Patient Care

New research from the Birmingham, Ala., Veterans Affairs Medical Center and the University of Alabama-Birmingham, published in the Journal of General Internal Medicine, finds that clinical techniques and care processes imported from home-based hospice professionals improved outcomes for hospitalized patients approaching the end of their lives.¹

The project, conducted in six VA medical centers, employed a multi-modal strategy for improving end-of-life care processes, with staff training for all hospital providers in how to identify actively dying patients and then communicate this information to their families. Best clinical practices, supported by electronic order sets and paper-based educational materials, were implemented. Patients also were encouraged to eat what—and when—they wanted, to sit up in bed, and to receive family visitors at all hours.

“I started the project years ago, when I noticed that patients on hospice care at home often seemed more comfortable, while if I brought them into the hospital, they sometimes got worse,” says lead author F. Amos Bailey, MD. “We went out to the home to observe what the hospice nurses were doing and then came back to the hospital to write order sets to reflect that practice.”

Key quality endpoints included:

• Rates of orders for opioid pain medications;
• Anti-psychotic medications and scopolamine for death rattle;
• Completion of advance directives; and
• Consultations for palliative care and pastoral care.

Patients were more likely to have their pain relieved and symptoms addressed, according to chart reviews of 6,066 patients who died before or after the intervention was launched.

“All of the processes we measured moved in the direction of increased comfort,” Dr. Bailey says.

This is the first study to show that palliative care techniques developed in the home setting can have an impact on end-of-life care. That’s important, he adds, because most patients die in hospitals or nursing homes.

Larry Beresford is a freelance writer in Alameda, Calif.

References

1. Bailey FA, Williams BR, Woodby LL, et al. Intervention to improve care at life's end in inpatient settings: The BEACON trial. J Gen Intern Med. 2014;29(6):836-843.
2. Burling S. Yogurt a solution to hospital infection? Philadelphia Inquirer website. December 10, 2013. Available at: http://articles.philly.com/2013-12-10/news/44946926_1_holy-redeemer-probiotics-yogurt. Accessed June 5, 2014.
3. Landelle C, Verachten M, Legrand P, Girou E, Barbut F, Buisson CB. Contamination of healthcare workers’ hands with Clostridium difficile spores after caring for patients with C. difficile infection. Infect Control Hosp Epidemiol. 2014;35(1):10-15.
4. Lewis K, Walker C. Development and application of information technology solutions to improve the quality and availability of discharge summaries. Journal of Hospital Medicine RIV abstracts website. Available at: http://www.shmabstracts.com/abstract.asp?MeetingID=793&id=104276&meeting=JHM201305. Published May 2013. Accessed June 14, 2014.
5. Snow V, Beck D, Budnitz T, et al. Transitions of Care Consensus Policy Statement. American College of Physicians; Society of General Internal Medicine; Society of Hospital Medicine; American Geriatrics Society; American College of Emergency Physicians; Society of Academic Emergency Medicine. J Gen Intern Med. 2009;24(8):971-976.
6. American Hospital Association: Uncompensated hospital care cost fact sheet. January 2014. Available at: http://www.aha.org/content/14/14uncompensatedcare.pdf. Accessed June 5, 2014.

New research from the Birmingham, Ala., Veterans Affairs Medical Center and the University of Alabama-Birmingham, published in the Journal of General Internal Medicine, finds that clinical techniques and care processes imported from home-based hospice professionals improved outcomes for hospitalized patients approaching the end of their lives.¹

The project, conducted in six VA medical centers, employed a multi-modal strategy for improving end-of-life care processes, with staff training for all hospital providers in how to identify actively dying patients and then communicate this information to their families. Best clinical practices, supported by electronic order sets and paper-based educational materials, were implemented. Patients also were encouraged to eat what—and when—they wanted, to sit up in bed, and to receive family visitors at all hours.

“I started the project years ago, when I noticed that patients on hospice care at home often seemed more comfortable, while if I brought them into the hospital, they sometimes got worse,” says lead author F. Amos Bailey, MD. “We went out to the home to observe what the hospice nurses were doing and then came back to the hospital to write order sets to reflect that practice.”

Key quality endpoints included:

• Rates of orders for opioid pain medications;
• Anti-psychotic medications and scopolamine for death rattle;
• Completion of advance directives; and
• Consultations for palliative care and pastoral care.

Patients were more likely to have their pain relieved and symptoms addressed, according to chart reviews of 6,066 patients who died before or after the intervention was launched.

“All of the processes we measured moved in the direction of increased comfort,” Dr. Bailey says.

This is the first study to show that palliative care techniques developed in the home setting can have an impact on end-of-life care. That’s important, he adds, because most patients die in hospitals or nursing homes.

Larry Beresford is a freelance writer in Alameda, Calif.

References

1. Bailey FA, Williams BR, Woodby LL, et al. Intervention to improve care at life's end in inpatient settings: The BEACON trial. J Gen Intern Med. 2014;29(6):836-843.
2. Burling S. Yogurt a solution to hospital infection? Philadelphia Inquirer website. December 10, 2013. Available at: http://articles.philly.com/2013-12-10/news/44946926_1_holy-redeemer-probiotics-yogurt. Accessed June 5, 2014.
3. Landelle C, Verachten M, Legrand P, Girou E, Barbut F, Buisson CB. Contamination of healthcare workers’ hands with Clostridium difficile spores after caring for patients with C. difficile infection. Infect Control Hosp Epidemiol. 2014;35(1):10-15.
4. Lewis K, Walker C. Development and application of information technology solutions to improve the quality and availability of discharge summaries. Journal of Hospital Medicine RIV abstracts website. Available at: http://www.shmabstracts.com/abstract.asp?MeetingID=793&id=104276&meeting=JHM201305. Published May 2013. Accessed June 14, 2014.
5. Snow V, Beck D, Budnitz T, et al. Transitions of Care Consensus Policy Statement. American College of Physicians; Society of General Internal Medicine; Society of Hospital Medicine; American Geriatrics Society; American College of Emergency Physicians; Society of Academic Emergency Medicine. J Gen Intern Med. 2009;24(8):971-976.
6. American Hospital Association: Uncompensated hospital care cost fact sheet. January 2014. Available at: http://www.aha.org/content/14/14uncompensatedcare.pdf. Accessed June 5, 2014.

New research from the Birmingham, Ala., Veterans Affairs Medical Center and the University of Alabama-Birmingham, published in the Journal of General Internal Medicine, finds that clinical techniques and care processes imported from home-based hospice professionals improved outcomes for hospitalized patients approaching the end of their lives.¹

The project, conducted in six VA medical centers, employed a multi-modal strategy for improving end-of-life care processes, with staff training for all hospital providers in how to identify actively dying patients and then communicate this information to their families. Best clinical practices, supported by electronic order sets and paper-based educational materials, were implemented. Patients also were encouraged to eat what—and when—they wanted, to sit up in bed, and to receive family visitors at all hours.

“I started the project years ago, when I noticed that patients on hospice care at home often seemed more comfortable, while if I brought them into the hospital, they sometimes got worse,” says lead author F. Amos Bailey, MD. “We went out to the home to observe what the hospice nurses were doing and then came back to the hospital to write order sets to reflect that practice.”

Key quality endpoints included:

• Rates of orders for opioid pain medications;
• Anti-psychotic medications and scopolamine for death rattle;
• Completion of advance directives; and
• Consultations for palliative care and pastoral care.

Patients were more likely to have their pain relieved and symptoms addressed, according to chart reviews of 6,066 patients who died before or after the intervention was launched.

“All of the processes we measured moved in the direction of increased comfort,” Dr. Bailey says.

This is the first study to show that palliative care techniques developed in the home setting can have an impact on end-of-life care. That’s important, he adds, because most patients die in hospitals or nursing homes.

Larry Beresford is a freelance writer in Alameda, Calif.

References

1. Bailey FA, Williams BR, Woodby LL, et al. Intervention to improve care at life's end in inpatient settings: The BEACON trial. J Gen Intern Med. 2014;29(6):836-843.
2. Burling S. Yogurt a solution to hospital infection? Philadelphia Inquirer website. December 10, 2013. Available at: http://articles.philly.com/2013-12-10/news/44946926_1_holy-redeemer-probiotics-yogurt. Accessed June 5, 2014.
3. Landelle C, Verachten M, Legrand P, Girou E, Barbut F, Buisson CB. Contamination of healthcare workers’ hands with Clostridium difficile spores after caring for patients with C. difficile infection. Infect Control Hosp Epidemiol. 2014;35(1):10-15.
4. Lewis K, Walker C. Development and application of information technology solutions to improve the quality and availability of discharge summaries. Journal of Hospital Medicine RIV abstracts website. Available at: http://www.shmabstracts.com/abstract.asp?MeetingID=793&id=104276&meeting=JHM201305. Published May 2013. Accessed June 14, 2014.
5. Snow V, Beck D, Budnitz T, et al. Transitions of Care Consensus Policy Statement. American College of Physicians; Society of General Internal Medicine; Society of Hospital Medicine; American Geriatrics Society; American College of Emergency Physicians; Society of Academic Emergency Medicine. J Gen Intern Med. 2009;24(8):971-976.
6. American Hospital Association: Uncompensated hospital care cost fact sheet. January 2014. Available at: http://www.aha.org/content/14/14uncompensatedcare.pdf. Accessed June 5, 2014.

Case

A seven-week-old Hispanic female with a history of prematurity (born at 35 weeks by C-section) presents to the ED with four days of fever as high as 102°F and new-onset cyanotic spells. Cultures of blood, urine, and cerebrospinal fluid obtained 48 hours prior to admission were negative, but she continued to have intermittent fevers and developed a macular, non-pruritic rash on her hands and feet, with associated non-bilious emesis. One day prior to admission, she began to have episodes of apnea, with color change and cyanosis of her lips and eyelids. In the ED, her vital signs include a rectal temperature of 38.4°C, heart rate of 178/min, respiratory rate of 27/min, and blood pressure of 79/66. Examination reveals a non-toxic-appearing infant, with no conjunctival or oropharyngeal abnormalities, unremarkable heart and lung exam, and a blanching, erythematous macular rash on her hands, lower legs, and feet.

When should you suspect Kawasaki disease (KD) as the cause of fever in an infant?

Background

KD is an acute systemic vasculitis of unknown etiology that occurs in children. Affecting the small- and medium-sized arteries, with a striking predilection for coronary arteries, it is the leading cause of acquired pediatric heart disease in Japan and the U.S.¹ Occurring predominantly in children younger than five years, KD has been diagnosed in infants and in young adults.² The incidence of KD is lowest among white children and highest among Asians and Pacific Islanders, with the highest incidence in children of Japanese descent.

A recent epidemiologic study performed in Taiwan showed an incidence of 69 cases per 100,000 per year among children younger than five years, with a male/female ratio of 1.62:1.³ The peak of mortality occurs 15-45 days after onset of fever, although sudden cardiac death may occur many years later. Recurrence rate is approximately 3%. In the U.S., the estimated incidence ranges from nine to 18 per 100,000 children younger than five years per year.⁴

Review of Data

Because there is no specific diagnostic test or pathognomonic clinical feature, clinical diagnostic criteria have been established to guide physicians. KD diagnosis traditionally requires fever for at least five days and the presence of at least four of the following five principal features:

• bilateral conjunctival injection;
• changes in the mucous membranes of the upper respiratory tract (injected pharynx, infected, fissured lips, strawberry tongue);
• polymorphous rash;
• changes of the extremities (peripheral edema, erythema, periungual desquamation); and
• cervical lymphadenopathy.⁵

Adapted from: Newburger JW, Takahashi M, Gerber MA. Diagnosis, treatment, and long-term management of Kawasaki Disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771.

The fever, which is remittent, typically peaks at 39ºC to 40ºC. The mean duration of untreated fever is 11 days; with prompt treatment, fever typically subsides in two days. Bilateral painless non-exudative conjunctival injection begins shortly after onset of fever, involves typically bulbar conjunctiva, and is not associated with edema.

Erythematous rash usually appears within five days of onset of fever and is often a diffuse, nonspecific maculopapular eruption that is commonly pronounced in the perineal region. The appearance might be urticarial, micropustular, or erythema multiforme-like. Changes in extremities include erythema of palms and soles and tender induration of the hands and feet. Subsequently, desquamation begins in the periungual area within two to three weeks after the onset of fever. Typically, peeling begins around the nail folds of fingers, followed by the toes. The least common of the principal clinical features is tender unilateral anterior cervical lymphadenopathy (1.5 cm or greater in diameter).

When a patient presents with a history, examination, and laboratory findings consistent with KD without meeting the typical diagnostic standard, incomplete KD should be considered. The term “incomplete” is favored over “atypical” for this pre-sentation, because these patients are otherwise similar to other patients with KD. Patients with fever for five or fewer days and fewer than four principal features can be diagnosed as having KD when coronary artery disease is detected by two-dimensional echocardiography or coronary angiography (see Figure 1, p. 10). In the presence of four or more principal criteria, KD can be diagnosed before day four of the illness by an experienced clinician.6 Features less consistent with KD include the presence of exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy.

If clinical features are consistent with KD, further risk stratification with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) will determine whether patients are followed daily (if low) or if supplementary laboratory tests should be done (see Figure 1, p. 10). If three or more of supplementary laboratory criteria are present (albumin ≤3.0 g/dL, anemia for age, elevation of alanine aminotransferase (ALT), platelet count after seven days is 450 000/mm3 or greater, white blood cell count is 15,000/mm3 or greater, and urinary sediment containing 10 white blood cells/high-power field or more), echocardiogram should be performed and treatment initiated if abnormal.⁶

Young infants are more likely to manifest an incomplete presentation of KD, with a polymorphous rash being the most common symptom other than fever in this age group.⁷ Acute phase symptoms were also more likely to progress rapidly in this age group, with a higher risk of developing cardiac sequelae.⁸ As a result, any infant under the age of six months with fever for more than seven days and no other clear etiology should be evaluated for KD even in the absence of other diagnostic criteria.⁹

Other clinical manifestations of KD may include:

• Irritability: more notable in KD than in other febrile illnesses;
• Arthralgia and arthritis: may occur in the first week;
• Gastrointestinal complaints and findings: hepatomegaly, jaundice; and
• Abnormal chest X-ray findings: may be present in as many as 15% of patients.

Cardiovascular manifestations can be prominent in the acute phase of KD and are the leading cause of long-term morbidity and mortality. Coronary artery aneurysms occur in 20% of affected children with KD. Other cardiovascular complications include myocardial ischemia and ensuing depressed contractility and arrhythmias, as well as vascular obstruction in peripheral arteries.

A subset of KD patients develops hemodynamic instability requiring management in a critical care setting. This phenomenon has been named Kawasaki disease shock syndrome, where hemodynamic instability is not related to administration of intravenous immunoglobulin (IVIG). Patients are more likely to be female, to have laboratory findings consistent with greater inflammation, and to have impaired systolic and diastolic function. They also exhibit resistance to IVIG more often and have higher rates of coronary artery dilation and aneurysm formation.¹⁰

Differential diagnoses for KD may include viral infections, scarlet fever, staphylococcal scalded skin syndrome, toxic shock syndrome, Rocky Mountain spotted fever, cervical lymphadenitis, drug hypersensitivity, Stevens-Johnson syndrome, systemic idiopathic arthritis, leptospirosis, and mercury hypersensitivity reaction.¹¹

Work-Up

Laboratory evaluation of a patient with suspected KD should include:

• Complete blood count (CBC) with differential: leukocytosis, anemia, thrombocytosis that peaks in the third week is characteristic. A manual differential may reveal an increase in band forms.
• Acute phase reactants: If C-reactive protein (CRP) is 3 mg/dL or greater and erythrocyte sedimentation rate (ESR) is 40 mm/hr or greater, supplementary laboratory work-up should be done. Make sure not to cloud classic with incomplete KD; the stepwise lab evaluation only pertains to the latter.
• Liver panel: Elevated ALT and gamma-glutamyl transferase (GGT), mild hyperbilirubinemia, or hypoalbuminemia may be present.
• Urinalysis: Sterile pyuria may be present; if present, it may be of urethral origin, and catheterized samples could miss this finding.¹²

Lack of elevated inflammatory markers (CRP is less than 3 mg/dl and ESR is less than 40 mm/hr) and the presence of two or three principal clinical features warrant ongoing daily monitoring of ESR, CRP, and fever until day seven of illness. If the fever resolves but is followed by peeling of extremities, an echocardiogram should be done. Lumbar puncture might help differentiate from CNS infectious etiologies, but about 50% of KD patients have a cerebrospinal fluid pleocytosis.

