Diana Mahoney

BOSTON — Reversible cerebral vasoconstriction syndromes resolve with simple, if any, treatment, whereas true cerebral vasculitis requires a lifetime of cytotoxic drug therapy. The clinical challenge is to distinguish the mimic from the real thing—and physicians frequently fall short of the mark, according to Leonard Calabrese, D.O.

A group of diverse conditions characterized by multifocal narrowing of the cerebral arteries, reversible cerebral vasoconstriction syndromes (RCVS) are the most common and most important clinical mimic of true cerebral vasculitis, particularly primary angiitis of the central nervous system (PACNS), Dr. Calabrese said at a meeting on rheumatology sponsored by Harvard Medical School.

Differentiating between the two conditions is of vital clinical importance because the respective management approaches differ substantially.

“While patients with true vasculitis of the central nervous system typically require long-term immunosuppressants and cytotoxic drugs, those with [RCVS] can often be treated with observation or calcium channel blockers alone,” said Dr. Calabrese.

This is because RCVS is self-limited, usually resolving on its own within days to weeks, whereas PACNS is a chronic, irreversible inflammatory condition.

Although both conditions share certain features, such as angiographic evidence of vasoconstriction and arteritis, variations in the clinical context provide the requisite clues for making a definitive diagnosis, noted Dr. Calabrese, head of clinical immunology at the Cleveland Clinic.

Unlike PACNS, in which there is no gender predominance, RCVS typically occurs in women aged 20–50 years. The condition often presents idiopathically or in a variety of clinical settings, such as after head trauma or neurovascular surgery, during pregnancy or the puerperium period, or in response to certain medications or illicit drugs, said Dr. Calabrese. It may also occur in the setting of catecholamine-secreting tumors, he said.

“The hallmark of RCVS is the thunderclap headache: extraordinarily intense, acute headache pain that crescendos within 1 minute and has a pattern of recurring over 7–14 days,” said Dr. Calabrese. “The headache may occur with or without neurological signs, and it may be spontaneous or precipitated by exercise, sex, coughing, bathing, or the Valsalva maneuver.”

Although headache is also the most common symptom in individuals with PACNS, “it is generally not of the acute, severe variety. Rather, headache associated with PACNS tends to be insidious and progressive, and is more often described as a dull ache.”

Because the apoplectic onset of headache in RCVS mimics subarachnoid hemorrhage, “the assumption should be that all of these patients have subarachnoid hemorrhage until proven otherwise,” Dr. Calabrese stressed. Toward this end, neuroimaging and analysis of cerebrospinal fluid are critical.

“The results of cerebrospinal fluid analysis in [RCVS] are always normal or near-normal, with no evidence of aneurysmal subarachnoid hemorrhage,” said Dr. Calabrese. In contrast, CSF examination uncovers abnormal results in more than 95% of patients with PACNS, he said, noting that the findings usually reflect aseptic meningitis, with modest pleocytosis and elevated protein levels.

Imaging studies of the brain parenchyma are normal in the majority of RCVS patients, “although MRI occasionally reveals evidence of infarction in watershed areas, parenchymal hemorrhages, small nonaneurysmal subarachnoid hemorrhages, or [posterior leukoencephalopathy syndrome],” Dr. Calabrese said. Brain MRI in true PACNS usually shows multifocal lesions in the deep white matter, and cortical infarctions in the distribution of separate vascular territories.

With respect to neurovascular imaging, RCVS cannot be differentiated from PACNS by a single cerebral angiogram. “There is no angiographic picture that is 100% specific for vasculitis,” said Dr. Calabrese. “Angiography is most useful when the pretest probability of vasculitis is high, based on presentation and clinical symptoms.”

Although angiography occasionally reveals findings in PACNS that are uncharacteristic of RCVS, such as nonsymmetrical vascular luminal abnormalities or extensive vascular cutoffs, the vascular abnormalities observed in PACNS patients can be indistinguishable from those seen in RCVS. The most specific finding for RCVS is evidence of substantial improvement in the characteristic vascular abnormalities—diffuse areas of multiple stenoses and dilatation involving intracranial cerebral arteries—within days or weeks of symptom onset, said Dr. Calabrese.

“In fact, the linchpin of the [RCVS] diagnosis is evidence of the reversibility of the vasoconstriction and arteritis.” The vascular abnormalities observed in PACNS patients rarely normalize and are frequently irreversible, he said.

In terms of treating RCVS, “there have been no controlled trials of any therapy to date,” said Dr. Calabrese, noting that empiric treatments include the use of calcium channel blockers or short course, high-dose glucocorticoids. “The choice of agent is best gauged by disease severity and course,” he noted.

In some patients, simple observation may be justified, whereas in others—particularly those in whom the thunderclap headache recurs, and those who have severe vasospasm or transient neurologic symptoms—agents such as nimodipine or verapamil have been used successfully as first-line treatments, he said.

“In all patients being treated for suspected RCVS,” Dr. Calabrese stressed, “a failure to demonstrate dynamic change in the condition should prompt a thorough reevaluation and search for another diagnosis.”

BOSTON — Reversible cerebral vasoconstriction syndromes resolve with simple, if any, treatment, whereas true cerebral vasculitis requires a lifetime of cytotoxic drug therapy. The clinical challenge is to distinguish the mimic from the real thing—and physicians frequently fall short of the mark, according to Leonard Calabrese, D.O.

A group of diverse conditions characterized by multifocal narrowing of the cerebral arteries, reversible cerebral vasoconstriction syndromes (RCVS) are the most common and most important clinical mimic of true cerebral vasculitis, particularly primary angiitis of the central nervous system (PACNS), Dr. Calabrese said at a meeting on rheumatology sponsored by Harvard Medical School.

Differentiating between the two conditions is of vital clinical importance because the respective management approaches differ substantially.

“While patients with true vasculitis of the central nervous system typically require long-term immunosuppressants and cytotoxic drugs, those with [RCVS] can often be treated with observation or calcium channel blockers alone,” said Dr. Calabrese.

This is because RCVS is self-limited, usually resolving on its own within days to weeks, whereas PACNS is a chronic, irreversible inflammatory condition.

Although both conditions share certain features, such as angiographic evidence of vasoconstriction and arteritis, variations in the clinical context provide the requisite clues for making a definitive diagnosis, noted Dr. Calabrese, head of clinical immunology at the Cleveland Clinic.

Unlike PACNS, in which there is no gender predominance, RCVS typically occurs in women aged 20–50 years. The condition often presents idiopathically or in a variety of clinical settings, such as after head trauma or neurovascular surgery, during pregnancy or the puerperium period, or in response to certain medications or illicit drugs, said Dr. Calabrese. It may also occur in the setting of catecholamine-secreting tumors, he said.

“The hallmark of RCVS is the thunderclap headache: extraordinarily intense, acute headache pain that crescendos within 1 minute and has a pattern of recurring over 7–14 days,” said Dr. Calabrese. “The headache may occur with or without neurological signs, and it may be spontaneous or precipitated by exercise, sex, coughing, bathing, or the Valsalva maneuver.”

Although headache is also the most common symptom in individuals with PACNS, “it is generally not of the acute, severe variety. Rather, headache associated with PACNS tends to be insidious and progressive, and is more often described as a dull ache.”

Because the apoplectic onset of headache in RCVS mimics subarachnoid hemorrhage, “the assumption should be that all of these patients have subarachnoid hemorrhage until proven otherwise,” Dr. Calabrese stressed. Toward this end, neuroimaging and analysis of cerebrospinal fluid are critical.

“The results of cerebrospinal fluid analysis in [RCVS] are always normal or near-normal, with no evidence of aneurysmal subarachnoid hemorrhage,” said Dr. Calabrese. In contrast, CSF examination uncovers abnormal results in more than 95% of patients with PACNS, he said, noting that the findings usually reflect aseptic meningitis, with modest pleocytosis and elevated protein levels.

Imaging studies of the brain parenchyma are normal in the majority of RCVS patients, “although MRI occasionally reveals evidence of infarction in watershed areas, parenchymal hemorrhages, small nonaneurysmal subarachnoid hemorrhages, or [posterior leukoencephalopathy syndrome],” Dr. Calabrese said. Brain MRI in true PACNS usually shows multifocal lesions in the deep white matter, and cortical infarctions in the distribution of separate vascular territories.

With respect to neurovascular imaging, RCVS cannot be differentiated from PACNS by a single cerebral angiogram. “There is no angiographic picture that is 100% specific for vasculitis,” said Dr. Calabrese. “Angiography is most useful when the pretest probability of vasculitis is high, based on presentation and clinical symptoms.”

Although angiography occasionally reveals findings in PACNS that are uncharacteristic of RCVS, such as nonsymmetrical vascular luminal abnormalities or extensive vascular cutoffs, the vascular abnormalities observed in PACNS patients can be indistinguishable from those seen in RCVS. The most specific finding for RCVS is evidence of substantial improvement in the characteristic vascular abnormalities—diffuse areas of multiple stenoses and dilatation involving intracranial cerebral arteries—within days or weeks of symptom onset, said Dr. Calabrese.

“In fact, the linchpin of the [RCVS] diagnosis is evidence of the reversibility of the vasoconstriction and arteritis.” The vascular abnormalities observed in PACNS patients rarely normalize and are frequently irreversible, he said.

In terms of treating RCVS, “there have been no controlled trials of any therapy to date,” said Dr. Calabrese, noting that empiric treatments include the use of calcium channel blockers or short course, high-dose glucocorticoids. “The choice of agent is best gauged by disease severity and course,” he noted.

In some patients, simple observation may be justified, whereas in others—particularly those in whom the thunderclap headache recurs, and those who have severe vasospasm or transient neurologic symptoms—agents such as nimodipine or verapamil have been used successfully as first-line treatments, he said.

“In all patients being treated for suspected RCVS,” Dr. Calabrese stressed, “a failure to demonstrate dynamic change in the condition should prompt a thorough reevaluation and search for another diagnosis.”

BOSTON — Reversible cerebral vasoconstriction syndromes resolve with simple, if any, treatment, whereas true cerebral vasculitis requires a lifetime of cytotoxic drug therapy. The clinical challenge is to distinguish the mimic from the real thing—and physicians frequently fall short of the mark, according to Leonard Calabrese, D.O.

A group of diverse conditions characterized by multifocal narrowing of the cerebral arteries, reversible cerebral vasoconstriction syndromes (RCVS) are the most common and most important clinical mimic of true cerebral vasculitis, particularly primary angiitis of the central nervous system (PACNS), Dr. Calabrese said at a meeting on rheumatology sponsored by Harvard Medical School.

Differentiating between the two conditions is of vital clinical importance because the respective management approaches differ substantially.

“While patients with true vasculitis of the central nervous system typically require long-term immunosuppressants and cytotoxic drugs, those with [RCVS] can often be treated with observation or calcium channel blockers alone,” said Dr. Calabrese.

This is because RCVS is self-limited, usually resolving on its own within days to weeks, whereas PACNS is a chronic, irreversible inflammatory condition.

Although both conditions share certain features, such as angiographic evidence of vasoconstriction and arteritis, variations in the clinical context provide the requisite clues for making a definitive diagnosis, noted Dr. Calabrese, head of clinical immunology at the Cleveland Clinic.

Unlike PACNS, in which there is no gender predominance, RCVS typically occurs in women aged 20–50 years. The condition often presents idiopathically or in a variety of clinical settings, such as after head trauma or neurovascular surgery, during pregnancy or the puerperium period, or in response to certain medications or illicit drugs, said Dr. Calabrese. It may also occur in the setting of catecholamine-secreting tumors, he said.

“The hallmark of RCVS is the thunderclap headache: extraordinarily intense, acute headache pain that crescendos within 1 minute and has a pattern of recurring over 7–14 days,” said Dr. Calabrese. “The headache may occur with or without neurological signs, and it may be spontaneous or precipitated by exercise, sex, coughing, bathing, or the Valsalva maneuver.”

Although headache is also the most common symptom in individuals with PACNS, “it is generally not of the acute, severe variety. Rather, headache associated with PACNS tends to be insidious and progressive, and is more often described as a dull ache.”

