necessary) for categorical variables and the Student’s t-test for continuous variables. All analyses were performed using SAS (Cary, North Carolina). All statistical tests were two-sided with alpha set to .05.

RESULTS

Of the 76 patients invited to participate after having a condom catheter placed, 49 consented (64.5%). Of those, 36 had sufficient data for inclusion in this analysis. The comparison group consisted of 44 patients with an indwelling urethral catheter. There were no statistically significant differences between the two groups in terms of age, race, or ethnicity (Table 1). There were statistically significant differences in patient-reported reasons for catheter placement, but these were due to the exclusion criteria used for indwelling urethral catheter patients.

Both patient-reported and clinician-reported (ie, recorded in the patient’s medical record) outcomes are described in Table 2. In total, 80.6% of condom catheter users reported experiencing at least one catheter-related complication during the month after initial catheter placement compared with 88.6% of indwelling catheter users (P = .32). A similar number of condom catheter patients and indwelling urethral catheter patients experienced an infectious complication according to both self-report data (8.3% condom, 6.8% indwelling; P = .99) and medical record review (11.1% condom, 6.8% indwelling; P = .69).

At least one noninfectious complication was identified in 77.8% of condom catheter patients (28 of 36) and 88.6% of indwelling urethral catheter patients (39 of 44) using combined self-report and medical record review data (P = .19); most of these were based on self-reported data. Significantly fewer condom catheter patients reported complications during placement (eg, pain, discomfort, bleeding, or other trauma) compared with those with indwelling catheters (13.9% vs 43.2%, P < .001). Pain, discomfort, bleeding, or other trauma during catheter removal were commonly reported by both condom catheter and indwelling urethral catheter patients (40.9% vs 42.1%, respectively; P = .99).

Patient-reported noninfectious complications were often not documented in the medical record: 75.0% of condom catheter patients and 86.4% of indwelling catheter patients reported complications, in comparison with the 25.0% of condom catheter patients and 27.3% of indwelling urethral catheter patients with noninfectious complications identified during medical record review.

 

 

DISCUSSION

Our study revealed three important findings. First, noninfectious complications greatly outnumbered infectious complications, regardless of the device type. Second, condom catheter users reported significantly less pain related to placement of their device compared with the indwelling urethral catheter group. Finally, many patients reported complications that were not documented in the medical record.

The only randomized trial comparing these devices enrolled 75 men hospitalized at a single VA medical center and found that using a condom catheter rather than an indwelling catheter in patients without urinary retention lowered the composite endpoint of bacteriuria, symptomatic UTI, or death.⁴ Additionally, patients in this trial reported that the condom catheter was significantly more comfortable (90% vs 58%; P = .02) and less painful (5% vs 36%; P = .02) than the indwelling catheter,⁴ supporting a previous study in hospitalized male Veterans.⁵

Importantly, we included patient-reported complications that may be of concern to patients but inconsistently documented in the medical record. Pain associated with removal of both condom catheters and indwelling urethral catheters was reported in over 40% in both groups but was not documented in the medical record. One patient with a condom catheter described removal this way: “It got stuck on my hair, so was hard to get off…” Condom catheters also posed some issues with staying in place as has been previously described.⁶ As one condom catheter user said: “When I was laying down it was okay, but every time I moved around…it would slide off.”

Recent efforts to reduce catheter-associated UTI,^7-9 which have focused on reducing the use of indwelling urethral catheters,^10,11 have been relatively successful. Clinical policy makers should consider similar efforts to address the noninfectious harms of both catheter types. Such efforts could include further decreasing any type of catheter use along with improved training of those placing such devices.¹² Substantial improvement will require a systematic approach to surveilling noninfectious complications of both types of urinary catheters.

Our study has several limitations. First, we conducted the study at two VA hospitals; therefore, the results may not be generalizable to a non-VA population. Second, we only included 80 patients because we recruited a limited number of condom catheter users. Third, although we tried to compare two similar groups of patients, it is possible that indwelling catheter patients had greater morbidity, which necessitated the use of an indwelling catheter instead of a condom catheter. Finally, we found a large discrepancy between what our patients reported and the information gained from a review of their medical records. While complications reported by the patient may not constitute a medically defined complication, due to the well-known phenomenon of poor documentation of catheter complications in general,¹³ we believe that what patients report is important for understanding the full scope of potential problems.

Limitations notwithstanding, we provide comparison data between condom and indwelling urethral catheters. Condom catheter users reported significantly less pain related to initial placement of their device compared with those using an indwelling urethral catheter. For both devices, patients experienced noninfectious complications much more commonly than infectious ones, underscoring the need to systematically address such complications, perhaps through a surveillance system that includes the patient’s perspective. The patient’s voice is important and necessary in view of the apparent underreporting of noninfectious harms in the medical record.

 

 

Acknowledgments

The authors thank the following individuals who assisted with data collection for the study: Laura Dillon, Jeanaya McKinley, Laura Peña, Jason Mann, Marylena Rouse, Kathy Swalwell, Suzanne Winter, Jane Wong, and Debbie Zawol.

Disclaimer

The funding sources played no role in the design, conducting, or evaluation of this study. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Department of Veterans Affairs.

Millions of patients use urinary collection devices. For men, both indwelling and condom-style urinary catheters (known as “external catheters”) are commonly used. National infection prevention guidelines recommend condom catheters as a preferred alternative to indwelling catheters for patients without urinary retention^1,2 to reduce the risk of catheter-associated urinary tract infection (UTI). Unfortunately, little outcome data comparing condom catheters with indwelling urethral catheters exists. We therefore assessed the incidence of infectious and noninfectious complications in condom catheter and indwelling urethral catheter users.

Study Overview

As part of a larger prospective, observational study,³ we compared complications in patients who received a condom catheter during hospitalization with those in patients who received an indwelling urethral catheter. Hospitalized patients with either a condom catheter or indwelling urethral catheter were identified at two Veterans Affairs (VA) medical centers and followed for 30 days after initial catheter placement. Patient-reported data were collected during in-person patient interviews at baseline (within three days of catheter placement), and by in-person or phone interviews at 14 days and 30 days postplacement (Supplementary Appendix A and B). Questions were primarily closed-ended, except for a final question inviting open comments. Information about the catheter and any reported complications was also collected from electronic medical record documentation for each patient. Institutional review board approval was received from both participating study sites.

Data Collection and Inclusion Criteria

Hospitalized patients who had a condom or indwelling urethral catheter placed were eligible to participate if they met the following criteria: (1) were hospitalized on an acute care unit; (2) had a new condom catheter or indwelling urethral catheter placed during this hospital stay that was not present on admission; (3) had a device in place for three days or less; (4) were at least 18 years old; and (5) were able to speak English. Patients were excluded if they: (1) did not have the capacity to give consent or participate in the interview/assessment process; (2) refused to provide written informed consent to participate; or (3) had previously participated in this project.

As the larger study was focused on indwelling urethral catheter users, participants with a condom catheter were recruited from only one facility, while those with an indwelling urethral catheter were recruited from both hospitals. Indwelling catheter patients that had a possible contraindication to condom catheter use (such as urinary retention or perioperative use for a surgical procedure) were excluded to make the groups comparable. Any indication for condom catheterization was permitted.

Information about catheter-related complications was collected from two sources: directly from patients and through medical record review. Patients were interviewed at baseline and approximately 14 days and 30 days after catheter placement. The follow-up assessments asked patients about their symptoms and experience over the previous two weeks. We also conducted a medical record review covering the 30 days after initial catheter placement.

Study Measures

A patient was considered to have an infectious complication in the medical record review if a medical professional documented a UTI (for condom catheter patients) or catheter-associated UTI (for indwelling urethral catheter patients) in the medical record. Patients who either reported being told they had a UTI or reported they had fever, chills, burning with urination, urinary frequency, urinary urgency, or other symptoms suggestive of an infection that required the patient to see a doctor were considered to have a self-reported infectious complication. Noninfectious complications included symptoms such as pain or discomfort, trauma, a sense of urgency or bladder spasms, blood in their urine, leaking urine after catheter removal, and difficulty with starting or stopping a urine stream. Secondary outcomes focused on patient perspectives about their devices, including sexual function.

Data Analysis

The primary outcome was the percentage of patients who experienced a complication related to a urinary catheter during the 30 days after the catheter was initially placed. Comparisons by group—condom versus indwelling catheter—were conducted using chi-square tests (Fisher’s exact test when necessary) for categorical variables and the Student’s t-test for continuous variables. All analyses were performed using SAS (Cary, North Carolina). All statistical tests were two-sided with alpha set to .05.

RESULTS

Of the 76 patients invited to participate after having a condom catheter placed, 49 consented (64.5%). Of those, 36 had sufficient data for inclusion in this analysis. The comparison group consisted of 44 patients with an indwelling urethral catheter. There were no statistically significant differences between the two groups in terms of age, race, or ethnicity (Table 1). There were statistically significant differences in patient-reported reasons for catheter placement, but these were due to the exclusion criteria used for indwelling urethral catheter patients.

Both patient-reported and clinician-reported (ie, recorded in the patient’s medical record) outcomes are described in Table 2. In total, 80.6% of condom catheter users reported experiencing at least one catheter-related complication during the month after initial catheter placement compared with 88.6% of indwelling catheter users (P = .32). A similar number of condom catheter patients and indwelling urethral catheter patients experienced an infectious complication according to both self-report data (8.3% condom, 6.8% indwelling; P = .99) and medical record review (11.1% condom, 6.8% indwelling; P = .69).

At least one noninfectious complication was identified in 77.8% of condom catheter patients (28 of 36) and 88.6% of indwelling urethral catheter patients (39 of 44) using combined self-report and medical record review data (P = .19); most of these were based on self-reported data. Significantly fewer condom catheter patients reported complications during placement (eg, pain, discomfort, bleeding, or other trauma) compared with those with indwelling catheters (13.9% vs 43.2%, P < .001). Pain, discomfort, bleeding, or other trauma during catheter removal were commonly reported by both condom catheter and indwelling urethral catheter patients (40.9% vs 42.1%, respectively; P = .99).

Patient-reported noninfectious complications were often not documented in the medical record: 75.0% of condom catheter patients and 86.4% of indwelling catheter patients reported complications, in comparison with the 25.0% of condom catheter patients and 27.3% of indwelling urethral catheter patients with noninfectious complications identified during medical record review.

 

 

DISCUSSION

Our study revealed three important findings. First, noninfectious complications greatly outnumbered infectious complications, regardless of the device type. Second, condom catheter users reported significantly less pain related to placement of their device compared with the indwelling urethral catheter group. Finally, many patients reported complications that were not documented in the medical record.