Echocardiography is the preferred imaging modality for the initial cardiovascular evaluation and follow-up.¹ It has a sensitivity of 100% and specificity of 96% for the detection of proximal coronary aneurysms.¹³ Coronary aneurysms are clinically silent in most cases and can manifest with delayed complications, such as myocardial infarction or sudden death. Imaging plays an important role in the early diagnosis of these aneurysms and in estimating their number, size, and location, important elements in making a therapeutic decision.¹⁴

Although the echocardiography should be done as soon as KD is suspected, definitive treatment must not be delayed. Evaluation of all coronary artery segments, as well as cardiac contractility and presence of effusion, should be noted on echocardiography. In the absence of complications, echocardiography is performed at the time of diagnosis and at two weeks and six to eight weeks after disease onset.¹¹

Treatment

Treatment goals for Kawasaki disease in the acute phase are reduction of systemic and coronary arterial inflammation and prevention of coronary thrombosis. The long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction.6 The current standard of care for the treatment of children in the U.S. is anti-inflammatory therapy with:

• immunoglobulin (IVIG) in a single 2 g/kg/dose infused over 10–12 hours, accompanied by;
• high-dose aspirin (80–100 mg/kg/day orally in four divided doses).^6,15

IVIG administration within 10 days of the onset of fever results in more favorable outcomes. Live virus vaccines should be delayed to 11 months after administration of IVIG. Both aspirin and IVIG have anti-inflammatory effects. This regimen applies to patients without abnormalities on initial echocardiography. High-dose aspirin typically is continued for 48-72 hours after the child becomes afebrile. Thereafter, low-dose aspirin (3-5 mg/kg/day) is prescribed until patient shows no evidence of coronary changes, typically by six to eight weeks after onset of illness. Children with coronary abnormalities should continue aspirin indefinitely.

Approximately 10% of patients are IVIG-resistant and have persistent or recurrent fever for at least 36 hours after completion of the infusion. The current recommendation is to re-treat with IVIG at the same dose. If the patient has fever 36 hours after the second dose of IVIG, this is considered true treatment failure.

Other possible treatments for KD refractory to IVIG include IV methylprednisolone (30 mg/kg over two to three hours daily for three days) or infliximab.¹⁶ Even with prompt treatment, 5% of children who have KD develop coronary artery dilation, and 1% develop giant aneurysms.

Back to the Case

Initial laboratory evaluation revealed white blood cell count of 19.0×103 cells/mm3, hemoglobin of 8.9 gm/dL, CRP of 17.9 mg/dL, and ESR of 73 mm/hr. Because of persistent fevers for 48 hours after admission in the absence of another cause to explain the illness, the KD service was consulted. Echocardiography revealed dilatation of the left main (z-score 4.23) and proximal right (z-score 2.59), confirming the diagnosis of KD. Ejection fraction was read as qualitatively normal.

The infant received infliximab and IVIG, as well as high-dose aspirin, clopidogrel, and propranolol. This treatment regimen was directed by a KD expert and was more aggressive than typical therapy due to the severity of presentation. She received blood transfusions for worsening symptomatic anemia (hemoglobin 7.0 gm/dL) with hypoxia.

Following her IVIG infusion, she remained afebrile with progressive reduction in her CRP. She was discharged on hospital day seven on aspirin until her next follow-up, with propranolol for three days to limit potential tachycardia. At her three-week follow-up visit, her ESR had improved to 8 mm/hr. Her echocardiogram revealed a normal ejection fraction. Echocardiography revealed resolution of all abnormalities except for a borderline prominence of the right coronary artery (z-score 2.11). At this time it was recommended that her aspirin be discontinued.

She continues to be followed by the KD service as an outpatient and has done well without cardiovascular symptoms four months after her diagnosis.

Bottom Line

KD can manifest an incomplete presentation, especially in infants under the age of six months. Clinicians should maintain a high level of suspicion for KD in young infants with unexplained fevers lasting more than seven days.

Dr. Gurevich-Panigrahi is a fellow in pediatric hospital medicine at Cleveland Clinic Children’s Hospital. Dr. Kanegaye is a clinical professor of pediatrics at the University of California San Diego (UCSD) School of Medicine and attending physician in the emergency care center at Rady Children’s Hospital San Diego. Dr. Chang is associate clinical professor of pediatrics and medicine at UCSD School of Medicine, a pediatric hospitalist at Rady Children’s, and pediatric editor of The Hospitalist.

References

1. Hendaoui L, Stanson AW, Habib Bouhaouala M, Joffre F, eds. Systemic Vasculitis: Imaging Features. New York: Springer; 2012.
2. Manlhiot C, Yeung RS, Clarizia NA, Chahal N, McCrindle BW. Kawasaki disease at the extremes of the age spectrum. Pediatrics. 2009;124(3):e410-e415.
3. Huang WC, Huang LM, Chang IS, et al. Epidemiologic features of Kawasaki disease in Taiwan, 2003-2006. Pediatrics. 2009;123(3):e401-405.
4. Holman RC, Belay ED, Christensen KY, Folkema AM, Steiner CA, Schonberger LB. Hospitalizations for Kawasaki syndrome among children in the United States, 1997-2007. Pediatr Infect Dis J. 2010;29(6):483-438.
5. Council on Cardiovascular Disease in the Young, Committee on Rheumatic Fever Endocarditis, Kawasaki Disease, American Heart Association. Diagnostic guidelines for Kawasaki disease. Circulation. 2001;103:335-336.
6. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2747-2771.
7. Shiozawa Y, Inuzuka R, Harita Y, Kagawa J. Age-related differences in the course of the acute phase symptoms of Kawasaki disease. Pediatr Infect Dis J. 2013;32(9):e365-369.
8. Genizi J, Miron D, Spiegel R, Fink D, Horowitz Y. Kawasaki disease in very young infants: high prevalence of atypical presentation and coronary arteritis. Clin Pediatr (Phila.). 2003;42(3):263-267.
9. Sundel R. Incomplete (atypical) Kawasaki disease. UpToDate. Available at: http://www.uptodate.com/contents/incomplete-atypical-kawasaki-disease. Accessed June 9, 2014.
10. Kanegaye JT, Wilder MS, Molkara D, et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics. 2009;123(5):e783-e789.
11. Fimbres AM, Shulman ST. Kawasaki disease. Pediatr Rev. 2008;29(9):308-315.
12. Shike H, Kanegaye JT, Best BM, Pancheri J, Burns JC. Pyuria associated with acute Kawasaki disease and fever from other causes. Pediatr Infect Dis J. 2009;28(5):440-443.
13. Capannari TE, Daniels SR, Meyer RA, Schwartz DC, Kaplan S. Sensitivity, specificity and predictive value of two-dimensional echocardiography in detecting coronary artery aneurysms in patients with Kawasaki disease. J Am Coll Cardiol. 1986;7(2):355-360.
14. Mavrogeni S, Papadopoulos G, Karanasios E, Cokkinos DV. How to image Kawasaki disease: a validation of different imaging techniques. Int J Cardiol. 2008;124(1):27-31.
15. Burns JC, Glodé MP. Kawasaki syndrome. Lancet. 2004;364(9433):533-544.
16. Ghelani SJ, Pastor W, Parikh K. Demographic and treatment variability of refractory Kawasaki Disease: a multicenter analysis from 2005 to 2009. Hosp Pediatr. 2012;2(2):71-76.

Case

A seven-week-old Hispanic female with a history of prematurity (born at 35 weeks by C-section) presents to the ED with four days of fever as high as 102°F and new-onset cyanotic spells. Cultures of blood, urine, and cerebrospinal fluid obtained 48 hours prior to admission were negative, but she continued to have intermittent fevers and developed a macular, non-pruritic rash on her hands and feet, with associated non-bilious emesis. One day prior to admission, she began to have episodes of apnea, with color change and cyanosis of her lips and eyelids. In the ED, her vital signs include a rectal temperature of 38.4°C, heart rate of 178/min, respiratory rate of 27/min, and blood pressure of 79/66. Examination reveals a non-toxic-appearing infant, with no conjunctival or oropharyngeal abnormalities, unremarkable heart and lung exam, and a blanching, erythematous macular rash on her hands, lower legs, and feet.

When should you suspect Kawasaki disease (KD) as the cause of fever in an infant?

Background

KD is an acute systemic vasculitis of unknown etiology that occurs in children. Affecting the small- and medium-sized arteries, with a striking predilection for coronary arteries, it is the leading cause of acquired pediatric heart disease in Japan and the U.S.¹ Occurring predominantly in children younger than five years, KD has been diagnosed in infants and in young adults.² The incidence of KD is lowest among white children and highest among Asians and Pacific Islanders, with the highest incidence in children of Japanese descent.

A recent epidemiologic study performed in Taiwan showed an incidence of 69 cases per 100,000 per year among children younger than five years, with a male/female ratio of 1.62:1.³ The peak of mortality occurs 15-45 days after onset of fever, although sudden cardiac death may occur many years later. Recurrence rate is approximately 3%. In the U.S., the estimated incidence ranges from nine to 18 per 100,000 children younger than five years per year.⁴

Review of Data

Because there is no specific diagnostic test or pathognomonic clinical feature, clinical diagnostic criteria have been established to guide physicians. KD diagnosis traditionally requires fever for at least five days and the presence of at least four of the following five principal features:

• bilateral conjunctival injection;
• changes in the mucous membranes of the upper respiratory tract (injected pharynx, infected, fissured lips, strawberry tongue);
• polymorphous rash;
• changes of the extremities (peripheral edema, erythema, periungual desquamation); and
• cervical lymphadenopathy.⁵

Adapted from: Newburger JW, Takahashi M, Gerber MA. Diagnosis, treatment, and long-term management of Kawasaki Disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771.

The fever, which is remittent, typically peaks at 39ºC to 40ºC. The mean duration of untreated fever is 11 days; with prompt treatment, fever typically subsides in two days. Bilateral painless non-exudative conjunctival injection begins shortly after onset of fever, involves typically bulbar conjunctiva, and is not associated with edema.

Erythematous rash usually appears within five days of onset of fever and is often a diffuse, nonspecific maculopapular eruption that is commonly pronounced in the perineal region. The appearance might be urticarial, micropustular, or erythema multiforme-like. Changes in extremities include erythema of palms and soles and tender induration of the hands and feet. Subsequently, desquamation begins in the periungual area within two to three weeks after the onset of fever. Typically, peeling begins around the nail folds of fingers, followed by the toes. The least common of the principal clinical features is tender unilateral anterior cervical lymphadenopathy (1.5 cm or greater in diameter).

When a patient presents with a history, examination, and laboratory findings consistent with KD without meeting the typical diagnostic standard, incomplete KD should be considered. The term “incomplete” is favored over “atypical” for this pre-sentation, because these patients are otherwise similar to other patients with KD. Patients with fever for five or fewer days and fewer than four principal features can be diagnosed as having KD when coronary artery disease is detected by two-dimensional echocardiography or coronary angiography (see Figure 1, p. 10). In the presence of four or more principal criteria, KD can be diagnosed before day four of the illness by an experienced clinician.6 Features less consistent with KD include the presence of exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy.

If clinical features are consistent with KD, further risk stratification with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) will determine whether patients are followed daily (if low) or if supplementary laboratory tests should be done (see Figure 1, p. 10). If three or more of supplementary laboratory criteria are present (albumin ≤3.0 g/dL, anemia for age, elevation of alanine aminotransferase (ALT), platelet count after seven days is 450 000/mm3 or greater, white blood cell count is 15,000/mm3 or greater, and urinary sediment containing 10 white blood cells/high-power field or more), echocardiogram should be performed and treatment initiated if abnormal.⁶

Young infants are more likely to manifest an incomplete presentation of KD, with a polymorphous rash being the most common symptom other than fever in this age group.⁷ Acute phase symptoms were also more likely to progress rapidly in this age group, with a higher risk of developing cardiac sequelae.⁸ As a result, any infant under the age of six months with fever for more than seven days and no other clear etiology should be evaluated for KD even in the absence of other diagnostic criteria.⁹

Other clinical manifestations of KD may include:

• Irritability: more notable in KD than in other febrile illnesses;
• Arthralgia and arthritis: may occur in the first week;
• Gastrointestinal complaints and findings: hepatomegaly, jaundice; and
• Abnormal chest X-ray findings: may be present in as many as 15% of patients.

Cardiovascular manifestations can be prominent in the acute phase of KD and are the leading cause of long-term morbidity and mortality. Coronary artery aneurysms occur in 20% of affected children with KD. Other cardiovascular complications include myocardial ischemia and ensuing depressed contractility and arrhythmias, as well as vascular obstruction in peripheral arteries.

A subset of KD patients develops hemodynamic instability requiring management in a critical care setting. This phenomenon has been named Kawasaki disease shock syndrome, where hemodynamic instability is not related to administration of intravenous immunoglobulin (IVIG). Patients are more likely to be female, to have laboratory findings consistent with greater inflammation, and to have impaired systolic and diastolic function. They also exhibit resistance to IVIG more often and have higher rates of coronary artery dilation and aneurysm formation.¹⁰

Differential diagnoses for KD may include viral infections, scarlet fever, staphylococcal scalded skin syndrome, toxic shock syndrome, Rocky Mountain spotted fever, cervical lymphadenitis, drug hypersensitivity, Stevens-Johnson syndrome, systemic idiopathic arthritis, leptospirosis, and mercury hypersensitivity reaction.¹¹

Work-Up

Laboratory evaluation of a patient with suspected KD should include:

• Complete blood count (CBC) with differential: leukocytosis, anemia, thrombocytosis that peaks in the third week is characteristic. A manual differential may reveal an increase in band forms.
• Acute phase reactants: If C-reactive protein (CRP) is 3 mg/dL or greater and erythrocyte sedimentation rate (ESR) is 40 mm/hr or greater, supplementary laboratory work-up should be done. Make sure not to cloud classic with incomplete KD; the stepwise lab evaluation only pertains to the latter.
• Liver panel: Elevated ALT and gamma-glutamyl transferase (GGT), mild hyperbilirubinemia, or hypoalbuminemia may be present.
• Urinalysis: Sterile pyuria may be present; if present, it may be of urethral origin, and catheterized samples could miss this finding.¹²

Lack of elevated inflammatory markers (CRP is less than 3 mg/dl and ESR is less than 40 mm/hr) and the presence of two or three principal clinical features warrant ongoing daily monitoring of ESR, CRP, and fever until day seven of illness. If the fever resolves but is followed by peeling of extremities, an echocardiogram should be done. Lumbar puncture might help differentiate from CNS infectious etiologies, but about 50% of KD patients have a cerebrospinal fluid pleocytosis.