Because the apoplectic onset of headache in RCVS mimics subarachnoid hemorrhage, “the assumption should be that all of these patients have subarachnoid hemorrhage until proven otherwise,” Dr. Calabrese stressed. Toward this end, neuroimaging and analysis of cerebrospinal fluid are critical.

“The results of cerebrospinal fluid analysis in [RCVS] are always normal or near-normal, with no evidence of aneurysmal subarachnoid hemorrhage,” said Dr. Calabrese. In contrast, CSF examination uncovers abnormal results in more than 95% of patients with PACNS, he said, noting that the findings usually reflect aseptic meningitis, with modest pleocytosis and elevated protein levels.

Imaging studies of the brain parenchyma are normal in the majority of RCVS patients, “although MRI occasionally reveals evidence of infarction in watershed areas, parenchymal hemorrhages, small nonaneurysmal subarachnoid hemorrhages, or [posterior leukoencephalopathy syndrome],” Dr. Calabrese said. Brain MRI in true PACNS usually shows multifocal lesions in the deep white matter, and cortical infarctions in the distribution of separate vascular territories.

With respect to neurovascular imaging, RCVS cannot be differentiated from PACNS by a single cerebral angiogram. “There is no angiographic picture that is 100% specific for vasculitis,” said Dr. Calabrese. “Angiography is most useful when the pretest probability of vasculitis is high, based on presentation and clinical symptoms.”

Although angiography occasionally reveals findings in PACNS that are uncharacteristic of RCVS, such as nonsymmetrical vascular luminal abnormalities or extensive vascular cutoffs, the vascular abnormalities observed in PACNS patients can be indistinguishable from those seen in RCVS. The most specific finding for RCVS is evidence of substantial improvement in the characteristic vascular abnormalities—diffuse areas of multiple stenoses and dilatation involving intracranial cerebral arteries—within days or weeks of symptom onset, said Dr. Calabrese.

“In fact, the linchpin of the [RCVS] diagnosis is evidence of the reversibility of the vasoconstriction and arteritis.” The vascular abnormalities observed in PACNS patients rarely normalize and are frequently irreversible, he said.

In terms of treating RCVS, “there have been no controlled trials of any therapy to date,” said Dr. Calabrese, noting that empiric treatments include the use of calcium channel blockers or short course, high-dose glucocorticoids. “The choice of agent is best gauged by disease severity and course,” he noted.

In some patients, simple observation may be justified, whereas in others—particularly those in whom the thunderclap headache recurs, and those who have severe vasospasm or transient neurologic symptoms—agents such as nimodipine or verapamil have been used successfully as first-line treatments, he said.

“In all patients being treated for suspected RCVS,” Dr. Calabrese stressed, “a failure to demonstrate dynamic change in the condition should prompt a thorough reevaluation and search for another diagnosis.”

BOSTON — Failure to respond to standard immunosuppressant therapy may be the first sign that a patient's apparent polymyositis actually is inclusion body myositis, according to Dr. Chester Oddis of the University of Pittsburgh.

The most common acquired muscle disease in people over 50 years of age, inclusion body myositis (IBM) is a distinct type of inflammatory myopathy characterized by slowly progressing, degenerative muscle changes caused by an antigen-driven inflammatory response, as well as vacuolar degeneration and abnormal protein deposits in distal and proximal muscle cells, Dr. Oddis said at a meeting on rheumatology sponsored by Harvard Medical School.

Because it shares certain clinical and pathologic features with polymyositis, such as varying degrees of muscle weakness, inflammation in the endomysium, muscle fiber necrosis, and elevation of serum muscle enzymes, inclusion body myositis is often mistaken for polymyositis or motor neuron disease by rheumatologists and neurologists, Dr. Oddis noted. “A number of studies have shown that the average time from symptom onset to diagnosis is between 4–6 years. Typically, the first indication that you're dealing with a mimic [of polymyositis] is the failure to respond to immunosuppressant therapy.”

The nature of disease onset and presentation also distinguishes IBM from polymyositis. While polymyositis tends to have a subacute onset, typically over a few weeks to months, IBM comes on insidiously over the course of many months and even years, Dr. Oddis explained. Additionally, IBM has a tendency for distal and asymmetric muscle involvement, such as a foot drop, he said. In contrast, polymyositis more commonly encompasses proximal, symmetric muscle weakness.

Pharyngeal muscle weakness is a common characteristic of IBM and polymyositis. In particular, however, proximal dysphagia resulting from cricopharyngeal spasm is more often seen in inclusion body myositis. “Patients often complain of a blocking sensation when they swallow that just doesn't go away,” said Dr. Oddis. “This is a little different than pharyngeal myopathy seen in polymyositis because it is persistent; pharyngeal myopathy waxes and wanes with the severity of the involvement of the proximal musculature.”

Unlike most connective tissue diseases, inclusion body myositis occurs predominantly in men. “It sneaks up on them in middle age and follows a characteristic pattern of painless muscle atrophy, including the forearm flexors, quadriceps, and the intrinsic muscles of the hands,” said Dr. Oddis. “The forearm and quadriceps atrophy is usually obvious on examination. To assess hand muscle strength, I'll often ask patients to form a circle with their fingers. Because of their intrinsic muscle weakness, the circle is often more like a teardrop. This teardrop sign is something you probably won't see in polymyositis.”

Magnetic resonance can be especially useful in differentiating IBM from polymyositis, said Dr. Oddis. “The results will be abnormal in both conditions, but MRIs from patients with inclusion body myositis are more likely to show fatty infiltration and atrophy and more widespread abnormalities, while in polymyositis, the predominant abnormality seen on MRI is inflammation distributed along the fascia.”

The only definitive test for inclusion body myositis is a muscle biopsy. Because of the possibility of skip lesions, “it sometimes takes two, three, or four biopsies before you get something you can hang your hat on, but when you do, there is no question,” said Dr. Oddis. “The distinctive histology that you're looking for includes endomysial inflammation, the presence of rimmed vacuoles, and intracellular amyloid deposits or twisted tubulofilaments [containing hyperphosphorylated tau].”

Management options for inclusion body myositis are often limited to supportive efforts, such as myotomy to relieve dysphagia caused by cricopharyngeal achalasia, said Dr. Oddis. While no definitive treatment has been proven effective in achieving sustained remission and improvement in whole body strength, some reports suggest there may be a subgroup of patients who experience a partial, transient response to anti-inflammatory, immunosuppressant therapy. For this reason, he said, an initial 6–8 week trial of prednisolone and an immunosuppressive drug such as methotrexate or azathioprine is a reasonable option for newly diagnosed patients.

BOSTON — Failure to respond to standard immunosuppressant therapy may be the first sign that a patient's apparent polymyositis actually is inclusion body myositis, according to Dr. Chester Oddis of the University of Pittsburgh.

The most common acquired muscle disease in people over 50 years of age, inclusion body myositis (IBM) is a distinct type of inflammatory myopathy characterized by slowly progressing, degenerative muscle changes caused by an antigen-driven inflammatory response, as well as vacuolar degeneration and abnormal protein deposits in distal and proximal muscle cells, Dr. Oddis said at a meeting on rheumatology sponsored by Harvard Medical School.

Because it shares certain clinical and pathologic features with polymyositis, such as varying degrees of muscle weakness, inflammation in the endomysium, muscle fiber necrosis, and elevation of serum muscle enzymes, inclusion body myositis is often mistaken for polymyositis or motor neuron disease by rheumatologists and neurologists, Dr. Oddis noted. “A number of studies have shown that the average time from symptom onset to diagnosis is between 4–6 years. Typically, the first indication that you're dealing with a mimic [of polymyositis] is the failure to respond to immunosuppressant therapy.”

The nature of disease onset and presentation also distinguishes IBM from polymyositis. While polymyositis tends to have a subacute onset, typically over a few weeks to months, IBM comes on insidiously over the course of many months and even years, Dr. Oddis explained. Additionally, IBM has a tendency for distal and asymmetric muscle involvement, such as a foot drop, he said. In contrast, polymyositis more commonly encompasses proximal, symmetric muscle weakness.

Pharyngeal muscle weakness is a common characteristic of IBM and polymyositis. In particular, however, proximal dysphagia resulting from cricopharyngeal spasm is more often seen in inclusion body myositis. “Patients often complain of a blocking sensation when they swallow that just doesn't go away,” said Dr. Oddis. “This is a little different than pharyngeal myopathy seen in polymyositis because it is persistent; pharyngeal myopathy waxes and wanes with the severity of the involvement of the proximal musculature.”

Unlike most connective tissue diseases, inclusion body myositis occurs predominantly in men. “It sneaks up on them in middle age and follows a characteristic pattern of painless muscle atrophy, including the forearm flexors, quadriceps, and the intrinsic muscles of the hands,” said Dr. Oddis. “The forearm and quadriceps atrophy is usually obvious on examination. To assess hand muscle strength, I'll often ask patients to form a circle with their fingers. Because of their intrinsic muscle weakness, the circle is often more like a teardrop. This teardrop sign is something you probably won't see in polymyositis.”

Magnetic resonance can be especially useful in differentiating IBM from polymyositis, said Dr. Oddis. “The results will be abnormal in both conditions, but MRIs from patients with inclusion body myositis are more likely to show fatty infiltration and atrophy and more widespread abnormalities, while in polymyositis, the predominant abnormality seen on MRI is inflammation distributed along the fascia.”

The only definitive test for inclusion body myositis is a muscle biopsy. Because of the possibility of skip lesions, “it sometimes takes two, three, or four biopsies before you get something you can hang your hat on, but when you do, there is no question,” said Dr. Oddis. “The distinctive histology that you're looking for includes endomysial inflammation, the presence of rimmed vacuoles, and intracellular amyloid deposits or twisted tubulofilaments [containing hyperphosphorylated tau].”

Management options for inclusion body myositis are often limited to supportive efforts, such as myotomy to relieve dysphagia caused by cricopharyngeal achalasia, said Dr. Oddis. While no definitive treatment has been proven effective in achieving sustained remission and improvement in whole body strength, some reports suggest there may be a subgroup of patients who experience a partial, transient response to anti-inflammatory, immunosuppressant therapy. For this reason, he said, an initial 6–8 week trial of prednisolone and an immunosuppressive drug such as methotrexate or azathioprine is a reasonable option for newly diagnosed patients.

BOSTON — Failure to respond to standard immunosuppressant therapy may be the first sign that a patient's apparent polymyositis actually is inclusion body myositis, according to Dr. Chester Oddis of the University of Pittsburgh.

The most common acquired muscle disease in people over 50 years of age, inclusion body myositis (IBM) is a distinct type of inflammatory myopathy characterized by slowly progressing, degenerative muscle changes caused by an antigen-driven inflammatory response, as well as vacuolar degeneration and abnormal protein deposits in distal and proximal muscle cells, Dr. Oddis said at a meeting on rheumatology sponsored by Harvard Medical School.

Because it shares certain clinical and pathologic features with polymyositis, such as varying degrees of muscle weakness, inflammation in the endomysium, muscle fiber necrosis, and elevation of serum muscle enzymes, inclusion body myositis is often mistaken for polymyositis or motor neuron disease by rheumatologists and neurologists, Dr. Oddis noted. “A number of studies have shown that the average time from symptom onset to diagnosis is between 4–6 years. Typically, the first indication that you're dealing with a mimic [of polymyositis] is the failure to respond to immunosuppressant therapy.”

The nature of disease onset and presentation also distinguishes IBM from polymyositis. While polymyositis tends to have a subacute onset, typically over a few weeks to months, IBM comes on insidiously over the course of many months and even years, Dr. Oddis explained. Additionally, IBM has a tendency for distal and asymmetric muscle involvement, such as a foot drop, he said. In contrast, polymyositis more commonly encompasses proximal, symmetric muscle weakness.

Pharyngeal muscle weakness is a common characteristic of IBM and polymyositis. In particular, however, proximal dysphagia resulting from cricopharyngeal spasm is more often seen in inclusion body myositis. “Patients often complain of a blocking sensation when they swallow that just doesn't go away,” said Dr. Oddis. “This is a little different than pharyngeal myopathy seen in polymyositis because it is persistent; pharyngeal myopathy waxes and wanes with the severity of the involvement of the proximal musculature.”