The only randomized trial comparing these devices enrolled 75 men hospitalized at a single VA medical center and found that using a condom catheter rather than an indwelling catheter in patients without urinary retention lowered the composite endpoint of bacteriuria, symptomatic UTI, or death.⁴ Additionally, patients in this trial reported that the condom catheter was significantly more comfortable (90% vs 58%; P = .02) and less painful (5% vs 36%; P = .02) than the indwelling catheter,⁴ supporting a previous study in hospitalized male Veterans.⁵

Importantly, we included patient-reported complications that may be of concern to patients but inconsistently documented in the medical record. Pain associated with removal of both condom catheters and indwelling urethral catheters was reported in over 40% in both groups but was not documented in the medical record. One patient with a condom catheter described removal this way: “It got stuck on my hair, so was hard to get off…” Condom catheters also posed some issues with staying in place as has been previously described.⁶ As one condom catheter user said: “When I was laying down it was okay, but every time I moved around…it would slide off.”

Recent efforts to reduce catheter-associated UTI,^7-9 which have focused on reducing the use of indwelling urethral catheters,^10,11 have been relatively successful. Clinical policy makers should consider similar efforts to address the noninfectious harms of both catheter types. Such efforts could include further decreasing any type of catheter use along with improved training of those placing such devices.¹² Substantial improvement will require a systematic approach to surveilling noninfectious complications of both types of urinary catheters.

Our study has several limitations. First, we conducted the study at two VA hospitals; therefore, the results may not be generalizable to a non-VA population. Second, we only included 80 patients because we recruited a limited number of condom catheter users. Third, although we tried to compare two similar groups of patients, it is possible that indwelling catheter patients had greater morbidity, which necessitated the use of an indwelling catheter instead of a condom catheter. Finally, we found a large discrepancy between what our patients reported and the information gained from a review of their medical records. While complications reported by the patient may not constitute a medically defined complication, due to the well-known phenomenon of poor documentation of catheter complications in general,¹³ we believe that what patients report is important for understanding the full scope of potential problems.

Limitations notwithstanding, we provide comparison data between condom and indwelling urethral catheters. Condom catheter users reported significantly less pain related to initial placement of their device compared with those using an indwelling urethral catheter. For both devices, patients experienced noninfectious complications much more commonly than infectious ones, underscoring the need to systematically address such complications, perhaps through a surveillance system that includes the patient’s perspective. The patient’s voice is important and necessary in view of the apparent underreporting of noninfectious harms in the medical record.

 

 

Acknowledgments

The authors thank the following individuals who assisted with data collection for the study: Laura Dillon, Jeanaya McKinley, Laura Peña, Jason Mann, Marylena Rouse, Kathy Swalwell, Suzanne Winter, Jane Wong, and Debbie Zawol.

Disclaimer

The funding sources played no role in the design, conducting, or evaluation of this study. The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official position of the Department of Veterans Affairs.

Frailty is associated with adverse outcomes in hospitalized patients, including longer length of stay, increased risk of institutionalization at discharge, and higher rates of readmissions or death postdischarge.^1-4 Multiple tools have been developed to evaluate frailty and in an earlier study,⁴ we compared the three most common of these and demonstrated that the Clinical Frailty Scale (CFS)⁵ was the most useful tool clinically as it was most strongly associated with adverse events in the first 30 days after discharge. However, it must be collected prospectively and requires contact with patients or proxies for the evaluator to assign the patient into one of nine categories depending on their disease state, mobility, cognition, and ability to perform instrumental and functional activities of daily living. Recently, a new score has been described which is based on an administrative data algorithm that assigns points to patients having any of 109 ICD-10 codes listed for their index hospitalization and all hospitalizations in the prior two years and can be generated retrospectively without trained observers.⁶ Although higher Hospital Frailty Risk Scores (HFRS) were associated with greater risk of postdischarge adverse events, the kappa when compared with the CFS was only 0.30 (95% CI 0.22-0.38) in that study.⁶ However, as the HFRS was developed and validated in patients aged ≥75 years within the UK National Health Service, the authors themselves recommended that it be evaluated in other healthcare systems, other populations, and with comparison to prospectively collected frailty data from cumulative deficit models such as the CFS.

The aim of this study was to compare frailty assessments using the CFS and the HFRS in a population of adult patients hospitalized on general medical wards in North America to determine the impact on prevalence estimates and prediction of outcomes within the first 30 days after hospital discharge (a timeframe highlighted in the Affordable Care Act and used by Centers for Medicare & Medicaid Services as an important hospital quality indicator).

As described previously,⁷ we performed a prospective cohort study of adults without cognitive impairment or life expectancy less than three months being discharged back to the community (not to long-term care facilities) from general medical wards in two teaching hospitals in Edmonton, Alberta, between October 2013 and November 2014. All patients provided signed consent, and the University of Alberta Health Research Ethics board (project ID Pro00036880) approved the study.

Trained observers assessed each patient’s frailty status within 24 hours of discharge based on the patient’s best status in the week prior to becoming ill with the reason for the index hospitalization. The research assistant classified patients into one of the following nine CFS categories: very fit, well, managing well, vulnerable, mildly frail (need help with at least one instrumental activities of daily living such as shopping, finances, meal preparation, or housework), moderately frail (need help with one or two activities of daily living such as bathing and dressing), severely frail (dependent for personal care), very severely frail (bedbound), and terminally ill. According to the CFS validation studies, the last five categories were defined as frail for the purposes of our analyses.

Independent of the trained observer’s assessments, we calculated the HFRS for each participant in our cohort by linking to Alberta administrative data holdings within the Alberta Health Services Data Integration and Measurement Reporting unit and examining all diagnostic codes for the index hospitalization and any other hospitalizations in the prior two years for the 109 ICD-10 codes listed in the original HFRS paper and used the same score cutpoints as they reported (HFRS <5 being low risk, 5-15 defined as intermediate risk, and >15 as high risk for frailty; scores ≥5 were defined as frail).⁶

All patients were followed after discharge by research personnel blinded to the patient’s frailty assessment. We used patient/caregiver self-report and the provincial electronic health record to collect information on all-cause readmissions or mortality within 30 days.

We have previously reported^4,7 the association between frailty defined by the CFS and unplanned readmissions or death within 30 days of discharge but in this study, we examined the correlation between CFS-defined frailty and the HFRS score (classifying those with intermediate or high scores as frail) using chance-corrected kappa coefficients. We also compared the prognostic accuracy of both models for predicting death and/or unplanned readmissions within 30 days using the C statistic and the integrated discrimination improvement index and examined patients aged >65 years as a subgroup.⁸ We used SAS version 9.4 (SAS Institute, Cary, North Carolina) for analyses, with P values of <.05 considered as statistically significant.

Of the 499 patients in our original cohort,⁷ we could not link 10 to the administrative data to calculate HFRS, and thus this study sample is only 489 patients (mean age 64 years, 50% women, 52% older than 65 years, a mean of 4.9 comorbidities, and median length of stay five days).

Overall, 276 (56%) patients were deemed frail according to at least one assessment (214 [44%] on the HFRS [35% intermediate risk and 9% high risk] and 161 [33%] on the CFS), and 99 (20%) met both frailty definitions (Appendix Figure). Among the 252 patients aged >65 years, 66 (26%) met both frailty definitions and 166 (66%) were frail according to at least one assessment. Agreement between HFRS and the CFS (kappa 0.24, 95% CI 0.16-0.33) was poor. The CFS definition of frailty was 46% sensitive and 77% specific in classifying frail patients compared with HFRS-defined frailty.

As we reported earlier,⁴ patients deemed frail were generally similar across scales in that they were older, had more comorbidities, more prescriptions, longer lengths of stay, and poorer quality of life than nonfrail patients (all P < .01, Table 1). However, patients classified as frail on the HFRS only but not meeting the CFS definition were younger, had higher quality of life, and despite a similar Charlson Score and number of comorbidities were much more likely to have been living independently prior to admission than those classified as frail on the CFS.

We have demonstrated that the prevalence of frailty in patients being discharged from medical wards was high, with the HFRS (44%) being higher than the CFS (33%), and that only 46% of patients deemed frail on the HFRS were also deemed frail on the CFS. We confirm the report by the developers of the HFRS that there was poor correlation between the CFS cumulative deficit model and the administrative-data-based HFRS model in our cohort, even among those older than 65 years.

Previous studies have reported marked heterogeneity in prevalence estimates between different frailty instruments.^2,9 For example, Aguayo et al. found that the prevalence of frailty in the English Longitudinal Study of Aging varied between 0.9% and 68% depending on which of the 35 frailty scales they tested were used, although the prevalence with comprehensive geriatric assessments (the gold standard) was 14.9% (and 15.3% on the CFS).⁹ Although frail patients are at higher risk for death and/or readmission after discharge, other investigators have also reported similar findings to ours that frailty-based risk models are surprisingly modest at predicting postdischarge readmission or death, with the C statistics ranging between 0.52 and 0.57, although the CFS appears to correlate best with the gold standard of comprehensive geriatric assessment.^10-14 This is not surprising since the CFS is multidimensional and as a cumulative deficit model, it incorporates assessment of the patient’s underlying diseases, cognition, function, mobility, and mood in the assignment of their CFS level. Regardless, others¹⁵ have pointed out the need for studies such as ours to compare the validity of published frailty scales.

Despite our prospective cohort design and blinded endpoint ascertainment, there are some potential limitations to our study. First, we excluded long-term care residents and patients with foreshortened life expectancy – the frailest of the frail – from our analysis of 30-day outcomes, thereby potentially reducing the magnitude of the association between frailty and adverse outcomes. However, we were interested only in situations where clinicians were faced with equipoise about patient prognosis. Second, we assessed only 30-day readmissions or deaths and cannot comment on the impact of frailty definitions on other postdischarge outcomes (such as discharge locale or need for home care services) or other timeframes. Finally, although the association between the HFRS definition of frailty and the 30-day mortality/readmission was not statistically significant, the 95% confidence intervals were wide and thus we cannot definitively rule out a positive association.

In conclusion, considering that it had the strongest association with postdischarge outcomes and is the fastest and easiest to perform, the most useful of the frailty assessment tools for clinicians at the bedside still appears to be the CFS (both overall and in those patients who are elderly). However, for researchers who are analyzing data retrospectively or policy planners looking at health services data where the CFS was not collected, the HFRS holds promise for risk adjustment in population-level studies comparing processes and outcomes between hospitals.

Acknowledgments

The authors would like to acknowledge Miriam Fradette, Debbie Boyko, Sara Belga, Darren Lau, Jenelle Pederson, and Sharry Kahlon for their important contributions in data acquisition in our original cohort study, as well as all the physicians rotating through the general internal medicine wards at the University of Alberta Hospital for their help in identifying the patients. We also thank Dr. Simon Conroy, MB ChB PhD, University of Leicester, UK, for his helpful comments on an earlier draft of this manuscript.

Disclosures

The authors declare no conflicts of interest. All authors had access to the data and played a role in writing and revising this manuscript.

