A 62-year-old African-American woman presented for evaluation of a bluish discoloration of the hard palate and nail beds, noticeable for several months. In addition, she had complaints of fatigue and arthralgia. She reported that she had been taking hydroxychloroquine 400 mg/d and quinacrine 100 mg/d for several years for the treatment of systemic lupus erythematosus (SLE). Her medical history was also significant for dry mouth syndrome treated with pilocarpine.

The patient’s vital signs included a temperature of 97°F;
respiratory rate, 15 breaths/min; pulse, 72 beats/min; and blood pressure, 130/80 mm Hg. Height was 62 in, weight was 189 lb, and BMI was 34.56. A bluish gray color was noted in the subungual areas of her nails (see Figure 1). There were several circumferential areas of skin hyperpigmentation resulting from healed lupus skin lesions on her arms. Nailfold capillaroscopy revealed several dilated blood vessels. The sclerae appeared dry, but no erythema or inflammation was noted.

Examination of the mouth revealed a bluish discoloration of the hard palate (see Figure 2) and decreased salivary pool. Respiratory, cardiovascular, and abdominal examination findings were normal. Musculoskeletal examination was unremarkable for acute joint tenderness or synovitis. Crepitation and bony changes were noted in the left knee, without effusion or decreased range of motion.

Laboratory studies were ordered, and the results are listed in the table.

DISCUSSION
Hyperpigmentation of the oral mucosa can be associated with a number of conditions, including adrenal insufficiency, Peutz-Jeghers syndrome, hemochromatosis, polyostotic fibrous dysplasia, hyperparathyroidism, neurofibromatosis, and bronchogenic malignancy.^1,2 Other causes of oral hyperpigmentation include physiologic pigmentary or postinflammatory changes, oral melanoacanthosis, blue nevus, and melanoma.^2,3 While these diagnoses should be considered when encountering a mucosal lesion, they were unlikely in this patient because of the color changes in her nail beds.

Systemic skin and mucous membrane discoloration can also occur with the use of certain drugs and other substances, including chemotherapeutic agents, benzodiazepines, hormones, carotenoids, phenolphthalein, heavy metal salts, and several antimicrobial agents.¹ In dark-skinned individuals, hyperpigmentation of the oral mucosa can be caused by a physiologic deposition of melanin.⁴

Pigmentary Changes
The use of antimalarial drugs, such as quinacrine, chloroquine, and hydroxychloroquine, has long been associated with pigmentary changes to the palatal mucosa and subungual areas.^1,3 These drugs can stimulate melanin production and cause hemosiderin deposition, resulting in pigmentary changes.⁵ Skin discoloration is believed to be the result of the formation of a melanin-drug complex in areas with an elevated affinity for melanin.¹ Besides malaria, these drugs are commonly used to treat SLE and discoid lupus erythematosus, rheumatoid arthritis, and other rheumatologic conditions.⁵

The diagnosis of drug-induced hyperpigmentation is generally clinical, supported by the patient’s history—which often includes the use of antimalarial drugs—and presentation.¹ If a clear cause cannot be determined by clinical evaluation, then a biopsy to confirm a drug-induced cause may be necessary.² A classic study by Tuffanelli et al reported that the onset of hyperpigmentation related to antimalarial drug therapy may not occur until 4 to 70 months after initiation of treatment.⁶ Once the offending drug is discontinued, pigmentation changes slowly fade but often do not completely resolve,⁷ and patients should be advised of this.

Ocular Retinopathy
While pigmentary changes associated with antimalarial drugs are benign,³ a rare but serious adverse effect of antimalarials is retinal toxicity. Ocular retinopathy related to chloroquine and hydroxychloroquine therapy has been well documented and may result in irreversible vision loss.^8,9 The most recent recommendations from the American Academy of Ophthalmology suggest a baseline eye examination at initiation of antimalarial treatment and annual examinations starting after five years of therapy because the risk for toxicity relates to the cumulative dose.⁸ More frequent ophthalmologic evaluations are recommended for individuals at higher risk, such as those with preexisting retinal or macular disease.⁹

Outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
A biopsy of the roof of the patient’s mouth confirmed that the palatal hyperpigmentation was caused by her antimalarial medications. Since the patient displayed no evidence of active lupus skin lesions and laboratory results indicated that her SLE was inactive, one of the drugs, quinacrine, was discontinued.

The patient was referred for an ophthalmologic evaluation. No evidence of retinal toxicity was found.

Follow-up evaluations at two months and six months revealed no significant improvement in the discoloration of the patient’s oral mucosa or nail beds. At the six-month visit, her dosage of hydroxychloroquine was reevaluated.

The patient’s hydroxychloroquine dosage was determined based on 7.3 mg/kg/d. In the case of an overweight patient, especially one of shorter-than-average stature, hydroxychloroquine dosing should be based on ideal body weight to minimize the risk for overdosage; in general, a maximum dosage of 6.5 mg/kg/d is recommended.^8,9 As a result, the patient’s dosage was decreased to 300 mg/d.

At her nine-month follow-up evaluation, the discoloration to the patient’s oral mucosa had faded but had not resolved completely (see Figure 3). No significant change was noted in the subungual discoloration. The patient had experienced no exacerbations of lupus-related symptoms since her medication adjustments.

CONCLUSION
Although this patient’s hyperpigmentation was benign, staying alert to this potential adverse effect of antimalarial drugs is important in making a diagnosis. As with many skin lesions, if the clinical evaluation does not provide a clear cause, a biopsy may be needed. For anyone taking antimalarial drugs, regular ophthalmologic evaluations are recommended to facilitate early detection of the rare adverse effect of retinal toxicity. Nevertheless, with careful monitoring, antimalarial drugs are safe and effective for the treatment of inflammatory conditions such as SLE and rheumatoid arthritis.

REFERENCES
1. Kleinegger CL, Hammond HL, Finkelstein MW. Oral mucosal hyperpigmentation secondary to antimalarial drug therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90(2):189-194.

2. Gondak R-O, da Silva-Jorge R, Jorge J, et al. Oral pigmented lesions: clinicopathologic features and review of the literature. Med Oral Pathol Oral Cir Bucal. 2012;17(6):e919-e924.

3. Lerman MA, Karimbux N, Guze KA, Woo SB. Pigmentation of the hard palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;
107:8-12.

4. Kalampalikis A, Goetze S, Elsner P. Isolated hyperpigmentation of the oral mucosa due to hydroxychloroquine. J Dtsch Dermatol Ges. 2012; 10(12):921-922.

5. de Andrade BA, Fonseca FP, Pires FR, et al. Hard palate hyperpigmentation secondary to chronic chloroquine therapy: report of five cases.
J Cutan Pathol. 2013;40(9):833-838.

6. Tuffanelli D, Abraham RK, Dubois EI. Pigmentation from antimalarial therapy: its possible relationship to the ocular lesions. Arch Derm. 1963; 88:419-426.

7. Melikoglu MA, Melikoglu M, Gurbuz U, et al. Hydroxychloroquine-induced hyperpigmentation: a case report. J Clin Pharm Ther. 2008; 33(6):699-701. 

8. Marmor MF, Kellner U, Lai YY, et al; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):
415-422.

9. Screening for hydroxychloroquine retinopathy. Position statement, American College of Rheumatology. www.rheumatology.org/Practice/Clinical/Position/Position_Statements/. Accessed July 17, 2014.

A 62-year-old African-American woman presented for evaluation of a bluish discoloration of the hard palate and nail beds, noticeable for several months. In addition, she had complaints of fatigue and arthralgia. She reported that she had been taking hydroxychloroquine 400 mg/d and quinacrine 100 mg/d for several years for the treatment of systemic lupus erythematosus (SLE). Her medical history was also significant for dry mouth syndrome treated with pilocarpine.

The patient’s vital signs included a temperature of 97°F;
respiratory rate, 15 breaths/min; pulse, 72 beats/min; and blood pressure, 130/80 mm Hg. Height was 62 in, weight was 189 lb, and BMI was 34.56. A bluish gray color was noted in the subungual areas of her nails (see Figure 1). There were several circumferential areas of skin hyperpigmentation resulting from healed lupus skin lesions on her arms. Nailfold capillaroscopy revealed several dilated blood vessels. The sclerae appeared dry, but no erythema or inflammation was noted.

Examination of the mouth revealed a bluish discoloration of the hard palate (see Figure 2) and decreased salivary pool. Respiratory, cardiovascular, and abdominal examination findings were normal. Musculoskeletal examination was unremarkable for acute joint tenderness or synovitis. Crepitation and bony changes were noted in the left knee, without effusion or decreased range of motion.

Laboratory studies were ordered, and the results are listed in the table.

DISCUSSION
Hyperpigmentation of the oral mucosa can be associated with a number of conditions, including adrenal insufficiency, Peutz-Jeghers syndrome, hemochromatosis, polyostotic fibrous dysplasia, hyperparathyroidism, neurofibromatosis, and bronchogenic malignancy.^1,2 Other causes of oral hyperpigmentation include physiologic pigmentary or postinflammatory changes, oral melanoacanthosis, blue nevus, and melanoma.^2,3 While these diagnoses should be considered when encountering a mucosal lesion, they were unlikely in this patient because of the color changes in her nail beds.

Systemic skin and mucous membrane discoloration can also occur with the use of certain drugs and other substances, including chemotherapeutic agents, benzodiazepines, hormones, carotenoids, phenolphthalein, heavy metal salts, and several antimicrobial agents.¹ In dark-skinned individuals, hyperpigmentation of the oral mucosa can be caused by a physiologic deposition of melanin.⁴

Pigmentary Changes
The use of antimalarial drugs, such as quinacrine, chloroquine, and hydroxychloroquine, has long been associated with pigmentary changes to the palatal mucosa and subungual areas.^1,3 These drugs can stimulate melanin production and cause hemosiderin deposition, resulting in pigmentary changes.⁵ Skin discoloration is believed to be the result of the formation of a melanin-drug complex in areas with an elevated affinity for melanin.¹ Besides malaria, these drugs are commonly used to treat SLE and discoid lupus erythematosus, rheumatoid arthritis, and other rheumatologic conditions.⁵

The diagnosis of drug-induced hyperpigmentation is generally clinical, supported by the patient’s history—which often includes the use of antimalarial drugs—and presentation.¹ If a clear cause cannot be determined by clinical evaluation, then a biopsy to confirm a drug-induced cause may be necessary.² A classic study by Tuffanelli et al reported that the onset of hyperpigmentation related to antimalarial drug therapy may not occur until 4 to 70 months after initiation of treatment.⁶ Once the offending drug is discontinued, pigmentation changes slowly fade but often do not completely resolve,⁷ and patients should be advised of this.

Ocular Retinopathy
While pigmentary changes associated with antimalarial drugs are benign,³ a rare but serious adverse effect of antimalarials is retinal toxicity. Ocular retinopathy related to chloroquine and hydroxychloroquine therapy has been well documented and may result in irreversible vision loss.^8,9 The most recent recommendations from the American Academy of Ophthalmology suggest a baseline eye examination at initiation of antimalarial treatment and annual examinations starting after five years of therapy because the risk for toxicity relates to the cumulative dose.⁸ More frequent ophthalmologic evaluations are recommended for individuals at higher risk, such as those with preexisting retinal or macular disease.⁹

Outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
A biopsy of the roof of the patient’s mouth confirmed that the palatal hyperpigmentation was caused by her antimalarial medications. Since the patient displayed no evidence of active lupus skin lesions and laboratory results indicated that her SLE was inactive, one of the drugs, quinacrine, was discontinued.

The patient was referred for an ophthalmologic evaluation. No evidence of retinal toxicity was found.

Follow-up evaluations at two months and six months revealed no significant improvement in the discoloration of the patient’s oral mucosa or nail beds. At the six-month visit, her dosage of hydroxychloroquine was reevaluated.

The patient’s hydroxychloroquine dosage was determined based on 7.3 mg/kg/d. In the case of an overweight patient, especially one of shorter-than-average stature, hydroxychloroquine dosing should be based on ideal body weight to minimize the risk for overdosage; in general, a maximum dosage of 6.5 mg/kg/d is recommended.^8,9 As a result, the patient’s dosage was decreased to 300 mg/d.

At her nine-month follow-up evaluation, the discoloration to the patient’s oral mucosa had faded but had not resolved completely (see Figure 3). No significant change was noted in the subungual discoloration. The patient had experienced no exacerbations of lupus-related symptoms since her medication adjustments.

CONCLUSION
Although this patient’s hyperpigmentation was benign, staying alert to this potential adverse effect of antimalarial drugs is important in making a diagnosis. As with many skin lesions, if the clinical evaluation does not provide a clear cause, a biopsy may be needed. For anyone taking antimalarial drugs, regular ophthalmologic evaluations are recommended to facilitate early detection of the rare adverse effect of retinal toxicity. Nevertheless, with careful monitoring, antimalarial drugs are safe and effective for the treatment of inflammatory conditions such as SLE and rheumatoid arthritis.

REFERENCES
1. Kleinegger CL, Hammond HL, Finkelstein MW. Oral mucosal hyperpigmentation secondary to antimalarial drug therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90(2):189-194.