Unlike most connective tissue diseases, inclusion body myositis occurs predominantly in men. “It sneaks up on them in middle age and follows a characteristic pattern of painless muscle atrophy, including the forearm flexors, quadriceps, and the intrinsic muscles of the hands,” said Dr. Oddis. “The forearm and quadriceps atrophy is usually obvious on examination. To assess hand muscle strength, I'll often ask patients to form a circle with their fingers. Because of their intrinsic muscle weakness, the circle is often more like a teardrop. This teardrop sign is something you probably won't see in polymyositis.”

Magnetic resonance can be especially useful in differentiating IBM from polymyositis, said Dr. Oddis. “The results will be abnormal in both conditions, but MRIs from patients with inclusion body myositis are more likely to show fatty infiltration and atrophy and more widespread abnormalities, while in polymyositis, the predominant abnormality seen on MRI is inflammation distributed along the fascia.”

The only definitive test for inclusion body myositis is a muscle biopsy. Because of the possibility of skip lesions, “it sometimes takes two, three, or four biopsies before you get something you can hang your hat on, but when you do, there is no question,” said Dr. Oddis. “The distinctive histology that you're looking for includes endomysial inflammation, the presence of rimmed vacuoles, and intracellular amyloid deposits or twisted tubulofilaments [containing hyperphosphorylated tau].”

Management options for inclusion body myositis are often limited to supportive efforts, such as myotomy to relieve dysphagia caused by cricopharyngeal achalasia, said Dr. Oddis. While no definitive treatment has been proven effective in achieving sustained remission and improvement in whole body strength, some reports suggest there may be a subgroup of patients who experience a partial, transient response to anti-inflammatory, immunosuppressant therapy. For this reason, he said, an initial 6–8 week trial of prednisolone and an immunosuppressive drug such as methotrexate or azathioprine is a reasonable option for newly diagnosed patients.

BOSTON — Antimicrobial therapy does not clear plasma cell endometritis in many women who have or are at risk for asymptomatic gonorrhea, chlamydia, or bacterial vaginosis, Dr. Harold C. Wiesenfeld reported at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Histologic endometritis—defined as the presence of at least five neutrophils in the superficial endometrial epithelium per 400× field and at least one plasma cell per 120× field of endometrial tissue—is common in women with lower genital tract infection who do not have signs or symptoms of acute pelvic inflammatory disease (PID), but there are conflicting data regarding whether treatment for the histologic diagnosis is warranted, said Dr. Wiesenfeld of the University of Pittsburgh.

To determine the effect of antibiotic therapy on the clearance of plasma cell endometritis, Dr. Wiesenfeld and his colleagues conducted a nested analysis of women who were enrolled in a larger observational cohort investigation of subclinical PID and infertility. Women between the ages of 15 and 30 years were eligible for study enrollment if they had clinical evidence of mucopurulent cervicitis (purulent cervical discharge), if they were recently diagnosed with gonorrhea or chlamydia and were not yet treated, if they were diagnosed with bacterial vaginosis, or if they reported sexual contact with a male diagnosed with gonorrhea, chlamydia, or nongonococcal urethritis. Women with signs and symptoms of acute PID were excluded.

The study participants—all of whom underwent a thorough history, gynecologic exam, microbiologic evaluation of the lower genital tract, and endometrial biopsy—were randomly assigned to a treatment regimen comprising either ceftriaxone, metronidazole, and doxycycline or ceftriaxone, metronidazole, and azithromycin. For the purposes of the current analysis, “those women with endometritis on the initial biopsy were asked to come back 12 weeks after treatment to undergo a second endometrial biopsy,” Dr. Wiesenfeld said.

Of 382 women enrolled in the larger study with adequate initial endometrial samples, 61 had plasma cell endometritis on enrollment. “Of these 61 women, 40 had a second evaluable endometrial biopsy specimen and were included in our analysis,” he said. The mean age of the nested cohort was 24 years, and 77% of the women were African American.

Based on the result of the second endometrial biopsy, “our key finding was that 16 of these 40 women—40% of them—had persistent plasma cell endometritis at 12 weeks following antibiotic therapy,” Dr. Wiesenfeld said. “We compared those women who cleared the endometritis with antibiotic therapy and those who did not and found no statistical differences in age, race, insurance, previous pregnancy status, smoking, douching prior to enrollment or during the trial, or interim antibiotic use since the trial.”

Additionally, infection status at time of enrollment did not impact clearance. “There was no difference [in postantibiotic clearance] among those women who had gonorrhea, chlamydia, or both organisms or bacterial vaginosis or trichomoniasis,” Dr. Wiesenfeld noted. “Looking at endometrial microbiology, we did not find any correlation between upper genital tract microbiology and presence of endometritis at 12 weeks,” he said, nor did they observe any differences associated with degree of plasma cell infiltrates on initial biopsy or with antibiotic regimen.

“The fact that plasma cell endometritis persisted in 40% of these women following antibiotic therapy with no identifiable variables that predicted failure raises questions about the importance of identifying plasma cells in the endometrium,” Dr. Wiesenfeld stated. Before therapeutic decisions can be made based on plasma cell endometritis, “we really need to define the role of plasma cells in the endometrium,” he said.

BOSTON — Antimicrobial therapy does not clear plasma cell endometritis in many women who have or are at risk for asymptomatic gonorrhea, chlamydia, or bacterial vaginosis, Dr. Harold C. Wiesenfeld reported at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Histologic endometritis—defined as the presence of at least five neutrophils in the superficial endometrial epithelium per 400× field and at least one plasma cell per 120× field of endometrial tissue—is common in women with lower genital tract infection who do not have signs or symptoms of acute pelvic inflammatory disease (PID), but there are conflicting data regarding whether treatment for the histologic diagnosis is warranted, said Dr. Wiesenfeld of the University of Pittsburgh.

To determine the effect of antibiotic therapy on the clearance of plasma cell endometritis, Dr. Wiesenfeld and his colleagues conducted a nested analysis of women who were enrolled in a larger observational cohort investigation of subclinical PID and infertility. Women between the ages of 15 and 30 years were eligible for study enrollment if they had clinical evidence of mucopurulent cervicitis (purulent cervical discharge), if they were recently diagnosed with gonorrhea or chlamydia and were not yet treated, if they were diagnosed with bacterial vaginosis, or if they reported sexual contact with a male diagnosed with gonorrhea, chlamydia, or nongonococcal urethritis. Women with signs and symptoms of acute PID were excluded.

The study participants—all of whom underwent a thorough history, gynecologic exam, microbiologic evaluation of the lower genital tract, and endometrial biopsy—were randomly assigned to a treatment regimen comprising either ceftriaxone, metronidazole, and doxycycline or ceftriaxone, metronidazole, and azithromycin. For the purposes of the current analysis, “those women with endometritis on the initial biopsy were asked to come back 12 weeks after treatment to undergo a second endometrial biopsy,” Dr. Wiesenfeld said.

Of 382 women enrolled in the larger study with adequate initial endometrial samples, 61 had plasma cell endometritis on enrollment. “Of these 61 women, 40 had a second evaluable endometrial biopsy specimen and were included in our analysis,” he said. The mean age of the nested cohort was 24 years, and 77% of the women were African American.

Based on the result of the second endometrial biopsy, “our key finding was that 16 of these 40 women—40% of them—had persistent plasma cell endometritis at 12 weeks following antibiotic therapy,” Dr. Wiesenfeld said. “We compared those women who cleared the endometritis with antibiotic therapy and those who did not and found no statistical differences in age, race, insurance, previous pregnancy status, smoking, douching prior to enrollment or during the trial, or interim antibiotic use since the trial.”

Additionally, infection status at time of enrollment did not impact clearance. “There was no difference [in postantibiotic clearance] among those women who had gonorrhea, chlamydia, or both organisms or bacterial vaginosis or trichomoniasis,” Dr. Wiesenfeld noted. “Looking at endometrial microbiology, we did not find any correlation between upper genital tract microbiology and presence of endometritis at 12 weeks,” he said, nor did they observe any differences associated with degree of plasma cell infiltrates on initial biopsy or with antibiotic regimen.

“The fact that plasma cell endometritis persisted in 40% of these women following antibiotic therapy with no identifiable variables that predicted failure raises questions about the importance of identifying plasma cells in the endometrium,” Dr. Wiesenfeld stated. Before therapeutic decisions can be made based on plasma cell endometritis, “we really need to define the role of plasma cells in the endometrium,” he said.

BOSTON — Antimicrobial therapy does not clear plasma cell endometritis in many women who have or are at risk for asymptomatic gonorrhea, chlamydia, or bacterial vaginosis, Dr. Harold C. Wiesenfeld reported at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Histologic endometritis—defined as the presence of at least five neutrophils in the superficial endometrial epithelium per 400× field and at least one plasma cell per 120× field of endometrial tissue—is common in women with lower genital tract infection who do not have signs or symptoms of acute pelvic inflammatory disease (PID), but there are conflicting data regarding whether treatment for the histologic diagnosis is warranted, said Dr. Wiesenfeld of the University of Pittsburgh.

To determine the effect of antibiotic therapy on the clearance of plasma cell endometritis, Dr. Wiesenfeld and his colleagues conducted a nested analysis of women who were enrolled in a larger observational cohort investigation of subclinical PID and infertility. Women between the ages of 15 and 30 years were eligible for study enrollment if they had clinical evidence of mucopurulent cervicitis (purulent cervical discharge), if they were recently diagnosed with gonorrhea or chlamydia and were not yet treated, if they were diagnosed with bacterial vaginosis, or if they reported sexual contact with a male diagnosed with gonorrhea, chlamydia, or nongonococcal urethritis. Women with signs and symptoms of acute PID were excluded.

The study participants—all of whom underwent a thorough history, gynecologic exam, microbiologic evaluation of the lower genital tract, and endometrial biopsy—were randomly assigned to a treatment regimen comprising either ceftriaxone, metronidazole, and doxycycline or ceftriaxone, metronidazole, and azithromycin. For the purposes of the current analysis, “those women with endometritis on the initial biopsy were asked to come back 12 weeks after treatment to undergo a second endometrial biopsy,” Dr. Wiesenfeld said.

Of 382 women enrolled in the larger study with adequate initial endometrial samples, 61 had plasma cell endometritis on enrollment. “Of these 61 women, 40 had a second evaluable endometrial biopsy specimen and were included in our analysis,” he said. The mean age of the nested cohort was 24 years, and 77% of the women were African American.

Based on the result of the second endometrial biopsy, “our key finding was that 16 of these 40 women—40% of them—had persistent plasma cell endometritis at 12 weeks following antibiotic therapy,” Dr. Wiesenfeld said. “We compared those women who cleared the endometritis with antibiotic therapy and those who did not and found no statistical differences in age, race, insurance, previous pregnancy status, smoking, douching prior to enrollment or during the trial, or interim antibiotic use since the trial.”

Additionally, infection status at time of enrollment did not impact clearance. “There was no difference [in postantibiotic clearance] among those women who had gonorrhea, chlamydia, or both organisms or bacterial vaginosis or trichomoniasis,” Dr. Wiesenfeld noted. “Looking at endometrial microbiology, we did not find any correlation between upper genital tract microbiology and presence of endometritis at 12 weeks,” he said, nor did they observe any differences associated with degree of plasma cell infiltrates on initial biopsy or with antibiotic regimen.

“The fact that plasma cell endometritis persisted in 40% of these women following antibiotic therapy with no identifiable variables that predicted failure raises questions about the importance of identifying plasma cells in the endometrium,” Dr. Wiesenfeld stated. Before therapeutic decisions can be made based on plasma cell endometritis, “we really need to define the role of plasma cells in the endometrium,” he said.

BOSTON — Antimicrobial therapy does not clear plasma cell endometritis in many women who have or are at risk for asymptomatic gonorrhea, chlamydia, or bacterial vaginosis, Dr. Harold C. Wiesenfeld reported at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Histologic endometritis—defined as the presence of at least five neutrophils in the superficial endometrial epithelium per 400x field and at least one plasma cell per 120x field of endometrial tissue—is common in women with lower genital tract infection who do not have signs or symptoms of acute pelvic inflammatory disease (PID), but there are conflicting data regarding whether treatment for the histologic diagnosis is warranted, said Dr. Wiesenfeld of the University of Pittsburgh.