Funding

Funding for this study was provided by an operating grant from Alberta Innovates - Health Solutions. F.A.M. holds the Chair in Cardiovascular Outcomes Research at the Mazankowski Heart Institute, University of Alberta. The authors have no affiliations or financial interests with any organization or entity with a financial interest in the contents of this manuscript.

Frailty is associated with adverse outcomes in hospitalized patients, including longer length of stay, increased risk of institutionalization at discharge, and higher rates of readmissions or death postdischarge.^1-4 Multiple tools have been developed to evaluate frailty and in an earlier study,⁴ we compared the three most common of these and demonstrated that the Clinical Frailty Scale (CFS)⁵ was the most useful tool clinically as it was most strongly associated with adverse events in the first 30 days after discharge. However, it must be collected prospectively and requires contact with patients or proxies for the evaluator to assign the patient into one of nine categories depending on their disease state, mobility, cognition, and ability to perform instrumental and functional activities of daily living. Recently, a new score has been described which is based on an administrative data algorithm that assigns points to patients having any of 109 ICD-10 codes listed for their index hospitalization and all hospitalizations in the prior two years and can be generated retrospectively without trained observers.⁶ Although higher Hospital Frailty Risk Scores (HFRS) were associated with greater risk of postdischarge adverse events, the kappa when compared with the CFS was only 0.30 (95% CI 0.22-0.38) in that study.⁶ However, as the HFRS was developed and validated in patients aged ≥75 years within the UK National Health Service, the authors themselves recommended that it be evaluated in other healthcare systems, other populations, and with comparison to prospectively collected frailty data from cumulative deficit models such as the CFS.

The aim of this study was to compare frailty assessments using the CFS and the HFRS in a population of adult patients hospitalized on general medical wards in North America to determine the impact on prevalence estimates and prediction of outcomes within the first 30 days after hospital discharge (a timeframe highlighted in the Affordable Care Act and used by Centers for Medicare & Medicaid Services as an important hospital quality indicator).

As described previously,⁷ we performed a prospective cohort study of adults without cognitive impairment or life expectancy less than three months being discharged back to the community (not to long-term care facilities) from general medical wards in two teaching hospitals in Edmonton, Alberta, between October 2013 and November 2014. All patients provided signed consent, and the University of Alberta Health Research Ethics board (project ID Pro00036880) approved the study.

Trained observers assessed each patient’s frailty status within 24 hours of discharge based on the patient’s best status in the week prior to becoming ill with the reason for the index hospitalization. The research assistant classified patients into one of the following nine CFS categories: very fit, well, managing well, vulnerable, mildly frail (need help with at least one instrumental activities of daily living such as shopping, finances, meal preparation, or housework), moderately frail (need help with one or two activities of daily living such as bathing and dressing), severely frail (dependent for personal care), very severely frail (bedbound), and terminally ill. According to the CFS validation studies, the last five categories were defined as frail for the purposes of our analyses.

Independent of the trained observer’s assessments, we calculated the HFRS for each participant in our cohort by linking to Alberta administrative data holdings within the Alberta Health Services Data Integration and Measurement Reporting unit and examining all diagnostic codes for the index hospitalization and any other hospitalizations in the prior two years for the 109 ICD-10 codes listed in the original HFRS paper and used the same score cutpoints as they reported (HFRS <5 being low risk, 5-15 defined as intermediate risk, and >15 as high risk for frailty; scores ≥5 were defined as frail).⁶

All patients were followed after discharge by research personnel blinded to the patient’s frailty assessment. We used patient/caregiver self-report and the provincial electronic health record to collect information on all-cause readmissions or mortality within 30 days.

We have previously reported^4,7 the association between frailty defined by the CFS and unplanned readmissions or death within 30 days of discharge but in this study, we examined the correlation between CFS-defined frailty and the HFRS score (classifying those with intermediate or high scores as frail) using chance-corrected kappa coefficients. We also compared the prognostic accuracy of both models for predicting death and/or unplanned readmissions within 30 days using the C statistic and the integrated discrimination improvement index and examined patients aged >65 years as a subgroup.⁸ We used SAS version 9.4 (SAS Institute, Cary, North Carolina) for analyses, with P values of <.05 considered as statistically significant.

Of the 499 patients in our original cohort,⁷ we could not link 10 to the administrative data to calculate HFRS, and thus this study sample is only 489 patients (mean age 64 years, 50% women, 52% older than 65 years, a mean of 4.9 comorbidities, and median length of stay five days).

Overall, 276 (56%) patients were deemed frail according to at least one assessment (214 [44%] on the HFRS [35% intermediate risk and 9% high risk] and 161 [33%] on the CFS), and 99 (20%) met both frailty definitions (Appendix Figure). Among the 252 patients aged >65 years, 66 (26%) met both frailty definitions and 166 (66%) were frail according to at least one assessment. Agreement between HFRS and the CFS (kappa 0.24, 95% CI 0.16-0.33) was poor. The CFS definition of frailty was 46% sensitive and 77% specific in classifying frail patients compared with HFRS-defined frailty.

As we reported earlier,⁴ patients deemed frail were generally similar across scales in that they were older, had more comorbidities, more prescriptions, longer lengths of stay, and poorer quality of life than nonfrail patients (all P < .01, Table 1). However, patients classified as frail on the HFRS only but not meeting the CFS definition were younger, had higher quality of life, and despite a similar Charlson Score and number of comorbidities were much more likely to have been living independently prior to admission than those classified as frail on the CFS.

We have demonstrated that the prevalence of frailty in patients being discharged from medical wards was high, with the HFRS (44%) being higher than the CFS (33%), and that only 46% of patients deemed frail on the HFRS were also deemed frail on the CFS. We confirm the report by the developers of the HFRS that there was poor correlation between the CFS cumulative deficit model and the administrative-data-based HFRS model in our cohort, even among those older than 65 years.

Previous studies have reported marked heterogeneity in prevalence estimates between different frailty instruments.^2,9 For example, Aguayo et al. found that the prevalence of frailty in the English Longitudinal Study of Aging varied between 0.9% and 68% depending on which of the 35 frailty scales they tested were used, although the prevalence with comprehensive geriatric assessments (the gold standard) was 14.9% (and 15.3% on the CFS).⁹ Although frail patients are at higher risk for death and/or readmission after discharge, other investigators have also reported similar findings to ours that frailty-based risk models are surprisingly modest at predicting postdischarge readmission or death, with the C statistics ranging between 0.52 and 0.57, although the CFS appears to correlate best with the gold standard of comprehensive geriatric assessment.^10-14 This is not surprising since the CFS is multidimensional and as a cumulative deficit model, it incorporates assessment of the patient’s underlying diseases, cognition, function, mobility, and mood in the assignment of their CFS level. Regardless, others¹⁵ have pointed out the need for studies such as ours to compare the validity of published frailty scales.

Despite our prospective cohort design and blinded endpoint ascertainment, there are some potential limitations to our study. First, we excluded long-term care residents and patients with foreshortened life expectancy – the frailest of the frail – from our analysis of 30-day outcomes, thereby potentially reducing the magnitude of the association between frailty and adverse outcomes. However, we were interested only in situations where clinicians were faced with equipoise about patient prognosis. Second, we assessed only 30-day readmissions or deaths and cannot comment on the impact of frailty definitions on other postdischarge outcomes (such as discharge locale or need for home care services) or other timeframes. Finally, although the association between the HFRS definition of frailty and the 30-day mortality/readmission was not statistically significant, the 95% confidence intervals were wide and thus we cannot definitively rule out a positive association.

In conclusion, considering that it had the strongest association with postdischarge outcomes and is the fastest and easiest to perform, the most useful of the frailty assessment tools for clinicians at the bedside still appears to be the CFS (both overall and in those patients who are elderly). However, for researchers who are analyzing data retrospectively or policy planners looking at health services data where the CFS was not collected, the HFRS holds promise for risk adjustment in population-level studies comparing processes and outcomes between hospitals.

Acknowledgments

The authors would like to acknowledge Miriam Fradette, Debbie Boyko, Sara Belga, Darren Lau, Jenelle Pederson, and Sharry Kahlon for their important contributions in data acquisition in our original cohort study, as well as all the physicians rotating through the general internal medicine wards at the University of Alberta Hospital for their help in identifying the patients. We also thank Dr. Simon Conroy, MB ChB PhD, University of Leicester, UK, for his helpful comments on an earlier draft of this manuscript.

Disclosures

The authors declare no conflicts of interest. All authors had access to the data and played a role in writing and revising this manuscript.

Funding

Funding for this study was provided by an operating grant from Alberta Innovates - Health Solutions. F.A.M. holds the Chair in Cardiovascular Outcomes Research at the Mazankowski Heart Institute, University of Alberta. The authors have no affiliations or financial interests with any organization or entity with a financial interest in the contents of this manuscript.

Frailty is associated with adverse outcomes in hospitalized patients, including longer length of stay, increased risk of institutionalization at discharge, and higher rates of readmissions or death postdischarge.^1-4 Multiple tools have been developed to evaluate frailty and in an earlier study,⁴ we compared the three most common of these and demonstrated that the Clinical Frailty Scale (CFS)⁵ was the most useful tool clinically as it was most strongly associated with adverse events in the first 30 days after discharge. However, it must be collected prospectively and requires contact with patients or proxies for the evaluator to assign the patient into one of nine categories depending on their disease state, mobility, cognition, and ability to perform instrumental and functional activities of daily living. Recently, a new score has been described which is based on an administrative data algorithm that assigns points to patients having any of 109 ICD-10 codes listed for their index hospitalization and all hospitalizations in the prior two years and can be generated retrospectively without trained observers.⁶ Although higher Hospital Frailty Risk Scores (HFRS) were associated with greater risk of postdischarge adverse events, the kappa when compared with the CFS was only 0.30 (95% CI 0.22-0.38) in that study.⁶ However, as the HFRS was developed and validated in patients aged ≥75 years within the UK National Health Service, the authors themselves recommended that it be evaluated in other healthcare systems, other populations, and with comparison to prospectively collected frailty data from cumulative deficit models such as the CFS.

The aim of this study was to compare frailty assessments using the CFS and the HFRS in a population of adult patients hospitalized on general medical wards in North America to determine the impact on prevalence estimates and prediction of outcomes within the first 30 days after hospital discharge (a timeframe highlighted in the Affordable Care Act and used by Centers for Medicare & Medicaid Services as an important hospital quality indicator).

As described previously,⁷ we performed a prospective cohort study of adults without cognitive impairment or life expectancy less than three months being discharged back to the community (not to long-term care facilities) from general medical wards in two teaching hospitals in Edmonton, Alberta, between October 2013 and November 2014. All patients provided signed consent, and the University of Alberta Health Research Ethics board (project ID Pro00036880) approved the study.