2. Gondak R-O, da Silva-Jorge R, Jorge J, et al. Oral pigmented lesions: clinicopathologic features and review of the literature. Med Oral Pathol Oral Cir Bucal. 2012;17(6):e919-e924.

3. Lerman MA, Karimbux N, Guze KA, Woo SB. Pigmentation of the hard palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;
107:8-12.

4. Kalampalikis A, Goetze S, Elsner P. Isolated hyperpigmentation of the oral mucosa due to hydroxychloroquine. J Dtsch Dermatol Ges. 2012; 10(12):921-922.

5. de Andrade BA, Fonseca FP, Pires FR, et al. Hard palate hyperpigmentation secondary to chronic chloroquine therapy: report of five cases.
J Cutan Pathol. 2013;40(9):833-838.

6. Tuffanelli D, Abraham RK, Dubois EI. Pigmentation from antimalarial therapy: its possible relationship to the ocular lesions. Arch Derm. 1963; 88:419-426.

7. Melikoglu MA, Melikoglu M, Gurbuz U, et al. Hydroxychloroquine-induced hyperpigmentation: a case report. J Clin Pharm Ther. 2008; 33(6):699-701. 

8. Marmor MF, Kellner U, Lai YY, et al; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):
415-422.

9. Screening for hydroxychloroquine retinopathy. Position statement, American College of Rheumatology. www.rheumatology.org/Practice/Clinical/Position/Position_Statements/. Accessed July 17, 2014.

A 62-year-old African-American woman presented for evaluation of a bluish discoloration of the hard palate and nail beds, noticeable for several months. In addition, she had complaints of fatigue and arthralgia. She reported that she had been taking hydroxychloroquine 400 mg/d and quinacrine 100 mg/d for several years for the treatment of systemic lupus erythematosus (SLE). Her medical history was also significant for dry mouth syndrome treated with pilocarpine.

The patient’s vital signs included a temperature of 97°F;
respiratory rate, 15 breaths/min; pulse, 72 beats/min; and blood pressure, 130/80 mm Hg. Height was 62 in, weight was 189 lb, and BMI was 34.56. A bluish gray color was noted in the subungual areas of her nails (see Figure 1). There were several circumferential areas of skin hyperpigmentation resulting from healed lupus skin lesions on her arms. Nailfold capillaroscopy revealed several dilated blood vessels. The sclerae appeared dry, but no erythema or inflammation was noted.

Examination of the mouth revealed a bluish discoloration of the hard palate (see Figure 2) and decreased salivary pool. Respiratory, cardiovascular, and abdominal examination findings were normal. Musculoskeletal examination was unremarkable for acute joint tenderness or synovitis. Crepitation and bony changes were noted in the left knee, without effusion or decreased range of motion.

Laboratory studies were ordered, and the results are listed in the table.

DISCUSSION
Hyperpigmentation of the oral mucosa can be associated with a number of conditions, including adrenal insufficiency, Peutz-Jeghers syndrome, hemochromatosis, polyostotic fibrous dysplasia, hyperparathyroidism, neurofibromatosis, and bronchogenic malignancy.^1,2 Other causes of oral hyperpigmentation include physiologic pigmentary or postinflammatory changes, oral melanoacanthosis, blue nevus, and melanoma.^2,3 While these diagnoses should be considered when encountering a mucosal lesion, they were unlikely in this patient because of the color changes in her nail beds.

Systemic skin and mucous membrane discoloration can also occur with the use of certain drugs and other substances, including chemotherapeutic agents, benzodiazepines, hormones, carotenoids, phenolphthalein, heavy metal salts, and several antimicrobial agents.¹ In dark-skinned individuals, hyperpigmentation of the oral mucosa can be caused by a physiologic deposition of melanin.⁴

Pigmentary Changes
The use of antimalarial drugs, such as quinacrine, chloroquine, and hydroxychloroquine, has long been associated with pigmentary changes to the palatal mucosa and subungual areas.^1,3 These drugs can stimulate melanin production and cause hemosiderin deposition, resulting in pigmentary changes.⁵ Skin discoloration is believed to be the result of the formation of a melanin-drug complex in areas with an elevated affinity for melanin.¹ Besides malaria, these drugs are commonly used to treat SLE and discoid lupus erythematosus, rheumatoid arthritis, and other rheumatologic conditions.⁵

The diagnosis of drug-induced hyperpigmentation is generally clinical, supported by the patient’s history—which often includes the use of antimalarial drugs—and presentation.¹ If a clear cause cannot be determined by clinical evaluation, then a biopsy to confirm a drug-induced cause may be necessary.² A classic study by Tuffanelli et al reported that the onset of hyperpigmentation related to antimalarial drug therapy may not occur until 4 to 70 months after initiation of treatment.⁶ Once the offending drug is discontinued, pigmentation changes slowly fade but often do not completely resolve,⁷ and patients should be advised of this.

Ocular Retinopathy
While pigmentary changes associated with antimalarial drugs are benign,³ a rare but serious adverse effect of antimalarials is retinal toxicity. Ocular retinopathy related to chloroquine and hydroxychloroquine therapy has been well documented and may result in irreversible vision loss.^8,9 The most recent recommendations from the American Academy of Ophthalmology suggest a baseline eye examination at initiation of antimalarial treatment and annual examinations starting after five years of therapy because the risk for toxicity relates to the cumulative dose.⁸ More frequent ophthalmologic evaluations are recommended for individuals at higher risk, such as those with preexisting retinal or macular disease.⁹

Outcome for the case patient >>

OUTCOME FOR THE CASE PATIENT
A biopsy of the roof of the patient’s mouth confirmed that the palatal hyperpigmentation was caused by her antimalarial medications. Since the patient displayed no evidence of active lupus skin lesions and laboratory results indicated that her SLE was inactive, one of the drugs, quinacrine, was discontinued.

The patient was referred for an ophthalmologic evaluation. No evidence of retinal toxicity was found.

Follow-up evaluations at two months and six months revealed no significant improvement in the discoloration of the patient’s oral mucosa or nail beds. At the six-month visit, her dosage of hydroxychloroquine was reevaluated.

The patient’s hydroxychloroquine dosage was determined based on 7.3 mg/kg/d. In the case of an overweight patient, especially one of shorter-than-average stature, hydroxychloroquine dosing should be based on ideal body weight to minimize the risk for overdosage; in general, a maximum dosage of 6.5 mg/kg/d is recommended.^8,9 As a result, the patient’s dosage was decreased to 300 mg/d.

At her nine-month follow-up evaluation, the discoloration to the patient’s oral mucosa had faded but had not resolved completely (see Figure 3). No significant change was noted in the subungual discoloration. The patient had experienced no exacerbations of lupus-related symptoms since her medication adjustments.

CONCLUSION
Although this patient’s hyperpigmentation was benign, staying alert to this potential adverse effect of antimalarial drugs is important in making a diagnosis. As with many skin lesions, if the clinical evaluation does not provide a clear cause, a biopsy may be needed. For anyone taking antimalarial drugs, regular ophthalmologic evaluations are recommended to facilitate early detection of the rare adverse effect of retinal toxicity. Nevertheless, with careful monitoring, antimalarial drugs are safe and effective for the treatment of inflammatory conditions such as SLE and rheumatoid arthritis.

REFERENCES
1. Kleinegger CL, Hammond HL, Finkelstein MW. Oral mucosal hyperpigmentation secondary to antimalarial drug therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000;90(2):189-194.

2. Gondak R-O, da Silva-Jorge R, Jorge J, et al. Oral pigmented lesions: clinicopathologic features and review of the literature. Med Oral Pathol Oral Cir Bucal. 2012;17(6):e919-e924.

3. Lerman MA, Karimbux N, Guze KA, Woo SB. Pigmentation of the hard palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;
107:8-12.

4. Kalampalikis A, Goetze S, Elsner P. Isolated hyperpigmentation of the oral mucosa due to hydroxychloroquine. J Dtsch Dermatol Ges. 2012; 10(12):921-922.

5. de Andrade BA, Fonseca FP, Pires FR, et al. Hard palate hyperpigmentation secondary to chronic chloroquine therapy: report of five cases.
J Cutan Pathol. 2013;40(9):833-838.

6. Tuffanelli D, Abraham RK, Dubois EI. Pigmentation from antimalarial therapy: its possible relationship to the ocular lesions. Arch Derm. 1963; 88:419-426.

7. Melikoglu MA, Melikoglu M, Gurbuz U, et al. Hydroxychloroquine-induced hyperpigmentation: a case report. J Clin Pharm Ther. 2008; 33(6):699-701. 

8. Marmor MF, Kellner U, Lai YY, et al; American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118(2):
415-422.

9. Screening for hydroxychloroquine retinopathy. Position statement, American College of Rheumatology. www.rheumatology.org/Practice/Clinical/Position/Position_Statements/. Accessed July 17, 2014.

Presenters

David Pressel, Jessica Tomaszewski, Emily Fingado, Adam Pressel

Summary

Behavioral emergencies occur when a patient is physically aggressive or potentially harmful to him/herself or others. Behavioral emergencies may be rare, but they are high-risk situations and staff might be untrained and uncomfortable dealing with these events.

Patients with underlying psychiatric or developmental disorders, have ingested substances, or have a medication side effect are at highest risk for becoming violent. Triggers for these events could be due to pain, hunger, isolation, change in routine, or even the hospital’s physical environment. Early warning signs for a behavioral emergency can include verbal threats, yelling, or silence. Physical signs may include pacing, crossed arms, furrowed brow, or throwing.

The first response to a potential behavioral emergency is to try to de-escalate the situation. Speak in a quiet, calm voice; back off and give personal space. Try to reduce a source of discomfort and use distractions or rewards. If de-escalation is not successful and a patient becomes violent, the provider’s first role is to be safe: get away and get help. Hospitals should have (or should develop) a violent patient response team, which may then physically restrain the patient. Medications can be used to treat medical issues, but should not be used solely for chemical restraint.

Once a patient is safely restrained, a number of JCAHO mandated actions must occur. The legal guardian and attending of record must be notified. A debrief must occur regarding the events; this must be documented in the medical record. Finally, a strategy must be formulated to enable the patient to be safely removed from restraints as soon as safe.

The presenters demonstrated various personal safety techniques to escape from a violent patient, as well as the use of physical restraints. Participants engaged in a mock behavioral emergency to experience the chaos of these events.

Hospitalists should ensure that their home institutions have developed policies and procedures, as well as ongoing training to address patient behavioral emergencies. TH

Dr. Pressel is a pediatric hospitalist and inpatient medical director at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and a member of Team Hospitalist.

Presenters

David Pressel, Jessica Tomaszewski, Emily Fingado, Adam Pressel

Summary

Behavioral emergencies occur when a patient is physically aggressive or potentially harmful to him/herself or others. Behavioral emergencies may be rare, but they are high-risk situations and staff might be untrained and uncomfortable dealing with these events.

Patients with underlying psychiatric or developmental disorders, have ingested substances, or have a medication side effect are at highest risk for becoming violent. Triggers for these events could be due to pain, hunger, isolation, change in routine, or even the hospital’s physical environment. Early warning signs for a behavioral emergency can include verbal threats, yelling, or silence. Physical signs may include pacing, crossed arms, furrowed brow, or throwing.

The first response to a potential behavioral emergency is to try to de-escalate the situation. Speak in a quiet, calm voice; back off and give personal space. Try to reduce a source of discomfort and use distractions or rewards. If de-escalation is not successful and a patient becomes violent, the provider’s first role is to be safe: get away and get help. Hospitals should have (or should develop) a violent patient response team, which may then physically restrain the patient. Medications can be used to treat medical issues, but should not be used solely for chemical restraint.

Once a patient is safely restrained, a number of JCAHO mandated actions must occur. The legal guardian and attending of record must be notified. A debrief must occur regarding the events; this must be documented in the medical record. Finally, a strategy must be formulated to enable the patient to be safely removed from restraints as soon as safe.

The presenters demonstrated various personal safety techniques to escape from a violent patient, as well as the use of physical restraints. Participants engaged in a mock behavioral emergency to experience the chaos of these events.

Hospitalists should ensure that their home institutions have developed policies and procedures, as well as ongoing training to address patient behavioral emergencies. TH

Dr. Pressel is a pediatric hospitalist and inpatient medical director at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and a member of Team Hospitalist.

Presenters

David Pressel, Jessica Tomaszewski, Emily Fingado, Adam Pressel

Summary

Behavioral emergencies occur when a patient is physically aggressive or potentially harmful to him/herself or others. Behavioral emergencies may be rare, but they are high-risk situations and staff might be untrained and uncomfortable dealing with these events.

Patients with underlying psychiatric or developmental disorders, have ingested substances, or have a medication side effect are at highest risk for becoming violent. Triggers for these events could be due to pain, hunger, isolation, change in routine, or even the hospital’s physical environment. Early warning signs for a behavioral emergency can include verbal threats, yelling, or silence. Physical signs may include pacing, crossed arms, furrowed brow, or throwing.

The first response to a potential behavioral emergency is to try to de-escalate the situation. Speak in a quiet, calm voice; back off and give personal space. Try to reduce a source of discomfort and use distractions or rewards. If de-escalation is not successful and a patient becomes violent, the provider’s first role is to be safe: get away and get help. Hospitals should have (or should develop) a violent patient response team, which may then physically restrain the patient. Medications can be used to treat medical issues, but should not be used solely for chemical restraint.