To determine the effect of antibiotic therapy on the clearance of plasma cell endometritis, Dr. Wiesenfeld and colleagues conducted a nested analysis of women enrolled in a larger observational cohort investigation of subclinical PID and infertility. Women between the ages of 15 and 30 years were eligible for study enrollment if they had clinical evidence of mucopurulent cervicitis (purulent cervical discharge), if they were recently diagnosed with gonorrhea or chlamydia and were not yet treated, if they were diagnosed with bacterial vaginosis, or if they reported sexual contact with a male diagnosed with gonorrhea, chlamydia, or nongonococcal urethritis.

Women who had signs and symptoms of acute PID were excluded.

The study participants—all of whom underwent a thorough history, gynecologic exam, microbiologic evaluation of the lower genital tract, and endometrial biopsy—were randomly assigned to a treatment regimen comprising either ceftriaxone, metronidazole, and doxycycline or ceftriaxone, metronidazole, and azithromycin.

For the purposes of the current analysis, “those women with endometritis on the initial biopsy were asked to come back 12 weeks after treatment to undergo a second endometrial biopsy,” reported Dr. Wiesenfeld.

Of 382 women enrolled in the larger study with adequate initial endometrial samples, 61 had plasma cell endometritis on enrollment.

“Of these 61 women, 40 had a second evaluable endometrial biopsy specimen and were included in our analysis,” said Dr. Wiesenfeld. The mean age of the nested cohort was 24 years and 77% of the women were African American.

Based on the result of the second endometrial biopsy, “Our key finding was that 16 of these 40 women—40% of them—had persistent plasma cell endometritis at 12 weeks following antibiotic therapy,” said Dr. Wiesenfeld.

“We compared those women who cleared the endometritis with antibiotic therapy and those who did not and found no statistical differences in age, race, insurance, previous pregnancy status, smoking, douching prior to enrollment or during the trial, or interim antibiotic use since the trial.”

Additionally, infection status at time of enrollment did not impact clearance. “There was no difference [in postantibiotic clearance] among those women who had gonorrhea, chlamydia, or both organisms or bacterial vaginosis or trichomoniasis,” Dr. Wiesenfeld noted.

“Looking at endometrial microbiology, we did not find any correlation between upper genital tract microbiology and presence of endometritis at 12 weeks,” he said, nor did they observe any differences associated with degree of plasma cell infiltrates on initial biopsy or with antibiotic regimen.

“The fact that plasma cell endometritis persisted in 40% of these women following antibiotic therapy with no identifiable variables that predicted failure raises questions about the importance of identifying plasma cells in the endometrium,” Dr. Wiesenfeld stated.

Before therapeutic decisions can be made based on plasma cell endometritis, “we really need to define the role of plasma cells in the endometrium,” he concluded.

BOSTON — Antimicrobial therapy does not clear plasma cell endometritis in many women who have or are at risk for asymptomatic gonorrhea, chlamydia, or bacterial vaginosis, Dr. Harold C. Wiesenfeld reported at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Histologic endometritis—defined as the presence of at least five neutrophils in the superficial endometrial epithelium per 400x field and at least one plasma cell per 120x field of endometrial tissue—is common in women with lower genital tract infection who do not have signs or symptoms of acute pelvic inflammatory disease (PID), but there are conflicting data regarding whether treatment for the histologic diagnosis is warranted, said Dr. Wiesenfeld of the University of Pittsburgh.

To determine the effect of antibiotic therapy on the clearance of plasma cell endometritis, Dr. Wiesenfeld and colleagues conducted a nested analysis of women enrolled in a larger observational cohort investigation of subclinical PID and infertility. Women between the ages of 15 and 30 years were eligible for study enrollment if they had clinical evidence of mucopurulent cervicitis (purulent cervical discharge), if they were recently diagnosed with gonorrhea or chlamydia and were not yet treated, if they were diagnosed with bacterial vaginosis, or if they reported sexual contact with a male diagnosed with gonorrhea, chlamydia, or nongonococcal urethritis.

Women who had signs and symptoms of acute PID were excluded.

The study participants—all of whom underwent a thorough history, gynecologic exam, microbiologic evaluation of the lower genital tract, and endometrial biopsy—were randomly assigned to a treatment regimen comprising either ceftriaxone, metronidazole, and doxycycline or ceftriaxone, metronidazole, and azithromycin.

For the purposes of the current analysis, “those women with endometritis on the initial biopsy were asked to come back 12 weeks after treatment to undergo a second endometrial biopsy,” reported Dr. Wiesenfeld.

Of 382 women enrolled in the larger study with adequate initial endometrial samples, 61 had plasma cell endometritis on enrollment.

“Of these 61 women, 40 had a second evaluable endometrial biopsy specimen and were included in our analysis,” said Dr. Wiesenfeld. The mean age of the nested cohort was 24 years and 77% of the women were African American.

Based on the result of the second endometrial biopsy, “Our key finding was that 16 of these 40 women—40% of them—had persistent plasma cell endometritis at 12 weeks following antibiotic therapy,” said Dr. Wiesenfeld.

“We compared those women who cleared the endometritis with antibiotic therapy and those who did not and found no statistical differences in age, race, insurance, previous pregnancy status, smoking, douching prior to enrollment or during the trial, or interim antibiotic use since the trial.”

Additionally, infection status at time of enrollment did not impact clearance. “There was no difference [in postantibiotic clearance] among those women who had gonorrhea, chlamydia, or both organisms or bacterial vaginosis or trichomoniasis,” Dr. Wiesenfeld noted.

“Looking at endometrial microbiology, we did not find any correlation between upper genital tract microbiology and presence of endometritis at 12 weeks,” he said, nor did they observe any differences associated with degree of plasma cell infiltrates on initial biopsy or with antibiotic regimen.

“The fact that plasma cell endometritis persisted in 40% of these women following antibiotic therapy with no identifiable variables that predicted failure raises questions about the importance of identifying plasma cells in the endometrium,” Dr. Wiesenfeld stated.

Before therapeutic decisions can be made based on plasma cell endometritis, “we really need to define the role of plasma cells in the endometrium,” he concluded.

BOSTON — Antimicrobial therapy does not clear plasma cell endometritis in many women who have or are at risk for asymptomatic gonorrhea, chlamydia, or bacterial vaginosis, Dr. Harold C. Wiesenfeld reported at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Histologic endometritis—defined as the presence of at least five neutrophils in the superficial endometrial epithelium per 400x field and at least one plasma cell per 120x field of endometrial tissue—is common in women with lower genital tract infection who do not have signs or symptoms of acute pelvic inflammatory disease (PID), but there are conflicting data regarding whether treatment for the histologic diagnosis is warranted, said Dr. Wiesenfeld of the University of Pittsburgh.

To determine the effect of antibiotic therapy on the clearance of plasma cell endometritis, Dr. Wiesenfeld and colleagues conducted a nested analysis of women enrolled in a larger observational cohort investigation of subclinical PID and infertility. Women between the ages of 15 and 30 years were eligible for study enrollment if they had clinical evidence of mucopurulent cervicitis (purulent cervical discharge), if they were recently diagnosed with gonorrhea or chlamydia and were not yet treated, if they were diagnosed with bacterial vaginosis, or if they reported sexual contact with a male diagnosed with gonorrhea, chlamydia, or nongonococcal urethritis.

Women who had signs and symptoms of acute PID were excluded.

The study participants—all of whom underwent a thorough history, gynecologic exam, microbiologic evaluation of the lower genital tract, and endometrial biopsy—were randomly assigned to a treatment regimen comprising either ceftriaxone, metronidazole, and doxycycline or ceftriaxone, metronidazole, and azithromycin.

For the purposes of the current analysis, “those women with endometritis on the initial biopsy were asked to come back 12 weeks after treatment to undergo a second endometrial biopsy,” reported Dr. Wiesenfeld.

Of 382 women enrolled in the larger study with adequate initial endometrial samples, 61 had plasma cell endometritis on enrollment.

“Of these 61 women, 40 had a second evaluable endometrial biopsy specimen and were included in our analysis,” said Dr. Wiesenfeld. The mean age of the nested cohort was 24 years and 77% of the women were African American.

Based on the result of the second endometrial biopsy, “Our key finding was that 16 of these 40 women—40% of them—had persistent plasma cell endometritis at 12 weeks following antibiotic therapy,” said Dr. Wiesenfeld.

“We compared those women who cleared the endometritis with antibiotic therapy and those who did not and found no statistical differences in age, race, insurance, previous pregnancy status, smoking, douching prior to enrollment or during the trial, or interim antibiotic use since the trial.”

Additionally, infection status at time of enrollment did not impact clearance. “There was no difference [in postantibiotic clearance] among those women who had gonorrhea, chlamydia, or both organisms or bacterial vaginosis or trichomoniasis,” Dr. Wiesenfeld noted.

“Looking at endometrial microbiology, we did not find any correlation between upper genital tract microbiology and presence of endometritis at 12 weeks,” he said, nor did they observe any differences associated with degree of plasma cell infiltrates on initial biopsy or with antibiotic regimen.

“The fact that plasma cell endometritis persisted in 40% of these women following antibiotic therapy with no identifiable variables that predicted failure raises questions about the importance of identifying plasma cells in the endometrium,” Dr. Wiesenfeld stated.

Before therapeutic decisions can be made based on plasma cell endometritis, “we really need to define the role of plasma cells in the endometrium,” he concluded.

BOSTON — The administration of supplemental perioperative oxygen did not decrease the risk of endometritis or wound infection associated with cesarean delivery in a randomized, double-blind study, Dr. Carolyn Gardella reported at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Based on colorectal surgery literature indicating that the administration of perioperative oxygen significantly decreases surgical infection rates, Dr. Gardella and colleagues at the University of Washington, Seattle, hypothesized that the same strategy might similarly decrease the incidence of surgical infections in women undergoing cesarean delivery.

To test the hypothesis, the investigators randomly assigned 143 women who were undergoing cesarean delivery under regional anesthesia after the onset of labor or rupture of membranes to receive 30% or 80% inspired oxygen via nonrebreather masks during surgery and for 2 hours after surgery between October 2002 and April 2007.

The 74 women assigned to the 30% oxygen group and 69 assigned to the 80% oxygen group represented approximately one-quarter of the planned data accrual, said Dr. Gardella.

“Our institutional postpartum endometritis rate was 15%. Assuming this as a baseline, and with an 80% study power, we determined we would need 225 women per study arm to detect a 50% decrease in the infection rate, and we planned to do an interim analysis at 25%,” she said.

The study population excluded women who were undergoing elective cesarean section prior to onset of labor or rupture of membranes “because the risk of infection in this population is so low,” Dr. Gardella noted.

“We also excluded women with truly emergent cesarean sections because we couldn't implement [the oxygen protocol] during an emergency, and [we excluded] those with clinical chorioamnionitis because it was too difficult for us to tell whether or not their infection was true postpartum wound infection or just a continuation of the chorioamnionitis.” Although women undergoing planned general endotracheal anesthesia were also excluded, those who were converted from regional to general were not, she said.

Blinded oxygen delivery during the study was a challenge, Dr. Gardella said. “In the colorectal surgery data, patients were under general anesthesia, so it was easy to dial up their oxygen. We were dealing with women undergoing regional anesthesia, so we developed a system where we could maintain blinding by giving all of the women 15 liters flow, but then used an oxygen blender under cover to blend 100% oxygen with air in order to establish two separate groups,” she said, noting that only the anesthesiologists were aware of patients' study assignments during and following the operation.

Dorsum venous oxygen was used as a proxy for arterial oxygen. In pretrial testing on volunteers, “we were able to achieve different oxygen levels using this method,” she said.

Postoperative infection was defined clinically as administration of antibiotics for postpartum endometritis or wound infection during the initial hospital stay or within 14 days of surgery. Secondary outcomes were length of hospital stay, whether the wound separated, and whether there was readmission for infection.