Trained observers assessed each patient’s frailty status within 24 hours of discharge based on the patient’s best status in the week prior to becoming ill with the reason for the index hospitalization. The research assistant classified patients into one of the following nine CFS categories: very fit, well, managing well, vulnerable, mildly frail (need help with at least one instrumental activities of daily living such as shopping, finances, meal preparation, or housework), moderately frail (need help with one or two activities of daily living such as bathing and dressing), severely frail (dependent for personal care), very severely frail (bedbound), and terminally ill. According to the CFS validation studies, the last five categories were defined as frail for the purposes of our analyses.

Independent of the trained observer’s assessments, we calculated the HFRS for each participant in our cohort by linking to Alberta administrative data holdings within the Alberta Health Services Data Integration and Measurement Reporting unit and examining all diagnostic codes for the index hospitalization and any other hospitalizations in the prior two years for the 109 ICD-10 codes listed in the original HFRS paper and used the same score cutpoints as they reported (HFRS <5 being low risk, 5-15 defined as intermediate risk, and >15 as high risk for frailty; scores ≥5 were defined as frail).⁶

All patients were followed after discharge by research personnel blinded to the patient’s frailty assessment. We used patient/caregiver self-report and the provincial electronic health record to collect information on all-cause readmissions or mortality within 30 days.

We have previously reported^4,7 the association between frailty defined by the CFS and unplanned readmissions or death within 30 days of discharge but in this study, we examined the correlation between CFS-defined frailty and the HFRS score (classifying those with intermediate or high scores as frail) using chance-corrected kappa coefficients. We also compared the prognostic accuracy of both models for predicting death and/or unplanned readmissions within 30 days using the C statistic and the integrated discrimination improvement index and examined patients aged >65 years as a subgroup.⁸ We used SAS version 9.4 (SAS Institute, Cary, North Carolina) for analyses, with P values of <.05 considered as statistically significant.

Of the 499 patients in our original cohort,⁷ we could not link 10 to the administrative data to calculate HFRS, and thus this study sample is only 489 patients (mean age 64 years, 50% women, 52% older than 65 years, a mean of 4.9 comorbidities, and median length of stay five days).

Overall, 276 (56%) patients were deemed frail according to at least one assessment (214 [44%] on the HFRS [35% intermediate risk and 9% high risk] and 161 [33%] on the CFS), and 99 (20%) met both frailty definitions (Appendix Figure). Among the 252 patients aged >65 years, 66 (26%) met both frailty definitions and 166 (66%) were frail according to at least one assessment. Agreement between HFRS and the CFS (kappa 0.24, 95% CI 0.16-0.33) was poor. The CFS definition of frailty was 46% sensitive and 77% specific in classifying frail patients compared with HFRS-defined frailty.

As we reported earlier,⁴ patients deemed frail were generally similar across scales in that they were older, had more comorbidities, more prescriptions, longer lengths of stay, and poorer quality of life than nonfrail patients (all P < .01, Table 1). However, patients classified as frail on the HFRS only but not meeting the CFS definition were younger, had higher quality of life, and despite a similar Charlson Score and number of comorbidities were much more likely to have been living independently prior to admission than those classified as frail on the CFS.

We have demonstrated that the prevalence of frailty in patients being discharged from medical wards was high, with the HFRS (44%) being higher than the CFS (33%), and that only 46% of patients deemed frail on the HFRS were also deemed frail on the CFS. We confirm the report by the developers of the HFRS that there was poor correlation between the CFS cumulative deficit model and the administrative-data-based HFRS model in our cohort, even among those older than 65 years.

Previous studies have reported marked heterogeneity in prevalence estimates between different frailty instruments.^2,9 For example, Aguayo et al. found that the prevalence of frailty in the English Longitudinal Study of Aging varied between 0.9% and 68% depending on which of the 35 frailty scales they tested were used, although the prevalence with comprehensive geriatric assessments (the gold standard) was 14.9% (and 15.3% on the CFS).⁹ Although frail patients are at higher risk for death and/or readmission after discharge, other investigators have also reported similar findings to ours that frailty-based risk models are surprisingly modest at predicting postdischarge readmission or death, with the C statistics ranging between 0.52 and 0.57, although the CFS appears to correlate best with the gold standard of comprehensive geriatric assessment.^10-14 This is not surprising since the CFS is multidimensional and as a cumulative deficit model, it incorporates assessment of the patient’s underlying diseases, cognition, function, mobility, and mood in the assignment of their CFS level. Regardless, others¹⁵ have pointed out the need for studies such as ours to compare the validity of published frailty scales.

Despite our prospective cohort design and blinded endpoint ascertainment, there are some potential limitations to our study. First, we excluded long-term care residents and patients with foreshortened life expectancy – the frailest of the frail – from our analysis of 30-day outcomes, thereby potentially reducing the magnitude of the association between frailty and adverse outcomes. However, we were interested only in situations where clinicians were faced with equipoise about patient prognosis. Second, we assessed only 30-day readmissions or deaths and cannot comment on the impact of frailty definitions on other postdischarge outcomes (such as discharge locale or need for home care services) or other timeframes. Finally, although the association between the HFRS definition of frailty and the 30-day mortality/readmission was not statistically significant, the 95% confidence intervals were wide and thus we cannot definitively rule out a positive association.

In conclusion, considering that it had the strongest association with postdischarge outcomes and is the fastest and easiest to perform, the most useful of the frailty assessment tools for clinicians at the bedside still appears to be the CFS (both overall and in those patients who are elderly). However, for researchers who are analyzing data retrospectively or policy planners looking at health services data where the CFS was not collected, the HFRS holds promise for risk adjustment in population-level studies comparing processes and outcomes between hospitals.

Acknowledgments

The authors would like to acknowledge Miriam Fradette, Debbie Boyko, Sara Belga, Darren Lau, Jenelle Pederson, and Sharry Kahlon for their important contributions in data acquisition in our original cohort study, as well as all the physicians rotating through the general internal medicine wards at the University of Alberta Hospital for their help in identifying the patients. We also thank Dr. Simon Conroy, MB ChB PhD, University of Leicester, UK, for his helpful comments on an earlier draft of this manuscript.

Disclosures

The authors declare no conflicts of interest. All authors had access to the data and played a role in writing and revising this manuscript.

Funding

Funding for this study was provided by an operating grant from Alberta Innovates - Health Solutions. F.A.M. holds the Chair in Cardiovascular Outcomes Research at the Mazankowski Heart Institute, University of Alberta. The authors have no affiliations or financial interests with any organization or entity with a financial interest in the contents of this manuscript.

Inspired by the ABIM Foundation’s Choosing Wisely® campaign, the “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

An 80-year-old male—with a past medical history significant for hypertension, atrial fibrillation, and type II diabetes mellitus—presented to the hospital with fevers, confusion, and urinary outflow tract difficulties. On exam, he was noted to have mild suprapubic tenderness with flank tenderness. Blood and urine cultures grew Enterococcus faecalis sensitive to ampicillin. Because of the patient’s listed penicillin (PCN) allergy, he was started on aztreonam and vancomycin instead of ampicillin.

Ten percent of the population in the United States reports an allergy to penicillin and derivatives—one of the most commonly reported drug allergies.¹ Allergic reactions to drugs are distinct immune reactions mediated by drug-specific immunoglobulin E (IgE) that are potentially life-threatening. Specifically these allergic reactions are called IgE-mediated, type 1 hypersensitivity reactions which are characterized by hives; itching; flushing; tissue swelling, especially in areas of the face and neck; bronchospasm; and gastrointestinal (GI) symptoms, including cramping and diarrhea. Head and neck swelling can quickly result in airway compromise. Profound fluid extravasation and release of mediators from mast cells and basophils can rapidly drop blood pressure. Anaphylaxis requires rapid intervention to prevent severe complications and death. Given the life-threatening consequences of anaphylaxis, a cautious approach before administering PCN to PCN-allergic patients is mandatory.

WHY YOU SHOULD QUESTION A REPORTED PCN ALLERGY

While 10% of the adult population and 15% of hospitalized adults report PCN allergy, clinical studies suggest that 90% of all patients reporting a PCN allergy can tolerate PCN antibiotics.^1-3 There are several reasons patients initially labeled as PCN allergic may later be able to tolerate this drug. First, patients can lose sensitivity to specific PCN IgE antibodies over time if PCN is avoided.⁴ Second, non-IgE-mediated immune reactions of skin or GI tract are often wrongly attributed to an IgE-mediated process from a concurrent medication (Table). For example, viral infections can cause exanthems or hives which may be mistaken for an antibiotic-associated IgE-meditated allergic reaction.⁶ These non-IgE skin reactions include severe manifestations including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis or benign adverse reactions such as GI upset, dizziness, or diarrhea which are often misclassified as an allergy, and this error is perpetuated in the medical record. Third, patients may report a PCN allergy for themselves when a family member is possibly allergic.

PCN allergy has risen to the level of a public health issue as PCN-allergic patients are often relegated to second-line broad-spectrum antibiotics.⁷ This public health issue is exacerbated when patients with faux or resolved PCN allergy receive the same treatment. Patients labeled as PCN allergic—whether correctly or incorrectly—have poorer outcomes as noted by increased rates of serious infections and tend to have longer hospital stays.^8-10 Treatment-related secondary infections from the use of broad-spectrum antibiotics, such as Clostridiiodes difficile and vancomycin-resistant Enterococcus, are identified more frequently in PCN-allergic patients.⁷ Additionally, pregnant women with PCN allergy, with or without group B streptococcus infections, have higher rates of cesarean sections and longer hospitalizations.¹¹ The misuse and overuse of antibiotics, especially broad-spectrum medications, has led to resistant bacteria that are increasingly difficult to treat.⁷ Treating with the most narrow-spectrum antibiotic whenever possible is critical. Overall, failure to address and assess PCN allergy can result in treatment failures and unnecessary broad-spectrum antibiotic use.

Avoid beta-lactams for patients with a reported allergy who are medically frail (eg, critically ill intensive care unit patients and those unable to communicate) or have a documented allergic reaction to a beta-lactam within five years. An estimated 50% of patients who had a documented true IgE-mediated allergic reaction within five years of a documented true allergic reaction remain allergic to PCN and are at risk for an allergic reaction with reexposure.¹ PCN allergy evaluation with PCN skin testing (PST) and oral challenge in patients who had a reaction within five years have a higher risk of a fatal outcome with an oral challenge despite negative skin testing. PCN allergy evaluation is best handled on a case by case basis in this population.