Once a patient is safely restrained, a number of JCAHO mandated actions must occur. The legal guardian and attending of record must be notified. A debrief must occur regarding the events; this must be documented in the medical record. Finally, a strategy must be formulated to enable the patient to be safely removed from restraints as soon as safe.

The presenters demonstrated various personal safety techniques to escape from a violent patient, as well as the use of physical restraints. Participants engaged in a mock behavioral emergency to experience the chaos of these events.

Hospitalists should ensure that their home institutions have developed policies and procedures, as well as ongoing training to address patient behavioral emergencies. TH

Dr. Pressel is a pediatric hospitalist and inpatient medical director at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and a member of Team Hospitalist.

Presenters

Sarah F. Denniston, Jack M. Percelay, David M. Pressel, David I. Rappaport, Elisabeth H. Villavicencio

Summary

Co-management is a growing area of pediatric HM involving both surgical and medical subspecialties. According to SHM, co-management is “shared responsibility, authority, and accountability for the care of a hospitalized patient across clinical specialties.”

Motivation for starting a co-management program may come from administrators due to quality, safety, or nursing concerns; surgeons or subspecialists driven by time or knowledge constraints; or from hospitalists looking to enhance patient safety, clinical skills, and practice development.

Pitfalls for hospitalists include patient “dumping,” care fragmentation, and working outside their scope of practice.

SHM identifies five keys to success for hospitalist co-management programs:

1. Identify obstacles and challenges, including the program’s stakeholders, goals, risks and assumptions.
2. Clarify roles and responsibilities for areas such as admission and discharge, communication, documentation and delineation of responsibilities. These should be specified in a service agreement.
3. Identify champions, ideally to include a surgeon or subspecialist, hospitalist, administrator, and input from a family advisory council.
4. Measure performance in areas such as length of stay, resource utilization, quality and safety metrics.
5. Address financial issues. Most programs require some financial support to supplement billing revenue.

The AMA ethical guidelines for co-management arrangements state that the highest-quality care, not economic considerations, should be the guiding factor. Additionally, one physician should ultimately be responsible for the patient, there can be no kickbacks, and co-management arrangements need to be disclosed to the patient or family. TH

David Pressel is a pediatric hospitalist and inpatient medical director at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and a member of Team Hospitalist.

Presenters

Sarah F. Denniston, Jack M. Percelay, David M. Pressel, David I. Rappaport, Elisabeth H. Villavicencio

Summary

Co-management is a growing area of pediatric HM involving both surgical and medical subspecialties. According to SHM, co-management is “shared responsibility, authority, and accountability for the care of a hospitalized patient across clinical specialties.”

Motivation for starting a co-management program may come from administrators due to quality, safety, or nursing concerns; surgeons or subspecialists driven by time or knowledge constraints; or from hospitalists looking to enhance patient safety, clinical skills, and practice development.

Pitfalls for hospitalists include patient “dumping,” care fragmentation, and working outside their scope of practice.

SHM identifies five keys to success for hospitalist co-management programs:

1. Identify obstacles and challenges, including the program’s stakeholders, goals, risks and assumptions.
2. Clarify roles and responsibilities for areas such as admission and discharge, communication, documentation and delineation of responsibilities. These should be specified in a service agreement.
3. Identify champions, ideally to include a surgeon or subspecialist, hospitalist, administrator, and input from a family advisory council.
4. Measure performance in areas such as length of stay, resource utilization, quality and safety metrics.
5. Address financial issues. Most programs require some financial support to supplement billing revenue.

The AMA ethical guidelines for co-management arrangements state that the highest-quality care, not economic considerations, should be the guiding factor. Additionally, one physician should ultimately be responsible for the patient, there can be no kickbacks, and co-management arrangements need to be disclosed to the patient or family. TH

David Pressel is a pediatric hospitalist and inpatient medical director at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and a member of Team Hospitalist.

Presenters

Sarah F. Denniston, Jack M. Percelay, David M. Pressel, David I. Rappaport, Elisabeth H. Villavicencio

Summary

Co-management is a growing area of pediatric HM involving both surgical and medical subspecialties. According to SHM, co-management is “shared responsibility, authority, and accountability for the care of a hospitalized patient across clinical specialties.”

Motivation for starting a co-management program may come from administrators due to quality, safety, or nursing concerns; surgeons or subspecialists driven by time or knowledge constraints; or from hospitalists looking to enhance patient safety, clinical skills, and practice development.

Pitfalls for hospitalists include patient “dumping,” care fragmentation, and working outside their scope of practice.

SHM identifies five keys to success for hospitalist co-management programs:

1. Identify obstacles and challenges, including the program’s stakeholders, goals, risks and assumptions.
2. Clarify roles and responsibilities for areas such as admission and discharge, communication, documentation and delineation of responsibilities. These should be specified in a service agreement.
3. Identify champions, ideally to include a surgeon or subspecialist, hospitalist, administrator, and input from a family advisory council.
4. Measure performance in areas such as length of stay, resource utilization, quality and safety metrics.
5. Address financial issues. Most programs require some financial support to supplement billing revenue.

The AMA ethical guidelines for co-management arrangements state that the highest-quality care, not economic considerations, should be the guiding factor. Additionally, one physician should ultimately be responsible for the patient, there can be no kickbacks, and co-management arrangements need to be disclosed to the patient or family. TH

David Pressel is a pediatric hospitalist and inpatient medical director at Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., and a member of Team Hospitalist.

Jerry, a 48-year-old white man, is referred to endocrinology for abnormal results of thyroid tests performed four weeks ago (see table for values). Two months ago, Jerry developed an upper respiratory infection (URI) with fever, odynophagia, and anterior neck discomfort. His symptoms resolved after two weeks; however, he has since developed fatigue and nervousness.

The remaining review of systems is unremarkable. Medical history is negative. Jerry denies any factors that can affect thyroid function: He does not take thyroid medication, OTC thyroid supplements, amiodarone, lithium, or interferon-α, does not have high iodine intake, and has not undergone head/neck irradiation. There is no personal or family history of thyroid disease, organ-specific autoimmune disease (ie, vitiligo, myasthenia gravis, or Sjögren syndrome) or systemic autoimmune disease (rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis).

Vital signs are stable. On physical examination, his thyroid gland is firm, with slight enlargement of the left lobe and mild tenderness. There are no palpable nodules or cervical adenopathy. The remainder of the exam is unremarkable.

Lab studies (see table) reveal an elevated erythrocyte sedimentation rate (ESR) and suppressed TSH, with normal free thyroxine (T4) and free triiodothyronine (T3) levels. His thyroid peroxidase antibody (Anti-TPO) is negative. Radioactive iodine uptake (RAIU) reveals a low 24-hour uptake of 4% (normal, 5% to 30%).

Jerry is given the presumptive diagnosis of subacute thyroiditis (SAT). He is advised that the condition will progress through multiple phases—from the initial thyrotoxicosis to euthyroidism
to transient hypothyroid—before resolution and is educated on the symptoms and signs to watch for. Since he presented in a euthyroid phase, with only mild anterior neck tenderness, no treatment is indicated. He is instructed to follow up for thyroid function testing in four to six weeks and to call with any symptomatic changes.

Two months later, Jerry returns with complaints of ongoing fatigue, unintentional weight gain, and “mental fog.” Physical exam findings are unremarkable except for a small, firm thyroid gland without the tenderness elicited previously. Labwork reveals an elevated TSH with low free T4 and free T3. He is again counseled regarding the natural history of SAT and reassured that his symptoms will abate as his thyroid hormone levels normalize. He is advised to continue the plan of follow-up testing every four to six weeks.

Approximately eight weeks later, Jerry’s thyroid function studies indicate normal levels, and he is notified of the results. Jerry comments that his symptoms have completely resolved and he is back to feeling like his usual self. He is discharged to follow-up as needed.

What is subacute thyroiditis? 

WHAT IS SUBACUTE ­THYROIDITIS?
Subacute thyroiditis  is also known as de Quervain thyroiditis or granulomatous giant cell thyroiditis.^1,2 The most common cause of thyroid pain, it is a self-limited inflammatory disorder in which a painful tender goiter is associated with malaise, fever, and transient thyroid dysfunction.^2,3 As with other thyroid disorders, SAT occurs most frequently in women ages 40 to 50.^2,3 Thought to be of viral origin, it usually occurs after a URI and commonly correlates with the peak incidence of viral infections (spring/fall).^2,3

The disruptive process begins with inflammatory destruction of thyroid follicles.² This causes leakage of stored colloid, which is broken down, releasing unregulated T4 and T3 into the circulation and resulting in a thyrotoxicosis that typically lasts six weeks.^1,2,4 Thyroid cells are incapable of producing new thyroid hormone during this time, so as excess circulating hormone is utilized, T4 and T3 levels become normal, then deficient, and the patient transitions through a period of euthyroidism to transient hypothyroidism.^1,2,4 As the disruption of thyroid parenchyma abates, recovery ensues. The follicles regenerate, colloid is repleted, and normal thyroid function is restored.^1-4

SAT typically lasts four to six months, although painful thyromegaly may persist for one year after resolution of thyroid dysfunction.² Throughout the course of SAT, thyroid test results can be confusing, and misdiagnosis of hyperthyroidism or hypothyroidism may occur unless each phase of SAT is recognized.

Phases of SAT >> 

PRODROME
The precursor URI is followed in days or weeks by the clinical manifestations of SAT. These typically include myalgia, pharyngitis, low-grade fever, and fatigue.²

There may be pain of varying degrees in part or all of one or both lobes; the pain often migrates to the entire gland and may radiate to the angle of the jaw or the ear of the affected side(s). Moving the head, swallowing, or coughing aggravates the pain.²

The hallmark of SAT is a markedly elevated ESR (often > 100 mm/h).^1-3 Leukocyte count is normal (50% of cases) or only slightly elevated (50%).²

THYROTOXIC PHASE
Fifty percent of patients have mild to moderate symptoms of hyperthyroidism, including nervousness, weight loss, heat intolerance, or palpitations; hoarseness or dysphagia may be present.² Signs include tremors or tachycardia. The thyroid gland may reveal slight to moderate unilateral enlargement, usually firm in the involved area, and tenderness may be mild, moderate, or severe.² Cervical lymphadenopathy is absent.²  Serum T4 and T3 levels are elevated, and TSH is suppressed.^1-4  

Thyroid antibodies (antithyroid peroxidase antibodies [Anti-TPO or TPOAb] or antithyroglobulin antibodies [Anti-TG or TgAb]) have been found in 42% to 62% of patients with SAT.² These transitory immunologic markers develop several weeks after the onset and appear to be a physiologic response to the inflammatory insult to the gland.² In most patients, the antibody titer gradually decreases, then disappears as the disease resolves.^2-4

The 24-hour RAIU is low
(< 5%) in the toxic phase of SAT, and thyroid scan will reveal a patchy and irregular distribution of the tracer.^2,3 The thyrotoxicosis during this early phase is caused by the inflammatory release of preformed thyroid hormones (not hyperfunctioning in the gland), resulting in a “low-uptake thyrotoxicosis.”² This differentiates SAT from the elevated uptake seen in Graves disease (> 30% at 24 hours).²

TRANSIENT HYPOTHYROIDISM PHASE
As circulating T4 and T3 are utilized but follicular function remains temporarily impaired, levels decline, resulting in a period of euthyroidism followed by hypothyroidism. TSH levels, previously suppressed in the thyrotoxic phase, now become elevated. This transient hypothyroidism occurs in two-thirds of patients, and the presentation varies from subclinical to pronounced.²

RECOVERY PHASE
After several weeks or months, all thyroid function studies return to normal and complete recovery commonly ensues. SAT rarely recurs, most likely due to immunity to the precipitating virus.^1,2,4

Management of SAT >> 

MANAGEMENT
Thyroid function should be monitored by testing every two to four weeks, dependent on the severity of the patient’s symptoms and rate of progression.¹ Often, no treatment is required.^1,2

Symptomatic relief of mild thyroid pain can be achieved with NSAIDs or aspirin (2 to 3 g/d). Severe symptoms can be treated with short-term prednisone, which should be tapered and discontinued.^1-3 Steroids suppress the inflammatory response, and the dramatic relief of thyroid pain within 24 hours can be diagnostic of SAT.²

During the thyrotoxic phase, β-blockers (propranolol) can alleviate adrenergic symptoms, with the dose tapered once the patient is euthyroid.^1-3 Antithyroid medications that directly inhibit thyroid hormone synthesis (eg, methimazole or propylthiouracil) are ineffective due to the lack of T4 and T3 production in the follicular cells after the inflammatory response.^2,3

During the transient hypothyroid phase, thyroid hormone replacement may be indicated if the TSH level is markedly elevated or the phase refractory. However, levothyroxine therapy should be low dose (< 100 μg) and not be considered lifelong.^2,3

DIFFERENTIAL DIAGNOSIS
During the prodrome, SAT is often misdiagnosed as pharyngitis. Acute suppurative thyroiditis initially may mimic SAT, but the febrile and leukocytic responses are greater, and localized edema, erythema, and tenderness become more evident as the condition progresses.