Antepartum and intrapartum characteristics were similar in both study groups. “We had a variable increase in the number of women with complications such as hypertension or preeclampsia assigned to the 30% [versus] the 80% group, and diabetes was slightly more likely in the 80% group, though the increases were not statistically significant,” said Dr. Gardella. Gestational age at delivery was approximately 38 weeks in both groups. The duration of labor was slightly longer in the 30% group, and those women were also slightly more likely to have intact membranes, she said.

The incidence of group B streptococcus was approximately 25% in the study population, “which is consistent with the prevalence in our labor and delivery population as a whole,” said Dr. Gardella. “The use of antibiotics in labor, primarily for group B strep prophylaxis, was between 34% and 40%.”

Deviations in study protocol were observed in eight patients from each group, Dr. Gardella reported. “In the 30% group, two patients were converted to endotracheal anesthesia, three patients required an increase in inspired oxygen because of neonatal distress observed in the operating room, and three patients had intermittent mask use either during the surgical procedure because of vomiting, nausea, or claustrophobia, or after surgery because they wanted to feel closer to their baby without the mask,” she said. In the 80% group, three were converted to general endotracheal anesthesia and five had intermittent mask use.

An analysis of patient outcomes showed that 25% of the women receiving 80% oxygen, compared with 14% of those receiving 30% oxygen, developed postpartum cellulitis or endometritis, or received intravenous antibiotics for either of those conditions, Dr. Gardella reported.

“Hospital readmission and wound separation were also more common in the 80% group,” she said. “None of the numbers reached statistical significance because the study was not powered for that, but the data [were trending] in the wrong direction.” Because the P value exceeded the P value for futility, suggesting the observed differences were unlikely to reach statistical significance with continued recruitment, the trial was stopped.

The study was limited by a number of considerations. The median duration of oxygen therapy was less than planned, there was significant overlap in the median level of venous oxygen in the 80% group and the 30% group, and it's possible a therapeutic level was not achieved, and the dorsum of the foot was used as a proxy measure of oxygen delivery. Finally, the outcome may have been 'muddled by antibiotic overuse in the study population, Dr. Gardella said.

BOSTON — The administration of supplemental perioperative oxygen did not decrease the risk of endometritis or wound infection associated with cesarean delivery in a randomized, double-blind study, Dr. Carolyn Gardella reported at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Based on colorectal surgery literature indicating that the administration of perioperative oxygen significantly decreases surgical infection rates, Dr. Gardella and colleagues at the University of Washington, Seattle, hypothesized that the same strategy might similarly decrease the incidence of surgical infections in women undergoing cesarean delivery.

To test the hypothesis, the investigators randomly assigned 143 women who were undergoing cesarean delivery under regional anesthesia after the onset of labor or rupture of membranes to receive 30% or 80% inspired oxygen via nonrebreather masks during surgery and for 2 hours after surgery between October 2002 and April 2007.

The 74 women assigned to the 30% oxygen group and 69 assigned to the 80% oxygen group represented approximately one-quarter of the planned data accrual, said Dr. Gardella.

“Our institutional postpartum endometritis rate was 15%. Assuming this as a baseline, and with an 80% study power, we determined we would need 225 women per study arm to detect a 50% decrease in the infection rate, and we planned to do an interim analysis at 25%,” she said.

The study population excluded women who were undergoing elective cesarean section prior to onset of labor or rupture of membranes “because the risk of infection in this population is so low,” Dr. Gardella noted.

“We also excluded women with truly emergent cesarean sections because we couldn't implement [the oxygen protocol] during an emergency, and [we excluded] those with clinical chorioamnionitis because it was too difficult for us to tell whether or not their infection was true postpartum wound infection or just a continuation of the chorioamnionitis.” Although women undergoing planned general endotracheal anesthesia were also excluded, those who were converted from regional to general were not, she said.

Blinded oxygen delivery during the study was a challenge, Dr. Gardella said. “In the colorectal surgery data, patients were under general anesthesia, so it was easy to dial up their oxygen. We were dealing with women undergoing regional anesthesia, so we developed a system where we could maintain blinding by giving all of the women 15 liters flow, but then used an oxygen blender under cover to blend 100% oxygen with air in order to establish two separate groups,” she said, noting that only the anesthesiologists were aware of patients' study assignments during and following the operation.

Dorsum venous oxygen was used as a proxy for arterial oxygen. In pretrial testing on volunteers, “we were able to achieve different oxygen levels using this method,” she said.

Postoperative infection was defined clinically as administration of antibiotics for postpartum endometritis or wound infection during the initial hospital stay or within 14 days of surgery. Secondary outcomes were length of hospital stay, whether the wound separated, and whether there was readmission for infection.

Antepartum and intrapartum characteristics were similar in both study groups. “We had a variable increase in the number of women with complications such as hypertension or preeclampsia assigned to the 30% [versus] the 80% group, and diabetes was slightly more likely in the 80% group, though the increases were not statistically significant,” said Dr. Gardella. Gestational age at delivery was approximately 38 weeks in both groups. The duration of labor was slightly longer in the 30% group, and those women were also slightly more likely to have intact membranes, she said.

The incidence of group B streptococcus was approximately 25% in the study population, “which is consistent with the prevalence in our labor and delivery population as a whole,” said Dr. Gardella. “The use of antibiotics in labor, primarily for group B strep prophylaxis, was between 34% and 40%.”

Deviations in study protocol were observed in eight patients from each group, Dr. Gardella reported. “In the 30% group, two patients were converted to endotracheal anesthesia, three patients required an increase in inspired oxygen because of neonatal distress observed in the operating room, and three patients had intermittent mask use either during the surgical procedure because of vomiting, nausea, or claustrophobia, or after surgery because they wanted to feel closer to their baby without the mask,” she said. In the 80% group, three were converted to general endotracheal anesthesia and five had intermittent mask use.

An analysis of patient outcomes showed that 25% of the women receiving 80% oxygen, compared with 14% of those receiving 30% oxygen, developed postpartum cellulitis or endometritis, or received intravenous antibiotics for either of those conditions, Dr. Gardella reported.

“Hospital readmission and wound separation were also more common in the 80% group,” she said. “None of the numbers reached statistical significance because the study was not powered for that, but the data [were trending] in the wrong direction.” Because the P value exceeded the P value for futility, suggesting the observed differences were unlikely to reach statistical significance with continued recruitment, the trial was stopped.

The study was limited by a number of considerations. The median duration of oxygen therapy was less than planned, there was significant overlap in the median level of venous oxygen in the 80% group and the 30% group, and it's possible a therapeutic level was not achieved, and the dorsum of the foot was used as a proxy measure of oxygen delivery. Finally, the outcome may have been 'muddled by antibiotic overuse in the study population, Dr. Gardella said.

BOSTON — The administration of supplemental perioperative oxygen did not decrease the risk of endometritis or wound infection associated with cesarean delivery in a randomized, double-blind study, Dr. Carolyn Gardella reported at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

Based on colorectal surgery literature indicating that the administration of perioperative oxygen significantly decreases surgical infection rates, Dr. Gardella and colleagues at the University of Washington, Seattle, hypothesized that the same strategy might similarly decrease the incidence of surgical infections in women undergoing cesarean delivery.

To test the hypothesis, the investigators randomly assigned 143 women who were undergoing cesarean delivery under regional anesthesia after the onset of labor or rupture of membranes to receive 30% or 80% inspired oxygen via nonrebreather masks during surgery and for 2 hours after surgery between October 2002 and April 2007.

The 74 women assigned to the 30% oxygen group and 69 assigned to the 80% oxygen group represented approximately one-quarter of the planned data accrual, said Dr. Gardella.

“Our institutional postpartum endometritis rate was 15%. Assuming this as a baseline, and with an 80% study power, we determined we would need 225 women per study arm to detect a 50% decrease in the infection rate, and we planned to do an interim analysis at 25%,” she said.

The study population excluded women who were undergoing elective cesarean section prior to onset of labor or rupture of membranes “because the risk of infection in this population is so low,” Dr. Gardella noted.

“We also excluded women with truly emergent cesarean sections because we couldn't implement [the oxygen protocol] during an emergency, and [we excluded] those with clinical chorioamnionitis because it was too difficult for us to tell whether or not their infection was true postpartum wound infection or just a continuation of the chorioamnionitis.” Although women undergoing planned general endotracheal anesthesia were also excluded, those who were converted from regional to general were not, she said.

Blinded oxygen delivery during the study was a challenge, Dr. Gardella said. “In the colorectal surgery data, patients were under general anesthesia, so it was easy to dial up their oxygen. We were dealing with women undergoing regional anesthesia, so we developed a system where we could maintain blinding by giving all of the women 15 liters flow, but then used an oxygen blender under cover to blend 100% oxygen with air in order to establish two separate groups,” she said, noting that only the anesthesiologists were aware of patients' study assignments during and following the operation.

Dorsum venous oxygen was used as a proxy for arterial oxygen. In pretrial testing on volunteers, “we were able to achieve different oxygen levels using this method,” she said.

Postoperative infection was defined clinically as administration of antibiotics for postpartum endometritis or wound infection during the initial hospital stay or within 14 days of surgery. Secondary outcomes were length of hospital stay, whether the wound separated, and whether there was readmission for infection.

Antepartum and intrapartum characteristics were similar in both study groups. “We had a variable increase in the number of women with complications such as hypertension or preeclampsia assigned to the 30% [versus] the 80% group, and diabetes was slightly more likely in the 80% group, though the increases were not statistically significant,” said Dr. Gardella. Gestational age at delivery was approximately 38 weeks in both groups. The duration of labor was slightly longer in the 30% group, and those women were also slightly more likely to have intact membranes, she said.

The incidence of group B streptococcus was approximately 25% in the study population, “which is consistent with the prevalence in our labor and delivery population as a whole,” said Dr. Gardella. “The use of antibiotics in labor, primarily for group B strep prophylaxis, was between 34% and 40%.”

Deviations in study protocol were observed in eight patients from each group, Dr. Gardella reported. “In the 30% group, two patients were converted to endotracheal anesthesia, three patients required an increase in inspired oxygen because of neonatal distress observed in the operating room, and three patients had intermittent mask use either during the surgical procedure because of vomiting, nausea, or claustrophobia, or after surgery because they wanted to feel closer to their baby without the mask,” she said. In the 80% group, three were converted to general endotracheal anesthesia and five had intermittent mask use.

An analysis of patient outcomes showed that 25% of the women receiving 80% oxygen, compared with 14% of those receiving 30% oxygen, developed postpartum cellulitis or endometritis, or received intravenous antibiotics for either of those conditions, Dr. Gardella reported.

“Hospital readmission and wound separation were also more common in the 80% group,” she said. “None of the numbers reached statistical significance because the study was not powered for that, but the data [were trending] in the wrong direction.” Because the P value exceeded the P value for futility, suggesting the observed differences were unlikely to reach statistical significance with continued recruitment, the trial was stopped.

The study was limited by a number of considerations. The median duration of oxygen therapy was less than planned, there was significant overlap in the median level of venous oxygen in the 80% group and the 30% group, and it's possible a therapeutic level was not achieved, and the dorsum of the foot was used as a proxy measure of oxygen delivery. Finally, the outcome may have been 'muddled by antibiotic overuse in the study population, Dr. Gardella said.

BOSTON — To differentiate definitively between acute gout and pseudogout, look at the crystals.

On UV light microscopy, fluid aspirated from the inflamed joint of a patient with pseudogout will be teeming with rhomboid-shaped calcium pyrophosphate dihydrate (CPPD) crystals, which are morphologically different from the needle-shaped monosodium urate (MSU) crystals implicated in the pain and swelling of acute gout, Dr. Dwight R. Robinson said at a meeting on rheumatology sponsored by Harvard Medical School. “[CPPD] crystals are less well formed and show more variation in size and shape than [MSU] crystals.”

Like MSU crystals in gout patients, the deposition of CPPD crystals in pseudogout causes acute pain and swelling the joints. The acute attacks can last from 1 day to 4 weeks and may be accompanied by fever, leukocytosis, and elevated acute-phase reactants, said Dr. Robinson, a rheumatologist and professor of medicine at Harvard Medical School, Boston. The latter signs also may be indicative of septic arthritis, so sepsis first must be excluded by Gram stain and culture of synovial fluid.