Obtain a thorough drug allergy history. If the history is not consistent with a personal history of an IgE-mediated reaction to PCN ever or if there is documentation that PCN was administered and tolerated since the reaction (eg, a dental prescription), a PCN or beta-lactam can be given. An exception to this rule are patients with a history of an allergic reaction to both a cephalosporin and a PCN—approach this as two separate allergies. Remove the PCN allergy if it is not consistent with the history of IgE-mediated reaction or the patient subsequently had tolerated a PCN/PCN derivative. Regarding the cephalosporin issue, patients are often allergic to a side chain of the cephalosporin and not to the beta-lactam ring. Patients should avoid the specific cephalosporin unless the history is also not consistent with an IgE-mediated reaction or the patient had subsequently tolerated this medication. An allergy evaluation can be useful to discern next steps for cephalosporin allergy. Once the antibiotic is administered and tolerated, the medical record should be updated as well to prevent future mislabeling.

If the symptoms associated with a reported history of a PCN allergy are unknown or consistent with an IgE-mediated reaction, or the patient has not been exposed to PCN since the allergic reaction, the patient should undergo PST followed by a supervised oral test dose to determine whether the allergy exists or persists. PCN allergy evaluation is a simple two-step process of PST followed by an oral challenge of amoxicillin. The use of PCN allergy testing as described is validated and safe.¹² A negative skin prick and intradermal test have a negative predictive value that approaches 100%.^12,13 Completing the final step—the oral challenge—eliminates concerns for false-negative testing results and patient fears. Additionally, once a patient has had negative skin testing and passed an oral challenge, he/she is not at increased risk of resensitization after PCN/PCN derivative use.¹⁴

Although the test takes one and a half hours on average, the benefits that follow are lifelong. Improving future management by disproving a reported allergy affects an individual patient’s clinical course globally, results in cost savings, and increases the use of narrow-spectrum antimicrobials. It is particularly important to test PCN-allergic patients preemptively who are at high risk of requiring PCN/PCN derivative antibiotics. High-risk patients include, but are not limited to, surgery, transplant, hematology/oncology, and immunosuppressed patients. Inpatients with PCN allergy have higher antibiotic costs—both for medications used during their hospitalization and also for discharge medications.¹⁵ A study by Macy and Contreras compared the cost of skin testing to money saved by shortening hospitalization days for 51,582 patients with PCN allergy.⁷ The cost for testing was $131.37 each (total of $6.7 million). The testing contributed to a $64 million savings for the three-year study period—savings that is 9.5 times larger than the cost of the evaluation.⁸ A smaller study that looked at cost-effectiveness of PST for 50 patients found an overall cost savings of $11,005 due to the antimicrobial choice alone ($297 per patient switched to a beta-lactam antibiotic).¹⁶

• Obtain a thorough drug allergy history as many “allergic reactions” can be removed by history alone. Update the medical record if you can confirm a patient has since tolerated PCN or a PCN derivative to which they were previously allergic. Offer a supervised oral challenge if the patient has any concerns.
• Perform PST if a patient has a PCN allergy listed in their chart and the allergy history is unclear. A negative skin test should be followed by a supervised oral challenge to PCN/PCN derivative if skin testing is negative.
• Test PCN-allergic patients preemptively who are at high risk of requiring PCN/PCN derivative antibiotics. High-risk patients include surgery, transplant, hematology/oncology, and immunosuppressed patients.
• Implement published protocols from allergists for healthcare systems that lack access to allergy physicians.
• Do not perform PST on patients with a history that is suggestive of a non-IgE-mediated allergic reaction. For these cases, patients are advised to avoid the medication. A supervised graded oral challenge can be considered on a case by case basis if the reaction was not a severe cutaneous adverse reaction syndrome, like SJS, and the benefit of using the medication outweighs the potential harm.

CONCLUSION

The patient, in this case, reported an allergic reaction to PCN over 50 years before this presentation. The reported reaction immediately after receiving IV PCN was a rash—a symptom concerning for an IgE-mediated reaction. Since the patient is well over 10 years from his allergic reaction and would benefit from a PCN derivative, PST testing should be pursued.

The patient passed his skin testing and an oral challenge dose of amoxicillin. With the PCN allergy removed from his chart, his medical team transitioned him from aztreonam and vancomycin to ampicillin. He was then discharged home on amoxicillin and informed that he might be safely treated with PCN/PCN derivatives in the future.

Given the rise in antimicrobial resistance and both the clinical implications and increased costs associated with PCN allergy, it is crucial to offer an allergy evaluation to patients identified as PCN allergic. Hospitalists play a crucial role in obtaining the initial history, determining if the patient has tolerated the antibiotic since the initial reaction, and identifying patients who may benefit from further evaluation for PCN allergy. In hospitals with PST available for inpatients, testing can be performed during the admission. Additionally, it is essential that allergists work with hospitalists and primary care physicians to provide seamless access to outpatient drug allergy evaluations (PST followed by oral challenge) to address the issue of PCN allergy before an acute need for a PCN/PCN derivative antibiotic in the hospital.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by e-mailing TWDFNR@hospitalmedicine.org.

Disclosures

The authors have no conflicts of interest.

Funding

This work is supported by the following NIH Grant: T-32 AI007062-39.

Inspired by the ABIM Foundation’s Choosing Wisely® campaign, the “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

An 80-year-old male—with a past medical history significant for hypertension, atrial fibrillation, and type II diabetes mellitus—presented to the hospital with fevers, confusion, and urinary outflow tract difficulties. On exam, he was noted to have mild suprapubic tenderness with flank tenderness. Blood and urine cultures grew Enterococcus faecalis sensitive to ampicillin. Because of the patient’s listed penicillin (PCN) allergy, he was started on aztreonam and vancomycin instead of ampicillin.

Ten percent of the population in the United States reports an allergy to penicillin and derivatives—one of the most commonly reported drug allergies.¹ Allergic reactions to drugs are distinct immune reactions mediated by drug-specific immunoglobulin E (IgE) that are potentially life-threatening. Specifically these allergic reactions are called IgE-mediated, type 1 hypersensitivity reactions which are characterized by hives; itching; flushing; tissue swelling, especially in areas of the face and neck; bronchospasm; and gastrointestinal (GI) symptoms, including cramping and diarrhea. Head and neck swelling can quickly result in airway compromise. Profound fluid extravasation and release of mediators from mast cells and basophils can rapidly drop blood pressure. Anaphylaxis requires rapid intervention to prevent severe complications and death. Given the life-threatening consequences of anaphylaxis, a cautious approach before administering PCN to PCN-allergic patients is mandatory.

WHY YOU SHOULD QUESTION A REPORTED PCN ALLERGY

While 10% of the adult population and 15% of hospitalized adults report PCN allergy, clinical studies suggest that 90% of all patients reporting a PCN allergy can tolerate PCN antibiotics.^1-3 There are several reasons patients initially labeled as PCN allergic may later be able to tolerate this drug. First, patients can lose sensitivity to specific PCN IgE antibodies over time if PCN is avoided.⁴ Second, non-IgE-mediated immune reactions of skin or GI tract are often wrongly attributed to an IgE-mediated process from a concurrent medication (Table). For example, viral infections can cause exanthems or hives which may be mistaken for an antibiotic-associated IgE-meditated allergic reaction.⁶ These non-IgE skin reactions include severe manifestations including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis or benign adverse reactions such as GI upset, dizziness, or diarrhea which are often misclassified as an allergy, and this error is perpetuated in the medical record. Third, patients may report a PCN allergy for themselves when a family member is possibly allergic.

PCN allergy has risen to the level of a public health issue as PCN-allergic patients are often relegated to second-line broad-spectrum antibiotics.⁷ This public health issue is exacerbated when patients with faux or resolved PCN allergy receive the same treatment. Patients labeled as PCN allergic—whether correctly or incorrectly—have poorer outcomes as noted by increased rates of serious infections and tend to have longer hospital stays.^8-10 Treatment-related secondary infections from the use of broad-spectrum antibiotics, such as Clostridiiodes difficile and vancomycin-resistant Enterococcus, are identified more frequently in PCN-allergic patients.⁷ Additionally, pregnant women with PCN allergy, with or without group B streptococcus infections, have higher rates of cesarean sections and longer hospitalizations.¹¹ The misuse and overuse of antibiotics, especially broad-spectrum medications, has led to resistant bacteria that are increasingly difficult to treat.⁷ Treating with the most narrow-spectrum antibiotic whenever possible is critical. Overall, failure to address and assess PCN allergy can result in treatment failures and unnecessary broad-spectrum antibiotic use.

Avoid beta-lactams for patients with a reported allergy who are medically frail (eg, critically ill intensive care unit patients and those unable to communicate) or have a documented allergic reaction to a beta-lactam within five years. An estimated 50% of patients who had a documented true IgE-mediated allergic reaction within five years of a documented true allergic reaction remain allergic to PCN and are at risk for an allergic reaction with reexposure.¹ PCN allergy evaluation with PCN skin testing (PST) and oral challenge in patients who had a reaction within five years have a higher risk of a fatal outcome with an oral challenge despite negative skin testing. PCN allergy evaluation is best handled on a case by case basis in this population.

Obtain a thorough drug allergy history. If the history is not consistent with a personal history of an IgE-mediated reaction to PCN ever or if there is documentation that PCN was administered and tolerated since the reaction (eg, a dental prescription), a PCN or beta-lactam can be given. An exception to this rule are patients with a history of an allergic reaction to both a cephalosporin and a PCN—approach this as two separate allergies. Remove the PCN allergy if it is not consistent with the history of IgE-mediated reaction or the patient subsequently had tolerated a PCN/PCN derivative. Regarding the cephalosporin issue, patients are often allergic to a side chain of the cephalosporin and not to the beta-lactam ring. Patients should avoid the specific cephalosporin unless the history is also not consistent with an IgE-mediated reaction or the patient had subsequently tolerated this medication. An allergy evaluation can be useful to discern next steps for cephalosporin allergy. Once the antibiotic is administered and tolerated, the medical record should be updated as well to prevent future mislabeling.