Echocardiography is the preferred imaging modality for the initial cardiovascular evaluation and follow-up.¹ It has a sensitivity of 100% and specificity of 96% for the detection of proximal coronary aneurysms.¹³ Coronary aneurysms are clinically silent in most cases and can manifest with delayed complications, such as myocardial infarction or sudden death. Imaging plays an important role in the early diagnosis of these aneurysms and in estimating their number, size, and location, important elements in making a therapeutic decision.¹⁴

Although the echocardiography should be done as soon as KD is suspected, definitive treatment must not be delayed. Evaluation of all coronary artery segments, as well as cardiac contractility and presence of effusion, should be noted on echocardiography. In the absence of complications, echocardiography is performed at the time of diagnosis and at two weeks and six to eight weeks after disease onset.¹¹

Treatment

Treatment goals for Kawasaki disease in the acute phase are reduction of systemic and coronary arterial inflammation and prevention of coronary thrombosis. The long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction.6 The current standard of care for the treatment of children in the U.S. is anti-inflammatory therapy with:

• immunoglobulin (IVIG) in a single 2 g/kg/dose infused over 10–12 hours, accompanied by;
• high-dose aspirin (80–100 mg/kg/day orally in four divided doses).^6,15

IVIG administration within 10 days of the onset of fever results in more favorable outcomes. Live virus vaccines should be delayed to 11 months after administration of IVIG. Both aspirin and IVIG have anti-inflammatory effects. This regimen applies to patients without abnormalities on initial echocardiography. High-dose aspirin typically is continued for 48-72 hours after the child becomes afebrile. Thereafter, low-dose aspirin (3-5 mg/kg/day) is prescribed until patient shows no evidence of coronary changes, typically by six to eight weeks after onset of illness. Children with coronary abnormalities should continue aspirin indefinitely.

Approximately 10% of patients are IVIG-resistant and have persistent or recurrent fever for at least 36 hours after completion of the infusion. The current recommendation is to re-treat with IVIG at the same dose. If the patient has fever 36 hours after the second dose of IVIG, this is considered true treatment failure.

Other possible treatments for KD refractory to IVIG include IV methylprednisolone (30 mg/kg over two to three hours daily for three days) or infliximab.¹⁶ Even with prompt treatment, 5% of children who have KD develop coronary artery dilation, and 1% develop giant aneurysms.

Back to the Case

Initial laboratory evaluation revealed white blood cell count of 19.0×103 cells/mm3, hemoglobin of 8.9 gm/dL, CRP of 17.9 mg/dL, and ESR of 73 mm/hr. Because of persistent fevers for 48 hours after admission in the absence of another cause to explain the illness, the KD service was consulted. Echocardiography revealed dilatation of the left main (z-score 4.23) and proximal right (z-score 2.59), confirming the diagnosis of KD. Ejection fraction was read as qualitatively normal.

The infant received infliximab and IVIG, as well as high-dose aspirin, clopidogrel, and propranolol. This treatment regimen was directed by a KD expert and was more aggressive than typical therapy due to the severity of presentation. She received blood transfusions for worsening symptomatic anemia (hemoglobin 7.0 gm/dL) with hypoxia.

Following her IVIG infusion, she remained afebrile with progressive reduction in her CRP. She was discharged on hospital day seven on aspirin until her next follow-up, with propranolol for three days to limit potential tachycardia. At her three-week follow-up visit, her ESR had improved to 8 mm/hr. Her echocardiogram revealed a normal ejection fraction. Echocardiography revealed resolution of all abnormalities except for a borderline prominence of the right coronary artery (z-score 2.11). At this time it was recommended that her aspirin be discontinued.

She continues to be followed by the KD service as an outpatient and has done well without cardiovascular symptoms four months after her diagnosis.

Bottom Line

KD can manifest an incomplete presentation, especially in infants under the age of six months. Clinicians should maintain a high level of suspicion for KD in young infants with unexplained fevers lasting more than seven days.

Dr. Gurevich-Panigrahi is a fellow in pediatric hospital medicine at Cleveland Clinic Children’s Hospital. Dr. Kanegaye is a clinical professor of pediatrics at the University of California San Diego (UCSD) School of Medicine and attending physician in the emergency care center at Rady Children’s Hospital San Diego. Dr. Chang is associate clinical professor of pediatrics and medicine at UCSD School of Medicine, a pediatric hospitalist at Rady Children’s, and pediatric editor of The Hospitalist.

References

1. Hendaoui L, Stanson AW, Habib Bouhaouala M, Joffre F, eds. Systemic Vasculitis: Imaging Features. New York: Springer; 2012.
2. Manlhiot C, Yeung RS, Clarizia NA, Chahal N, McCrindle BW. Kawasaki disease at the extremes of the age spectrum. Pediatrics. 2009;124(3):e410-e415.
3. Huang WC, Huang LM, Chang IS, et al. Epidemiologic features of Kawasaki disease in Taiwan, 2003-2006. Pediatrics. 2009;123(3):e401-405.
4. Holman RC, Belay ED, Christensen KY, Folkema AM, Steiner CA, Schonberger LB. Hospitalizations for Kawasaki syndrome among children in the United States, 1997-2007. Pediatr Infect Dis J. 2010;29(6):483-438.
5. Council on Cardiovascular Disease in the Young, Committee on Rheumatic Fever Endocarditis, Kawasaki Disease, American Heart Association. Diagnostic guidelines for Kawasaki disease. Circulation. 2001;103:335-336.
6. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2747-2771.
7. Shiozawa Y, Inuzuka R, Harita Y, Kagawa J. Age-related differences in the course of the acute phase symptoms of Kawasaki disease. Pediatr Infect Dis J. 2013;32(9):e365-369.
8. Genizi J, Miron D, Spiegel R, Fink D, Horowitz Y. Kawasaki disease in very young infants: high prevalence of atypical presentation and coronary arteritis. Clin Pediatr (Phila.). 2003;42(3):263-267.
9. Sundel R. Incomplete (atypical) Kawasaki disease. UpToDate. Available at: http://www.uptodate.com/contents/incomplete-atypical-kawasaki-disease. Accessed June 9, 2014.
10. Kanegaye JT, Wilder MS, Molkara D, et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics. 2009;123(5):e783-e789.
11. Fimbres AM, Shulman ST. Kawasaki disease. Pediatr Rev. 2008;29(9):308-315.
12. Shike H, Kanegaye JT, Best BM, Pancheri J, Burns JC. Pyuria associated with acute Kawasaki disease and fever from other causes. Pediatr Infect Dis J. 2009;28(5):440-443.
13. Capannari TE, Daniels SR, Meyer RA, Schwartz DC, Kaplan S. Sensitivity, specificity and predictive value of two-dimensional echocardiography in detecting coronary artery aneurysms in patients with Kawasaki disease. J Am Coll Cardiol. 1986;7(2):355-360.
14. Mavrogeni S, Papadopoulos G, Karanasios E, Cokkinos DV. How to image Kawasaki disease: a validation of different imaging techniques. Int J Cardiol. 2008;124(1):27-31.
15. Burns JC, Glodé MP. Kawasaki syndrome. Lancet. 2004;364(9433):533-544.
16. Ghelani SJ, Pastor W, Parikh K. Demographic and treatment variability of refractory Kawasaki Disease: a multicenter analysis from 2005 to 2009. Hosp Pediatr. 2012;2(2):71-76.

Case

A seven-week-old Hispanic female with a history of prematurity (born at 35 weeks by C-section) presents to the ED with four days of fever as high as 102°F and new-onset cyanotic spells. Cultures of blood, urine, and cerebrospinal fluid obtained 48 hours prior to admission were negative, but she continued to have intermittent fevers and developed a macular, non-pruritic rash on her hands and feet, with associated non-bilious emesis. One day prior to admission, she began to have episodes of apnea, with color change and cyanosis of her lips and eyelids. In the ED, her vital signs include a rectal temperature of 38.4°C, heart rate of 178/min, respiratory rate of 27/min, and blood pressure of 79/66. Examination reveals a non-toxic-appearing infant, with no conjunctival or oropharyngeal abnormalities, unremarkable heart and lung exam, and a blanching, erythematous macular rash on her hands, lower legs, and feet.

When should you suspect Kawasaki disease (KD) as the cause of fever in an infant?

Background

KD is an acute systemic vasculitis of unknown etiology that occurs in children. Affecting the small- and medium-sized arteries, with a striking predilection for coronary arteries, it is the leading cause of acquired pediatric heart disease in Japan and the U.S.¹ Occurring predominantly in children younger than five years, KD has been diagnosed in infants and in young adults.² The incidence of KD is lowest among white children and highest among Asians and Pacific Islanders, with the highest incidence in children of Japanese descent.

A recent epidemiologic study performed in Taiwan showed an incidence of 69 cases per 100,000 per year among children younger than five years, with a male/female ratio of 1.62:1.³ The peak of mortality occurs 15-45 days after onset of fever, although sudden cardiac death may occur many years later. Recurrence rate is approximately 3%. In the U.S., the estimated incidence ranges from nine to 18 per 100,000 children younger than five years per year.⁴

Review of Data

Because there is no specific diagnostic test or pathognomonic clinical feature, clinical diagnostic criteria have been established to guide physicians. KD diagnosis traditionally requires fever for at least five days and the presence of at least four of the following five principal features:

• bilateral conjunctival injection;
• changes in the mucous membranes of the upper respiratory tract (injected pharynx, infected, fissured lips, strawberry tongue);
• polymorphous rash;
• changes of the extremities (peripheral edema, erythema, periungual desquamation); and
• cervical lymphadenopathy.⁵

Adapted from: Newburger JW, Takahashi M, Gerber MA. Diagnosis, treatment, and long-term management of Kawasaki Disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771.

The fever, which is remittent, typically peaks at 39ºC to 40ºC. The mean duration of untreated fever is 11 days; with prompt treatment, fever typically subsides in two days. Bilateral painless non-exudative conjunctival injection begins shortly after onset of fever, involves typically bulbar conjunctiva, and is not associated with edema.

Erythematous rash usually appears within five days of onset of fever and is often a diffuse, nonspecific maculopapular eruption that is commonly pronounced in the perineal region. The appearance might be urticarial, micropustular, or erythema multiforme-like. Changes in extremities include erythema of palms and soles and tender induration of the hands and feet. Subsequently, desquamation begins in the periungual area within two to three weeks after the onset of fever. Typically, peeling begins around the nail folds of fingers, followed by the toes. The least common of the principal clinical features is tender unilateral anterior cervical lymphadenopathy (1.5 cm or greater in diameter).

When a patient presents with a history, examination, and laboratory findings consistent with KD without meeting the typical diagnostic standard, incomplete KD should be considered. The term “incomplete” is favored over “atypical” for this pre-sentation, because these patients are otherwise similar to other patients with KD. Patients with fever for five or fewer days and fewer than four principal features can be diagnosed as having KD when coronary artery disease is detected by two-dimensional echocardiography or coronary angiography (see Figure 1, p. 10). In the presence of four or more principal criteria, KD can be diagnosed before day four of the illness by an experienced clinician.6 Features less consistent with KD include the presence of exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, or generalized adenopathy.

If clinical features are consistent with KD, further risk stratification with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) will determine whether patients are followed daily (if low) or if supplementary laboratory tests should be done (see Figure 1, p. 10). If three or more of supplementary laboratory criteria are present (albumin ≤3.0 g/dL, anemia for age, elevation of alanine aminotransferase (ALT), platelet count after seven days is 450 000/mm3 or greater, white blood cell count is 15,000/mm3 or greater, and urinary sediment containing 10 white blood cells/high-power field or more), echocardiogram should be performed and treatment initiated if abnormal.⁶

Young infants are more likely to manifest an incomplete presentation of KD, with a polymorphous rash being the most common symptom other than fever in this age group.⁷ Acute phase symptoms were also more likely to progress rapidly in this age group, with a higher risk of developing cardiac sequelae.⁸ As a result, any infant under the age of six months with fever for more than seven days and no other clear etiology should be evaluated for KD even in the absence of other diagnostic criteria.⁹

Other clinical manifestations of KD may include:

• Irritability: more notable in KD than in other febrile illnesses;
• Arthralgia and arthritis: may occur in the first week;
• Gastrointestinal complaints and findings: hepatomegaly, jaundice; and
• Abnormal chest X-ray findings: may be present in as many as 15% of patients.

Cardiovascular manifestations can be prominent in the acute phase of KD and are the leading cause of long-term morbidity and mortality. Coronary artery aneurysms occur in 20% of affected children with KD. Other cardiovascular complications include myocardial ischemia and ensuing depressed contractility and arrhythmias, as well as vascular obstruction in peripheral arteries.

A subset of KD patients develops hemodynamic instability requiring management in a critical care setting. This phenomenon has been named Kawasaki disease shock syndrome, where hemodynamic instability is not related to administration of intravenous immunoglobulin (IVIG). Patients are more likely to be female, to have laboratory findings consistent with greater inflammation, and to have impaired systolic and diastolic function. They also exhibit resistance to IVIG more often and have higher rates of coronary artery dilation and aneurysm formation.¹⁰

Differential diagnoses for KD may include viral infections, scarlet fever, staphylococcal scalded skin syndrome, toxic shock syndrome, Rocky Mountain spotted fever, cervical lymphadenitis, drug hypersensitivity, Stevens-Johnson syndrome, systemic idiopathic arthritis, leptospirosis, and mercury hypersensitivity reaction.¹¹

Work-Up

Laboratory evaluation of a patient with suspected KD should include:

• Complete blood count (CBC) with differential: leukocytosis, anemia, thrombocytosis that peaks in the third week is characteristic. A manual differential may reveal an increase in band forms.
• Acute phase reactants: If C-reactive protein (CRP) is 3 mg/dL or greater and erythrocyte sedimentation rate (ESR) is 40 mm/hr or greater, supplementary laboratory work-up should be done. Make sure not to cloud classic with incomplete KD; the stepwise lab evaluation only pertains to the latter.
• Liver panel: Elevated ALT and gamma-glutamyl transferase (GGT), mild hyperbilirubinemia, or hypoalbuminemia may be present.
• Urinalysis: Sterile pyuria may be present; if present, it may be of urethral origin, and catheterized samples could miss this finding.¹²

Lack of elevated inflammatory markers (CRP is less than 3 mg/dl and ESR is less than 40 mm/hr) and the presence of two or three principal clinical features warrant ongoing daily monitoring of ESR, CRP, and fever until day seven of illness. If the fever resolves but is followed by peeling of extremities, an echocardiogram should be done. Lumbar puncture might help differentiate from CNS infectious etiologies, but about 50% of KD patients have a cerebrospinal fluid pleocytosis.

Echocardiography is the preferred imaging modality for the initial cardiovascular evaluation and follow-up.¹ It has a sensitivity of 100% and specificity of 96% for the detection of proximal coronary aneurysms.¹³ Coronary aneurysms are clinically silent in most cases and can manifest with delayed complications, such as myocardial infarction or sudden death. Imaging plays an important role in the early diagnosis of these aneurysms and in estimating their number, size, and location, important elements in making a therapeutic decision.¹⁴

Although the echocardiography should be done as soon as KD is suspected, definitive treatment must not be delayed. Evaluation of all coronary artery segments, as well as cardiac contractility and presence of effusion, should be noted on echocardiography. In the absence of complications, echocardiography is performed at the time of diagnosis and at two weeks and six to eight weeks after disease onset.¹¹

Treatment

Treatment goals for Kawasaki disease in the acute phase are reduction of systemic and coronary arterial inflammation and prevention of coronary thrombosis. The long-term therapy in individuals who develop coronary aneurysms is aimed at preventing myocardial ischemia or infarction.6 The current standard of care for the treatment of children in the U.S. is anti-inflammatory therapy with:

• immunoglobulin (IVIG) in a single 2 g/kg/dose infused over 10–12 hours, accompanied by;
• high-dose aspirin (80–100 mg/kg/day orally in four divided doses).^6,15

IVIG administration within 10 days of the onset of fever results in more favorable outcomes. Live virus vaccines should be delayed to 11 months after administration of IVIG. Both aspirin and IVIG have anti-inflammatory effects. This regimen applies to patients without abnormalities on initial echocardiography. High-dose aspirin typically is continued for 48-72 hours after the child becomes afebrile. Thereafter, low-dose aspirin (3-5 mg/kg/day) is prescribed until patient shows no evidence of coronary changes, typically by six to eight weeks after onset of illness. Children with coronary abnormalities should continue aspirin indefinitely.