CPPD crystals have a predilection for depositing in articular and fibrocartilage, said Dr. Robinson. In pseudogout, this process commonly involves the knee or wrist joint but also may involve the first metatarsophalangeal joint, as occurs in gout, or almost any other joint. Radiographically, the diagnosis of pseudogout often can be confirmed by evidence of chondrocalcinosis in the affected joint.

In addition to mimicking the clinical patterns of gout, CPPD joint disease symptoms may overlap with other inflammatory conditions. It may be asymptomatic in many patients.

CPPD disease develops in patients older than age 50. In younger patients, “it's more likely to be a complication of osteoarthritis, a late consequence of joint trauma or knee meniscectomy, or related to an underlying metabolic disease.” There also may be a familial component.

The exact mechanism for the development of CPPD deposition disease is uncertain, but an overactivity of enzymes that break down nucleoside triphosphates has been implicated, as have genetic defects.

Acute attacks can be treated effectively with nonsteroidal anti-inflammatory drugs, said Dr. Robinson. Given the risks of gastrointestinal and renal toxicities associated with NSAIDs, particularly in elderly patients, intra-articular corticosteroid injection into the affected joint is a reasonable treatment option, he said.

BOSTON — To differentiate definitively between acute gout and pseudogout, look at the crystals.

On UV light microscopy, fluid aspirated from the inflamed joint of a patient with pseudogout will be teeming with rhomboid-shaped calcium pyrophosphate dihydrate (CPPD) crystals, which are morphologically different from the needle-shaped monosodium urate (MSU) crystals implicated in the pain and swelling of acute gout, Dr. Dwight R. Robinson said at a meeting on rheumatology sponsored by Harvard Medical School. “[CPPD] crystals are less well formed and show more variation in size and shape than [MSU] crystals.”

Like MSU crystals in gout patients, the deposition of CPPD crystals in pseudogout causes acute pain and swelling the joints. The acute attacks can last from 1 day to 4 weeks and may be accompanied by fever, leukocytosis, and elevated acute-phase reactants, said Dr. Robinson, a rheumatologist and professor of medicine at Harvard Medical School, Boston. The latter signs also may be indicative of septic arthritis, so sepsis first must be excluded by Gram stain and culture of synovial fluid.

CPPD crystals have a predilection for depositing in articular and fibrocartilage, said Dr. Robinson. In pseudogout, this process commonly involves the knee or wrist joint but also may involve the first metatarsophalangeal joint, as occurs in gout, or almost any other joint. Radiographically, the diagnosis of pseudogout often can be confirmed by evidence of chondrocalcinosis in the affected joint.

In addition to mimicking the clinical patterns of gout, CPPD joint disease symptoms may overlap with other inflammatory conditions. It may be asymptomatic in many patients.

CPPD disease develops in patients older than age 50. In younger patients, “it's more likely to be a complication of osteoarthritis, a late consequence of joint trauma or knee meniscectomy, or related to an underlying metabolic disease.” There also may be a familial component.

The exact mechanism for the development of CPPD deposition disease is uncertain, but an overactivity of enzymes that break down nucleoside triphosphates has been implicated, as have genetic defects.

Acute attacks can be treated effectively with nonsteroidal anti-inflammatory drugs, said Dr. Robinson. Given the risks of gastrointestinal and renal toxicities associated with NSAIDs, particularly in elderly patients, intra-articular corticosteroid injection into the affected joint is a reasonable treatment option, he said.

BOSTON — To differentiate definitively between acute gout and pseudogout, look at the crystals.

On UV light microscopy, fluid aspirated from the inflamed joint of a patient with pseudogout will be teeming with rhomboid-shaped calcium pyrophosphate dihydrate (CPPD) crystals, which are morphologically different from the needle-shaped monosodium urate (MSU) crystals implicated in the pain and swelling of acute gout, Dr. Dwight R. Robinson said at a meeting on rheumatology sponsored by Harvard Medical School. “[CPPD] crystals are less well formed and show more variation in size and shape than [MSU] crystals.”

Like MSU crystals in gout patients, the deposition of CPPD crystals in pseudogout causes acute pain and swelling the joints. The acute attacks can last from 1 day to 4 weeks and may be accompanied by fever, leukocytosis, and elevated acute-phase reactants, said Dr. Robinson, a rheumatologist and professor of medicine at Harvard Medical School, Boston. The latter signs also may be indicative of septic arthritis, so sepsis first must be excluded by Gram stain and culture of synovial fluid.

CPPD crystals have a predilection for depositing in articular and fibrocartilage, said Dr. Robinson. In pseudogout, this process commonly involves the knee or wrist joint but also may involve the first metatarsophalangeal joint, as occurs in gout, or almost any other joint. Radiographically, the diagnosis of pseudogout often can be confirmed by evidence of chondrocalcinosis in the affected joint.

In addition to mimicking the clinical patterns of gout, CPPD joint disease symptoms may overlap with other inflammatory conditions. It may be asymptomatic in many patients.

CPPD disease develops in patients older than age 50. In younger patients, “it's more likely to be a complication of osteoarthritis, a late consequence of joint trauma or knee meniscectomy, or related to an underlying metabolic disease.” There also may be a familial component.

The exact mechanism for the development of CPPD deposition disease is uncertain, but an overactivity of enzymes that break down nucleoside triphosphates has been implicated, as have genetic defects.

Acute attacks can be treated effectively with nonsteroidal anti-inflammatory drugs, said Dr. Robinson. Given the risks of gastrointestinal and renal toxicities associated with NSAIDs, particularly in elderly patients, intra-articular corticosteroid injection into the affected joint is a reasonable treatment option, he said.

BOSTON — Women with increased levels of type-specific serum antibody against group B streptococci may be protected from vaginal colonization by those serotypes, a study has shown.

The findings support current efforts to develop a vaccine to decrease vaginal acquisition and fetal transmission of the bacteria, lead investigator Dr. Sharon Hillier said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

It has long been recognized that vaginal colonization by group B streptococci (GBS) is probably the single most important risk factor for neonatal sepsis, and while wider use of prophylactic intrapartum antibiotics has led to a substantial decline in the incidence of GBS infection in newborns, “a lot of women do develop amniotic fluid infections, preterm delivery, or even pregnancy loss” due to the bacteria, said Dr. Hillier of the University of Pittsburgh's Magee-Women's Hospital. “We really haven't understood why women become vaginally colonized with GBS, and we have few options for interrupting vaginal colonization. Prophylactic antibiotic treatment has been useful as an interim strategy, but it is just that—an interim strategy.”

The longer-term objective, she said, is to develop a vaccine against GBS that will reduce vaginal colonization, prevent transmission to the neonate, and reduce overall morbidity.

The testing of potential vaccines is a logistical challenge, however, “because the incidence of neonatal sepsis is so low,” Dr. Hillier said. “Even if an effective vaccine is developed, it would require more than 100,000 participants to achieve an even modestly powered vaccine trial.”

In an effort to uncover surrogate end points for measuring GBS vaccine efficacy, Dr. Hillier and her colleagues designed the current study to evaluate the impact of naturally acquired antibodies on GBS acquisition, based on data from Haemophilus influenzae type b (Hib) vaccine research demonstrating that the Hib vaccine not only decreases Hib infection, but also reduces nasopharyngeal Hib colonization. As with GBS, a crucial factor in Hib virulence is the production of an antigenically variable polysaccharide capsule, she noted.

To test their hypothesis, the investigators enrolled 1,248 sexually active nonpregnant women aged 18–30 years in the study. At quarterly visits during the course of the study year, serum was collected from each of the women for evaluation of type-specific IgG antibody against the most common GBS serotypes. In addition, vaginal cultures were performed using selective broth medium for GBS; demographic and behavioral information, and vaginal flora assessments were also obtained. Based on the results from 1,089 women who returned for the quarterly visits, 973 women-years of follow-up were collected, Dr. Hillier said.

The median age of the predominantly white (61% vs. 35% black) study population was 21 years. “We specifically targeted younger women because of their higher level of sexual activity and increased incidence of GBS sepsis,” Dr. Hillier noted.

During the evaluation period, the investigators recorded 298 GBS acquisitions, including 111 of serotype Ia, 26 of serotype II, 116 of serotype III, and 45 of serotype V, Dr. Hillier reported. Within and across the serotypes, “there was a strong association between the concentration of humeral antibody and acquisition of GBS,” said Dr. Hillier, noting that overall, 61% of the GBS acquisitions occurred among women with 0.5 mcg/mL or less serum antibody to the respective serotype, while only 5% occurred among women with 3.0–5.0 mcg/mL of serum antibody.

“There was a strong relationship between the concentration of humeral antibody in the visit before the acquisition of GBS and the protective effect against acquisition,” Dr. Hillier explained. “In type Ia, for example, about 50% of the GBS acquisitions occurred in women who had less than 0.5 mcg/mL of humeral antibody against type Ia at the previous visit.” Similar percentages were observed for the other serotypes, she said. The linear association between concentration of antibody and acquisition of GBS was especially robust in serotype III, which is one of the most common serotypes that colonize women, she said.

The results of an adjusted hazards ratio using a Cox proportional hazards model for vaginal type III GBS acquisition showed a 70% reduction in acquisition of type III GBS among women with high levels of type III antibodies, said Dr. Hillier, noting that the independent association was consistent across multiple models.

“This finding leads us to believe that vaccination to induce high levels of serum antibody to type III GBS may result in decreased vaginal colonization of that serotype,” Dr. Hillier said. To test this, she and her colleagues are currently conducting a National Institutes of Health-funded phase II randomized, double-blind clinical trial called SPIN (Streptococcal Prevention in Nonpregnant Women) of 50-mcg type III GBS polysaccharide-tetanus toxoid conjugate vaccine.

“This will be the study to answer the question of whether or not induced antibody can provide colonization resistance to GBS,” she said. “If the answer is yes, it may allow us to move forward in vaccine development in GBS because we can use colonization as a surrogate end point.”

'There was a strong association between the concentration of humeral antibody and acquisition of GBS.' DR. HILLIER

BOSTON — Women with increased levels of type-specific serum antibody against group B streptococci may be protected from vaginal colonization by those serotypes, a study has shown.

The findings support current efforts to develop a vaccine to decrease vaginal acquisition and fetal transmission of the bacteria, lead investigator Dr. Sharon Hillier said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

It has long been recognized that vaginal colonization by group B streptococci (GBS) is probably the single most important risk factor for neonatal sepsis, and while wider use of prophylactic intrapartum antibiotics has led to a substantial decline in the incidence of GBS infection in newborns, “a lot of women do develop amniotic fluid infections, preterm delivery, or even pregnancy loss” due to the bacteria, said Dr. Hillier of the University of Pittsburgh's Magee-Women's Hospital. “We really haven't understood why women become vaginally colonized with GBS, and we have few options for interrupting vaginal colonization. Prophylactic antibiotic treatment has been useful as an interim strategy, but it is just that—an interim strategy.”

The longer-term objective, she said, is to develop a vaccine against GBS that will reduce vaginal colonization, prevent transmission to the neonate, and reduce overall morbidity.

The testing of potential vaccines is a logistical challenge, however, “because the incidence of neonatal sepsis is so low,” Dr. Hillier said. “Even if an effective vaccine is developed, it would require more than 100,000 participants to achieve an even modestly powered vaccine trial.”

In an effort to uncover surrogate end points for measuring GBS vaccine efficacy, Dr. Hillier and her colleagues designed the current study to evaluate the impact of naturally acquired antibodies on GBS acquisition, based on data from Haemophilus influenzae type b (Hib) vaccine research demonstrating that the Hib vaccine not only decreases Hib infection, but also reduces nasopharyngeal Hib colonization. As with GBS, a crucial factor in Hib virulence is the production of an antigenically variable polysaccharide capsule, she noted.

To test their hypothesis, the investigators enrolled 1,248 sexually active nonpregnant women aged 18–30 years in the study. At quarterly visits during the course of the study year, serum was collected from each of the women for evaluation of type-specific IgG antibody against the most common GBS serotypes. In addition, vaginal cultures were performed using selective broth medium for GBS; demographic and behavioral information, and vaginal flora assessments were also obtained. Based on the results from 1,089 women who returned for the quarterly visits, 973 women-years of follow-up were collected, Dr. Hillier said.