Painless or silent thyroiditis is distinguished from SAT by the lack of pain or tenderness and a normal ESR in the presence of a similar pattern of thyroid dysfunction. Graves disease presents with symptoms similar to the thyrotoxic phase of SAT, but T3 is usually disproportionately elevated compared to T4, RAIU is elevated, and thyroid antibodies are prevalent.²

CONCLUSION
Primary care providers may encounter SAT at some point, and a level of clinical suspicion must be maintained. Referral to endocrinology may be warranted in some cases; however, textbook cases can often be followed in primary care. Patient education is the foundation of SAT care. Symptomatic treatments may be employed as needed. Fortunately, for most patients, this self-limited disease state rarely leads to complications.

REFERENCES
1. Cooper DS. The thyroid gland. In: Gardner D, Shobeck D (eds). Greenspan’s Basic and Clinical Endocrinology. 9th ed. China: McGraw-Hill; 2011:163-226.

2. Guimaraes VC. Subacute and Riedel’s thyroiditis. In: Jameson JL, De Groot LJ (eds). Endocrinology Adult and Pediatric. 6th ed. Philadelphia: Saunders; 2010:1595-1600.

3. Jameson JL. Disorders of the thyroid gland.  In: Jameson JL (ed). Harrison’s Endocrin­ology. 2nd ed. China: McGraw-Hill; 2010: 62-98.

4. Smallridge RC. Thyroiditis. In: McDermott MT (ed). Endocrine Secrets. 6th ed. Philadelphia, PA: Elsevier Saunders; 2013:289-293.

Jerry, a 48-year-old white man, is referred to endocrinology for abnormal results of thyroid tests performed four weeks ago (see table for values). Two months ago, Jerry developed an upper respiratory infection (URI) with fever, odynophagia, and anterior neck discomfort. His symptoms resolved after two weeks; however, he has since developed fatigue and nervousness.

The remaining review of systems is unremarkable. Medical history is negative. Jerry denies any factors that can affect thyroid function: He does not take thyroid medication, OTC thyroid supplements, amiodarone, lithium, or interferon-α, does not have high iodine intake, and has not undergone head/neck irradiation. There is no personal or family history of thyroid disease, organ-specific autoimmune disease (ie, vitiligo, myasthenia gravis, or Sjögren syndrome) or systemic autoimmune disease (rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis).

Vital signs are stable. On physical examination, his thyroid gland is firm, with slight enlargement of the left lobe and mild tenderness. There are no palpable nodules or cervical adenopathy. The remainder of the exam is unremarkable.

Lab studies (see table) reveal an elevated erythrocyte sedimentation rate (ESR) and suppressed TSH, with normal free thyroxine (T4) and free triiodothyronine (T3) levels. His thyroid peroxidase antibody (Anti-TPO) is negative. Radioactive iodine uptake (RAIU) reveals a low 24-hour uptake of 4% (normal, 5% to 30%).

Jerry is given the presumptive diagnosis of subacute thyroiditis (SAT). He is advised that the condition will progress through multiple phases—from the initial thyrotoxicosis to euthyroidism
to transient hypothyroid—before resolution and is educated on the symptoms and signs to watch for. Since he presented in a euthyroid phase, with only mild anterior neck tenderness, no treatment is indicated. He is instructed to follow up for thyroid function testing in four to six weeks and to call with any symptomatic changes.

Two months later, Jerry returns with complaints of ongoing fatigue, unintentional weight gain, and “mental fog.” Physical exam findings are unremarkable except for a small, firm thyroid gland without the tenderness elicited previously. Labwork reveals an elevated TSH with low free T4 and free T3. He is again counseled regarding the natural history of SAT and reassured that his symptoms will abate as his thyroid hormone levels normalize. He is advised to continue the plan of follow-up testing every four to six weeks.

Approximately eight weeks later, Jerry’s thyroid function studies indicate normal levels, and he is notified of the results. Jerry comments that his symptoms have completely resolved and he is back to feeling like his usual self. He is discharged to follow-up as needed.

What is subacute thyroiditis? 

WHAT IS SUBACUTE ­THYROIDITIS?
Subacute thyroiditis  is also known as de Quervain thyroiditis or granulomatous giant cell thyroiditis.^1,2 The most common cause of thyroid pain, it is a self-limited inflammatory disorder in which a painful tender goiter is associated with malaise, fever, and transient thyroid dysfunction.^2,3 As with other thyroid disorders, SAT occurs most frequently in women ages 40 to 50.^2,3 Thought to be of viral origin, it usually occurs after a URI and commonly correlates with the peak incidence of viral infections (spring/fall).^2,3

The disruptive process begins with inflammatory destruction of thyroid follicles.² This causes leakage of stored colloid, which is broken down, releasing unregulated T4 and T3 into the circulation and resulting in a thyrotoxicosis that typically lasts six weeks.^1,2,4 Thyroid cells are incapable of producing new thyroid hormone during this time, so as excess circulating hormone is utilized, T4 and T3 levels become normal, then deficient, and the patient transitions through a period of euthyroidism to transient hypothyroidism.^1,2,4 As the disruption of thyroid parenchyma abates, recovery ensues. The follicles regenerate, colloid is repleted, and normal thyroid function is restored.^1-4

SAT typically lasts four to six months, although painful thyromegaly may persist for one year after resolution of thyroid dysfunction.² Throughout the course of SAT, thyroid test results can be confusing, and misdiagnosis of hyperthyroidism or hypothyroidism may occur unless each phase of SAT is recognized.

Phases of SAT >> 

PRODROME
The precursor URI is followed in days or weeks by the clinical manifestations of SAT. These typically include myalgia, pharyngitis, low-grade fever, and fatigue.²

There may be pain of varying degrees in part or all of one or both lobes; the pain often migrates to the entire gland and may radiate to the angle of the jaw or the ear of the affected side(s). Moving the head, swallowing, or coughing aggravates the pain.²

The hallmark of SAT is a markedly elevated ESR (often > 100 mm/h).^1-3 Leukocyte count is normal (50% of cases) or only slightly elevated (50%).²

THYROTOXIC PHASE
Fifty percent of patients have mild to moderate symptoms of hyperthyroidism, including nervousness, weight loss, heat intolerance, or palpitations; hoarseness or dysphagia may be present.² Signs include tremors or tachycardia. The thyroid gland may reveal slight to moderate unilateral enlargement, usually firm in the involved area, and tenderness may be mild, moderate, or severe.² Cervical lymphadenopathy is absent.²  Serum T4 and T3 levels are elevated, and TSH is suppressed.^1-4  

Thyroid antibodies (antithyroid peroxidase antibodies [Anti-TPO or TPOAb] or antithyroglobulin antibodies [Anti-TG or TgAb]) have been found in 42% to 62% of patients with SAT.² These transitory immunologic markers develop several weeks after the onset and appear to be a physiologic response to the inflammatory insult to the gland.² In most patients, the antibody titer gradually decreases, then disappears as the disease resolves.^2-4

The 24-hour RAIU is low
(< 5%) in the toxic phase of SAT, and thyroid scan will reveal a patchy and irregular distribution of the tracer.^2,3 The thyrotoxicosis during this early phase is caused by the inflammatory release of preformed thyroid hormones (not hyperfunctioning in the gland), resulting in a “low-uptake thyrotoxicosis.”² This differentiates SAT from the elevated uptake seen in Graves disease (> 30% at 24 hours).²

TRANSIENT HYPOTHYROIDISM PHASE
As circulating T4 and T3 are utilized but follicular function remains temporarily impaired, levels decline, resulting in a period of euthyroidism followed by hypothyroidism. TSH levels, previously suppressed in the thyrotoxic phase, now become elevated. This transient hypothyroidism occurs in two-thirds of patients, and the presentation varies from subclinical to pronounced.²

RECOVERY PHASE
After several weeks or months, all thyroid function studies return to normal and complete recovery commonly ensues. SAT rarely recurs, most likely due to immunity to the precipitating virus.^1,2,4

Management of SAT >> 

MANAGEMENT
Thyroid function should be monitored by testing every two to four weeks, dependent on the severity of the patient’s symptoms and rate of progression.¹ Often, no treatment is required.^1,2

Symptomatic relief of mild thyroid pain can be achieved with NSAIDs or aspirin (2 to 3 g/d). Severe symptoms can be treated with short-term prednisone, which should be tapered and discontinued.^1-3 Steroids suppress the inflammatory response, and the dramatic relief of thyroid pain within 24 hours can be diagnostic of SAT.²

During the thyrotoxic phase, β-blockers (propranolol) can alleviate adrenergic symptoms, with the dose tapered once the patient is euthyroid.^1-3 Antithyroid medications that directly inhibit thyroid hormone synthesis (eg, methimazole or propylthiouracil) are ineffective due to the lack of T4 and T3 production in the follicular cells after the inflammatory response.^2,3

During the transient hypothyroid phase, thyroid hormone replacement may be indicated if the TSH level is markedly elevated or the phase refractory. However, levothyroxine therapy should be low dose (< 100 μg) and not be considered lifelong.^2,3

DIFFERENTIAL DIAGNOSIS
During the prodrome, SAT is often misdiagnosed as pharyngitis. Acute suppurative thyroiditis initially may mimic SAT, but the febrile and leukocytic responses are greater, and localized edema, erythema, and tenderness become more evident as the condition progresses.

Painless or silent thyroiditis is distinguished from SAT by the lack of pain or tenderness and a normal ESR in the presence of a similar pattern of thyroid dysfunction. Graves disease presents with symptoms similar to the thyrotoxic phase of SAT, but T3 is usually disproportionately elevated compared to T4, RAIU is elevated, and thyroid antibodies are prevalent.²

CONCLUSION
Primary care providers may encounter SAT at some point, and a level of clinical suspicion must be maintained. Referral to endocrinology may be warranted in some cases; however, textbook cases can often be followed in primary care. Patient education is the foundation of SAT care. Symptomatic treatments may be employed as needed. Fortunately, for most patients, this self-limited disease state rarely leads to complications.

REFERENCES
1. Cooper DS. The thyroid gland. In: Gardner D, Shobeck D (eds). Greenspan’s Basic and Clinical Endocrinology. 9th ed. China: McGraw-Hill; 2011:163-226.

2. Guimaraes VC. Subacute and Riedel’s thyroiditis. In: Jameson JL, De Groot LJ (eds). Endocrinology Adult and Pediatric. 6th ed. Philadelphia: Saunders; 2010:1595-1600.

3. Jameson JL. Disorders of the thyroid gland.  In: Jameson JL (ed). Harrison’s Endocrin­ology. 2nd ed. China: McGraw-Hill; 2010: 62-98.

4. Smallridge RC. Thyroiditis. In: McDermott MT (ed). Endocrine Secrets. 6th ed. Philadelphia, PA: Elsevier Saunders; 2013:289-293.

Jerry, a 48-year-old white man, is referred to endocrinology for abnormal results of thyroid tests performed four weeks ago (see table for values). Two months ago, Jerry developed an upper respiratory infection (URI) with fever, odynophagia, and anterior neck discomfort. His symptoms resolved after two weeks; however, he has since developed fatigue and nervousness.

The remaining review of systems is unremarkable. Medical history is negative. Jerry denies any factors that can affect thyroid function: He does not take thyroid medication, OTC thyroid supplements, amiodarone, lithium, or interferon-α, does not have high iodine intake, and has not undergone head/neck irradiation. There is no personal or family history of thyroid disease, organ-specific autoimmune disease (ie, vitiligo, myasthenia gravis, or Sjögren syndrome) or systemic autoimmune disease (rheumatoid arthritis, systemic lupus erythematosus, or progressive systemic sclerosis).

Vital signs are stable. On physical examination, his thyroid gland is firm, with slight enlargement of the left lobe and mild tenderness. There are no palpable nodules or cervical adenopathy. The remainder of the exam is unremarkable.

Lab studies (see table) reveal an elevated erythrocyte sedimentation rate (ESR) and suppressed TSH, with normal free thyroxine (T4) and free triiodothyronine (T3) levels. His thyroid peroxidase antibody (Anti-TPO) is negative. Radioactive iodine uptake (RAIU) reveals a low 24-hour uptake of 4% (normal, 5% to 30%).

Jerry is given the presumptive diagnosis of subacute thyroiditis (SAT). He is advised that the condition will progress through multiple phases—from the initial thyrotoxicosis to euthyroidism
to transient hypothyroid—before resolution and is educated on the symptoms and signs to watch for. Since he presented in a euthyroid phase, with only mild anterior neck tenderness, no treatment is indicated. He is instructed to follow up for thyroid function testing in four to six weeks and to call with any symptomatic changes.

Two months later, Jerry returns with complaints of ongoing fatigue, unintentional weight gain, and “mental fog.” Physical exam findings are unremarkable except for a small, firm thyroid gland without the tenderness elicited previously. Labwork reveals an elevated TSH with low free T4 and free T3. He is again counseled regarding the natural history of SAT and reassured that his symptoms will abate as his thyroid hormone levels normalize. He is advised to continue the plan of follow-up testing every four to six weeks.