Approximately 10% of patients are IVIG-resistant and have persistent or recurrent fever for at least 36 hours after completion of the infusion. The current recommendation is to re-treat with IVIG at the same dose. If the patient has fever 36 hours after the second dose of IVIG, this is considered true treatment failure.

Other possible treatments for KD refractory to IVIG include IV methylprednisolone (30 mg/kg over two to three hours daily for three days) or infliximab.¹⁶ Even with prompt treatment, 5% of children who have KD develop coronary artery dilation, and 1% develop giant aneurysms.

Back to the Case

Initial laboratory evaluation revealed white blood cell count of 19.0×103 cells/mm3, hemoglobin of 8.9 gm/dL, CRP of 17.9 mg/dL, and ESR of 73 mm/hr. Because of persistent fevers for 48 hours after admission in the absence of another cause to explain the illness, the KD service was consulted. Echocardiography revealed dilatation of the left main (z-score 4.23) and proximal right (z-score 2.59), confirming the diagnosis of KD. Ejection fraction was read as qualitatively normal.

The infant received infliximab and IVIG, as well as high-dose aspirin, clopidogrel, and propranolol. This treatment regimen was directed by a KD expert and was more aggressive than typical therapy due to the severity of presentation. She received blood transfusions for worsening symptomatic anemia (hemoglobin 7.0 gm/dL) with hypoxia.

Following her IVIG infusion, she remained afebrile with progressive reduction in her CRP. She was discharged on hospital day seven on aspirin until her next follow-up, with propranolol for three days to limit potential tachycardia. At her three-week follow-up visit, her ESR had improved to 8 mm/hr. Her echocardiogram revealed a normal ejection fraction. Echocardiography revealed resolution of all abnormalities except for a borderline prominence of the right coronary artery (z-score 2.11). At this time it was recommended that her aspirin be discontinued.

She continues to be followed by the KD service as an outpatient and has done well without cardiovascular symptoms four months after her diagnosis.

Bottom Line

KD can manifest an incomplete presentation, especially in infants under the age of six months. Clinicians should maintain a high level of suspicion for KD in young infants with unexplained fevers lasting more than seven days.

Dr. Gurevich-Panigrahi is a fellow in pediatric hospital medicine at Cleveland Clinic Children’s Hospital. Dr. Kanegaye is a clinical professor of pediatrics at the University of California San Diego (UCSD) School of Medicine and attending physician in the emergency care center at Rady Children’s Hospital San Diego. Dr. Chang is associate clinical professor of pediatrics and medicine at UCSD School of Medicine, a pediatric hospitalist at Rady Children’s, and pediatric editor of The Hospitalist.

References

1. Hendaoui L, Stanson AW, Habib Bouhaouala M, Joffre F, eds. Systemic Vasculitis: Imaging Features. New York: Springer; 2012.
2. Manlhiot C, Yeung RS, Clarizia NA, Chahal N, McCrindle BW. Kawasaki disease at the extremes of the age spectrum. Pediatrics. 2009;124(3):e410-e415.
3. Huang WC, Huang LM, Chang IS, et al. Epidemiologic features of Kawasaki disease in Taiwan, 2003-2006. Pediatrics. 2009;123(3):e401-405.
4. Holman RC, Belay ED, Christensen KY, Folkema AM, Steiner CA, Schonberger LB. Hospitalizations for Kawasaki syndrome among children in the United States, 1997-2007. Pediatr Infect Dis J. 2010;29(6):483-438.
5. Council on Cardiovascular Disease in the Young, Committee on Rheumatic Fever Endocarditis, Kawasaki Disease, American Heart Association. Diagnostic guidelines for Kawasaki disease. Circulation. 2001;103:335-336.
6. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2747-2771.
7. Shiozawa Y, Inuzuka R, Harita Y, Kagawa J. Age-related differences in the course of the acute phase symptoms of Kawasaki disease. Pediatr Infect Dis J. 2013;32(9):e365-369.
8. Genizi J, Miron D, Spiegel R, Fink D, Horowitz Y. Kawasaki disease in very young infants: high prevalence of atypical presentation and coronary arteritis. Clin Pediatr (Phila.). 2003;42(3):263-267.
9. Sundel R. Incomplete (atypical) Kawasaki disease. UpToDate. Available at: http://www.uptodate.com/contents/incomplete-atypical-kawasaki-disease. Accessed June 9, 2014.
10. Kanegaye JT, Wilder MS, Molkara D, et al. Recognition of a Kawasaki disease shock syndrome. Pediatrics. 2009;123(5):e783-e789.
11. Fimbres AM, Shulman ST. Kawasaki disease. Pediatr Rev. 2008;29(9):308-315.
12. Shike H, Kanegaye JT, Best BM, Pancheri J, Burns JC. Pyuria associated with acute Kawasaki disease and fever from other causes. Pediatr Infect Dis J. 2009;28(5):440-443.
13. Capannari TE, Daniels SR, Meyer RA, Schwartz DC, Kaplan S. Sensitivity, specificity and predictive value of two-dimensional echocardiography in detecting coronary artery aneurysms in patients with Kawasaki disease. J Am Coll Cardiol. 1986;7(2):355-360.
14. Mavrogeni S, Papadopoulos G, Karanasios E, Cokkinos DV. How to image Kawasaki disease: a validation of different imaging techniques. Int J Cardiol. 2008;124(1):27-31.
15. Burns JC, Glodé MP. Kawasaki syndrome. Lancet. 2004;364(9433):533-544.
16. Ghelani SJ, Pastor W, Parikh K. Demographic and treatment variability of refractory Kawasaki Disease: a multicenter analysis from 2005 to 2009. Hosp Pediatr. 2012;2(2):71-76.

Improving the quality of care in your hospital isn’t just good for your hospital medicine group or your hospital; it’s good for the community. Each year, SHM leads some of the best quality improvement programs in healthcare, and you can get involved.

SHM is now accepting applications for the Glycemic Control Mentored Implementation Program. An informational webinar about the program will be available on Aug. 14. For details, visit www.hospitalmedicine.org/gcmi.

There is still time to apply for the Project BOOST fall cohort. For details, visit www.hospitalmedicine.org/boost.

Are you implementing Choosing Wisely in your hospital? You could win SHM’s Choosing Wisely competition and share your expertise with thousands of other hospitalists.

Visit www.hospitalmedicine.org/choosingwisely to learn more.

Improving the quality of care in your hospital isn’t just good for your hospital medicine group or your hospital; it’s good for the community. Each year, SHM leads some of the best quality improvement programs in healthcare, and you can get involved.

SHM is now accepting applications for the Glycemic Control Mentored Implementation Program. An informational webinar about the program will be available on Aug. 14. For details, visit www.hospitalmedicine.org/gcmi.

There is still time to apply for the Project BOOST fall cohort. For details, visit www.hospitalmedicine.org/boost.

Are you implementing Choosing Wisely in your hospital? You could win SHM’s Choosing Wisely competition and share your expertise with thousands of other hospitalists.

Visit www.hospitalmedicine.org/choosingwisely to learn more.

Improving the quality of care in your hospital isn’t just good for your hospital medicine group or your hospital; it’s good for the community. Each year, SHM leads some of the best quality improvement programs in healthcare, and you can get involved.

SHM is now accepting applications for the Glycemic Control Mentored Implementation Program. An informational webinar about the program will be available on Aug. 14. For details, visit www.hospitalmedicine.org/gcmi.

There is still time to apply for the Project BOOST fall cohort. For details, visit www.hospitalmedicine.org/boost.

Are you implementing Choosing Wisely in your hospital? You could win SHM’s Choosing Wisely competition and share your expertise with thousands of other hospitalists.

Visit www.hospitalmedicine.org/choosingwisely to learn more.

The American Board of Internal Medicine (ABIM) established the ABIM Foundation to advance professionalism in improving healthcare. The foundation initiated the Choosing Wisely campaign [www.choosingwisely.org] in April 2012 to promote conversations that help physicians guide patients in selecting care that is supported by evidence, not duplicative of other tests or procedures, not harmful, and truly necessary. In order to achieve this, national organizations representing medical specialists were asked to identify five common tests or procedures whose necessity should be questioned.

John Bulger, DO, MBA, SFHM, chief quality officer at Geisinger Health System in Danville, Pa., chaired SHM’s Choosing Wisely recommendations committee. He says the “proximal concern over these tests may be the unnecessary cost of the test itself, [but] there are other unintended consequences.

“False positive or false negative results of unsupported testing may cause unwarranted emotional harm for the patient or may give a false sense of security,” he adds. “The latter may also be true for physicians who may fail to further investigate other ailments based on a previous false negative test. Tests ordered with little evidence tend to lead to more tests ordered with little evidence.”

To date, more than 60 specialty societies and 17 consumer groups have joined the Choosing Wisely effort, citing more than 300 potentially harmful tests and procedures that physicians should discuss with patients. New lists will be published throughout 2014.

—Karen Appold

The American Board of Internal Medicine (ABIM) established the ABIM Foundation to advance professionalism in improving healthcare. The foundation initiated the Choosing Wisely campaign [www.choosingwisely.org] in April 2012 to promote conversations that help physicians guide patients in selecting care that is supported by evidence, not duplicative of other tests or procedures, not harmful, and truly necessary. In order to achieve this, national organizations representing medical specialists were asked to identify five common tests or procedures whose necessity should be questioned.

John Bulger, DO, MBA, SFHM, chief quality officer at Geisinger Health System in Danville, Pa., chaired SHM’s Choosing Wisely recommendations committee. He says the “proximal concern over these tests may be the unnecessary cost of the test itself, [but] there are other unintended consequences.

“False positive or false negative results of unsupported testing may cause unwarranted emotional harm for the patient or may give a false sense of security,” he adds. “The latter may also be true for physicians who may fail to further investigate other ailments based on a previous false negative test. Tests ordered with little evidence tend to lead to more tests ordered with little evidence.”

To date, more than 60 specialty societies and 17 consumer groups have joined the Choosing Wisely effort, citing more than 300 potentially harmful tests and procedures that physicians should discuss with patients. New lists will be published throughout 2014.

—Karen Appold

The American Board of Internal Medicine (ABIM) established the ABIM Foundation to advance professionalism in improving healthcare. The foundation initiated the Choosing Wisely campaign [www.choosingwisely.org] in April 2012 to promote conversations that help physicians guide patients in selecting care that is supported by evidence, not duplicative of other tests or procedures, not harmful, and truly necessary. In order to achieve this, national organizations representing medical specialists were asked to identify five common tests or procedures whose necessity should be questioned.

John Bulger, DO, MBA, SFHM, chief quality officer at Geisinger Health System in Danville, Pa., chaired SHM’s Choosing Wisely recommendations committee. He says the “proximal concern over these tests may be the unnecessary cost of the test itself, [but] there are other unintended consequences.

“False positive or false negative results of unsupported testing may cause unwarranted emotional harm for the patient or may give a false sense of security,” he adds. “The latter may also be true for physicians who may fail to further investigate other ailments based on a previous false negative test. Tests ordered with little evidence tend to lead to more tests ordered with little evidence.”

To date, more than 60 specialty societies and 17 consumer groups have joined the Choosing Wisely effort, citing more than 300 potentially harmful tests and procedures that physicians should discuss with patients. New lists will be published throughout 2014.

—Karen Appold

Background

Hospitalists commonly order red blood cell (RBC) transfusion as a therapy for patients with anemia resulting from a variety of clinical conditions. There has been lack of consensus on when to transfuse, because patients with anemia frequently have multiple co-morbidities, including coronary artery disease and congestive heart failure, which may influence their ability to tolerate a potentially ischemic state related to anemia or to accommodate volume fluctuations related to transfusion.

Furthermore, RBC transfusions are not without inherent risk. Life-threatening transfusion reactions occur in approximately seven per million transfused blood components, and transfusion-associated circulatory overload (TACO) can develop in one in 100 transfusions.¹

Recently published guidelines provide recommendations for management of hemodynamically stable adults with anemia.

Guideline Update

The AABB published guidelines in the Annals of Internal Medicine in 2012 addressing RBC transfusion thresholds.¹ The updated guideline makes a recommendation that clinicians utilize a restrictive transfusion strategy. Transfusion is strongly recommended for ICU patients with hemoglobin ≤7g/dL. In post-operative surgical patients and for post-operative patients with symptomatic anemia, transfusion is recommended for hemoglobin ≤8g/dL. The authors also made a weak recommendation to transfuse for hemoglobin ≤8g/dL or for symptoms in hospitalized hemodynamically stable patients with preexisting cardiovascular disease.

These recommendations draw from past literature, along with two more recent trials examining liberal or restrictive transfusion thresholds. The newer trials increased the total number of patients studied by nearly one third compared with prior reviews.^2,3 The authors also incorporated recently published systematic reviews in their analysis.

Although the definition of a restrictive transfusion threshold varied across trials, including hemoglobin ≤7g/dL and ≤8g/dL, the authors used the pooled data to provide several recommendations in the new guideline. Of note, the pooled data was underpowered to detect up to a twofold increase in risk of myocardial infarction in patients in the restrictive strategy group.¹

There were insufficient data for the authors to recommend for or against a restrictive transfusion strategy in patients with acute coronary syndrome, based on very low quality evidence.

Finally, the authors recommended that symptoms and hemoglobin level should both be used in determining transfusion criteria, based on low quality of evidence.

Analysis

The current AABB guidelines have two primary differences from earlier guidelines. First, the AABB authors used GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to formalize evidence-based practice in their analysis of the literature. The authors purposely used the GRADE methodology to systematically evaluate the quality of the evidence base and explicitly state the strength of the recommendation for a particular transfusion threshold.⁴

Second, the AABB guidelines incorporated data from the more recently published FOCUS (Functional Outcomes in Cardiovascular patients Undergoing Surgical repair of hip fracture) and TRACS (Transfusion Requirements After Cardiac Surgery) trials, resulting in a stronger recommendation supporting the use of a restrictive transfusion strategy in non-ICU and post-operative patients. The findings of the FOCUS trial are especially applicable to hospitalists, because many patients who undergo hip fracture repair are directly cared for or are co-managed by hospitalists.

The current guidelines built upon previous guidelines that advocated a restrictive strategy (hemoglobin ≤7g/dL) in hemodynamically stable, critically ill adult patients.⁵ In general, restrictive transfusion strategy led to nearly 40% fewer patients receiving transfusion compared with the use of a liberal transfusion strategy.1 No additional harm to patients was evidenced in the restrictive transfusion group, though the trials were not designed to answer this question; moreover, there was no statistically significant difference in mortality or functional outcome between the two groups.

The authors of the current AABB guidelines recognized the importance of replicating the current findings in a more diverse patient population. An area where further study is indicated is in the use of specific transfusion thresholds in patients with acute coronary syndrome. These guidelines did not clarify whether or not there is a physiologic difference between use of different restrictive transfusion thresholds such as <8g/dL and <7g/dL.

The authors of the AABB guidelines also commented that performing a future trial to compare RBC transfusion for symptoms vs. hemoglobin “trigger” would be useful; however, they recognized that this may not be feasible due to the need to blind providers in the trial to hemoglobin values. Various society guidelines currently call for different transfusion thresholds or do not make a specific recommendation at all.¹

Key Takeaways for Hospitalists

For the vast majority of medical patients, hospitalists can safely use a restrictive RBC transfusion threshold (≤7g/dL or ≤8g/dL), which can lead to a significant decrease in RBC transfusions without adversely affecting overall mortality.

Drs. Bortinger and Carbo are hospitalists at Beth Israel Deaconess Medical Center in Boston.

References

1. Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Inter Med. 2012;157(1):49-58.
2. Carson AL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;367(26):2453-2462.
3. Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-1567.
4. Carson JL, Carless PA, Herbert PC. Transfusion threshold and other strategies for guiding allogenic red blood cell transfusion. Cochrane Database Syst Rev. 2012;CD002042.
5. Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37(12):3124-3157.