If the symptoms associated with a reported history of a PCN allergy are unknown or consistent with an IgE-mediated reaction, or the patient has not been exposed to PCN since the allergic reaction, the patient should undergo PST followed by a supervised oral test dose to determine whether the allergy exists or persists. PCN allergy evaluation is a simple two-step process of PST followed by an oral challenge of amoxicillin. The use of PCN allergy testing as described is validated and safe.¹² A negative skin prick and intradermal test have a negative predictive value that approaches 100%.^12,13 Completing the final step—the oral challenge—eliminates concerns for false-negative testing results and patient fears. Additionally, once a patient has had negative skin testing and passed an oral challenge, he/she is not at increased risk of resensitization after PCN/PCN derivative use.¹⁴

Although the test takes one and a half hours on average, the benefits that follow are lifelong. Improving future management by disproving a reported allergy affects an individual patient’s clinical course globally, results in cost savings, and increases the use of narrow-spectrum antimicrobials. It is particularly important to test PCN-allergic patients preemptively who are at high risk of requiring PCN/PCN derivative antibiotics. High-risk patients include, but are not limited to, surgery, transplant, hematology/oncology, and immunosuppressed patients. Inpatients with PCN allergy have higher antibiotic costs—both for medications used during their hospitalization and also for discharge medications.¹⁵ A study by Macy and Contreras compared the cost of skin testing to money saved by shortening hospitalization days for 51,582 patients with PCN allergy.⁷ The cost for testing was $131.37 each (total of $6.7 million). The testing contributed to a $64 million savings for the three-year study period—savings that is 9.5 times larger than the cost of the evaluation.⁸ A smaller study that looked at cost-effectiveness of PST for 50 patients found an overall cost savings of $11,005 due to the antimicrobial choice alone ($297 per patient switched to a beta-lactam antibiotic).¹⁶

• Obtain a thorough drug allergy history as many “allergic reactions” can be removed by history alone. Update the medical record if you can confirm a patient has since tolerated PCN or a PCN derivative to which they were previously allergic. Offer a supervised oral challenge if the patient has any concerns.
• Perform PST if a patient has a PCN allergy listed in their chart and the allergy history is unclear. A negative skin test should be followed by a supervised oral challenge to PCN/PCN derivative if skin testing is negative.
• Test PCN-allergic patients preemptively who are at high risk of requiring PCN/PCN derivative antibiotics. High-risk patients include surgery, transplant, hematology/oncology, and immunosuppressed patients.
• Implement published protocols from allergists for healthcare systems that lack access to allergy physicians.
• Do not perform PST on patients with a history that is suggestive of a non-IgE-mediated allergic reaction. For these cases, patients are advised to avoid the medication. A supervised graded oral challenge can be considered on a case by case basis if the reaction was not a severe cutaneous adverse reaction syndrome, like SJS, and the benefit of using the medication outweighs the potential harm.

CONCLUSION

The patient, in this case, reported an allergic reaction to PCN over 50 years before this presentation. The reported reaction immediately after receiving IV PCN was a rash—a symptom concerning for an IgE-mediated reaction. Since the patient is well over 10 years from his allergic reaction and would benefit from a PCN derivative, PST testing should be pursued.

The patient passed his skin testing and an oral challenge dose of amoxicillin. With the PCN allergy removed from his chart, his medical team transitioned him from aztreonam and vancomycin to ampicillin. He was then discharged home on amoxicillin and informed that he might be safely treated with PCN/PCN derivatives in the future.

Given the rise in antimicrobial resistance and both the clinical implications and increased costs associated with PCN allergy, it is crucial to offer an allergy evaluation to patients identified as PCN allergic. Hospitalists play a crucial role in obtaining the initial history, determining if the patient has tolerated the antibiotic since the initial reaction, and identifying patients who may benefit from further evaluation for PCN allergy. In hospitals with PST available for inpatients, testing can be performed during the admission. Additionally, it is essential that allergists work with hospitalists and primary care physicians to provide seamless access to outpatient drug allergy evaluations (PST followed by oral challenge) to address the issue of PCN allergy before an acute need for a PCN/PCN derivative antibiotic in the hospital.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by e-mailing TWDFNR@hospitalmedicine.org.

Disclosures

The authors have no conflicts of interest.

Funding

This work is supported by the following NIH Grant: T-32 AI007062-39.

Inspired by the ABIM Foundation’s Choosing Wisely® campaign, the “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

An 80-year-old male—with a past medical history significant for hypertension, atrial fibrillation, and type II diabetes mellitus—presented to the hospital with fevers, confusion, and urinary outflow tract difficulties. On exam, he was noted to have mild suprapubic tenderness with flank tenderness. Blood and urine cultures grew Enterococcus faecalis sensitive to ampicillin. Because of the patient’s listed penicillin (PCN) allergy, he was started on aztreonam and vancomycin instead of ampicillin.

Ten percent of the population in the United States reports an allergy to penicillin and derivatives—one of the most commonly reported drug allergies.¹ Allergic reactions to drugs are distinct immune reactions mediated by drug-specific immunoglobulin E (IgE) that are potentially life-threatening. Specifically these allergic reactions are called IgE-mediated, type 1 hypersensitivity reactions which are characterized by hives; itching; flushing; tissue swelling, especially in areas of the face and neck; bronchospasm; and gastrointestinal (GI) symptoms, including cramping and diarrhea. Head and neck swelling can quickly result in airway compromise. Profound fluid extravasation and release of mediators from mast cells and basophils can rapidly drop blood pressure. Anaphylaxis requires rapid intervention to prevent severe complications and death. Given the life-threatening consequences of anaphylaxis, a cautious approach before administering PCN to PCN-allergic patients is mandatory.

WHY YOU SHOULD QUESTION A REPORTED PCN ALLERGY

While 10% of the adult population and 15% of hospitalized adults report PCN allergy, clinical studies suggest that 90% of all patients reporting a PCN allergy can tolerate PCN antibiotics.^1-3 There are several reasons patients initially labeled as PCN allergic may later be able to tolerate this drug. First, patients can lose sensitivity to specific PCN IgE antibodies over time if PCN is avoided.⁴ Second, non-IgE-mediated immune reactions of skin or GI tract are often wrongly attributed to an IgE-mediated process from a concurrent medication (Table). For example, viral infections can cause exanthems or hives which may be mistaken for an antibiotic-associated IgE-meditated allergic reaction.⁶ These non-IgE skin reactions include severe manifestations including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis or benign adverse reactions such as GI upset, dizziness, or diarrhea which are often misclassified as an allergy, and this error is perpetuated in the medical record. Third, patients may report a PCN allergy for themselves when a family member is possibly allergic.

PCN allergy has risen to the level of a public health issue as PCN-allergic patients are often relegated to second-line broad-spectrum antibiotics.⁷ This public health issue is exacerbated when patients with faux or resolved PCN allergy receive the same treatment. Patients labeled as PCN allergic—whether correctly or incorrectly—have poorer outcomes as noted by increased rates of serious infections and tend to have longer hospital stays.^8-10 Treatment-related secondary infections from the use of broad-spectrum antibiotics, such as Clostridiiodes difficile and vancomycin-resistant Enterococcus, are identified more frequently in PCN-allergic patients.⁷ Additionally, pregnant women with PCN allergy, with or without group B streptococcus infections, have higher rates of cesarean sections and longer hospitalizations.¹¹ The misuse and overuse of antibiotics, especially broad-spectrum medications, has led to resistant bacteria that are increasingly difficult to treat.⁷ Treating with the most narrow-spectrum antibiotic whenever possible is critical. Overall, failure to address and assess PCN allergy can result in treatment failures and unnecessary broad-spectrum antibiotic use.

Avoid beta-lactams for patients with a reported allergy who are medically frail (eg, critically ill intensive care unit patients and those unable to communicate) or have a documented allergic reaction to a beta-lactam within five years. An estimated 50% of patients who had a documented true IgE-mediated allergic reaction within five years of a documented true allergic reaction remain allergic to PCN and are at risk for an allergic reaction with reexposure.¹ PCN allergy evaluation with PCN skin testing (PST) and oral challenge in patients who had a reaction within five years have a higher risk of a fatal outcome with an oral challenge despite negative skin testing. PCN allergy evaluation is best handled on a case by case basis in this population.

Obtain a thorough drug allergy history. If the history is not consistent with a personal history of an IgE-mediated reaction to PCN ever or if there is documentation that PCN was administered and tolerated since the reaction (eg, a dental prescription), a PCN or beta-lactam can be given. An exception to this rule are patients with a history of an allergic reaction to both a cephalosporin and a PCN—approach this as two separate allergies. Remove the PCN allergy if it is not consistent with the history of IgE-mediated reaction or the patient subsequently had tolerated a PCN/PCN derivative. Regarding the cephalosporin issue, patients are often allergic to a side chain of the cephalosporin and not to the beta-lactam ring. Patients should avoid the specific cephalosporin unless the history is also not consistent with an IgE-mediated reaction or the patient had subsequently tolerated this medication. An allergy evaluation can be useful to discern next steps for cephalosporin allergy. Once the antibiotic is administered and tolerated, the medical record should be updated as well to prevent future mislabeling.

If the symptoms associated with a reported history of a PCN allergy are unknown or consistent with an IgE-mediated reaction, or the patient has not been exposed to PCN since the allergic reaction, the patient should undergo PST followed by a supervised oral test dose to determine whether the allergy exists or persists. PCN allergy evaluation is a simple two-step process of PST followed by an oral challenge of amoxicillin. The use of PCN allergy testing as described is validated and safe.¹² A negative skin prick and intradermal test have a negative predictive value that approaches 100%.^12,13 Completing the final step—the oral challenge—eliminates concerns for false-negative testing results and patient fears. Additionally, once a patient has had negative skin testing and passed an oral challenge, he/she is not at increased risk of resensitization after PCN/PCN derivative use.¹⁴

Although the test takes one and a half hours on average, the benefits that follow are lifelong. Improving future management by disproving a reported allergy affects an individual patient’s clinical course globally, results in cost savings, and increases the use of narrow-spectrum antimicrobials. It is particularly important to test PCN-allergic patients preemptively who are at high risk of requiring PCN/PCN derivative antibiotics. High-risk patients include, but are not limited to, surgery, transplant, hematology/oncology, and immunosuppressed patients. Inpatients with PCN allergy have higher antibiotic costs—both for medications used during their hospitalization and also for discharge medications.¹⁵ A study by Macy and Contreras compared the cost of skin testing to money saved by shortening hospitalization days for 51,582 patients with PCN allergy.⁷ The cost for testing was $131.37 each (total of $6.7 million). The testing contributed to a $64 million savings for the three-year study period—savings that is 9.5 times larger than the cost of the evaluation.⁸ A smaller study that looked at cost-effectiveness of PST for 50 patients found an overall cost savings of $11,005 due to the antimicrobial choice alone ($297 per patient switched to a beta-lactam antibiotic).¹⁶

• Obtain a thorough drug allergy history as many “allergic reactions” can be removed by history alone. Update the medical record if you can confirm a patient has since tolerated PCN or a PCN derivative to which they were previously allergic. Offer a supervised oral challenge if the patient has any concerns.
• Perform PST if a patient has a PCN allergy listed in their chart and the allergy history is unclear. A negative skin test should be followed by a supervised oral challenge to PCN/PCN derivative if skin testing is negative.
• Test PCN-allergic patients preemptively who are at high risk of requiring PCN/PCN derivative antibiotics. High-risk patients include surgery, transplant, hematology/oncology, and immunosuppressed patients.
• Implement published protocols from allergists for healthcare systems that lack access to allergy physicians.
• Do not perform PST on patients with a history that is suggestive of a non-IgE-mediated allergic reaction. For these cases, patients are advised to avoid the medication. A supervised graded oral challenge can be considered on a case by case basis if the reaction was not a severe cutaneous adverse reaction syndrome, like SJS, and the benefit of using the medication outweighs the potential harm.