Approximately eight weeks later, Jerry’s thyroid function studies indicate normal levels, and he is notified of the results. Jerry comments that his symptoms have completely resolved and he is back to feeling like his usual self. He is discharged to follow-up as needed.

What is subacute thyroiditis? 

WHAT IS SUBACUTE ­THYROIDITIS?
Subacute thyroiditis  is also known as de Quervain thyroiditis or granulomatous giant cell thyroiditis.^1,2 The most common cause of thyroid pain, it is a self-limited inflammatory disorder in which a painful tender goiter is associated with malaise, fever, and transient thyroid dysfunction.^2,3 As with other thyroid disorders, SAT occurs most frequently in women ages 40 to 50.^2,3 Thought to be of viral origin, it usually occurs after a URI and commonly correlates with the peak incidence of viral infections (spring/fall).^2,3

The disruptive process begins with inflammatory destruction of thyroid follicles.² This causes leakage of stored colloid, which is broken down, releasing unregulated T4 and T3 into the circulation and resulting in a thyrotoxicosis that typically lasts six weeks.^1,2,4 Thyroid cells are incapable of producing new thyroid hormone during this time, so as excess circulating hormone is utilized, T4 and T3 levels become normal, then deficient, and the patient transitions through a period of euthyroidism to transient hypothyroidism.^1,2,4 As the disruption of thyroid parenchyma abates, recovery ensues. The follicles regenerate, colloid is repleted, and normal thyroid function is restored.^1-4

SAT typically lasts four to six months, although painful thyromegaly may persist for one year after resolution of thyroid dysfunction.² Throughout the course of SAT, thyroid test results can be confusing, and misdiagnosis of hyperthyroidism or hypothyroidism may occur unless each phase of SAT is recognized.

Phases of SAT >> 

PRODROME
The precursor URI is followed in days or weeks by the clinical manifestations of SAT. These typically include myalgia, pharyngitis, low-grade fever, and fatigue.²

There may be pain of varying degrees in part or all of one or both lobes; the pain often migrates to the entire gland and may radiate to the angle of the jaw or the ear of the affected side(s). Moving the head, swallowing, or coughing aggravates the pain.²

The hallmark of SAT is a markedly elevated ESR (often > 100 mm/h).^1-3 Leukocyte count is normal (50% of cases) or only slightly elevated (50%).²

THYROTOXIC PHASE
Fifty percent of patients have mild to moderate symptoms of hyperthyroidism, including nervousness, weight loss, heat intolerance, or palpitations; hoarseness or dysphagia may be present.² Signs include tremors or tachycardia. The thyroid gland may reveal slight to moderate unilateral enlargement, usually firm in the involved area, and tenderness may be mild, moderate, or severe.² Cervical lymphadenopathy is absent.²  Serum T4 and T3 levels are elevated, and TSH is suppressed.^1-4  

Thyroid antibodies (antithyroid peroxidase antibodies [Anti-TPO or TPOAb] or antithyroglobulin antibodies [Anti-TG or TgAb]) have been found in 42% to 62% of patients with SAT.² These transitory immunologic markers develop several weeks after the onset and appear to be a physiologic response to the inflammatory insult to the gland.² In most patients, the antibody titer gradually decreases, then disappears as the disease resolves.^2-4

The 24-hour RAIU is low
(< 5%) in the toxic phase of SAT, and thyroid scan will reveal a patchy and irregular distribution of the tracer.^2,3 The thyrotoxicosis during this early phase is caused by the inflammatory release of preformed thyroid hormones (not hyperfunctioning in the gland), resulting in a “low-uptake thyrotoxicosis.”² This differentiates SAT from the elevated uptake seen in Graves disease (> 30% at 24 hours).²

TRANSIENT HYPOTHYROIDISM PHASE
As circulating T4 and T3 are utilized but follicular function remains temporarily impaired, levels decline, resulting in a period of euthyroidism followed by hypothyroidism. TSH levels, previously suppressed in the thyrotoxic phase, now become elevated. This transient hypothyroidism occurs in two-thirds of patients, and the presentation varies from subclinical to pronounced.²

RECOVERY PHASE
After several weeks or months, all thyroid function studies return to normal and complete recovery commonly ensues. SAT rarely recurs, most likely due to immunity to the precipitating virus.^1,2,4

Management of SAT >> 

MANAGEMENT
Thyroid function should be monitored by testing every two to four weeks, dependent on the severity of the patient’s symptoms and rate of progression.¹ Often, no treatment is required.^1,2

Symptomatic relief of mild thyroid pain can be achieved with NSAIDs or aspirin (2 to 3 g/d). Severe symptoms can be treated with short-term prednisone, which should be tapered and discontinued.^1-3 Steroids suppress the inflammatory response, and the dramatic relief of thyroid pain within 24 hours can be diagnostic of SAT.²

During the thyrotoxic phase, β-blockers (propranolol) can alleviate adrenergic symptoms, with the dose tapered once the patient is euthyroid.^1-3 Antithyroid medications that directly inhibit thyroid hormone synthesis (eg, methimazole or propylthiouracil) are ineffective due to the lack of T4 and T3 production in the follicular cells after the inflammatory response.^2,3

During the transient hypothyroid phase, thyroid hormone replacement may be indicated if the TSH level is markedly elevated or the phase refractory. However, levothyroxine therapy should be low dose (< 100 μg) and not be considered lifelong.^2,3

DIFFERENTIAL DIAGNOSIS
During the prodrome, SAT is often misdiagnosed as pharyngitis. Acute suppurative thyroiditis initially may mimic SAT, but the febrile and leukocytic responses are greater, and localized edema, erythema, and tenderness become more evident as the condition progresses.

Painless or silent thyroiditis is distinguished from SAT by the lack of pain or tenderness and a normal ESR in the presence of a similar pattern of thyroid dysfunction. Graves disease presents with symptoms similar to the thyrotoxic phase of SAT, but T3 is usually disproportionately elevated compared to T4, RAIU is elevated, and thyroid antibodies are prevalent.²

CONCLUSION
Primary care providers may encounter SAT at some point, and a level of clinical suspicion must be maintained. Referral to endocrinology may be warranted in some cases; however, textbook cases can often be followed in primary care. Patient education is the foundation of SAT care. Symptomatic treatments may be employed as needed. Fortunately, for most patients, this self-limited disease state rarely leads to complications.

REFERENCES
1. Cooper DS. The thyroid gland. In: Gardner D, Shobeck D (eds). Greenspan’s Basic and Clinical Endocrinology. 9th ed. China: McGraw-Hill; 2011:163-226.

2. Guimaraes VC. Subacute and Riedel’s thyroiditis. In: Jameson JL, De Groot LJ (eds). Endocrinology Adult and Pediatric. 6th ed. Philadelphia: Saunders; 2010:1595-1600.

3. Jameson JL. Disorders of the thyroid gland.  In: Jameson JL (ed). Harrison’s Endocrin­ology. 2nd ed. China: McGraw-Hill; 2010: 62-98.

4. Smallridge RC. Thyroiditis. In: McDermott MT (ed). Endocrine Secrets. 6th ed. Philadelphia, PA: Elsevier Saunders; 2013:289-293.

PRACTICE CHANGER
Do not recommend elastic compression stockings to decrease the incidence of postthrombotic syndrome after deep vein thrombosis.¹

STRENGTH OF RECOMMENDATION
B: Based on a large randomized controlled trial¹

ILLUSTRATIVE CASE
A 56-year-old man presents to your clinic three days after receiving a diagnosis of lower extremity deep vein thrombosis (DVT). He was prescribed warfarin (5 mg/d) with enoxaparin bridging (120 mg/d). He has read about postthrombotic syndrome (PTS) online and is very concerned about this possible adverse effect. He asks about using elastic compression stockings (ECS). What should you tell him?

PTS can be a frustrating, debilitating condition. Its clinical features range from minor limb swelling to severe edema and pain, irreversible skin changes, and leg ulcerations.² It occurs in 25% to 50% of patients after DVT.³ Because current PTS treatments are not very effective, prevention is essential.^4,5

Patients are frequently encouraged to wear ECS after DVT to reduce the incidence of PTS by decreasing venous hypertension and reflux. These stockings are expensive and uncomfortable. Prior research suggested that use of ECS can reduce PTS incidence by half, but the studies were small, single-center, and not placebo-controlled.^6,7

On the next page: Study summary >> 

STUDY SUMMARY
RCT sets aside a common practice
Kahn et al¹ conducted a randomized, placebo-controlled trial of active versus placebo ECS in patients from 24 centers in the United States and Canada who’d had an ultrasound-confirmed proximal DVT (in the popliteal or more proximal deep leg vein) within the previous 14 days. Most patients received standard anticoagulation therapy to treat their DVT (five to 10 days of heparin and three to six months of warfarin). Patients were excluded if they had received thrombolytics, had arterial claudication, had a life expectancy of less than six months, were unable to put on ECS due to physical disabilities or allergy, or were unable to participate in follow-up visits.

Patients were randomly assigned to wear active (30 to 40 mm Hg graduated) ECS or identical-looking placebo ECS (< 5 mm Hg compression at the ankle) for two years. Providers, study personnel and statisticians, and patients were all blinded to treatment allocation. Patients were asked to wear the stocking on the affected leg each day from waking until bedtime.

Follow-up occurred at one, six, 12, 18, and 24 months. The primary outcome was cumulative incidence of PTS diagnosed at six months or later using the Ginsberg criteria of ipsilateral pain and swelling of at least one month’s duration.⁸ Secondary outcomes included severity of PTS, leg ulcers, recurrence of ­venous thromboembolism (VTE), death, adverse events, venous valvular reflux, and quality of life (QOL). Outcomes were measured objectively through use of a validated scale (the Villalta scale) for PTS severity and two questionnaires to assess QOL.^9-11

There were 409 patients in the ECS group and 394 in the placebo group. Baseline characteristics, including BMI, VTE risk factors, and anticoagulation treatment regimens, were similar between groups. The average age of participants in the study group was 55.4 years and in the placebo group, 54.8 years. Men comprised 62.4% of the active group and 57.9% of the placebo group. Approximately 90% of the participants in both groups were white.

At one month, approximately 95% of participants in both groups used the stockings; at 24 months, that was reduced to a little less than 70%. The percentage of people who used the stockings for at least three days per week was similar in both groups.

The cumulative incidence of PTS during follow-up was 14.2% in the active group and 12.7% in the placebo group (hazard ratio, 1.13). There were no differences in any of the secondary outcomes. Prespecified subgroup analyses found that age, BMI, and severity of DVT had no effect on outcomes. There was a marginal benefit for ECS for women versus men, but this does not likely reflect a true difference because the confidence intervals surrounding the hazard ratios for men and women overlapped and crossed the null value.

On the next page: What's new & challenges to implementation >>

WHAT’S NEW
New evidence contradicts ­previous studies
Two prior studies showed that using 30 to 40 mm Hg ECS decreased the incidence of PTS after proximal DVT.^6,7 However, these were smaller, open-label, single-center studies. This study by Kahn et al¹ was the first placebo-controlled, randomized, multicenter study that used validated instruments to measure PTS and QOL. It found no benefit in using ECS, thus contradicting the results of the prior studies.

There are currently no guidelines or consensus statements that recommend for or against the use of ECS after DVT.

CAVEATS
High nonadherence rates might have affected results
In both groups, adherence to the assigned intervention diminished throughout the study (from 95% at one month to slightly less than 70% at two years). Theoretically, this could have affected efficacy outcomes. However, the decrease was similar in both groups and represents what is observed in clinical practice. A prespecified per protocol analysis of patients who wore their ECS more regularly found no benefit.

It is possible that a “placebo effect” could explain the lack of difference between groups. However, the placebo stockings provided virtually no compression, and the two-year cumulative incidence of PTS in both the treatment and placebo groups was similar to that seen in control groups in prior studies.^6,7

Finally, the incidence of PTS in this study was much lower than the 25% to 50% incidence reported previously. Kahn et al¹ suggested that this was because they used more stringent and standardized criteria for PTS than was used in previous research.

CHALLENGES TO IMPLEMENTATION
There are no barriers to ending this practice
We can identify no challenges to implementation of this recommendation.

On the next page: References >>

REFERENCES
1. Kahn SR, Shapiro S, Wells PS, et al; SOX trial investigators. Compression stockings to ­prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880-888.

2. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698-707.

3. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996; 125:1-7.

4. Cohen JM, Akl EA, Kahn SR. Pharmacologic and compression therapies for postthrombotic syndrome: a systematic review of randomized controlled trials. Chest. 2012;141: 308-320.

5. Henke PK, Comerota AJ. An update on etiology, prevention, and therapy of postthrombotic syndrome. J Vasc Surg. 2011;53:
500-509.

6. Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:
759-762.

7. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.

8. Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med. 2001;161:2105-2109.

9. Villalta S, Bagatella P, Piccioli A, et al. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis. 1994;24:158a.

10. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31:247-263.

11. Kahn SR, Lamping DL, Ducruet T, et al; VETO Study Investigators. VEINES-QOL/Sym questionnaire was a reliable and valid disease-specific quality of life measure for deep venous thrombosis. J Clin Epidemiol. 2006; 59:1049-1056.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(7):388-390.