Background

Hospitalists commonly order red blood cell (RBC) transfusion as a therapy for patients with anemia resulting from a variety of clinical conditions. There has been lack of consensus on when to transfuse, because patients with anemia frequently have multiple co-morbidities, including coronary artery disease and congestive heart failure, which may influence their ability to tolerate a potentially ischemic state related to anemia or to accommodate volume fluctuations related to transfusion.

Furthermore, RBC transfusions are not without inherent risk. Life-threatening transfusion reactions occur in approximately seven per million transfused blood components, and transfusion-associated circulatory overload (TACO) can develop in one in 100 transfusions.¹

Recently published guidelines provide recommendations for management of hemodynamically stable adults with anemia.

Guideline Update

The AABB published guidelines in the Annals of Internal Medicine in 2012 addressing RBC transfusion thresholds.¹ The updated guideline makes a recommendation that clinicians utilize a restrictive transfusion strategy. Transfusion is strongly recommended for ICU patients with hemoglobin ≤7g/dL. In post-operative surgical patients and for post-operative patients with symptomatic anemia, transfusion is recommended for hemoglobin ≤8g/dL. The authors also made a weak recommendation to transfuse for hemoglobin ≤8g/dL or for symptoms in hospitalized hemodynamically stable patients with preexisting cardiovascular disease.

These recommendations draw from past literature, along with two more recent trials examining liberal or restrictive transfusion thresholds. The newer trials increased the total number of patients studied by nearly one third compared with prior reviews.^2,3 The authors also incorporated recently published systematic reviews in their analysis.

Although the definition of a restrictive transfusion threshold varied across trials, including hemoglobin ≤7g/dL and ≤8g/dL, the authors used the pooled data to provide several recommendations in the new guideline. Of note, the pooled data was underpowered to detect up to a twofold increase in risk of myocardial infarction in patients in the restrictive strategy group.¹

There were insufficient data for the authors to recommend for or against a restrictive transfusion strategy in patients with acute coronary syndrome, based on very low quality evidence.

Finally, the authors recommended that symptoms and hemoglobin level should both be used in determining transfusion criteria, based on low quality of evidence.

Analysis

The current AABB guidelines have two primary differences from earlier guidelines. First, the AABB authors used GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to formalize evidence-based practice in their analysis of the literature. The authors purposely used the GRADE methodology to systematically evaluate the quality of the evidence base and explicitly state the strength of the recommendation for a particular transfusion threshold.⁴

Second, the AABB guidelines incorporated data from the more recently published FOCUS (Functional Outcomes in Cardiovascular patients Undergoing Surgical repair of hip fracture) and TRACS (Transfusion Requirements After Cardiac Surgery) trials, resulting in a stronger recommendation supporting the use of a restrictive transfusion strategy in non-ICU and post-operative patients. The findings of the FOCUS trial are especially applicable to hospitalists, because many patients who undergo hip fracture repair are directly cared for or are co-managed by hospitalists.

The current guidelines built upon previous guidelines that advocated a restrictive strategy (hemoglobin ≤7g/dL) in hemodynamically stable, critically ill adult patients.⁵ In general, restrictive transfusion strategy led to nearly 40% fewer patients receiving transfusion compared with the use of a liberal transfusion strategy.1 No additional harm to patients was evidenced in the restrictive transfusion group, though the trials were not designed to answer this question; moreover, there was no statistically significant difference in mortality or functional outcome between the two groups.

The authors of the current AABB guidelines recognized the importance of replicating the current findings in a more diverse patient population. An area where further study is indicated is in the use of specific transfusion thresholds in patients with acute coronary syndrome. These guidelines did not clarify whether or not there is a physiologic difference between use of different restrictive transfusion thresholds such as <8g/dL and <7g/dL.

The authors of the AABB guidelines also commented that performing a future trial to compare RBC transfusion for symptoms vs. hemoglobin “trigger” would be useful; however, they recognized that this may not be feasible due to the need to blind providers in the trial to hemoglobin values. Various society guidelines currently call for different transfusion thresholds or do not make a specific recommendation at all.¹

Key Takeaways for Hospitalists

For the vast majority of medical patients, hospitalists can safely use a restrictive RBC transfusion threshold (≤7g/dL or ≤8g/dL), which can lead to a significant decrease in RBC transfusions without adversely affecting overall mortality.

Drs. Bortinger and Carbo are hospitalists at Beth Israel Deaconess Medical Center in Boston.

References

1. Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Inter Med. 2012;157(1):49-58.
2. Carson AL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;367(26):2453-2462.
3. Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-1567.
4. Carson JL, Carless PA, Herbert PC. Transfusion threshold and other strategies for guiding allogenic red blood cell transfusion. Cochrane Database Syst Rev. 2012;CD002042.
5. Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37(12):3124-3157.

Background

Hospitalists commonly order red blood cell (RBC) transfusion as a therapy for patients with anemia resulting from a variety of clinical conditions. There has been lack of consensus on when to transfuse, because patients with anemia frequently have multiple co-morbidities, including coronary artery disease and congestive heart failure, which may influence their ability to tolerate a potentially ischemic state related to anemia or to accommodate volume fluctuations related to transfusion.

Furthermore, RBC transfusions are not without inherent risk. Life-threatening transfusion reactions occur in approximately seven per million transfused blood components, and transfusion-associated circulatory overload (TACO) can develop in one in 100 transfusions.¹

Recently published guidelines provide recommendations for management of hemodynamically stable adults with anemia.

Guideline Update

The AABB published guidelines in the Annals of Internal Medicine in 2012 addressing RBC transfusion thresholds.¹ The updated guideline makes a recommendation that clinicians utilize a restrictive transfusion strategy. Transfusion is strongly recommended for ICU patients with hemoglobin ≤7g/dL. In post-operative surgical patients and for post-operative patients with symptomatic anemia, transfusion is recommended for hemoglobin ≤8g/dL. The authors also made a weak recommendation to transfuse for hemoglobin ≤8g/dL or for symptoms in hospitalized hemodynamically stable patients with preexisting cardiovascular disease.

These recommendations draw from past literature, along with two more recent trials examining liberal or restrictive transfusion thresholds. The newer trials increased the total number of patients studied by nearly one third compared with prior reviews.^2,3 The authors also incorporated recently published systematic reviews in their analysis.

Although the definition of a restrictive transfusion threshold varied across trials, including hemoglobin ≤7g/dL and ≤8g/dL, the authors used the pooled data to provide several recommendations in the new guideline. Of note, the pooled data was underpowered to detect up to a twofold increase in risk of myocardial infarction in patients in the restrictive strategy group.¹

There were insufficient data for the authors to recommend for or against a restrictive transfusion strategy in patients with acute coronary syndrome, based on very low quality evidence.

Finally, the authors recommended that symptoms and hemoglobin level should both be used in determining transfusion criteria, based on low quality of evidence.

Analysis

The current AABB guidelines have two primary differences from earlier guidelines. First, the AABB authors used GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to formalize evidence-based practice in their analysis of the literature. The authors purposely used the GRADE methodology to systematically evaluate the quality of the evidence base and explicitly state the strength of the recommendation for a particular transfusion threshold.⁴

Second, the AABB guidelines incorporated data from the more recently published FOCUS (Functional Outcomes in Cardiovascular patients Undergoing Surgical repair of hip fracture) and TRACS (Transfusion Requirements After Cardiac Surgery) trials, resulting in a stronger recommendation supporting the use of a restrictive transfusion strategy in non-ICU and post-operative patients. The findings of the FOCUS trial are especially applicable to hospitalists, because many patients who undergo hip fracture repair are directly cared for or are co-managed by hospitalists.

The current guidelines built upon previous guidelines that advocated a restrictive strategy (hemoglobin ≤7g/dL) in hemodynamically stable, critically ill adult patients.⁵ In general, restrictive transfusion strategy led to nearly 40% fewer patients receiving transfusion compared with the use of a liberal transfusion strategy.1 No additional harm to patients was evidenced in the restrictive transfusion group, though the trials were not designed to answer this question; moreover, there was no statistically significant difference in mortality or functional outcome between the two groups.

The authors of the current AABB guidelines recognized the importance of replicating the current findings in a more diverse patient population. An area where further study is indicated is in the use of specific transfusion thresholds in patients with acute coronary syndrome. These guidelines did not clarify whether or not there is a physiologic difference between use of different restrictive transfusion thresholds such as <8g/dL and <7g/dL.

The authors of the AABB guidelines also commented that performing a future trial to compare RBC transfusion for symptoms vs. hemoglobin “trigger” would be useful; however, they recognized that this may not be feasible due to the need to blind providers in the trial to hemoglobin values. Various society guidelines currently call for different transfusion thresholds or do not make a specific recommendation at all.¹

Key Takeaways for Hospitalists

For the vast majority of medical patients, hospitalists can safely use a restrictive RBC transfusion threshold (≤7g/dL or ≤8g/dL), which can lead to a significant decrease in RBC transfusions without adversely affecting overall mortality.

Drs. Bortinger and Carbo are hospitalists at Beth Israel Deaconess Medical Center in Boston.

References

1. Carson JL, Grossman BJ, Kleinman S, et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Inter Med. 2012;157(1):49-58.
2. Carson AL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med. 2011;367(26):2453-2462.
3. Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-1567.
4. Carson JL, Carless PA, Herbert PC. Transfusion threshold and other strategies for guiding allogenic red blood cell transfusion. Cochrane Database Syst Rev. 2012;CD002042.
5. Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37(12):3124-3157.

click for large version

Case

A 65-year-old male with a history of a motor vehicle accident that required emergency surgery in 1982 is hospitalized for acute renal failure. He reports a distant history of IV heroin use and a brief incarceration. He does not currently use illicit drugs. He has no signs or symptoms of liver disease. Should this patient be screened for chronic hepatitis C virus (HCV) infection?

Brief Overview

HCV is a major public health concern in the United States and worldwide. It is estimated that more than 4.1 million people in the U.S. (1.6% prevalence) and more than 180 million worldwide (2.8% prevalence) are HCV antibody-positive.^1,2 The acute infection is most often asymptomatic, and 80% to 100% of patients will remain HCV RNA-positive, 60% to 80% will have persistently elevated liver enzymes, and 16% will develop evidence of cirrhosis at 20 years after initial infection.³

A number of organizations in the United States have released HCV screening guidelines, including the CDC, the American Association for the Study of Liver Disease (AASLD), and the U.S. Preventive Services Task Force (USPSTF); however, despite these established recommendations, an estimated 50% of individuals with chronic HCV infection are unscreened and unaware of their infection status.⁴ Furthermore, in a recent study of one managed care network, even when one or more risk factors were present, only 29% of individuals underwent screening for HCV antibodies detection.⁵ The importance of detecting chronic HCV infection will have greater significance as newer and better-tolerated treatment options become available.⁶

Multiple organizations recommend screening for chronic HCV infection. This screening is recommended for patients with known risk factors and those in populations with a high prevalence of HCV infection.

Risk Factors and High-Prevalence Populations

IV or intranasal drug use. IV drug use is the main identifiable source of HCV infection in the U.S. It is estimated that 60% of new HCV infections occur in people who have injected drugs in the past six months.⁷ The prevalence of HCV antibodies in current IV drug users is between 72% and 96%.8 Intranasal cocaine use is also associated with a higher prevalence of HCV antibodies than the general population.⁸

Blood transfusion prior to July 1992. Testing of donor blood was not routinely done until 1990, and more sensitive testing was not implemented until July 1992.⁸ The prevalence of HCV antibodies in people who received blood transfusions prior to 1990 is 6%.8 Prior to 1990, the risk for transfusion-associated HCV infection was one in 526 units transfused.⁹ Since implementation of highly sensitive screening techniques, the risk of infection has dropped to less than one in 1.9 million units transfused.¹⁰

Clotting factors prior to 1987 or transplanted tissue prior to 1992. Individuals who have received clotting factors, other blood product transfusions, or transplanted tissue prior to 1987 are at an increased risk for developing HCV infection. For instance, individuals with hemophilia treated with clotting factors prior to 1987 had chronic HCV infection rates of up to 90%.⁸ In 1987, widespread use of protocols to inactivate HCV in clotting factors and other blood products was adopted.⁸ In addition, widespread screening of potential tissue donors and the use of HCV antibody-negative donors became routine.⁸

Alanine aminotransferase elevation. This can be considered screening or part of the diagnostic work-up of transaminitis. Regardless of the classification, this is a cohort of people with a high prevalence of HCV antibody. For individuals with one isolated alanine aminotransferase elevation, the prevalence is 3.2%.⁴ With two or more elevated aminotransferase results, the prevalence rises to 8.2%.⁴

Hemodialysis. Two major studies have estimated the prevalence of HCV antibody-positive in end-stage renal disease individuals on hemodialysis to be 7.8% and 10.4%.^11,12 This prevalence can reach 64% at some dialysis centers.¹¹ The risk of HCV infection has been associated with blood transfusions, longer duration of hemodialysis, and higher rates of HCV infection in the dialysis unit.¹³ With implementation of infection control practices in dialysis units, the incidence and prevalence of HCV infection are declining.¹³

Born in the U.S. between 1945 and 1965. The CDC and USPSTF recommend a one-time screening for HCV infection for people born in the U.S. between 1945 and 1965, regardless of the presence or absence of risk factors.^6,14 This age group has an increased prevalence of HCV antibodies, at 3.25%.⁶

Human immunodeficiency virus (HIV). HCV has a prevalence of 30% in people infected with HIV.¹⁵ The rate of co-infection is likely secondary to shared routes of transmission. For example, 72.7% of HIV-infected individuals who used IV drugs had HCV antibodies, but only 3.5% of “low-risk” HIV-infected individuals had HCV antibodies.¹⁶

Born in a high prevalence country. In the U.S., a significant number of immigrants are from areas with a high endemic rate of HCV infection. High prevalence areas (greater than 3.5%) include Central Asia and East Asia, North Africa, and the Middle East.⁷ Of note, Egypt is thought to have the highest prevalence of chronic HCV infection in the world, with well over 10% of the population being antibody-positive.¹⁷ Although major guidelines do not currently recommend it, the high prevalence of chronic HCV infection in this population may warrant screening.

Other high-risk or high-prevalence populations. The prevalence of HCV infection in people who have had over 10 lifetime sexual partners (3% to 9%), those with a history of sexually transmitted disease (6%), men who have had sex with men (5%), and children born to HCV-infected mothers (5%) is increased compared with the general population.⁸ Incarcerated people in the U.S. have an HCV antibody prevalence of 16% to 41%.¹⁸ In addition, people who have sustained needle-stick injury or mucosal exposure, or those with potential exposures in unregulated tattoo or piercing salons, may also benefit from HCV antibody screening.¹⁴

Table 1 reviews HCV screening recommendations for the CDC, AASLD, and USPSTF.^1,6,8,14

click for large version

Screening Method

The most common initial screening test for the diagnosis of chronic HCV infection is the HCV antibody test. A positive antibody test should be followed by an HCV RNA test. In an individual with recent exposure, it takes between four and 10 weeks for the antibody to be detectable. HCV RNA testing can be positive as soon as two to three weeks after infection.⁸

Hospitalist Role in HCV Screening

None of the U.S.-based guidelines make recommendations on the preferred setting for HCV screening. According to the CDC, 60.4% of HCV screening was done in a physician office and 5.9% was done as a hospital inpatient.¹⁹ Traditionally, the PCP is responsible for screening for chronic diseases, including HCV infection; however, the current screening rate is insufficient, as 50% of people with chronic HCV infection remain unscreened.⁴

Given the insufficient rate of HCV screening at present, hospital medicine (HM) physicians have an opportunity to help improve this rate. Currently, there is no established standard of care for HCV screening in hospitalized patients. HM physicians could use the following strategies:

• Continue the current system and defer screening to outpatient providers;
• Offer screening to selected inpatients at high risk for chronic HCV infection; or
• Offer screening to all inpatients who meet screening criteria based on current guidelines.