CONCLUSION

The patient, in this case, reported an allergic reaction to PCN over 50 years before this presentation. The reported reaction immediately after receiving IV PCN was a rash—a symptom concerning for an IgE-mediated reaction. Since the patient is well over 10 years from his allergic reaction and would benefit from a PCN derivative, PST testing should be pursued.

The patient passed his skin testing and an oral challenge dose of amoxicillin. With the PCN allergy removed from his chart, his medical team transitioned him from aztreonam and vancomycin to ampicillin. He was then discharged home on amoxicillin and informed that he might be safely treated with PCN/PCN derivatives in the future.

Given the rise in antimicrobial resistance and both the clinical implications and increased costs associated with PCN allergy, it is crucial to offer an allergy evaluation to patients identified as PCN allergic. Hospitalists play a crucial role in obtaining the initial history, determining if the patient has tolerated the antibiotic since the initial reaction, and identifying patients who may benefit from further evaluation for PCN allergy. In hospitals with PST available for inpatients, testing can be performed during the admission. Additionally, it is essential that allergists work with hospitalists and primary care physicians to provide seamless access to outpatient drug allergy evaluations (PST followed by oral challenge) to address the issue of PCN allergy before an acute need for a PCN/PCN derivative antibiotic in the hospital.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason?” Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by e-mailing TWDFNR@hospitalmedicine.org.

Disclosures

The authors have no conflicts of interest.

Funding

This work is supported by the following NIH Grant: T-32 AI007062-39.

Potential advances in precision medicine could reshape multiple sclerosis care. Also today, the CDC has a plan to cut undiagnosed and untreated HIV, which patients who have diabetes benefit the most from long-term metformin, and why amlodopine may be the best choice for lowering blood pressure in black patients.
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Potential advances in precision medicine could reshape multiple sclerosis care. Also today, the CDC has a plan to cut undiagnosed and untreated HIV, which patients who have diabetes benefit the most from long-term metformin, and why amlodopine may be the best choice for lowering blood pressure in black patients.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

Potential advances in precision medicine could reshape multiple sclerosis care. Also today, the CDC has a plan to cut undiagnosed and untreated HIV, which patients who have diabetes benefit the most from long-term metformin, and why amlodopine may be the best choice for lowering blood pressure in black patients.
Amazon Alexa
Apple Podcasts
Google Podcasts
Spotify
 

The findings could lead the way to understanding the brain’s intake and output of energy in good health and bad and the part that alcohol plays.

In previous studies, the researchers have shown that alcohol significantly affects brain glucose metabolism, a measure of energy use, as well as regional brain activity, assessed through changes in blood oxygenation. But regional differences in glucose metabolism are hard to interpret, they say. In a study with healthy volunteers, they used brain imaging techniques to help quantify “match and mismatch” in energy consumption and expenditure across the brain—what they termed power and cost.

The researchers assessed power by observing to what extent brain regions are active and use energy, and cost by observing how brain regions expended energy. They found that different brain regions that serve distinct functions have “notably different power and different cost.”

Next, they tested a group of light drinkers and heavy drinkers and found both acute and chronic exposure to alcohol affected power and cost. In heavy drinkers, the researchers say, they saw less regional power, for example, in the thalamus, the sensory gateway, and frontal cortex. The researchers interpreted the decreases in power as reflecting the toxic effects of long-term exposure to alcohol on the brain cells.

They also found power dropped in the visual regions during acute alcohol exposure, which was related to disruption of visual processing. Visual regions also had the most significant drops in cost of activity during intoxication. That is consistent with the reliance of those regions on alternative energy sources, such as acetate (a byproduct of alcohol metabolism), the researchers say.

Their approach for characterizing brain energetic patterns related to alcohol use could be useful in other ways, the researchers say. “Studying energetic signatures of brain regions in different neuropsychiatric diseases is an important future direction,” said co-lead investigator Dr. Ehsan Schokri-Kojori. “The measures of power and cost may provide new multimodal biomarkers.”

The findings could lead the way to understanding the brain’s intake and output of energy in good health and bad and the part that alcohol plays.

In previous studies, the researchers have shown that alcohol significantly affects brain glucose metabolism, a measure of energy use, as well as regional brain activity, assessed through changes in blood oxygenation. But regional differences in glucose metabolism are hard to interpret, they say. In a study with healthy volunteers, they used brain imaging techniques to help quantify “match and mismatch” in energy consumption and expenditure across the brain—what they termed power and cost.

The researchers assessed power by observing to what extent brain regions are active and use energy, and cost by observing how brain regions expended energy. They found that different brain regions that serve distinct functions have “notably different power and different cost.”

Next, they tested a group of light drinkers and heavy drinkers and found both acute and chronic exposure to alcohol affected power and cost. In heavy drinkers, the researchers say, they saw less regional power, for example, in the thalamus, the sensory gateway, and frontal cortex. The researchers interpreted the decreases in power as reflecting the toxic effects of long-term exposure to alcohol on the brain cells.

They also found power dropped in the visual regions during acute alcohol exposure, which was related to disruption of visual processing. Visual regions also had the most significant drops in cost of activity during intoxication. That is consistent with the reliance of those regions on alternative energy sources, such as acetate (a byproduct of alcohol metabolism), the researchers say.

Their approach for characterizing brain energetic patterns related to alcohol use could be useful in other ways, the researchers say. “Studying energetic signatures of brain regions in different neuropsychiatric diseases is an important future direction,” said co-lead investigator Dr. Ehsan Schokri-Kojori. “The measures of power and cost may provide new multimodal biomarkers.”

The findings could lead the way to understanding the brain’s intake and output of energy in good health and bad and the part that alcohol plays.

In previous studies, the researchers have shown that alcohol significantly affects brain glucose metabolism, a measure of energy use, as well as regional brain activity, assessed through changes in blood oxygenation. But regional differences in glucose metabolism are hard to interpret, they say. In a study with healthy volunteers, they used brain imaging techniques to help quantify “match and mismatch” in energy consumption and expenditure across the brain—what they termed power and cost.

The researchers assessed power by observing to what extent brain regions are active and use energy, and cost by observing how brain regions expended energy. They found that different brain regions that serve distinct functions have “notably different power and different cost.”

Next, they tested a group of light drinkers and heavy drinkers and found both acute and chronic exposure to alcohol affected power and cost. In heavy drinkers, the researchers say, they saw less regional power, for example, in the thalamus, the sensory gateway, and frontal cortex. The researchers interpreted the decreases in power as reflecting the toxic effects of long-term exposure to alcohol on the brain cells.

They also found power dropped in the visual regions during acute alcohol exposure, which was related to disruption of visual processing. Visual regions also had the most significant drops in cost of activity during intoxication. That is consistent with the reliance of those regions on alternative energy sources, such as acetate (a byproduct of alcohol metabolism), the researchers say.

Their approach for characterizing brain energetic patterns related to alcohol use could be useful in other ways, the researchers say. “Studying energetic signatures of brain regions in different neuropsychiatric diseases is an important future direction,” said co-lead investigator Dr. Ehsan Schokri-Kojori. “The measures of power and cost may provide new multimodal biomarkers.”

Patients with a history of infection have nearly double the risk of developing Sjögren’s syndrome when compared with the general population (odds ratio, 1.9; 95% confidence interval, 1.6-2.3), according to new findings reported online March 20 in the Journal of Internal Medicine (doi: 10.1111/joim.12888).

The risk is almost three times higher among patients with a history of infection plus Ro/SSA and La/SSB antibodies (OR, 2.7; 95% CI, 2.0-3.5). The study included 945 Swedish patients with primary Sjögren’s syndrome and compared their data with those from 9,048 matched controls from the general population.

We previously covered results from this study when they were presented at the International Symposium on Sjögren’s Syndrome in Washington. Read our previous story at the link above.

cpalmer@mdedge.com

Patients with a history of infection have nearly double the risk of developing Sjögren’s syndrome when compared with the general population (odds ratio, 1.9; 95% confidence interval, 1.6-2.3), according to new findings reported online March 20 in the Journal of Internal Medicine (doi: 10.1111/joim.12888).

The risk is almost three times higher among patients with a history of infection plus Ro/SSA and La/SSB antibodies (OR, 2.7; 95% CI, 2.0-3.5). The study included 945 Swedish patients with primary Sjögren’s syndrome and compared their data with those from 9,048 matched controls from the general population.

We previously covered results from this study when they were presented at the International Symposium on Sjögren’s Syndrome in Washington. Read our previous story at the link above.

cpalmer@mdedge.com

Patients with a history of infection have nearly double the risk of developing Sjögren’s syndrome when compared with the general population (odds ratio, 1.9; 95% confidence interval, 1.6-2.3), according to new findings reported online March 20 in the Journal of Internal Medicine (doi: 10.1111/joim.12888).

The risk is almost three times higher among patients with a history of infection plus Ro/SSA and La/SSB antibodies (OR, 2.7; 95% CI, 2.0-3.5). The study included 945 Swedish patients with primary Sjögren’s syndrome and compared their data with those from 9,048 matched controls from the general population.

We previously covered results from this study when they were presented at the International Symposium on Sjögren’s Syndrome in Washington. Read our previous story at the link above.

cpalmer@mdedge.com

Patients with osteoarthritis (OA) have RAPID3 scores at their initial visit (16.0) similar to patients with rheumatoid arthritis (RA) and either prior use of disease-modifying antirheumatic drugs (DMARDs) or no exposure to DMARDs (15.6 and 15.5, respectively). After 6 months of treatment, the RAPID3 (Routine Assessment of Patient Index Data 3) score fell by just 1.7 points for patients with OA, compared with 5.7 points in RA patients naive to DMARDs and 4.3 points in those with prior DMARD exposure. These findings were published March 20 in Arthritis & Rheumatology (doi: 10.1002/art.40869).

We reported this story at the 2018 World Congress on Osteoarthritis before it was published in the journal. Read the story at the link above.

lfranki@mdedge.com

Patients with osteoarthritis (OA) have RAPID3 scores at their initial visit (16.0) similar to patients with rheumatoid arthritis (RA) and either prior use of disease-modifying antirheumatic drugs (DMARDs) or no exposure to DMARDs (15.6 and 15.5, respectively). After 6 months of treatment, the RAPID3 (Routine Assessment of Patient Index Data 3) score fell by just 1.7 points for patients with OA, compared with 5.7 points in RA patients naive to DMARDs and 4.3 points in those with prior DMARD exposure. These findings were published March 20 in Arthritis & Rheumatology (doi: 10.1002/art.40869).