PRACTICE CHANGER
Do not recommend elastic compression stockings to decrease the incidence of postthrombotic syndrome after deep vein thrombosis.¹

STRENGTH OF RECOMMENDATION
B: Based on a large randomized controlled trial¹

ILLUSTRATIVE CASE
A 56-year-old man presents to your clinic three days after receiving a diagnosis of lower extremity deep vein thrombosis (DVT). He was prescribed warfarin (5 mg/d) with enoxaparin bridging (120 mg/d). He has read about postthrombotic syndrome (PTS) online and is very concerned about this possible adverse effect. He asks about using elastic compression stockings (ECS). What should you tell him?

PTS can be a frustrating, debilitating condition. Its clinical features range from minor limb swelling to severe edema and pain, irreversible skin changes, and leg ulcerations.² It occurs in 25% to 50% of patients after DVT.³ Because current PTS treatments are not very effective, prevention is essential.^4,5

Patients are frequently encouraged to wear ECS after DVT to reduce the incidence of PTS by decreasing venous hypertension and reflux. These stockings are expensive and uncomfortable. Prior research suggested that use of ECS can reduce PTS incidence by half, but the studies were small, single-center, and not placebo-controlled.^6,7

On the next page: Study summary >> 

STUDY SUMMARY
RCT sets aside a common practice
Kahn et al¹ conducted a randomized, placebo-controlled trial of active versus placebo ECS in patients from 24 centers in the United States and Canada who’d had an ultrasound-confirmed proximal DVT (in the popliteal or more proximal deep leg vein) within the previous 14 days. Most patients received standard anticoagulation therapy to treat their DVT (five to 10 days of heparin and three to six months of warfarin). Patients were excluded if they had received thrombolytics, had arterial claudication, had a life expectancy of less than six months, were unable to put on ECS due to physical disabilities or allergy, or were unable to participate in follow-up visits.

Patients were randomly assigned to wear active (30 to 40 mm Hg graduated) ECS or identical-looking placebo ECS (< 5 mm Hg compression at the ankle) for two years. Providers, study personnel and statisticians, and patients were all blinded to treatment allocation. Patients were asked to wear the stocking on the affected leg each day from waking until bedtime.

Follow-up occurred at one, six, 12, 18, and 24 months. The primary outcome was cumulative incidence of PTS diagnosed at six months or later using the Ginsberg criteria of ipsilateral pain and swelling of at least one month’s duration.⁸ Secondary outcomes included severity of PTS, leg ulcers, recurrence of ­venous thromboembolism (VTE), death, adverse events, venous valvular reflux, and quality of life (QOL). Outcomes were measured objectively through use of a validated scale (the Villalta scale) for PTS severity and two questionnaires to assess QOL.^9-11

There were 409 patients in the ECS group and 394 in the placebo group. Baseline characteristics, including BMI, VTE risk factors, and anticoagulation treatment regimens, were similar between groups. The average age of participants in the study group was 55.4 years and in the placebo group, 54.8 years. Men comprised 62.4% of the active group and 57.9% of the placebo group. Approximately 90% of the participants in both groups were white.

At one month, approximately 95% of participants in both groups used the stockings; at 24 months, that was reduced to a little less than 70%. The percentage of people who used the stockings for at least three days per week was similar in both groups.

The cumulative incidence of PTS during follow-up was 14.2% in the active group and 12.7% in the placebo group (hazard ratio, 1.13). There were no differences in any of the secondary outcomes. Prespecified subgroup analyses found that age, BMI, and severity of DVT had no effect on outcomes. There was a marginal benefit for ECS for women versus men, but this does not likely reflect a true difference because the confidence intervals surrounding the hazard ratios for men and women overlapped and crossed the null value.

On the next page: What's new & challenges to implementation >>

WHAT’S NEW
New evidence contradicts ­previous studies
Two prior studies showed that using 30 to 40 mm Hg ECS decreased the incidence of PTS after proximal DVT.^6,7 However, these were smaller, open-label, single-center studies. This study by Kahn et al¹ was the first placebo-controlled, randomized, multicenter study that used validated instruments to measure PTS and QOL. It found no benefit in using ECS, thus contradicting the results of the prior studies.

There are currently no guidelines or consensus statements that recommend for or against the use of ECS after DVT.

CAVEATS
High nonadherence rates might have affected results
In both groups, adherence to the assigned intervention diminished throughout the study (from 95% at one month to slightly less than 70% at two years). Theoretically, this could have affected efficacy outcomes. However, the decrease was similar in both groups and represents what is observed in clinical practice. A prespecified per protocol analysis of patients who wore their ECS more regularly found no benefit.

It is possible that a “placebo effect” could explain the lack of difference between groups. However, the placebo stockings provided virtually no compression, and the two-year cumulative incidence of PTS in both the treatment and placebo groups was similar to that seen in control groups in prior studies.^6,7

Finally, the incidence of PTS in this study was much lower than the 25% to 50% incidence reported previously. Kahn et al¹ suggested that this was because they used more stringent and standardized criteria for PTS than was used in previous research.

CHALLENGES TO IMPLEMENTATION
There are no barriers to ending this practice
We can identify no challenges to implementation of this recommendation.

On the next page: References >>

REFERENCES
1. Kahn SR, Shapiro S, Wells PS, et al; SOX trial investigators. Compression stockings to ­prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880-888.

2. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698-707.

3. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996; 125:1-7.

4. Cohen JM, Akl EA, Kahn SR. Pharmacologic and compression therapies for postthrombotic syndrome: a systematic review of randomized controlled trials. Chest. 2012;141: 308-320.

5. Henke PK, Comerota AJ. An update on etiology, prevention, and therapy of postthrombotic syndrome. J Vasc Surg. 2011;53:
500-509.

6. Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:
759-762.

7. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.

8. Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med. 2001;161:2105-2109.

9. Villalta S, Bagatella P, Piccioli A, et al. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis. 1994;24:158a.

10. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31:247-263.

11. Kahn SR, Lamping DL, Ducruet T, et al; VETO Study Investigators. VEINES-QOL/Sym questionnaire was a reliable and valid disease-specific quality of life measure for deep venous thrombosis. J Clin Epidemiol. 2006; 59:1049-1056.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(7):388-390.

PRACTICE CHANGER
Do not recommend elastic compression stockings to decrease the incidence of postthrombotic syndrome after deep vein thrombosis.¹

STRENGTH OF RECOMMENDATION
B: Based on a large randomized controlled trial¹

ILLUSTRATIVE CASE
A 56-year-old man presents to your clinic three days after receiving a diagnosis of lower extremity deep vein thrombosis (DVT). He was prescribed warfarin (5 mg/d) with enoxaparin bridging (120 mg/d). He has read about postthrombotic syndrome (PTS) online and is very concerned about this possible adverse effect. He asks about using elastic compression stockings (ECS). What should you tell him?

PTS can be a frustrating, debilitating condition. Its clinical features range from minor limb swelling to severe edema and pain, irreversible skin changes, and leg ulcerations.² It occurs in 25% to 50% of patients after DVT.³ Because current PTS treatments are not very effective, prevention is essential.^4,5

Patients are frequently encouraged to wear ECS after DVT to reduce the incidence of PTS by decreasing venous hypertension and reflux. These stockings are expensive and uncomfortable. Prior research suggested that use of ECS can reduce PTS incidence by half, but the studies were small, single-center, and not placebo-controlled.^6,7

On the next page: Study summary >> 

STUDY SUMMARY
RCT sets aside a common practice
Kahn et al¹ conducted a randomized, placebo-controlled trial of active versus placebo ECS in patients from 24 centers in the United States and Canada who’d had an ultrasound-confirmed proximal DVT (in the popliteal or more proximal deep leg vein) within the previous 14 days. Most patients received standard anticoagulation therapy to treat their DVT (five to 10 days of heparin and three to six months of warfarin). Patients were excluded if they had received thrombolytics, had arterial claudication, had a life expectancy of less than six months, were unable to put on ECS due to physical disabilities or allergy, or were unable to participate in follow-up visits.

Patients were randomly assigned to wear active (30 to 40 mm Hg graduated) ECS or identical-looking placebo ECS (< 5 mm Hg compression at the ankle) for two years. Providers, study personnel and statisticians, and patients were all blinded to treatment allocation. Patients were asked to wear the stocking on the affected leg each day from waking until bedtime.

Follow-up occurred at one, six, 12, 18, and 24 months. The primary outcome was cumulative incidence of PTS diagnosed at six months or later using the Ginsberg criteria of ipsilateral pain and swelling of at least one month’s duration.⁸ Secondary outcomes included severity of PTS, leg ulcers, recurrence of ­venous thromboembolism (VTE), death, adverse events, venous valvular reflux, and quality of life (QOL). Outcomes were measured objectively through use of a validated scale (the Villalta scale) for PTS severity and two questionnaires to assess QOL.^9-11

There were 409 patients in the ECS group and 394 in the placebo group. Baseline characteristics, including BMI, VTE risk factors, and anticoagulation treatment regimens, were similar between groups. The average age of participants in the study group was 55.4 years and in the placebo group, 54.8 years. Men comprised 62.4% of the active group and 57.9% of the placebo group. Approximately 90% of the participants in both groups were white.

At one month, approximately 95% of participants in both groups used the stockings; at 24 months, that was reduced to a little less than 70%. The percentage of people who used the stockings for at least three days per week was similar in both groups.

The cumulative incidence of PTS during follow-up was 14.2% in the active group and 12.7% in the placebo group (hazard ratio, 1.13). There were no differences in any of the secondary outcomes. Prespecified subgroup analyses found that age, BMI, and severity of DVT had no effect on outcomes. There was a marginal benefit for ECS for women versus men, but this does not likely reflect a true difference because the confidence intervals surrounding the hazard ratios for men and women overlapped and crossed the null value.

On the next page: What's new & challenges to implementation >>

WHAT’S NEW
New evidence contradicts ­previous studies
Two prior studies showed that using 30 to 40 mm Hg ECS decreased the incidence of PTS after proximal DVT.^6,7 However, these were smaller, open-label, single-center studies. This study by Kahn et al¹ was the first placebo-controlled, randomized, multicenter study that used validated instruments to measure PTS and QOL. It found no benefit in using ECS, thus contradicting the results of the prior studies.

There are currently no guidelines or consensus statements that recommend for or against the use of ECS after DVT.

CAVEATS
High nonadherence rates might have affected results
In both groups, adherence to the assigned intervention diminished throughout the study (from 95% at one month to slightly less than 70% at two years). Theoretically, this could have affected efficacy outcomes. However, the decrease was similar in both groups and represents what is observed in clinical practice. A prespecified per protocol analysis of patients who wore their ECS more regularly found no benefit.

It is possible that a “placebo effect” could explain the lack of difference between groups. However, the placebo stockings provided virtually no compression, and the two-year cumulative incidence of PTS in both the treatment and placebo groups was similar to that seen in control groups in prior studies.^6,7

Finally, the incidence of PTS in this study was much lower than the 25% to 50% incidence reported previously. Kahn et al¹ suggested that this was because they used more stringent and standardized criteria for PTS than was used in previous research.

CHALLENGES TO IMPLEMENTATION
There are no barriers to ending this practice
We can identify no challenges to implementation of this recommendation.

On the next page: References >>

REFERENCES
1. Kahn SR, Shapiro S, Wells PS, et al; SOX trial investigators. Compression stockings to ­prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880-888.

2. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698-707.

3. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996; 125:1-7.

4. Cohen JM, Akl EA, Kahn SR. Pharmacologic and compression therapies for postthrombotic syndrome: a systematic review of randomized controlled trials. Chest. 2012;141: 308-320.

5. Henke PK, Comerota AJ. An update on etiology, prevention, and therapy of postthrombotic syndrome. J Vasc Surg. 2011;53:
500-509.

6. Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997;349:
759-762.

7. Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249-256.

8. Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med. 2001;161:2105-2109.

9. Villalta S, Bagatella P, Piccioli A, et al. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis. 1994;24:158a.

10. McHorney CA, Ware JE Jr, Raczek AE. The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care. 1993;31:247-263.

11. Kahn SR, Lamping DL, Ducruet T, et al; VETO Study Investigators. VEINES-QOL/Sym questionnaire was a reliable and valid disease-specific quality of life measure for deep venous thrombosis. J Clin Epidemiol. 2006; 59:1049-1056.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2014. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2014;63(7):388-390.

ANSWER
There are degenerative changes present. Bilateral hip prostheses are noted. Within the coccyx, there is bone remodeling and angulation that are likely chronic and related to remote trauma or injury (arrow). Below this, some cortical lucency (circled) is noted, most likely consistent with an acute fracture. The patient was prescribed a nonsteroidal medication and a mild narcotic pain medication. 

ANSWER
There are degenerative changes present. Bilateral hip prostheses are noted. Within the coccyx, there is bone remodeling and angulation that are likely chronic and related to remote trauma or injury (arrow). Below this, some cortical lucency (circled) is noted, most likely consistent with an acute fracture. The patient was prescribed a nonsteroidal medication and a mild narcotic pain medication. 