Given the shortcomings of the current screening strategies, these authors would recommend widespread screening for chronic HCV infection in hospitalized people who meet screening criteria per current guidelines.

If HM physicians are to take an increased role in HCV screening, there are a number of important considerations. Because hospitalized patients have a limited length of stay, it would be unreasonable to expect HM physicians to test for HCV RNA viral load or genotype for all patients with a positive antibody test, because the duration of the inpatient stay may be shorter than the time it takes for these test results to return. These tests are often indicated after a positive HCV antibody test, however. Thus, communication of HCV antibody results to PCPs or other responsible providers is essential. If no follow-up is available or there are no responsible outpatient providers, HM physicians should continue with a limited screening strategy.

Back to the Case

This individual has multiple indications for chronic HCV infection screening. His risk factors include date of birth between 1945 and 1965, a history of IV drug use, and a history of incarceration. He also notes a history of emergency surgery, for which he may have received blood products prior to 1987. These factors significantly raise the likelihood of chronic HCV infection when compared with the general population. He was screened and found to be HCV antibody-positive. A follow-up HCV RNA viral load was also positive. He did not have any evidence of liver disease but did have a mild transaminitis. He has followed up as an outpatient with plans to start therapy.

Bottom Line

The current screening strategies for individuals with high prevalence of chronic HCV infection are insufficient. HM physicians have an opportunity to improve the rates of screening in this population.

Dr. Theisen-Toupal is an internist, Dr. Rosenthal is a clinical fellow in medicine, and Dr. Carbo is an assistant professor of medicine, all at Beth Israel Deaconess Medical Center in Boston. Dr. Li is an internist and associate professor of medicine at Harvard Medical School and director of the hospital medicine division at Beth Israel Deaconess Medical Center.

References

1. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374.
2. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57(4):1333-1342.
3. Chopra S. Clinical manifestations and natural history of chronic hepatitis C virus infection. UpToDate. Available at: http://www.uptodate.com/contents/clinical-manifestations-and-natural-history-of-chronic-hepatitis-c-virus-infection. Accessed March 5, 2014.
4. Spradling PR, Rupp L, Moorman AC, et al. Hepatitis B and C virus infection among 1.2 million people with access to care: factors associated with testing and infection prevalence. Clin Infect Dis. 2012;55(8):1047-1055.
5. Roblin DW, Smith BD, Weinbaum CM, Sabin ME. HCV screening practices and prevalence in an MCO, 2000-2007. Am J Manag Care. 2011;17(8):548-555.
6. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among people born during 1945-1965. MMWR. August 17, 2012. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm. Accessed March 5, 2014.
7. Chopra S. Epidemiology and transmission of hepatitis C virus infection. UpToDate. Available at: http://www.uptodate.com/contents/epidemiology-and-transmission-of-hepatitis-c-virus-infection?source=search_result&search=%22Epidemiology+and+transmission+of+hepatitis+C+virus+infection%22&selectedTitle=1~150. Accessed March 5, 2014.
8. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR. October 16, 1998. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/00055154.htm. Accessed March 5, 2014.
9. Donahue JG, Muñoz A, Ness PM, et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med. 1992;327(6):369-373.
10. Pomper GJ, Wu Y, Snyder EL. Risks of transfusion-transmitted infections: 2003. Curr Opin Hematol. 2003;10(6):412-418.
11. Tokars JI, Miller ER, Alter MJ, Arduino MJ. National surveillance of dialysis associated diseases in the United States, 1995. ASAIO J. 1998;44(1):98-107.
12. Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ. National surveillance of dialysis-associated diseases in the United States, 2002. Semin Dial. 2005;18(1):52-61.
13. Natov S, Pereira BJG. Hepatitis C virus infection in patients on maintenance dialysis. UpToDate. Available at: http://www.uptodate.com/contents/hepatitis-c-virus-infection-in-patients-on-maintenance-dialysis?source=search_result&search=Hepatitis+C+virus+infection+in+patients+on+maintenance+dialysis.&selectedTitle=1~150. Accessed March 5, 2014.
14. Moyer VA, U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(5):349-357.
15. Staples CT II, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis. 1999;29(1):150-154.
16. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the U.S. adult AIDS clinical trials group. Clin Infect Dis. 2002;34(6):831-837.
17. Averhoff FM, Glass N, Holtzman D. Global burden of hepatitis C: considerations for healthcare providers in the United States. Clin Infect Dis. 2012;55 Suppl 1:S10-15.
18. Centers for Disease Control and Prevention. Prevention and control of infections with hepatitis viruses in correctional settings. MMWR. January 24, 2003. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5201a1.htm. Accessed March 5, 2014.
19. Centers for Disease Control and Prevention. Locations and reasons for initial testing for hepatitis C infection—chronic hepatitis cohort study, United States, 2006-2010. MMWR. August 16, 2013. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6232a3.htm?s_cid=mm6232a3_w. Accessed March 5, 2014.

click for large version

Case

A 65-year-old male with a history of a motor vehicle accident that required emergency surgery in 1982 is hospitalized for acute renal failure. He reports a distant history of IV heroin use and a brief incarceration. He does not currently use illicit drugs. He has no signs or symptoms of liver disease. Should this patient be screened for chronic hepatitis C virus (HCV) infection?

Brief Overview

HCV is a major public health concern in the United States and worldwide. It is estimated that more than 4.1 million people in the U.S. (1.6% prevalence) and more than 180 million worldwide (2.8% prevalence) are HCV antibody-positive.^1,2 The acute infection is most often asymptomatic, and 80% to 100% of patients will remain HCV RNA-positive, 60% to 80% will have persistently elevated liver enzymes, and 16% will develop evidence of cirrhosis at 20 years after initial infection.³

A number of organizations in the United States have released HCV screening guidelines, including the CDC, the American Association for the Study of Liver Disease (AASLD), and the U.S. Preventive Services Task Force (USPSTF); however, despite these established recommendations, an estimated 50% of individuals with chronic HCV infection are unscreened and unaware of their infection status.⁴ Furthermore, in a recent study of one managed care network, even when one or more risk factors were present, only 29% of individuals underwent screening for HCV antibodies detection.⁵ The importance of detecting chronic HCV infection will have greater significance as newer and better-tolerated treatment options become available.⁶

Multiple organizations recommend screening for chronic HCV infection. This screening is recommended for patients with known risk factors and those in populations with a high prevalence of HCV infection.

Risk Factors and High-Prevalence Populations

IV or intranasal drug use. IV drug use is the main identifiable source of HCV infection in the U.S. It is estimated that 60% of new HCV infections occur in people who have injected drugs in the past six months.⁷ The prevalence of HCV antibodies in current IV drug users is between 72% and 96%.8 Intranasal cocaine use is also associated with a higher prevalence of HCV antibodies than the general population.⁸

Blood transfusion prior to July 1992. Testing of donor blood was not routinely done until 1990, and more sensitive testing was not implemented until July 1992.⁸ The prevalence of HCV antibodies in people who received blood transfusions prior to 1990 is 6%.8 Prior to 1990, the risk for transfusion-associated HCV infection was one in 526 units transfused.⁹ Since implementation of highly sensitive screening techniques, the risk of infection has dropped to less than one in 1.9 million units transfused.¹⁰

Clotting factors prior to 1987 or transplanted tissue prior to 1992. Individuals who have received clotting factors, other blood product transfusions, or transplanted tissue prior to 1987 are at an increased risk for developing HCV infection. For instance, individuals with hemophilia treated with clotting factors prior to 1987 had chronic HCV infection rates of up to 90%.⁸ In 1987, widespread use of protocols to inactivate HCV in clotting factors and other blood products was adopted.⁸ In addition, widespread screening of potential tissue donors and the use of HCV antibody-negative donors became routine.⁸

Alanine aminotransferase elevation. This can be considered screening or part of the diagnostic work-up of transaminitis. Regardless of the classification, this is a cohort of people with a high prevalence of HCV antibody. For individuals with one isolated alanine aminotransferase elevation, the prevalence is 3.2%.⁴ With two or more elevated aminotransferase results, the prevalence rises to 8.2%.⁴

Hemodialysis. Two major studies have estimated the prevalence of HCV antibody-positive in end-stage renal disease individuals on hemodialysis to be 7.8% and 10.4%.^11,12 This prevalence can reach 64% at some dialysis centers.¹¹ The risk of HCV infection has been associated with blood transfusions, longer duration of hemodialysis, and higher rates of HCV infection in the dialysis unit.¹³ With implementation of infection control practices in dialysis units, the incidence and prevalence of HCV infection are declining.¹³

Born in the U.S. between 1945 and 1965. The CDC and USPSTF recommend a one-time screening for HCV infection for people born in the U.S. between 1945 and 1965, regardless of the presence or absence of risk factors.^6,14 This age group has an increased prevalence of HCV antibodies, at 3.25%.⁶

Human immunodeficiency virus (HIV). HCV has a prevalence of 30% in people infected with HIV.¹⁵ The rate of co-infection is likely secondary to shared routes of transmission. For example, 72.7% of HIV-infected individuals who used IV drugs had HCV antibodies, but only 3.5% of “low-risk” HIV-infected individuals had HCV antibodies.¹⁶

Born in a high prevalence country. In the U.S., a significant number of immigrants are from areas with a high endemic rate of HCV infection. High prevalence areas (greater than 3.5%) include Central Asia and East Asia, North Africa, and the Middle East.⁷ Of note, Egypt is thought to have the highest prevalence of chronic HCV infection in the world, with well over 10% of the population being antibody-positive.¹⁷ Although major guidelines do not currently recommend it, the high prevalence of chronic HCV infection in this population may warrant screening.

Other high-risk or high-prevalence populations. The prevalence of HCV infection in people who have had over 10 lifetime sexual partners (3% to 9%), those with a history of sexually transmitted disease (6%), men who have had sex with men (5%), and children born to HCV-infected mothers (5%) is increased compared with the general population.⁸ Incarcerated people in the U.S. have an HCV antibody prevalence of 16% to 41%.¹⁸ In addition, people who have sustained needle-stick injury or mucosal exposure, or those with potential exposures in unregulated tattoo or piercing salons, may also benefit from HCV antibody screening.¹⁴

Table 1 reviews HCV screening recommendations for the CDC, AASLD, and USPSTF.^1,6,8,14

click for large version

Screening Method

The most common initial screening test for the diagnosis of chronic HCV infection is the HCV antibody test. A positive antibody test should be followed by an HCV RNA test. In an individual with recent exposure, it takes between four and 10 weeks for the antibody to be detectable. HCV RNA testing can be positive as soon as two to three weeks after infection.⁸

Hospitalist Role in HCV Screening

None of the U.S.-based guidelines make recommendations on the preferred setting for HCV screening. According to the CDC, 60.4% of HCV screening was done in a physician office and 5.9% was done as a hospital inpatient.¹⁹ Traditionally, the PCP is responsible for screening for chronic diseases, including HCV infection; however, the current screening rate is insufficient, as 50% of people with chronic HCV infection remain unscreened.⁴

Given the insufficient rate of HCV screening at present, hospital medicine (HM) physicians have an opportunity to help improve this rate. Currently, there is no established standard of care for HCV screening in hospitalized patients. HM physicians could use the following strategies:

• Continue the current system and defer screening to outpatient providers;
• Offer screening to selected inpatients at high risk for chronic HCV infection; or
• Offer screening to all inpatients who meet screening criteria based on current guidelines.

Given the shortcomings of the current screening strategies, these authors would recommend widespread screening for chronic HCV infection in hospitalized people who meet screening criteria per current guidelines.

If HM physicians are to take an increased role in HCV screening, there are a number of important considerations. Because hospitalized patients have a limited length of stay, it would be unreasonable to expect HM physicians to test for HCV RNA viral load or genotype for all patients with a positive antibody test, because the duration of the inpatient stay may be shorter than the time it takes for these test results to return. These tests are often indicated after a positive HCV antibody test, however. Thus, communication of HCV antibody results to PCPs or other responsible providers is essential. If no follow-up is available or there are no responsible outpatient providers, HM physicians should continue with a limited screening strategy.

Back to the Case

This individual has multiple indications for chronic HCV infection screening. His risk factors include date of birth between 1945 and 1965, a history of IV drug use, and a history of incarceration. He also notes a history of emergency surgery, for which he may have received blood products prior to 1987. These factors significantly raise the likelihood of chronic HCV infection when compared with the general population. He was screened and found to be HCV antibody-positive. A follow-up HCV RNA viral load was also positive. He did not have any evidence of liver disease but did have a mild transaminitis. He has followed up as an outpatient with plans to start therapy.

Bottom Line

The current screening strategies for individuals with high prevalence of chronic HCV infection are insufficient. HM physicians have an opportunity to improve the rates of screening in this population.

Dr. Theisen-Toupal is an internist, Dr. Rosenthal is a clinical fellow in medicine, and Dr. Carbo is an assistant professor of medicine, all at Beth Israel Deaconess Medical Center in Boston. Dr. Li is an internist and associate professor of medicine at Harvard Medical School and director of the hospital medicine division at Beth Israel Deaconess Medical Center.

References

1. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374.
2. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57(4):1333-1342.
3. Chopra S. Clinical manifestations and natural history of chronic hepatitis C virus infection. UpToDate. Available at: http://www.uptodate.com/contents/clinical-manifestations-and-natural-history-of-chronic-hepatitis-c-virus-infection. Accessed March 5, 2014.
4. Spradling PR, Rupp L, Moorman AC, et al. Hepatitis B and C virus infection among 1.2 million people with access to care: factors associated with testing and infection prevalence. Clin Infect Dis. 2012;55(8):1047-1055.
5. Roblin DW, Smith BD, Weinbaum CM, Sabin ME. HCV screening practices and prevalence in an MCO, 2000-2007. Am J Manag Care. 2011;17(8):548-555.
6. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among people born during 1945-1965. MMWR. August 17, 2012. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm. Accessed March 5, 2014.
7. Chopra S. Epidemiology and transmission of hepatitis C virus infection. UpToDate. Available at: http://www.uptodate.com/contents/epidemiology-and-transmission-of-hepatitis-c-virus-infection?source=search_result&search=%22Epidemiology+and+transmission+of+hepatitis+C+virus+infection%22&selectedTitle=1~150. Accessed March 5, 2014.
8. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR. October 16, 1998. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/00055154.htm. Accessed March 5, 2014.
9. Donahue JG, Muñoz A, Ness PM, et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med. 1992;327(6):369-373.
10. Pomper GJ, Wu Y, Snyder EL. Risks of transfusion-transmitted infections: 2003. Curr Opin Hematol. 2003;10(6):412-418.
11. Tokars JI, Miller ER, Alter MJ, Arduino MJ. National surveillance of dialysis associated diseases in the United States, 1995. ASAIO J. 1998;44(1):98-107.
12. Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ. National surveillance of dialysis-associated diseases in the United States, 2002. Semin Dial. 2005;18(1):52-61.
13. Natov S, Pereira BJG. Hepatitis C virus infection in patients on maintenance dialysis. UpToDate. Available at: http://www.uptodate.com/contents/hepatitis-c-virus-infection-in-patients-on-maintenance-dialysis?source=search_result&search=Hepatitis+C+virus+infection+in+patients+on+maintenance+dialysis.&selectedTitle=1~150. Accessed March 5, 2014.
14. Moyer VA, U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(5):349-357.
15. Staples CT II, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis. 1999;29(1):150-154.
16. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the U.S. adult AIDS clinical trials group. Clin Infect Dis. 2002;34(6):831-837.
17. Averhoff FM, Glass N, Holtzman D. Global burden of hepatitis C: considerations for healthcare providers in the United States. Clin Infect Dis. 2012;55 Suppl 1:S10-15.
18. Centers for Disease Control and Prevention. Prevention and control of infections with hepatitis viruses in correctional settings. MMWR. January 24, 2003. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5201a1.htm. Accessed March 5, 2014.
19. Centers for Disease Control and Prevention. Locations and reasons for initial testing for hepatitis C infection—chronic hepatitis cohort study, United States, 2006-2010. MMWR. August 16, 2013. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6232a3.htm?s_cid=mm6232a3_w. Accessed March 5, 2014.

click for large version

Case

A 65-year-old male with a history of a motor vehicle accident that required emergency surgery in 1982 is hospitalized for acute renal failure. He reports a distant history of IV heroin use and a brief incarceration. He does not currently use illicit drugs. He has no signs or symptoms of liver disease. Should this patient be screened for chronic hepatitis C virus (HCV) infection?