The median age of the predominantly white (61% vs. 35% black) study population was 21 years. “We specifically targeted younger women because of their higher level of sexual activity and increased incidence of GBS sepsis,” Dr. Hillier noted.

During the evaluation period, the investigators recorded 298 GBS acquisitions, including 111 of serotype Ia, 26 of serotype II, 116 of serotype III, and 45 of serotype V, Dr. Hillier reported. Within and across the serotypes, “there was a strong association between the concentration of humeral antibody and acquisition of GBS,” said Dr. Hillier, noting that overall, 61% of the GBS acquisitions occurred among women with 0.5 mcg/mL or less serum antibody to the respective serotype, while only 5% occurred among women with 3.0–5.0 mcg/mL of serum antibody.

“There was a strong relationship between the concentration of humeral antibody in the visit before the acquisition of GBS and the protective effect against acquisition,” Dr. Hillier explained. “In type Ia, for example, about 50% of the GBS acquisitions occurred in women who had less than 0.5 mcg/mL of humeral antibody against type Ia at the previous visit.” Similar percentages were observed for the other serotypes, she said. The linear association between concentration of antibody and acquisition of GBS was especially robust in serotype III, which is one of the most common serotypes that colonize women, she said.

The results of an adjusted hazards ratio using a Cox proportional hazards model for vaginal type III GBS acquisition showed a 70% reduction in acquisition of type III GBS among women with high levels of type III antibodies, said Dr. Hillier, noting that the independent association was consistent across multiple models.

“This finding leads us to believe that vaccination to induce high levels of serum antibody to type III GBS may result in decreased vaginal colonization of that serotype,” Dr. Hillier said. To test this, she and her colleagues are currently conducting a National Institutes of Health-funded phase II randomized, double-blind clinical trial called SPIN (Streptococcal Prevention in Nonpregnant Women) of 50-mcg type III GBS polysaccharide-tetanus toxoid conjugate vaccine.

“This will be the study to answer the question of whether or not induced antibody can provide colonization resistance to GBS,” she said. “If the answer is yes, it may allow us to move forward in vaccine development in GBS because we can use colonization as a surrogate end point.”

'There was a strong association between the concentration of humeral antibody and acquisition of GBS.' DR. HILLIER

BOSTON — Women with increased levels of type-specific serum antibody against group B streptococci may be protected from vaginal colonization by those serotypes, a study has shown.

The findings support current efforts to develop a vaccine to decrease vaginal acquisition and fetal transmission of the bacteria, lead investigator Dr. Sharon Hillier said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

It has long been recognized that vaginal colonization by group B streptococci (GBS) is probably the single most important risk factor for neonatal sepsis, and while wider use of prophylactic intrapartum antibiotics has led to a substantial decline in the incidence of GBS infection in newborns, “a lot of women do develop amniotic fluid infections, preterm delivery, or even pregnancy loss” due to the bacteria, said Dr. Hillier of the University of Pittsburgh's Magee-Women's Hospital. “We really haven't understood why women become vaginally colonized with GBS, and we have few options for interrupting vaginal colonization. Prophylactic antibiotic treatment has been useful as an interim strategy, but it is just that—an interim strategy.”

The longer-term objective, she said, is to develop a vaccine against GBS that will reduce vaginal colonization, prevent transmission to the neonate, and reduce overall morbidity.

The testing of potential vaccines is a logistical challenge, however, “because the incidence of neonatal sepsis is so low,” Dr. Hillier said. “Even if an effective vaccine is developed, it would require more than 100,000 participants to achieve an even modestly powered vaccine trial.”

In an effort to uncover surrogate end points for measuring GBS vaccine efficacy, Dr. Hillier and her colleagues designed the current study to evaluate the impact of naturally acquired antibodies on GBS acquisition, based on data from Haemophilus influenzae type b (Hib) vaccine research demonstrating that the Hib vaccine not only decreases Hib infection, but also reduces nasopharyngeal Hib colonization. As with GBS, a crucial factor in Hib virulence is the production of an antigenically variable polysaccharide capsule, she noted.

To test their hypothesis, the investigators enrolled 1,248 sexually active nonpregnant women aged 18–30 years in the study. At quarterly visits during the course of the study year, serum was collected from each of the women for evaluation of type-specific IgG antibody against the most common GBS serotypes. In addition, vaginal cultures were performed using selective broth medium for GBS; demographic and behavioral information, and vaginal flora assessments were also obtained. Based on the results from 1,089 women who returned for the quarterly visits, 973 women-years of follow-up were collected, Dr. Hillier said.

The median age of the predominantly white (61% vs. 35% black) study population was 21 years. “We specifically targeted younger women because of their higher level of sexual activity and increased incidence of GBS sepsis,” Dr. Hillier noted.

During the evaluation period, the investigators recorded 298 GBS acquisitions, including 111 of serotype Ia, 26 of serotype II, 116 of serotype III, and 45 of serotype V, Dr. Hillier reported. Within and across the serotypes, “there was a strong association between the concentration of humeral antibody and acquisition of GBS,” said Dr. Hillier, noting that overall, 61% of the GBS acquisitions occurred among women with 0.5 mcg/mL or less serum antibody to the respective serotype, while only 5% occurred among women with 3.0–5.0 mcg/mL of serum antibody.

“There was a strong relationship between the concentration of humeral antibody in the visit before the acquisition of GBS and the protective effect against acquisition,” Dr. Hillier explained. “In type Ia, for example, about 50% of the GBS acquisitions occurred in women who had less than 0.5 mcg/mL of humeral antibody against type Ia at the previous visit.” Similar percentages were observed for the other serotypes, she said. The linear association between concentration of antibody and acquisition of GBS was especially robust in serotype III, which is one of the most common serotypes that colonize women, she said.

The results of an adjusted hazards ratio using a Cox proportional hazards model for vaginal type III GBS acquisition showed a 70% reduction in acquisition of type III GBS among women with high levels of type III antibodies, said Dr. Hillier, noting that the independent association was consistent across multiple models.

“This finding leads us to believe that vaccination to induce high levels of serum antibody to type III GBS may result in decreased vaginal colonization of that serotype,” Dr. Hillier said. To test this, she and her colleagues are currently conducting a National Institutes of Health-funded phase II randomized, double-blind clinical trial called SPIN (Streptococcal Prevention in Nonpregnant Women) of 50-mcg type III GBS polysaccharide-tetanus toxoid conjugate vaccine.

“This will be the study to answer the question of whether or not induced antibody can provide colonization resistance to GBS,” she said. “If the answer is yes, it may allow us to move forward in vaccine development in GBS because we can use colonization as a surrogate end point.”

'There was a strong association between the concentration of humeral antibody and acquisition of GBS.' DR. HILLIER

BOSTON — Women with increased levels of type-specific serum antibody against group B streptococci may be protected from vaginal colonization by those serotypes, a study has shown.

The findings support current efforts to develop a vaccine to decrease vaginal acquisition and fetal transmission of the bacteria, lead investigator Dr. Sharon Hillier said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

It has long been recognized that vaginal colonization by group B streptococci (GBS) is probably the single most important risk factor for neonatal sepsis, and while wider use of prophylactic intrapartum antibiotics has led to a substantial decline in the incidence of GBS infection in newborns, “a lot of women do develop amniotic fluid infections, preterm delivery, or even pregnancy loss due to [the bacteria],” said Dr. Hillier of the University of Pittsburgh's Magee-Women's Hospital. “We really haven't understood why women become vaginally colonized with GBS and we have few options for interrupting vaginal colonization. Prophylactic antibiotic treatment has been useful as an interim strategy, but it is just that—an interim strategy.” The longer-term objective, she said, is to develop a vaccine against GBS that will reduce vaginal colonization, prevent transmission to the neonate, and reduce overall morbidity.

The testing of potential vaccines is a logistical challenge, however, “because the incidence of neonatal sepsis is so low,” Dr. Hillier said. “Even if an effective vaccine is developed, it would require more than 100,000 participants to achieve an even modestly powered vaccine trial.”

In an effort to uncover surrogate end points for measuring GBS vaccine efficacy, Dr. Hillier and her colleagues designed the current study to evaluate the impact of naturally acquired antibodies on GBS acquisition, based on data from Haemophilus influenzae type b (Hib) vaccine research demonstrating that the Hib vaccine not only decreases Hib infection, but also reduces nasopharyngeal Hib colonization. As with GBS, a crucial factor in Hib virulence is the production of an antigenically variable polysaccharide capsule, she noted.

To test their hypothesis, the investigators enrolled 1,248 sexually active nonpregnant women aged 18–30 years in the study. At quarterly visits during the course of the study year, serum was collected from each of the women for evaluation of type-specific IgG antibody against the most common GBS serotypes. In addition, vaginal cultures were performed using selective broth medium for GBS; demographic and behavioral information, and vaginal flora assessments were also obtained. Based on the results from 1,089 women who returned for the quarterly visits, 973 women-years of follow-up were collected, said Dr. Hillier.

The median age of the predominantly white (61% vs. 35% black) study population was 21 years. “We specifically targeted younger women because of their higher level of sexual activity and increased incidence of GBS sepsis,” noted Dr. Hillier.

During the evaluation period, the investigators recorded 298 GBS acquisitions, including 111 of serotype Ia, 26 of serotype II, 116 of serotype III, and 45 of serotype V, Dr. Hillier reported. Within and across the serotypes, “there was a strong association between the concentration of humeral antibody and acquisition of GBS,” said Dr. Hillier, noting that overall, 61% of the GBS acquisitions occurred among women with 0.5 mcg/mL or less serum antibody to the respective serotype, while only 5% occurred among women with 3.0–5.0 mcg/mL of serum antibody.

“There was a strong relationship between the concentration of humeral antibody in the visit before the acquisition of GBS and the protective effect against acquisition,” Dr. Hillier explained. “In type Ia, for example, about 50% of the GBS acquisitions occurred in women who had less than 0.5 mcg/mL of humeral antibody against type Ia at the previous visit.” Similar percentages were observed for the other serotypes, she said, noting that the linear association between concentration of antibody and acquisition of GBS was especially robust in serotype III, one of the most common serotypes that colonize women.

The results of an adjusted hazards ratio using a Cox proportional hazards model for vaginal type III GBS acquisition showed a 70% reduction in acquisition of type III GBS among women with high levels of type III antibodies, said Dr. Hillier, noting that the independent association was consistent across multiple models.

“This finding leads us to believe that vaccination to induce high levels of serum antibody to type III GBS may result in decreased vaginal colonization of that serotype,” said Dr. Hillier. To test this, she and her colleagues are conducting a National Institutes of Health-funded phase II randomized, double-blind clinical trial called SPIN (Streptococcal Prevention in Nonpregnant Women) of 50-mcg type III GBS polysaccharide-tetanus toxoid conjugate vaccine.

“This will be the study to answer the question of whether or not induced antibody can provide colonization resistance to GBS,” she said. “If the answer is yes, it may allow us to move forward in vaccine development in GBS because we can use colonization as a surrogate end point.”

BOSTON — Women with increased levels of type-specific serum antibody against group B streptococci may be protected from vaginal colonization by those serotypes, a study has shown.

The findings support current efforts to develop a vaccine to decrease vaginal acquisition and fetal transmission of the bacteria, lead investigator Dr. Sharon Hillier said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

It has long been recognized that vaginal colonization by group B streptococci (GBS) is probably the single most important risk factor for neonatal sepsis, and while wider use of prophylactic intrapartum antibiotics has led to a substantial decline in the incidence of GBS infection in newborns, “a lot of women do develop amniotic fluid infections, preterm delivery, or even pregnancy loss due to [the bacteria],” said Dr. Hillier of the University of Pittsburgh's Magee-Women's Hospital. “We really haven't understood why women become vaginally colonized with GBS and we have few options for interrupting vaginal colonization. Prophylactic antibiotic treatment has been useful as an interim strategy, but it is just that—an interim strategy.” The longer-term objective, she said, is to develop a vaccine against GBS that will reduce vaginal colonization, prevent transmission to the neonate, and reduce overall morbidity.

The testing of potential vaccines is a logistical challenge, however, “because the incidence of neonatal sepsis is so low,” Dr. Hillier said. “Even if an effective vaccine is developed, it would require more than 100,000 participants to achieve an even modestly powered vaccine trial.”