ANSWER
There are degenerative changes present. Bilateral hip prostheses are noted. Within the coccyx, there is bone remodeling and angulation that are likely chronic and related to remote trauma or injury (arrow). Below this, some cortical lucency (circled) is noted, most likely consistent with an acute fracture. The patient was prescribed a nonsteroidal medication and a mild narcotic pain medication. 

ANSWER
The correct interpretation of this ECG includes sinus tachycardia and left ventricular hypertrophy.

Sinus tachycardia is evidenced by an atrial rate greater than 100 beats/min with a P wave for every QRS complex and a QRS complex for every P wave.

Left ventricular hypertrophy is present when either the sum of the R wave voltage in lead I and the S wave in lead III is 25 mm or higher or the sum of the S wave in lead V₁ and the R wave in either V₅ or V₆ is 35 mm or higher.

In follow-up to these findings, an echocardiogram was recommended and performed. It revealed a normal heart consistent with that of a young athlete.

The patient and his parents were reassured as to the young man’s condition but decided to seek a second opinion.  

ANSWER
The correct interpretation of this ECG includes sinus tachycardia and left ventricular hypertrophy.

Sinus tachycardia is evidenced by an atrial rate greater than 100 beats/min with a P wave for every QRS complex and a QRS complex for every P wave.

Left ventricular hypertrophy is present when either the sum of the R wave voltage in lead I and the S wave in lead III is 25 mm or higher or the sum of the S wave in lead V₁ and the R wave in either V₅ or V₆ is 35 mm or higher.

In follow-up to these findings, an echocardiogram was recommended and performed. It revealed a normal heart consistent with that of a young athlete.

The patient and his parents were reassured as to the young man’s condition but decided to seek a second opinion.  

ANSWER
The correct interpretation of this ECG includes sinus tachycardia and left ventricular hypertrophy.

Sinus tachycardia is evidenced by an atrial rate greater than 100 beats/min with a P wave for every QRS complex and a QRS complex for every P wave.

Left ventricular hypertrophy is present when either the sum of the R wave voltage in lead I and the S wave in lead III is 25 mm or higher or the sum of the S wave in lead V₁ and the R wave in either V₅ or V₆ is 35 mm or higher.

In follow-up to these findings, an echocardiogram was recommended and performed. It revealed a normal heart consistent with that of a young athlete.

The patient and his parents were reassured as to the young man’s condition but decided to seek a second opinion.  

Researchers in the lab

Credit: Rhoda Baer

Investigators have identified drug combinations that may overcome resistance to ibrutinib in patients with mantle cell lymphoma (MCL).

The group discovered a mutation in Bruton’s tyrosine kinase (BTK) that confers resistance to the drug.

They also found that high levels of PI3K-AKT and CDK4 signaling could explain innate resistance to ibrutinib, so combining a CDK4 inhibitor and a PI3K inhibitor might be effective in patients who don’t respond to ibrutinib.

Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, and her colleagues detailed these findings in Cancer Discovery. Some of Dr Chen-Kiang’s colleagues reported relationships with Janssen and Pharmacyclics, the companies developing ibrutinib.

“[Ibrutinib] doesn’t work for about 32% of patients, and their lymphomas are said to have primary resistance to ibrutinib,” Dr Chen-Kiang noted. “We are also learning that most patients whose lymphomas respond to ibrutinib eventually relapse because their tumors acquire resistance to the drug.”

“The knowledge that we gained from longitudinal RNA and genomic sequencing of mantle cell lymphomas with primary and acquired resistance to ibrutinib allowed us to identify rational drug combinations that may overcome resistance in these 2 settings.”

Dr Chen-Kiang and her colleagues conducted whole-exome and whole-transcriptome analyses of 5 serial biopsies from a patient with MCL who initially responded to ibrutinib before progressing.

After comparing these data with results from an analysis of healthy tissues from the same patient, the investigators found that a mutation in BTK, the C481S mutation, appeared at relapse.

The researchers found the same mutation at relapse in a second MCL patient with acquired resistance to ibrutinib but not in any patients with primary resistance to the drug.

Further analyses revealed the consequences of the relapse-specific BTK C481S mutation, including activation of the PI3K and CDK4 signaling pathways, which promote cell survival and proliferation.

Inhibiting CDK4 with the investigational anticancer drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C481S mutation sensitive to investigational drugs that inhibit PI3K.

And palbociclib made ibrutinib-resistant lymphoma cells harboring normal BTK sensitive to both ibrutinib and investigational drugs that inhibit PI3K. The researchers recently opened a clinical trial to test ibrutinib and palbociclib in combination (NCT02159755).

“We are very excited to have generated data . . . that may be meaningful for patients,” Dr Chen-Kiang said. “It is also exciting because CDK4 is a new kind of drug target. It controls the cell cycle, which is a central cancer pathway. As such, it is not just important for mantle cell lymphoma but for many forms of cancer.”

Researchers in the lab

Credit: Rhoda Baer

Investigators have identified drug combinations that may overcome resistance to ibrutinib in patients with mantle cell lymphoma (MCL).

The group discovered a mutation in Bruton’s tyrosine kinase (BTK) that confers resistance to the drug.

They also found that high levels of PI3K-AKT and CDK4 signaling could explain innate resistance to ibrutinib, so combining a CDK4 inhibitor and a PI3K inhibitor might be effective in patients who don’t respond to ibrutinib.

Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, and her colleagues detailed these findings in Cancer Discovery. Some of Dr Chen-Kiang’s colleagues reported relationships with Janssen and Pharmacyclics, the companies developing ibrutinib.

“[Ibrutinib] doesn’t work for about 32% of patients, and their lymphomas are said to have primary resistance to ibrutinib,” Dr Chen-Kiang noted. “We are also learning that most patients whose lymphomas respond to ibrutinib eventually relapse because their tumors acquire resistance to the drug.”

“The knowledge that we gained from longitudinal RNA and genomic sequencing of mantle cell lymphomas with primary and acquired resistance to ibrutinib allowed us to identify rational drug combinations that may overcome resistance in these 2 settings.”

Dr Chen-Kiang and her colleagues conducted whole-exome and whole-transcriptome analyses of 5 serial biopsies from a patient with MCL who initially responded to ibrutinib before progressing.

After comparing these data with results from an analysis of healthy tissues from the same patient, the investigators found that a mutation in BTK, the C481S mutation, appeared at relapse.

The researchers found the same mutation at relapse in a second MCL patient with acquired resistance to ibrutinib but not in any patients with primary resistance to the drug.

Further analyses revealed the consequences of the relapse-specific BTK C481S mutation, including activation of the PI3K and CDK4 signaling pathways, which promote cell survival and proliferation.

Inhibiting CDK4 with the investigational anticancer drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C481S mutation sensitive to investigational drugs that inhibit PI3K.

And palbociclib made ibrutinib-resistant lymphoma cells harboring normal BTK sensitive to both ibrutinib and investigational drugs that inhibit PI3K. The researchers recently opened a clinical trial to test ibrutinib and palbociclib in combination (NCT02159755).

“We are very excited to have generated data . . . that may be meaningful for patients,” Dr Chen-Kiang said. “It is also exciting because CDK4 is a new kind of drug target. It controls the cell cycle, which is a central cancer pathway. As such, it is not just important for mantle cell lymphoma but for many forms of cancer.”

Researchers in the lab

Credit: Rhoda Baer

Investigators have identified drug combinations that may overcome resistance to ibrutinib in patients with mantle cell lymphoma (MCL).

The group discovered a mutation in Bruton’s tyrosine kinase (BTK) that confers resistance to the drug.

They also found that high levels of PI3K-AKT and CDK4 signaling could explain innate resistance to ibrutinib, so combining a CDK4 inhibitor and a PI3K inhibitor might be effective in patients who don’t respond to ibrutinib.

Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, and her colleagues detailed these findings in Cancer Discovery. Some of Dr Chen-Kiang’s colleagues reported relationships with Janssen and Pharmacyclics, the companies developing ibrutinib.

“[Ibrutinib] doesn’t work for about 32% of patients, and their lymphomas are said to have primary resistance to ibrutinib,” Dr Chen-Kiang noted. “We are also learning that most patients whose lymphomas respond to ibrutinib eventually relapse because their tumors acquire resistance to the drug.”

“The knowledge that we gained from longitudinal RNA and genomic sequencing of mantle cell lymphomas with primary and acquired resistance to ibrutinib allowed us to identify rational drug combinations that may overcome resistance in these 2 settings.”

Dr Chen-Kiang and her colleagues conducted whole-exome and whole-transcriptome analyses of 5 serial biopsies from a patient with MCL who initially responded to ibrutinib before progressing.

After comparing these data with results from an analysis of healthy tissues from the same patient, the investigators found that a mutation in BTK, the C481S mutation, appeared at relapse.

The researchers found the same mutation at relapse in a second MCL patient with acquired resistance to ibrutinib but not in any patients with primary resistance to the drug.

Further analyses revealed the consequences of the relapse-specific BTK C481S mutation, including activation of the PI3K and CDK4 signaling pathways, which promote cell survival and proliferation.

Inhibiting CDK4 with the investigational anticancer drug palbociclib made ibrutinib-resistant lymphoma cells carrying the BTK C481S mutation sensitive to investigational drugs that inhibit PI3K.

And palbociclib made ibrutinib-resistant lymphoma cells harboring normal BTK sensitive to both ibrutinib and investigational drugs that inhibit PI3K. The researchers recently opened a clinical trial to test ibrutinib and palbociclib in combination (NCT02159755).

“We are very excited to have generated data . . . that may be meaningful for patients,” Dr Chen-Kiang said. “It is also exciting because CDK4 is a new kind of drug target. It controls the cell cycle, which is a central cancer pathway. As such, it is not just important for mantle cell lymphoma but for many forms of cancer.”

Sickle cells in blood

Credit: Graham Beards

Researchers have found evidence suggesting that beneficial variants of a gene controlling hematopoiesis exist in nearly all human populations.

The team analyzed genomic data from world populations, looking at HMIP-2, a human quantitative trait locus that affects the production of fetal hemoglobin in adults.

The analysis revealed 2 alleles that promote fetal hemoglobin production and can therefore reduce the severity of thalassemia and sickle cell anemia (SCA).

“Patients who have milder versions of [these] blood disorders, thanks to their ability to keep producing fetal hemoglobin, carry genetic clues that are helping us to understand the function of the genes and biological pathways involved in these diseases,” said Stephan Menzel, MD, of King’s College London in the UK.

He and his colleagues conducted this research and reported the results in Annals of Human Genetics.

The researchers noted that HMIP (HBS1L-MYB intergenic polymorphism) on chromosome 6q23.3 was first detected in a large Asian Indian family, where it was shown to be responsible for the persistence of fetal hemoglobin production in adulthood.

And HMIP-2 occupies a 24-kb stretch of DNA that acts as a distal upstream enhancer for MYB, the gene for cMYB, which is essential to hematopoiesis.

While studying 4 groups of SCA patients of diverse African descent, Dr Menzel and his colleagues discovered 2 alleles at HMIP-2 that promote fetal hemoglobin—HMIP-2A and HMIP2-B.

Subsequent analyses revealed the alleles were present, either alone or together, in major human populations and nearly all of the ethnic groups studied.

Both HMIP-2A and HMIP2-B occur in Sub-Saharan Africa, but only at low frequencies. In much of the rest of the world, the alleles have combined, forming HMIP-2A-B, and this combination is relatively common in Europe, South Asia, and China. HMIP-2B alone is common in Far-East Asian peoples and in Amerindians.

The researchers also analyzed genomic data from Neanderthals, Denisovans, and Great Apes, but detected neither HMIP-2A nor HMIP-2B.

The team said these results suggest MYB enhancer variants that modulate the severity of SCA and thalassemia have arisen twice in modern humans, in Africa, and then spread to the rest of the world.

However, this likely occurred long before inherited blood disorders became prevalent, so the environmental factors that favored such variants in these early humans are not clear.

For the next stage of this research, Dr Menzel and his colleagues plan to explore which selection pressures or benefits might have contributed to the present population distribution of the variants.

Selection pressures could include nutritional factors, such as the availability of iron in the diet, or specific demands on red blood cell production, such as adaptation to high altitudes.

Sickle cells in blood

Credit: Graham Beards

Researchers have found evidence suggesting that beneficial variants of a gene controlling hematopoiesis exist in nearly all human populations.

The team analyzed genomic data from world populations, looking at HMIP-2, a human quantitative trait locus that affects the production of fetal hemoglobin in adults.

The analysis revealed 2 alleles that promote fetal hemoglobin production and can therefore reduce the severity of thalassemia and sickle cell anemia (SCA).

“Patients who have milder versions of [these] blood disorders, thanks to their ability to keep producing fetal hemoglobin, carry genetic clues that are helping us to understand the function of the genes and biological pathways involved in these diseases,” said Stephan Menzel, MD, of King’s College London in the UK.

He and his colleagues conducted this research and reported the results in Annals of Human Genetics.

The researchers noted that HMIP (HBS1L-MYB intergenic polymorphism) on chromosome 6q23.3 was first detected in a large Asian Indian family, where it was shown to be responsible for the persistence of fetal hemoglobin production in adulthood.