Brief Overview

HCV is a major public health concern in the United States and worldwide. It is estimated that more than 4.1 million people in the U.S. (1.6% prevalence) and more than 180 million worldwide (2.8% prevalence) are HCV antibody-positive.^1,2 The acute infection is most often asymptomatic, and 80% to 100% of patients will remain HCV RNA-positive, 60% to 80% will have persistently elevated liver enzymes, and 16% will develop evidence of cirrhosis at 20 years after initial infection.³

A number of organizations in the United States have released HCV screening guidelines, including the CDC, the American Association for the Study of Liver Disease (AASLD), and the U.S. Preventive Services Task Force (USPSTF); however, despite these established recommendations, an estimated 50% of individuals with chronic HCV infection are unscreened and unaware of their infection status.⁴ Furthermore, in a recent study of one managed care network, even when one or more risk factors were present, only 29% of individuals underwent screening for HCV antibodies detection.⁵ The importance of detecting chronic HCV infection will have greater significance as newer and better-tolerated treatment options become available.⁶

Multiple organizations recommend screening for chronic HCV infection. This screening is recommended for patients with known risk factors and those in populations with a high prevalence of HCV infection.

Risk Factors and High-Prevalence Populations

IV or intranasal drug use. IV drug use is the main identifiable source of HCV infection in the U.S. It is estimated that 60% of new HCV infections occur in people who have injected drugs in the past six months.⁷ The prevalence of HCV antibodies in current IV drug users is between 72% and 96%.8 Intranasal cocaine use is also associated with a higher prevalence of HCV antibodies than the general population.⁸

Blood transfusion prior to July 1992. Testing of donor blood was not routinely done until 1990, and more sensitive testing was not implemented until July 1992.⁸ The prevalence of HCV antibodies in people who received blood transfusions prior to 1990 is 6%.8 Prior to 1990, the risk for transfusion-associated HCV infection was one in 526 units transfused.⁹ Since implementation of highly sensitive screening techniques, the risk of infection has dropped to less than one in 1.9 million units transfused.¹⁰

Clotting factors prior to 1987 or transplanted tissue prior to 1992. Individuals who have received clotting factors, other blood product transfusions, or transplanted tissue prior to 1987 are at an increased risk for developing HCV infection. For instance, individuals with hemophilia treated with clotting factors prior to 1987 had chronic HCV infection rates of up to 90%.⁸ In 1987, widespread use of protocols to inactivate HCV in clotting factors and other blood products was adopted.⁸ In addition, widespread screening of potential tissue donors and the use of HCV antibody-negative donors became routine.⁸

Alanine aminotransferase elevation. This can be considered screening or part of the diagnostic work-up of transaminitis. Regardless of the classification, this is a cohort of people with a high prevalence of HCV antibody. For individuals with one isolated alanine aminotransferase elevation, the prevalence is 3.2%.⁴ With two or more elevated aminotransferase results, the prevalence rises to 8.2%.⁴

Hemodialysis. Two major studies have estimated the prevalence of HCV antibody-positive in end-stage renal disease individuals on hemodialysis to be 7.8% and 10.4%.^11,12 This prevalence can reach 64% at some dialysis centers.¹¹ The risk of HCV infection has been associated with blood transfusions, longer duration of hemodialysis, and higher rates of HCV infection in the dialysis unit.¹³ With implementation of infection control practices in dialysis units, the incidence and prevalence of HCV infection are declining.¹³

Born in the U.S. between 1945 and 1965. The CDC and USPSTF recommend a one-time screening for HCV infection for people born in the U.S. between 1945 and 1965, regardless of the presence or absence of risk factors.^6,14 This age group has an increased prevalence of HCV antibodies, at 3.25%.⁶

Human immunodeficiency virus (HIV). HCV has a prevalence of 30% in people infected with HIV.¹⁵ The rate of co-infection is likely secondary to shared routes of transmission. For example, 72.7% of HIV-infected individuals who used IV drugs had HCV antibodies, but only 3.5% of “low-risk” HIV-infected individuals had HCV antibodies.¹⁶

Born in a high prevalence country. In the U.S., a significant number of immigrants are from areas with a high endemic rate of HCV infection. High prevalence areas (greater than 3.5%) include Central Asia and East Asia, North Africa, and the Middle East.⁷ Of note, Egypt is thought to have the highest prevalence of chronic HCV infection in the world, with well over 10% of the population being antibody-positive.¹⁷ Although major guidelines do not currently recommend it, the high prevalence of chronic HCV infection in this population may warrant screening.

Other high-risk or high-prevalence populations. The prevalence of HCV infection in people who have had over 10 lifetime sexual partners (3% to 9%), those with a history of sexually transmitted disease (6%), men who have had sex with men (5%), and children born to HCV-infected mothers (5%) is increased compared with the general population.⁸ Incarcerated people in the U.S. have an HCV antibody prevalence of 16% to 41%.¹⁸ In addition, people who have sustained needle-stick injury or mucosal exposure, or those with potential exposures in unregulated tattoo or piercing salons, may also benefit from HCV antibody screening.¹⁴

Table 1 reviews HCV screening recommendations for the CDC, AASLD, and USPSTF.^1,6,8,14

click for large version

Screening Method

The most common initial screening test for the diagnosis of chronic HCV infection is the HCV antibody test. A positive antibody test should be followed by an HCV RNA test. In an individual with recent exposure, it takes between four and 10 weeks for the antibody to be detectable. HCV RNA testing can be positive as soon as two to three weeks after infection.⁸

Hospitalist Role in HCV Screening

None of the U.S.-based guidelines make recommendations on the preferred setting for HCV screening. According to the CDC, 60.4% of HCV screening was done in a physician office and 5.9% was done as a hospital inpatient.¹⁹ Traditionally, the PCP is responsible for screening for chronic diseases, including HCV infection; however, the current screening rate is insufficient, as 50% of people with chronic HCV infection remain unscreened.⁴

Given the insufficient rate of HCV screening at present, hospital medicine (HM) physicians have an opportunity to help improve this rate. Currently, there is no established standard of care for HCV screening in hospitalized patients. HM physicians could use the following strategies:

• Continue the current system and defer screening to outpatient providers;
• Offer screening to selected inpatients at high risk for chronic HCV infection; or
• Offer screening to all inpatients who meet screening criteria based on current guidelines.

Given the shortcomings of the current screening strategies, these authors would recommend widespread screening for chronic HCV infection in hospitalized people who meet screening criteria per current guidelines.

If HM physicians are to take an increased role in HCV screening, there are a number of important considerations. Because hospitalized patients have a limited length of stay, it would be unreasonable to expect HM physicians to test for HCV RNA viral load or genotype for all patients with a positive antibody test, because the duration of the inpatient stay may be shorter than the time it takes for these test results to return. These tests are often indicated after a positive HCV antibody test, however. Thus, communication of HCV antibody results to PCPs or other responsible providers is essential. If no follow-up is available or there are no responsible outpatient providers, HM physicians should continue with a limited screening strategy.

Back to the Case

This individual has multiple indications for chronic HCV infection screening. His risk factors include date of birth between 1945 and 1965, a history of IV drug use, and a history of incarceration. He also notes a history of emergency surgery, for which he may have received blood products prior to 1987. These factors significantly raise the likelihood of chronic HCV infection when compared with the general population. He was screened and found to be HCV antibody-positive. A follow-up HCV RNA viral load was also positive. He did not have any evidence of liver disease but did have a mild transaminitis. He has followed up as an outpatient with plans to start therapy.

Bottom Line

The current screening strategies for individuals with high prevalence of chronic HCV infection are insufficient. HM physicians have an opportunity to improve the rates of screening in this population.

Dr. Theisen-Toupal is an internist, Dr. Rosenthal is a clinical fellow in medicine, and Dr. Carbo is an assistant professor of medicine, all at Beth Israel Deaconess Medical Center in Boston. Dr. Li is an internist and associate professor of medicine at Harvard Medical School and director of the hospital medicine division at Beth Israel Deaconess Medical Center.

References

1. Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49(4):1335-1374.
2. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57(4):1333-1342.
3. Chopra S. Clinical manifestations and natural history of chronic hepatitis C virus infection. UpToDate. Available at: http://www.uptodate.com/contents/clinical-manifestations-and-natural-history-of-chronic-hepatitis-c-virus-infection. Accessed March 5, 2014.
4. Spradling PR, Rupp L, Moorman AC, et al. Hepatitis B and C virus infection among 1.2 million people with access to care: factors associated with testing and infection prevalence. Clin Infect Dis. 2012;55(8):1047-1055.
5. Roblin DW, Smith BD, Weinbaum CM, Sabin ME. HCV screening practices and prevalence in an MCO, 2000-2007. Am J Manag Care. 2011;17(8):548-555.
6. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among people born during 1945-1965. MMWR. August 17, 2012. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6104a1.htm. Accessed March 5, 2014.
7. Chopra S. Epidemiology and transmission of hepatitis C virus infection. UpToDate. Available at: http://www.uptodate.com/contents/epidemiology-and-transmission-of-hepatitis-c-virus-infection?source=search_result&search=%22Epidemiology+and+transmission+of+hepatitis+C+virus+infection%22&selectedTitle=1~150. Accessed March 5, 2014.
8. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR. October 16, 1998. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/00055154.htm. Accessed March 5, 2014.
9. Donahue JG, Muñoz A, Ness PM, et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med. 1992;327(6):369-373.
10. Pomper GJ, Wu Y, Snyder EL. Risks of transfusion-transmitted infections: 2003. Curr Opin Hematol. 2003;10(6):412-418.
11. Tokars JI, Miller ER, Alter MJ, Arduino MJ. National surveillance of dialysis associated diseases in the United States, 1995. ASAIO J. 1998;44(1):98-107.
12. Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ. National surveillance of dialysis-associated diseases in the United States, 2002. Semin Dial. 2005;18(1):52-61.
13. Natov S, Pereira BJG. Hepatitis C virus infection in patients on maintenance dialysis. UpToDate. Available at: http://www.uptodate.com/contents/hepatitis-c-virus-infection-in-patients-on-maintenance-dialysis?source=search_result&search=Hepatitis+C+virus+infection+in+patients+on+maintenance+dialysis.&selectedTitle=1~150. Accessed March 5, 2014.
14. Moyer VA, U.S. Preventive Services Task Force. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159(5):349-357.
15. Staples CT II, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis. 1999;29(1):150-154.
16. Sherman KE, Rouster SD, Chung RT, Rajicic N. Hepatitis C virus prevalence among patients infected with human immunodeficiency virus: a cross-sectional analysis of the U.S. adult AIDS clinical trials group. Clin Infect Dis. 2002;34(6):831-837.
17. Averhoff FM, Glass N, Holtzman D. Global burden of hepatitis C: considerations for healthcare providers in the United States. Clin Infect Dis. 2012;55 Suppl 1:S10-15.
18. Centers for Disease Control and Prevention. Prevention and control of infections with hepatitis viruses in correctional settings. MMWR. January 24, 2003. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5201a1.htm. Accessed March 5, 2014.
19. Centers for Disease Control and Prevention. Locations and reasons for initial testing for hepatitis C infection—chronic hepatitis cohort study, United States, 2006-2010. MMWR. August 16, 2013. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6232a3.htm?s_cid=mm6232a3_w. Accessed March 5, 2014.

Clinical question: Does the risk of pneumonia vary for different inhaled agents?

Background: Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in COPD patients; duration, dosage, and various agents were investigated, especially fluticasone and budesonide.

Study design: Nested, case-control analysis.

Setting: Quebec health insurance database for new users with COPD, 1990-2005, with follow-up through 2007.

Synopsis: Investigators analyzed 163,514 patients, including 20,344 patients with serious pneumonia; current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63-1.75). The increased risk was sustained with long-term use but declined gradually to zero at six months after stopping ICS. The risk of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93-2.10) than budesonide (RR 1.17; 95% CI 1.09-1.26).

Bottom line: Fluticasone was associated with an increased risk of pneumonia in COPD patients, consistent with earlier clinical trials, but the risk with budesonide was much lower.

Citation: Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036.

Clinical question: Does the risk of pneumonia vary for different inhaled agents?

Background: Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in COPD patients; duration, dosage, and various agents were investigated, especially fluticasone and budesonide.

Study design: Nested, case-control analysis.

Setting: Quebec health insurance database for new users with COPD, 1990-2005, with follow-up through 2007.

Synopsis: Investigators analyzed 163,514 patients, including 20,344 patients with serious pneumonia; current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63-1.75). The increased risk was sustained with long-term use but declined gradually to zero at six months after stopping ICS. The risk of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93-2.10) than budesonide (RR 1.17; 95% CI 1.09-1.26).

Bottom line: Fluticasone was associated with an increased risk of pneumonia in COPD patients, consistent with earlier clinical trials, but the risk with budesonide was much lower.

Citation: Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036.

Clinical question: Does the risk of pneumonia vary for different inhaled agents?

Background: Inhaled corticosteroids (ICS) are known to increase the risk of pneumonia in COPD patients; duration, dosage, and various agents were investigated, especially fluticasone and budesonide.

Study design: Nested, case-control analysis.

Setting: Quebec health insurance database for new users with COPD, 1990-2005, with follow-up through 2007.

Synopsis: Investigators analyzed 163,514 patients, including 20,344 patients with serious pneumonia; current use of ICS was associated with a 69% increase in the rate of serious pneumonia (RR 1.69; 95% CI 1.63-1.75). The increased risk was sustained with long-term use but declined gradually to zero at six months after stopping ICS. The risk of serious pneumonia was higher with fluticasone (RR 2.01; 95% CI 1.93-2.10) than budesonide (RR 1.17; 95% CI 1.09-1.26).

Bottom line: Fluticasone was associated with an increased risk of pneumonia in COPD patients, consistent with earlier clinical trials, but the risk with budesonide was much lower.

Citation: Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68(11):1029-1036.

Clinical question: Which criteria identify ambulatory patients with exacerbations of mild to moderate COPD who do not need antibiotics?

Background: The Anthonisen criteria (increased dyspnea, sputum volume, sputum purulence) are commonly used to identify which patients with COPD exacerbations would benefit from antibiotics. These criteria, however, were derived in patients with severe COPD. It is unknown whether these criteria are predictive in patients with mild to moderate COPD.

Study design: Multivariate logistic regression analysis of placebo group of a double-blinded RCT.

Setting: Multicenter, ambulatory, primary care clinics in Spain.

Synopsis: The original RCT enrolled 310 ambulatory patients with exacerbations of mild to moderate COPD and tested the efficacy of amoxicillin/clavulanate. Clinical failure without antibiotics was 19.9% compared to 9.5% with antibiotics (P=0.022). Here they analyzed the 152 patients from the placebo group to identify factors associated with increased risk of clinical failure. Only increased sputum purulence (OR 6.1, CI 1.5-25; P=0.005) or C-reactive protein (CRP) >40 mg/L (OR 13.4, CI 4.5-38.8, P<0.001) were independently associated with increased risk of failure. Presence of both predicted a 63.7% failure without antibiotics.

The study did not define “increased sputum purulence,” but this is similar to real-life clinical practice. Placebo effect cannot be ruled out, but correlation of the objective measures with the clinical assessments suggests that the clinical assessments were accurate. The study did not have a protocol for administering co-medications such as steroids and inhalers. Despite these limitations, the criteria of increased sputum purulence and CRP >40 mg/L identified COPD patients likely to have a clinical failure without antibiotics.