We reported this story at the 2018 World Congress on Osteoarthritis before it was published in the journal. Read the story at the link above.

lfranki@mdedge.com

Patients with osteoarthritis (OA) have RAPID3 scores at their initial visit (16.0) similar to patients with rheumatoid arthritis (RA) and either prior use of disease-modifying antirheumatic drugs (DMARDs) or no exposure to DMARDs (15.6 and 15.5, respectively). After 6 months of treatment, the RAPID3 (Routine Assessment of Patient Index Data 3) score fell by just 1.7 points for patients with OA, compared with 5.7 points in RA patients naive to DMARDs and 4.3 points in those with prior DMARD exposure. These findings were published March 20 in Arthritis & Rheumatology (doi: 10.1002/art.40869).

We reported this story at the 2018 World Congress on Osteoarthritis before it was published in the journal. Read the story at the link above.

lfranki@mdedge.com

Women at high risk of ovarian cancer secondary to genetic predisposition (BRCA gene mutation, Lynch syndrome) still are recommended to undergo bilateral salpingo-oophorectomy after completion of child bearing or by age 40-45 years depending on the specific mutation and family history. For a woman not at risk of hereditary-related ovarian cancer, opportunistic salpingectomy would appear to reduce the risk of ovarian cancer.

Unlike bilateral tubal ligation, which has a greater protective risk of endometrioid and clear-cell carcinoma of the ovary, bilateral salpingectomy appears to further reduce risk of serous carcinoma of the ovaries as well. A Swedish population-based cohort study involving over a quarter of a million women undergoing benign surgery noted a statistically significant decrease in ovarian cancer risk with salpingectomy. The degree of risk reduction was greater when bilateral salpingectomy was performed.¹ Moreover, a Danish case-control study of over 13,000 women with ovarian cancer demonstrated a 42% decrease in epithelial carcinoma risk following bilateral salpingectomy.²

Bilateral salpingectomy does not appear to decrease ovarian function. A study by Venturella et al. that compared 91 women undergoing bilateral salpingectomy with 95 women with mesosalpinx removal within the tubes during salpingectomy observed no significant difference in change of ovarian reserve.³ Moreover, Kotlyar et al. performed a literature review and noted similar findings.⁴ Finally, in another study by Venturella et al. no effects were noted 3-5 years following prophylactic bilateral salpingectomy on ovarian reserve in women undergoing total laparoscopic hysterectomy in their late reproductive years, compared with healthy women with intact uterus and adnexa.⁵

Introduction of opportunistic salpingectomy secondary to potential ovarian cancer reduction has seen increased adoption over the years. A U.S. study of 400,000 hysterectomies performed for benign indications from 1998 to 2011 showed an increased annual rate of bilateral salpingectomy of 8% (1998-2008) and a 24% annual increase (2008-2011).⁶ A retrospective study of 12,143 hysterectomies performed within a large U.S. health care system reported an increased rate of salpingectomy from 15% in 2011 to 45% in 2012 to 73% in 2014.⁷

Given the fact that the American College of Obstetricians and Gynecologists and the AAGL recommend vaginal hysterectomy as the approach of choice when feasible, tips and tricks on opportunistic salpingectomy form an important topic.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Rosanne M. Kho, MD. Dr. Kho’s academic and clinical work focuses on advancing vaginal and minimally invasive surgery. Dr. Kho is a strong advocate of the vaginal approach for benign hysterectomy and is recognized for her passion for bringing vaginal surgery back into the armamentarium of the gynecologic surgeon. Dr. Kho is published in the field of gynecologic surgery, having authored many peer-reviewed manuscripts and book chapters. She is currently an associate editor for the Journal of Minimally Invasive Gynecology (JMIG).

It is truly a pleasure to welcome Dr. Kho to this edition of the Master Class in Gynecologic Surgery.

Dr. Miller is a clinical associate professor at the University of Illinois in Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He has no disclosures relevant to this Master Class.

References

1. J Natl Cancer Inst. 2015 Jan 27. doi: 10.1093/jnci/dju410.

2. Acta Obstet Gynecol Scand. 2015 Jan;94(1):86-94.

3. Fertil Steril. 2015 Nov;104(5):1332-9.

4. J Minim Invasive Gynecol. 2017 May-Jun;24(4):563-78.

5. J Minim Invasive Gynecol. 2017 Jan 1;24(1):145-50.

6. Am J Obstet Gynecol. 2015 Nov;213(5):713.e1-13.

7. Obstet Gynecol. 2016 Aug;128(2):277-83.

Women at high risk of ovarian cancer secondary to genetic predisposition (BRCA gene mutation, Lynch syndrome) still are recommended to undergo bilateral salpingo-oophorectomy after completion of child bearing or by age 40-45 years depending on the specific mutation and family history. For a woman not at risk of hereditary-related ovarian cancer, opportunistic salpingectomy would appear to reduce the risk of ovarian cancer.

Unlike bilateral tubal ligation, which has a greater protective risk of endometrioid and clear-cell carcinoma of the ovary, bilateral salpingectomy appears to further reduce risk of serous carcinoma of the ovaries as well. A Swedish population-based cohort study involving over a quarter of a million women undergoing benign surgery noted a statistically significant decrease in ovarian cancer risk with salpingectomy. The degree of risk reduction was greater when bilateral salpingectomy was performed.¹ Moreover, a Danish case-control study of over 13,000 women with ovarian cancer demonstrated a 42% decrease in epithelial carcinoma risk following bilateral salpingectomy.²

Bilateral salpingectomy does not appear to decrease ovarian function. A study by Venturella et al. that compared 91 women undergoing bilateral salpingectomy with 95 women with mesosalpinx removal within the tubes during salpingectomy observed no significant difference in change of ovarian reserve.³ Moreover, Kotlyar et al. performed a literature review and noted similar findings.⁴ Finally, in another study by Venturella et al. no effects were noted 3-5 years following prophylactic bilateral salpingectomy on ovarian reserve in women undergoing total laparoscopic hysterectomy in their late reproductive years, compared with healthy women with intact uterus and adnexa.⁵

Introduction of opportunistic salpingectomy secondary to potential ovarian cancer reduction has seen increased adoption over the years. A U.S. study of 400,000 hysterectomies performed for benign indications from 1998 to 2011 showed an increased annual rate of bilateral salpingectomy of 8% (1998-2008) and a 24% annual increase (2008-2011).⁶ A retrospective study of 12,143 hysterectomies performed within a large U.S. health care system reported an increased rate of salpingectomy from 15% in 2011 to 45% in 2012 to 73% in 2014.⁷

Given the fact that the American College of Obstetricians and Gynecologists and the AAGL recommend vaginal hysterectomy as the approach of choice when feasible, tips and tricks on opportunistic salpingectomy form an important topic.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Rosanne M. Kho, MD. Dr. Kho’s academic and clinical work focuses on advancing vaginal and minimally invasive surgery. Dr. Kho is a strong advocate of the vaginal approach for benign hysterectomy and is recognized for her passion for bringing vaginal surgery back into the armamentarium of the gynecologic surgeon. Dr. Kho is published in the field of gynecologic surgery, having authored many peer-reviewed manuscripts and book chapters. She is currently an associate editor for the Journal of Minimally Invasive Gynecology (JMIG).

It is truly a pleasure to welcome Dr. Kho to this edition of the Master Class in Gynecologic Surgery.

Dr. Miller is a clinical associate professor at the University of Illinois in Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He has no disclosures relevant to this Master Class.

References

1. J Natl Cancer Inst. 2015 Jan 27. doi: 10.1093/jnci/dju410.

2. Acta Obstet Gynecol Scand. 2015 Jan;94(1):86-94.

3. Fertil Steril. 2015 Nov;104(5):1332-9.

4. J Minim Invasive Gynecol. 2017 May-Jun;24(4):563-78.

5. J Minim Invasive Gynecol. 2017 Jan 1;24(1):145-50.

6. Am J Obstet Gynecol. 2015 Nov;213(5):713.e1-13.

7. Obstet Gynecol. 2016 Aug;128(2):277-83.

Women at high risk of ovarian cancer secondary to genetic predisposition (BRCA gene mutation, Lynch syndrome) still are recommended to undergo bilateral salpingo-oophorectomy after completion of child bearing or by age 40-45 years depending on the specific mutation and family history. For a woman not at risk of hereditary-related ovarian cancer, opportunistic salpingectomy would appear to reduce the risk of ovarian cancer.

Unlike bilateral tubal ligation, which has a greater protective risk of endometrioid and clear-cell carcinoma of the ovary, bilateral salpingectomy appears to further reduce risk of serous carcinoma of the ovaries as well. A Swedish population-based cohort study involving over a quarter of a million women undergoing benign surgery noted a statistically significant decrease in ovarian cancer risk with salpingectomy. The degree of risk reduction was greater when bilateral salpingectomy was performed.¹ Moreover, a Danish case-control study of over 13,000 women with ovarian cancer demonstrated a 42% decrease in epithelial carcinoma risk following bilateral salpingectomy.²

Bilateral salpingectomy does not appear to decrease ovarian function. A study by Venturella et al. that compared 91 women undergoing bilateral salpingectomy with 95 women with mesosalpinx removal within the tubes during salpingectomy observed no significant difference in change of ovarian reserve.³ Moreover, Kotlyar et al. performed a literature review and noted similar findings.⁴ Finally, in another study by Venturella et al. no effects were noted 3-5 years following prophylactic bilateral salpingectomy on ovarian reserve in women undergoing total laparoscopic hysterectomy in their late reproductive years, compared with healthy women with intact uterus and adnexa.⁵

Introduction of opportunistic salpingectomy secondary to potential ovarian cancer reduction has seen increased adoption over the years. A U.S. study of 400,000 hysterectomies performed for benign indications from 1998 to 2011 showed an increased annual rate of bilateral salpingectomy of 8% (1998-2008) and a 24% annual increase (2008-2011).⁶ A retrospective study of 12,143 hysterectomies performed within a large U.S. health care system reported an increased rate of salpingectomy from 15% in 2011 to 45% in 2012 to 73% in 2014.⁷

Given the fact that the American College of Obstetricians and Gynecologists and the AAGL recommend vaginal hysterectomy as the approach of choice when feasible, tips and tricks on opportunistic salpingectomy form an important topic.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Rosanne M. Kho, MD. Dr. Kho’s academic and clinical work focuses on advancing vaginal and minimally invasive surgery. Dr. Kho is a strong advocate of the vaginal approach for benign hysterectomy and is recognized for her passion for bringing vaginal surgery back into the armamentarium of the gynecologic surgeon. Dr. Kho is published in the field of gynecologic surgery, having authored many peer-reviewed manuscripts and book chapters. She is currently an associate editor for the Journal of Minimally Invasive Gynecology (JMIG).

It is truly a pleasure to welcome Dr. Kho to this edition of the Master Class in Gynecologic Surgery.

Dr. Miller is a clinical associate professor at the University of Illinois in Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He has no disclosures relevant to this Master Class.

References

1. J Natl Cancer Inst. 2015 Jan 27. doi: 10.1093/jnci/dju410.

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