And HMIP-2 occupies a 24-kb stretch of DNA that acts as a distal upstream enhancer for MYB, the gene for cMYB, which is essential to hematopoiesis.

While studying 4 groups of SCA patients of diverse African descent, Dr Menzel and his colleagues discovered 2 alleles at HMIP-2 that promote fetal hemoglobin—HMIP-2A and HMIP2-B.

Subsequent analyses revealed the alleles were present, either alone or together, in major human populations and nearly all of the ethnic groups studied.

Both HMIP-2A and HMIP2-B occur in Sub-Saharan Africa, but only at low frequencies. In much of the rest of the world, the alleles have combined, forming HMIP-2A-B, and this combination is relatively common in Europe, South Asia, and China. HMIP-2B alone is common in Far-East Asian peoples and in Amerindians.

The researchers also analyzed genomic data from Neanderthals, Denisovans, and Great Apes, but detected neither HMIP-2A nor HMIP-2B.

The team said these results suggest MYB enhancer variants that modulate the severity of SCA and thalassemia have arisen twice in modern humans, in Africa, and then spread to the rest of the world.

However, this likely occurred long before inherited blood disorders became prevalent, so the environmental factors that favored such variants in these early humans are not clear.

For the next stage of this research, Dr Menzel and his colleagues plan to explore which selection pressures or benefits might have contributed to the present population distribution of the variants.

Selection pressures could include nutritional factors, such as the availability of iron in the diet, or specific demands on red blood cell production, such as adaptation to high altitudes.

Sickle cells in blood

Credit: Graham Beards

Researchers have found evidence suggesting that beneficial variants of a gene controlling hematopoiesis exist in nearly all human populations.

The team analyzed genomic data from world populations, looking at HMIP-2, a human quantitative trait locus that affects the production of fetal hemoglobin in adults.

The analysis revealed 2 alleles that promote fetal hemoglobin production and can therefore reduce the severity of thalassemia and sickle cell anemia (SCA).

“Patients who have milder versions of [these] blood disorders, thanks to their ability to keep producing fetal hemoglobin, carry genetic clues that are helping us to understand the function of the genes and biological pathways involved in these diseases,” said Stephan Menzel, MD, of King’s College London in the UK.

He and his colleagues conducted this research and reported the results in Annals of Human Genetics.

The researchers noted that HMIP (HBS1L-MYB intergenic polymorphism) on chromosome 6q23.3 was first detected in a large Asian Indian family, where it was shown to be responsible for the persistence of fetal hemoglobin production in adulthood.

And HMIP-2 occupies a 24-kb stretch of DNA that acts as a distal upstream enhancer for MYB, the gene for cMYB, which is essential to hematopoiesis.

While studying 4 groups of SCA patients of diverse African descent, Dr Menzel and his colleagues discovered 2 alleles at HMIP-2 that promote fetal hemoglobin—HMIP-2A and HMIP2-B.

Subsequent analyses revealed the alleles were present, either alone or together, in major human populations and nearly all of the ethnic groups studied.

Both HMIP-2A and HMIP2-B occur in Sub-Saharan Africa, but only at low frequencies. In much of the rest of the world, the alleles have combined, forming HMIP-2A-B, and this combination is relatively common in Europe, South Asia, and China. HMIP-2B alone is common in Far-East Asian peoples and in Amerindians.

The researchers also analyzed genomic data from Neanderthals, Denisovans, and Great Apes, but detected neither HMIP-2A nor HMIP-2B.

The team said these results suggest MYB enhancer variants that modulate the severity of SCA and thalassemia have arisen twice in modern humans, in Africa, and then spread to the rest of the world.

However, this likely occurred long before inherited blood disorders became prevalent, so the environmental factors that favored such variants in these early humans are not clear.

For the next stage of this research, Dr Menzel and his colleagues plan to explore which selection pressures or benefits might have contributed to the present population distribution of the variants.

Selection pressures could include nutritional factors, such as the availability of iron in the diet, or specific demands on red blood cell production, such as adaptation to high altitudes.

Child receiving RTS,S/AS01

Credit: Caitlin Kleiboer

A candidate malaria vaccine is more effective in children aged 5 months to 17 months than in infants 3 months of age or younger, results of a phase 3 study suggest.

Previous research indicated the vaccine— RTS,S/AS01—may prevent malaria in young children, but its efficacy wanes over time.

Now, researchers have reported that RTS,S/AS01 can sometimes prevent clinical malaria, severe malaria, and malaria hospitalization in children aged 5 to 17 months.

In the younger age group, the vaccine offered some protection against clinical malaria but did not significantly impact the rates of severe malaria or hospitalization.

The RTS,S Clinical Trials Partnership committee reported these findings in PLOS Medicine.

The study was sponsored by GSK Biologicals SA, the developer and manufacturer of RTS,S/AS01, and funded by both GSK Biologicals SA and the PATH Malaria Vaccine Initiative.

The researchers studied 6537 infants aged 6 to 12 weeks and 8923 children aged 5 to 17 months treated at 11 sites in Africa.

Subjects were randomized to receive 3 doses of RTS,S/AS01 or a comparator vaccine—a rabies vaccine (VeroRab) for the children and a meningococcal C conjugate vaccine (Menjugate) for the infants.

The primary outcome, vaccine efficacy (VE), was the reduction in malaria incidence among subjects who received RTS,S/AS01 compared to the incidence among subjects who received a comparator vaccine.

In the 18 months following vaccination, VE was 46% in children aged 5 to 17 months and 27% in infants aged 6 to 12 weeks. In both age groups, VE was highest in the first 6 months after vaccination.

RTS,S/AS01 averted an average of 829 cases of clinical malaria per 1000 children vaccinated (range, 37 to 2365) and 449 cases per 1000 infants (range, -10 to 1402) within 18 months of vaccination.

In children aged 5 to 17 months, VE was 34% for severe malaria, 41% for malaria hospitalization, and 19% for all-cause hospitalization. In the infants, there was no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.

Serious adverse events occurred less often in children who received RTS,S/AS01 than in those who received a comparator vaccine—18.6% and 22.7%, respectively. In infants, the rate of serious adverse events was similar between the 2 vaccination groups.

Meningitis was more common in subjects who received RTS,S/AS01 than in those who received a comparator. However, the researchers have not established a causal relationship.

There were 16 cases of meningitis among the 5949 children in the RTS,S/AS01 group, 1 case among the 2974 children in the control group, 9 cases among the 4358 infants in the RTS,S/AS01 group, and 3 cases among the 2179 infants in the control group.

Despite the adverse events associated with RTS,S/AS01 and its decreased efficacy over time, the researchers believe the vaccine shows promise. They noted that, “even at modest levels of VE, the number of malaria cases averted was substantial.”

Now, the group is evaluating whether a booster immunization given 18 months after the primary vaccination can improve the efficacy of RTS,S/AS01.

Results of this study were previously reported at the Multilateral Initiative on Malaria Pan African Conference in October 2013 and published in The New England Journal of Medicine in October 2011 and November 2012. Long-term results of a phase 2 trial of RTS,S/AS01 were published in The New England Journal of Medicine in March 2013.

Child receiving RTS,S/AS01

Credit: Caitlin Kleiboer

A candidate malaria vaccine is more effective in children aged 5 months to 17 months than in infants 3 months of age or younger, results of a phase 3 study suggest.

Previous research indicated the vaccine— RTS,S/AS01—may prevent malaria in young children, but its efficacy wanes over time.

Now, researchers have reported that RTS,S/AS01 can sometimes prevent clinical malaria, severe malaria, and malaria hospitalization in children aged 5 to 17 months.

In the younger age group, the vaccine offered some protection against clinical malaria but did not significantly impact the rates of severe malaria or hospitalization.

The RTS,S Clinical Trials Partnership committee reported these findings in PLOS Medicine.

The study was sponsored by GSK Biologicals SA, the developer and manufacturer of RTS,S/AS01, and funded by both GSK Biologicals SA and the PATH Malaria Vaccine Initiative.

The researchers studied 6537 infants aged 6 to 12 weeks and 8923 children aged 5 to 17 months treated at 11 sites in Africa.

Subjects were randomized to receive 3 doses of RTS,S/AS01 or a comparator vaccine—a rabies vaccine (VeroRab) for the children and a meningococcal C conjugate vaccine (Menjugate) for the infants.

The primary outcome, vaccine efficacy (VE), was the reduction in malaria incidence among subjects who received RTS,S/AS01 compared to the incidence among subjects who received a comparator vaccine.

In the 18 months following vaccination, VE was 46% in children aged 5 to 17 months and 27% in infants aged 6 to 12 weeks. In both age groups, VE was highest in the first 6 months after vaccination.

RTS,S/AS01 averted an average of 829 cases of clinical malaria per 1000 children vaccinated (range, 37 to 2365) and 449 cases per 1000 infants (range, -10 to 1402) within 18 months of vaccination.

In children aged 5 to 17 months, VE was 34% for severe malaria, 41% for malaria hospitalization, and 19% for all-cause hospitalization. In the infants, there was no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.

Serious adverse events occurred less often in children who received RTS,S/AS01 than in those who received a comparator vaccine—18.6% and 22.7%, respectively. In infants, the rate of serious adverse events was similar between the 2 vaccination groups.

Meningitis was more common in subjects who received RTS,S/AS01 than in those who received a comparator. However, the researchers have not established a causal relationship.

There were 16 cases of meningitis among the 5949 children in the RTS,S/AS01 group, 1 case among the 2974 children in the control group, 9 cases among the 4358 infants in the RTS,S/AS01 group, and 3 cases among the 2179 infants in the control group.

Despite the adverse events associated with RTS,S/AS01 and its decreased efficacy over time, the researchers believe the vaccine shows promise. They noted that, “even at modest levels of VE, the number of malaria cases averted was substantial.”

Now, the group is evaluating whether a booster immunization given 18 months after the primary vaccination can improve the efficacy of RTS,S/AS01.

Results of this study were previously reported at the Multilateral Initiative on Malaria Pan African Conference in October 2013 and published in The New England Journal of Medicine in October 2011 and November 2012. Long-term results of a phase 2 trial of RTS,S/AS01 were published in The New England Journal of Medicine in March 2013.

Child receiving RTS,S/AS01

Credit: Caitlin Kleiboer

A candidate malaria vaccine is more effective in children aged 5 months to 17 months than in infants 3 months of age or younger, results of a phase 3 study suggest.

Previous research indicated the vaccine— RTS,S/AS01—may prevent malaria in young children, but its efficacy wanes over time.

Now, researchers have reported that RTS,S/AS01 can sometimes prevent clinical malaria, severe malaria, and malaria hospitalization in children aged 5 to 17 months.

In the younger age group, the vaccine offered some protection against clinical malaria but did not significantly impact the rates of severe malaria or hospitalization.

The RTS,S Clinical Trials Partnership committee reported these findings in PLOS Medicine.

The study was sponsored by GSK Biologicals SA, the developer and manufacturer of RTS,S/AS01, and funded by both GSK Biologicals SA and the PATH Malaria Vaccine Initiative.

The researchers studied 6537 infants aged 6 to 12 weeks and 8923 children aged 5 to 17 months treated at 11 sites in Africa.

Subjects were randomized to receive 3 doses of RTS,S/AS01 or a comparator vaccine—a rabies vaccine (VeroRab) for the children and a meningococcal C conjugate vaccine (Menjugate) for the infants.

The primary outcome, vaccine efficacy (VE), was the reduction in malaria incidence among subjects who received RTS,S/AS01 compared to the incidence among subjects who received a comparator vaccine.

In the 18 months following vaccination, VE was 46% in children aged 5 to 17 months and 27% in infants aged 6 to 12 weeks. In both age groups, VE was highest in the first 6 months after vaccination.

RTS,S/AS01 averted an average of 829 cases of clinical malaria per 1000 children vaccinated (range, 37 to 2365) and 449 cases per 1000 infants (range, -10 to 1402) within 18 months of vaccination.

In children aged 5 to 17 months, VE was 34% for severe malaria, 41% for malaria hospitalization, and 19% for all-cause hospitalization. In the infants, there was no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization.

Serious adverse events occurred less often in children who received RTS,S/AS01 than in those who received a comparator vaccine—18.6% and 22.7%, respectively. In infants, the rate of serious adverse events was similar between the 2 vaccination groups.

Meningitis was more common in subjects who received RTS,S/AS01 than in those who received a comparator. However, the researchers have not established a causal relationship.

There were 16 cases of meningitis among the 5949 children in the RTS,S/AS01 group, 1 case among the 2974 children in the control group, 9 cases among the 4358 infants in the RTS,S/AS01 group, and 3 cases among the 2179 infants in the control group.

Despite the adverse events associated with RTS,S/AS01 and its decreased efficacy over time, the researchers believe the vaccine shows promise. They noted that, “even at modest levels of VE, the number of malaria cases averted was substantial.”

Now, the group is evaluating whether a booster immunization given 18 months after the primary vaccination can improve the efficacy of RTS,S/AS01.

Results of this study were previously reported at the Multilateral Initiative on Malaria Pan African Conference in October 2013 and published in The New England Journal of Medicine in October 2011 and November 2012. Long-term results of a phase 2 trial of RTS,S/AS01 were published in The New England Journal of Medicine in March 2013.