Bottom line: Patients with exacerbations of mild to moderate COPD who do not have increased sputum purulence or CRP >40 mg/L can be safely managed without antibiotics.

Citation: Maravitlles M, Moravas A, Hernandez S, Bayona C, Llor C. Is it possible to identify exacerbations of mild to moderate COPD that do not require antibiotic treatment? Chest. 2013;144(5):1571-1577.

Clinical question: Which criteria identify ambulatory patients with exacerbations of mild to moderate COPD who do not need antibiotics?

Background: The Anthonisen criteria (increased dyspnea, sputum volume, sputum purulence) are commonly used to identify which patients with COPD exacerbations would benefit from antibiotics. These criteria, however, were derived in patients with severe COPD. It is unknown whether these criteria are predictive in patients with mild to moderate COPD.

Study design: Multivariate logistic regression analysis of placebo group of a double-blinded RCT.

Setting: Multicenter, ambulatory, primary care clinics in Spain.

Synopsis: The original RCT enrolled 310 ambulatory patients with exacerbations of mild to moderate COPD and tested the efficacy of amoxicillin/clavulanate. Clinical failure without antibiotics was 19.9% compared to 9.5% with antibiotics (P=0.022). Here they analyzed the 152 patients from the placebo group to identify factors associated with increased risk of clinical failure. Only increased sputum purulence (OR 6.1, CI 1.5-25; P=0.005) or C-reactive protein (CRP) >40 mg/L (OR 13.4, CI 4.5-38.8, P<0.001) were independently associated with increased risk of failure. Presence of both predicted a 63.7% failure without antibiotics.

The study did not define “increased sputum purulence,” but this is similar to real-life clinical practice. Placebo effect cannot be ruled out, but correlation of the objective measures with the clinical assessments suggests that the clinical assessments were accurate. The study did not have a protocol for administering co-medications such as steroids and inhalers. Despite these limitations, the criteria of increased sputum purulence and CRP >40 mg/L identified COPD patients likely to have a clinical failure without antibiotics.

Bottom line: Patients with exacerbations of mild to moderate COPD who do not have increased sputum purulence or CRP >40 mg/L can be safely managed without antibiotics.

Citation: Maravitlles M, Moravas A, Hernandez S, Bayona C, Llor C. Is it possible to identify exacerbations of mild to moderate COPD that do not require antibiotic treatment? Chest. 2013;144(5):1571-1577.

Clinical question: Which criteria identify ambulatory patients with exacerbations of mild to moderate COPD who do not need antibiotics?

Background: The Anthonisen criteria (increased dyspnea, sputum volume, sputum purulence) are commonly used to identify which patients with COPD exacerbations would benefit from antibiotics. These criteria, however, were derived in patients with severe COPD. It is unknown whether these criteria are predictive in patients with mild to moderate COPD.

Study design: Multivariate logistic regression analysis of placebo group of a double-blinded RCT.

Setting: Multicenter, ambulatory, primary care clinics in Spain.

Synopsis: The original RCT enrolled 310 ambulatory patients with exacerbations of mild to moderate COPD and tested the efficacy of amoxicillin/clavulanate. Clinical failure without antibiotics was 19.9% compared to 9.5% with antibiotics (P=0.022). Here they analyzed the 152 patients from the placebo group to identify factors associated with increased risk of clinical failure. Only increased sputum purulence (OR 6.1, CI 1.5-25; P=0.005) or C-reactive protein (CRP) >40 mg/L (OR 13.4, CI 4.5-38.8, P<0.001) were independently associated with increased risk of failure. Presence of both predicted a 63.7% failure without antibiotics.

The study did not define “increased sputum purulence,” but this is similar to real-life clinical practice. Placebo effect cannot be ruled out, but correlation of the objective measures with the clinical assessments suggests that the clinical assessments were accurate. The study did not have a protocol for administering co-medications such as steroids and inhalers. Despite these limitations, the criteria of increased sputum purulence and CRP >40 mg/L identified COPD patients likely to have a clinical failure without antibiotics.

Bottom line: Patients with exacerbations of mild to moderate COPD who do not have increased sputum purulence or CRP >40 mg/L can be safely managed without antibiotics.

Citation: Maravitlles M, Moravas A, Hernandez S, Bayona C, Llor C. Is it possible to identify exacerbations of mild to moderate COPD that do not require antibiotic treatment? Chest. 2013;144(5):1571-1577.

Clinical question: Do patients receiving pre-operative angiotensin axis blockade (AAB) prior to elective major orthopedic surgery have an increased risk of peri-operative hypotension and acute kidney injury (AKI)?

Background: Patients with pre-operative AAB from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have an increased incidence of peri-operative hypotension. Patients undergoing cardiothoracic and vascular surgery with pre-operative AAB have increased incidence of post-operative AKI; however, there is scant literature evaluating the hypotensive and renal effects of pre-operative AAB prior to elective major orthopedic surgery.

Study design: Retrospective, cohort study.

Setting: Academic medical center.

Synopsis: Retrospective review of 922 patients undergoing spinal fusion, total knee arthroplasty, or total hip arthroplasty in one academic medical center in 2010 found that 37% received pre-operative AAB. Post-induction hypotension (systolic blood pressure ≤80 mm Hg for five minutes) was significantly higher in patients receiving AAB (12.2% vs. 6.7%; odds ratio [OR] 1.93, P=0.005). Post-operative AKI was significantly higher in patients receiving AAB (8.3% vs. 1.7%; OR 5.40, P<0.001), remaining significant after adjusting for intra-operative hypotension (OR 2.60, P=0.042). Developing AKI resulted in a significantly higher mean length of stay (5.76 vs. 3.28 days, P<0.001) but no difference in two-year mortality.

The findings suggest an association exists between pre-operative angiotensin-converting enzyme inhibitors/ARB, hypotension, and AKI following major orthopedic surgeries but does not demonstrate causality. A prospective, multi-center, randomized trial is needed to confirm that holding pre-operative AAB would decrease the incidence of AKI in patients undergoing major orthopedic procedures under general anesthesia.

Bottom line: Patients who underwent elective major orthopedic surgery who received pre-operative AAB therapy had an associated increased risk of post-induction hypotension and post-operative AKI, resulting in a greater hospital length of stay.

Citation: Nielson E, Hennrikus E, Lehman E, Mets B. Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9(5):283-288.

Clinical question: Do patients receiving pre-operative angiotensin axis blockade (AAB) prior to elective major orthopedic surgery have an increased risk of peri-operative hypotension and acute kidney injury (AKI)?

Background: Patients with pre-operative AAB from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have an increased incidence of peri-operative hypotension. Patients undergoing cardiothoracic and vascular surgery with pre-operative AAB have increased incidence of post-operative AKI; however, there is scant literature evaluating the hypotensive and renal effects of pre-operative AAB prior to elective major orthopedic surgery.

Study design: Retrospective, cohort study.

Setting: Academic medical center.

Synopsis: Retrospective review of 922 patients undergoing spinal fusion, total knee arthroplasty, or total hip arthroplasty in one academic medical center in 2010 found that 37% received pre-operative AAB. Post-induction hypotension (systolic blood pressure ≤80 mm Hg for five minutes) was significantly higher in patients receiving AAB (12.2% vs. 6.7%; odds ratio [OR] 1.93, P=0.005). Post-operative AKI was significantly higher in patients receiving AAB (8.3% vs. 1.7%; OR 5.40, P<0.001), remaining significant after adjusting for intra-operative hypotension (OR 2.60, P=0.042). Developing AKI resulted in a significantly higher mean length of stay (5.76 vs. 3.28 days, P<0.001) but no difference in two-year mortality.

The findings suggest an association exists between pre-operative angiotensin-converting enzyme inhibitors/ARB, hypotension, and AKI following major orthopedic surgeries but does not demonstrate causality. A prospective, multi-center, randomized trial is needed to confirm that holding pre-operative AAB would decrease the incidence of AKI in patients undergoing major orthopedic procedures under general anesthesia.

Bottom line: Patients who underwent elective major orthopedic surgery who received pre-operative AAB therapy had an associated increased risk of post-induction hypotension and post-operative AKI, resulting in a greater hospital length of stay.

Citation: Nielson E, Hennrikus E, Lehman E, Mets B. Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9(5):283-288.

Clinical question: Do patients receiving pre-operative angiotensin axis blockade (AAB) prior to elective major orthopedic surgery have an increased risk of peri-operative hypotension and acute kidney injury (AKI)?

Background: Patients with pre-operative AAB from angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have an increased incidence of peri-operative hypotension. Patients undergoing cardiothoracic and vascular surgery with pre-operative AAB have increased incidence of post-operative AKI; however, there is scant literature evaluating the hypotensive and renal effects of pre-operative AAB prior to elective major orthopedic surgery.

Study design: Retrospective, cohort study.

Setting: Academic medical center.

Synopsis: Retrospective review of 922 patients undergoing spinal fusion, total knee arthroplasty, or total hip arthroplasty in one academic medical center in 2010 found that 37% received pre-operative AAB. Post-induction hypotension (systolic blood pressure ≤80 mm Hg for five minutes) was significantly higher in patients receiving AAB (12.2% vs. 6.7%; odds ratio [OR] 1.93, P=0.005). Post-operative AKI was significantly higher in patients receiving AAB (8.3% vs. 1.7%; OR 5.40, P<0.001), remaining significant after adjusting for intra-operative hypotension (OR 2.60, P=0.042). Developing AKI resulted in a significantly higher mean length of stay (5.76 vs. 3.28 days, P<0.001) but no difference in two-year mortality.

The findings suggest an association exists between pre-operative angiotensin-converting enzyme inhibitors/ARB, hypotension, and AKI following major orthopedic surgeries but does not demonstrate causality. A prospective, multi-center, randomized trial is needed to confirm that holding pre-operative AAB would decrease the incidence of AKI in patients undergoing major orthopedic procedures under general anesthesia.

Bottom line: Patients who underwent elective major orthopedic surgery who received pre-operative AAB therapy had an associated increased risk of post-induction hypotension and post-operative AKI, resulting in a greater hospital length of stay.

Citation: Nielson E, Hennrikus E, Lehman E, Mets B. Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. J Hosp Med. 2014;9(5):283-288.

Clinical question: What is the recommended threshold for red blood cell (RBC) transfusion and erythropoiesis-stimulating agents (ESA) in anemic hospitalized patients with coronary heart disease?

Background: Anemia can worsen cardiac function and is associated with increased risk of hospitalization and death in patients with coronary heart disease (CHD) or congestive heart failure (CHF). It is unclear if treatments such as RBC transfusion, ESA, or iron replacement improve outcomes in patients with heart disease.

Study design: Systematic review.

Setting: Studies of hospitalized medical and surgical patients.

Synopsis: The guideline was developed by reviewing studies evaluating anemia treatment outcomes, including mortality, hospitalization, exercise tolerance, quality of life, and cardiovascular events. Six studies evaluated the benefits and harms resulting from RBC transfusion, each determined to be low-quality evidence. The current evidence showed no benefit when comparing liberal (hemoglobin (Hgb) >10 g/dL) versus restrictive (Hgb <10 g/dL) transfusion thresholds. Potential harms of transfusion included fever, transfusion-related acute lung injury, and CHF.

Given the low-quality evidence, the American College of Physicians (ACP) makes a weak recommendation for a restrictive transfusion strategy of Hgb 7-8 g/dL in patients with CHD.

A review of 16 RCTs (moderate-quality evidence) evaluated the effects of ESAs in mild to moderate anemia and showed no difference in outcomes for patients with CHD and CHF. Harms associated with ESA therapy included hypertension and venous thrombosis. The ACP makes a strong recommendation not to use ESAs in patients with heart disease.

Bottom line: The ACP recommends restrictive transfusion with hemoglobin threshold of 7-8 g/dL in hospitalized patients with CHD (weak recommendation, low-quality evidence) and recommends against using erythropoiesis-stimulating agents for mild to moderate anemia in patients with CHF or CHD (strong recommendation, moderate-quality evidence).

Citation: Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013;159(11):770-779.

Clinical question: What is the recommended threshold for red blood cell (RBC) transfusion and erythropoiesis-stimulating agents (ESA) in anemic hospitalized patients with coronary heart disease?

Background: Anemia can worsen cardiac function and is associated with increased risk of hospitalization and death in patients with coronary heart disease (CHD) or congestive heart failure (CHF). It is unclear if treatments such as RBC transfusion, ESA, or iron replacement improve outcomes in patients with heart disease.

Study design: Systematic review.

Setting: Studies of hospitalized medical and surgical patients.

Synopsis: The guideline was developed by reviewing studies evaluating anemia treatment outcomes, including mortality, hospitalization, exercise tolerance, quality of life, and cardiovascular events. Six studies evaluated the benefits and harms resulting from RBC transfusion, each determined to be low-quality evidence. The current evidence showed no benefit when comparing liberal (hemoglobin (Hgb) >10 g/dL) versus restrictive (Hgb <10 g/dL) transfusion thresholds. Potential harms of transfusion included fever, transfusion-related acute lung injury, and CHF.

Given the low-quality evidence, the American College of Physicians (ACP) makes a weak recommendation for a restrictive transfusion strategy of Hgb 7-8 g/dL in patients with CHD.

A review of 16 RCTs (moderate-quality evidence) evaluated the effects of ESAs in mild to moderate anemia and showed no difference in outcomes for patients with CHD and CHF. Harms associated with ESA therapy included hypertension and venous thrombosis. The ACP makes a strong recommendation not to use ESAs in patients with heart disease.

Bottom line: The ACP recommends restrictive transfusion with hemoglobin threshold of 7-8 g/dL in hospitalized patients with CHD (weak recommendation, low-quality evidence) and recommends against using erythropoiesis-stimulating agents for mild to moderate anemia in patients with CHF or CHD (strong recommendation, moderate-quality evidence).

Citation: Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013;159(11):770-779.

Clinical question: What is the recommended threshold for red blood cell (RBC) transfusion and erythropoiesis-stimulating agents (ESA) in anemic hospitalized patients with coronary heart disease?

Background: Anemia can worsen cardiac function and is associated with increased risk of hospitalization and death in patients with coronary heart disease (CHD) or congestive heart failure (CHF). It is unclear if treatments such as RBC transfusion, ESA, or iron replacement improve outcomes in patients with heart disease.

Study design: Systematic review.

Setting: Studies of hospitalized medical and surgical patients.

Synopsis: The guideline was developed by reviewing studies evaluating anemia treatment outcomes, including mortality, hospitalization, exercise tolerance, quality of life, and cardiovascular events. Six studies evaluated the benefits and harms resulting from RBC transfusion, each determined to be low-quality evidence. The current evidence showed no benefit when comparing liberal (hemoglobin (Hgb) >10 g/dL) versus restrictive (Hgb <10 g/dL) transfusion thresholds. Potential harms of transfusion included fever, transfusion-related acute lung injury, and CHF.

Given the low-quality evidence, the American College of Physicians (ACP) makes a weak recommendation for a restrictive transfusion strategy of Hgb 7-8 g/dL in patients with CHD.

A review of 16 RCTs (moderate-quality evidence) evaluated the effects of ESAs in mild to moderate anemia and showed no difference in outcomes for patients with CHD and CHF. Harms associated with ESA therapy included hypertension and venous thrombosis. The ACP makes a strong recommendation not to use ESAs in patients with heart disease.

Bottom line: The ACP recommends restrictive transfusion with hemoglobin threshold of 7-8 g/dL in hospitalized patients with CHD (weak recommendation, low-quality evidence) and recommends against using erythropoiesis-stimulating agents for mild to moderate anemia in patients with CHF or CHD (strong recommendation, moderate-quality evidence).

Citation: Qaseem A, Humphrey LL, Fitterman N, Starkey M, Shekelle P. Treatment of anemia in patients with heart disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2013;159(11):770-779.