In an effort to uncover surrogate end points for measuring GBS vaccine efficacy, Dr. Hillier and her colleagues designed the current study to evaluate the impact of naturally acquired antibodies on GBS acquisition, based on data from Haemophilus influenzae type b (Hib) vaccine research demonstrating that the Hib vaccine not only decreases Hib infection, but also reduces nasopharyngeal Hib colonization. As with GBS, a crucial factor in Hib virulence is the production of an antigenically variable polysaccharide capsule, she noted.

To test their hypothesis, the investigators enrolled 1,248 sexually active nonpregnant women aged 18–30 years in the study. At quarterly visits during the course of the study year, serum was collected from each of the women for evaluation of type-specific IgG antibody against the most common GBS serotypes. In addition, vaginal cultures were performed using selective broth medium for GBS; demographic and behavioral information, and vaginal flora assessments were also obtained. Based on the results from 1,089 women who returned for the quarterly visits, 973 women-years of follow-up were collected, said Dr. Hillier.

The median age of the predominantly white (61% vs. 35% black) study population was 21 years. “We specifically targeted younger women because of their higher level of sexual activity and increased incidence of GBS sepsis,” noted Dr. Hillier.

During the evaluation period, the investigators recorded 298 GBS acquisitions, including 111 of serotype Ia, 26 of serotype II, 116 of serotype III, and 45 of serotype V, Dr. Hillier reported. Within and across the serotypes, “there was a strong association between the concentration of humeral antibody and acquisition of GBS,” said Dr. Hillier, noting that overall, 61% of the GBS acquisitions occurred among women with 0.5 mcg/mL or less serum antibody to the respective serotype, while only 5% occurred among women with 3.0–5.0 mcg/mL of serum antibody.

“There was a strong relationship between the concentration of humeral antibody in the visit before the acquisition of GBS and the protective effect against acquisition,” Dr. Hillier explained. “In type Ia, for example, about 50% of the GBS acquisitions occurred in women who had less than 0.5 mcg/mL of humeral antibody against type Ia at the previous visit.” Similar percentages were observed for the other serotypes, she said, noting that the linear association between concentration of antibody and acquisition of GBS was especially robust in serotype III, one of the most common serotypes that colonize women.

The results of an adjusted hazards ratio using a Cox proportional hazards model for vaginal type III GBS acquisition showed a 70% reduction in acquisition of type III GBS among women with high levels of type III antibodies, said Dr. Hillier, noting that the independent association was consistent across multiple models.

“This finding leads us to believe that vaccination to induce high levels of serum antibody to type III GBS may result in decreased vaginal colonization of that serotype,” said Dr. Hillier. To test this, she and her colleagues are conducting a National Institutes of Health-funded phase II randomized, double-blind clinical trial called SPIN (Streptococcal Prevention in Nonpregnant Women) of 50-mcg type III GBS polysaccharide-tetanus toxoid conjugate vaccine.

“This will be the study to answer the question of whether or not induced antibody can provide colonization resistance to GBS,” she said. “If the answer is yes, it may allow us to move forward in vaccine development in GBS because we can use colonization as a surrogate end point.”

BOSTON — Women with increased levels of type-specific serum antibody against group B streptococci may be protected from vaginal colonization by those serotypes, a study has shown.

The findings support current efforts to develop a vaccine to decrease vaginal acquisition and fetal transmission of the bacteria, lead investigator Dr. Sharon Hillier said at the annual meeting of the Infectious Diseases Society for Obstetrics and Gynecology.

It has long been recognized that vaginal colonization by group B streptococci (GBS) is probably the single most important risk factor for neonatal sepsis, and while wider use of prophylactic intrapartum antibiotics has led to a substantial decline in the incidence of GBS infection in newborns, “a lot of women do develop amniotic fluid infections, preterm delivery, or even pregnancy loss due to [the bacteria],” said Dr. Hillier of the University of Pittsburgh's Magee-Women's Hospital. “We really haven't understood why women become vaginally colonized with GBS and we have few options for interrupting vaginal colonization. Prophylactic antibiotic treatment has been useful as an interim strategy, but it is just that—an interim strategy.” The longer-term objective, she said, is to develop a vaccine against GBS that will reduce vaginal colonization, prevent transmission to the neonate, and reduce overall morbidity.

The testing of potential vaccines is a logistical challenge, however, “because the incidence of neonatal sepsis is so low,” Dr. Hillier said. “Even if an effective vaccine is developed, it would require more than 100,000 participants to achieve an even modestly powered vaccine trial.”

In an effort to uncover surrogate end points for measuring GBS vaccine efficacy, Dr. Hillier and her colleagues designed the current study to evaluate the impact of naturally acquired antibodies on GBS acquisition, based on data from Haemophilus influenzae type b (Hib) vaccine research demonstrating that the Hib vaccine not only decreases Hib infection, but also reduces nasopharyngeal Hib colonization. As with GBS, a crucial factor in Hib virulence is the production of an antigenically variable polysaccharide capsule, she noted.

To test their hypothesis, the investigators enrolled 1,248 sexually active nonpregnant women aged 18–30 years in the study. At quarterly visits during the course of the study year, serum was collected from each of the women for evaluation of type-specific IgG antibody against the most common GBS serotypes. In addition, vaginal cultures were performed using selective broth medium for GBS; demographic and behavioral information, and vaginal flora assessments were also obtained. Based on the results from 1,089 women who returned for the quarterly visits, 973 women-years of follow-up were collected, said Dr. Hillier.

The median age of the predominantly white (61% vs. 35% black) study population was 21 years. “We specifically targeted younger women because of their higher level of sexual activity and increased incidence of GBS sepsis,” noted Dr. Hillier.

During the evaluation period, the investigators recorded 298 GBS acquisitions, including 111 of serotype Ia, 26 of serotype II, 116 of serotype III, and 45 of serotype V, Dr. Hillier reported. Within and across the serotypes, “there was a strong association between the concentration of humeral antibody and acquisition of GBS,” said Dr. Hillier, noting that overall, 61% of the GBS acquisitions occurred among women with 0.5 mcg/mL or less serum antibody to the respective serotype, while only 5% occurred among women with 3.0–5.0 mcg/mL of serum antibody.

“There was a strong relationship between the concentration of humeral antibody in the visit before the acquisition of GBS and the protective effect against acquisition,” Dr. Hillier explained. “In type Ia, for example, about 50% of the GBS acquisitions occurred in women who had less than 0.5 mcg/mL of humeral antibody against type Ia at the previous visit.” Similar percentages were observed for the other serotypes, she said, noting that the linear association between concentration of antibody and acquisition of GBS was especially robust in serotype III, one of the most common serotypes that colonize women.

The results of an adjusted hazards ratio using a Cox proportional hazards model for vaginal type III GBS acquisition showed a 70% reduction in acquisition of type III GBS among women with high levels of type III antibodies, said Dr. Hillier, noting that the independent association was consistent across multiple models.

“This finding leads us to believe that vaccination to induce high levels of serum antibody to type III GBS may result in decreased vaginal colonization of that serotype,” said Dr. Hillier. To test this, she and her colleagues are conducting a National Institutes of Health-funded phase II randomized, double-blind clinical trial called SPIN (Streptococcal Prevention in Nonpregnant Women) of 50-mcg type III GBS polysaccharide-tetanus toxoid conjugate vaccine.

“This will be the study to answer the question of whether or not induced antibody can provide colonization resistance to GBS,” she said. “If the answer is yes, it may allow us to move forward in vaccine development in GBS because we can use colonization as a surrogate end point.”

BOSTON— To differentiate definitively between acute gout and pseudogout, look at the crystals.

On UV light microscopy, fluid aspirated from the inflamed joint of a patient with pseudogout will be teeming with rhomboid-shaped calcium pyrophosphate dihydrate (CPPD) crystals, which are morphologically different from the needle-shaped monosodium urate (MSU) crystals implicated in the pain and swelling of acute gout, Dr. Dwight R. Robinson said at a meeting on rheumatology sponsored by Harvard Medical School. “Calcium pyrophosphate dihydrate crystals are less well formed and show more variation in size and shape than monosodium urate crystals. In that way, they are a little more difficult to identify.”

Like MSU crystals in the joints of gout patients, the deposition of CPPD crystals in pseudogout causes acute pain and swelling in one or multiple joints. The acute attacks can last anywhere from 1 day to 4 weeks and sometimes are accompanied by fever, leukocytosis, and elevated acute-phase reactants said Dr. Robinson, a rheumatologist and professor of medicine at Harvard Medical School, Boston. Because the latter signs also may be indicative of septic arthritis, sepsis first must be excluded by gram stain and culture of synovial fluid.

In general, CPPD crystals have a predilection for depositing in articular and fibrocartilage, said Dr. Robinson. In pseudogout, this process commonly involves the knee or wrist joint but also may involve the first metatarsophalangeal joint, as occurs in gout, or almost any other joint, he said. Radiographically, the diagnosis of pseudogout often can be confirmed by evidence of chondrocalcinosis in the affected joint space.

In addition to mimicking the clinical patterns of gout, the symptoms of CPPD joint disease may overlap with other inflammatory conditions. “The disease may present as pseudorheumatoid arthritis, pseudo-osteoarthritis with or without pseudogout, or pseudoneuropathic arthritis,” said Dr. Robinson. “In many patients, the condition is actually asymptomatic.”

CPPD disease develops idiopathically in individuals older than age 50. In younger patients, “it's more likely to be a complication of osteoarthritis, a late consequence of joint trauma or knee meniscectomy, or related to an underlying metabolic disease, such as hyperparathyroidism, dialysis-dependent renal failure, hemochromatosis, and hypomagnesemia,” said Dr. Robinson, noting that there also may be a familial component.

Although the exact mechanism for the development of CPPD deposition disease is uncertain, an overactivity of enzymes that break down nucleoside triphosphates has been implicated, as have genetic defects, specifically mutations in the human homologue of the murine ANK gene. “Several mutations in the [human homologue] may be responsible for human disease, including CPPD arthropath,” said Dr. Robinson.

There currently are no proven prophylactic therapies for pseudogout, but acute attacks can be treated effectively with, primarily, nonsteroidal anti-inflammatory drugs, said Dr. Robinson. Given the risks of gastrointestinal and renal toxicities associated with NSAIDs, particularly in elderly patients, intra-articular corticosteroid injection into the affected joint is a reasonable treatment option, he said, as is a short course of systemic corticosteroids for polyarticular pseudogout attacks. Oral or intravenous colchicine should be considered only as a treatment of last resort because of the associated risks of gastrointestinal and other toxicities.

BOSTON— To differentiate definitively between acute gout and pseudogout, look at the crystals.

On UV light microscopy, fluid aspirated from the inflamed joint of a patient with pseudogout will be teeming with rhomboid-shaped calcium pyrophosphate dihydrate (CPPD) crystals, which are morphologically different from the needle-shaped monosodium urate (MSU) crystals implicated in the pain and swelling of acute gout, Dr. Dwight R. Robinson said at a meeting on rheumatology sponsored by Harvard Medical School. “Calcium pyrophosphate dihydrate crystals are less well formed and show more variation in size and shape than monosodium urate crystals. In that way, they are a little more difficult to identify.”

Like MSU crystals in the joints of gout patients, the deposition of CPPD crystals in pseudogout causes acute pain and swelling in one or multiple joints. The acute attacks can last anywhere from 1 day to 4 weeks and sometimes are accompanied by fever, leukocytosis, and elevated acute-phase reactants said Dr. Robinson, a rheumatologist and professor of medicine at Harvard Medical School, Boston. Because the latter signs also may be indicative of septic arthritis, sepsis first must be excluded by gram stain and culture of synovial fluid.

In general, CPPD crystals have a predilection for depositing in articular and fibrocartilage, said Dr. Robinson. In pseudogout, this process commonly involves the knee or wrist joint but also may involve the first metatarsophalangeal joint, as occurs in gout, or almost any other joint, he said. Radiographically, the diagnosis of pseudogout often can be confirmed by evidence of chondrocalcinosis in the affected joint space.

In addition to mimicking the clinical patterns of gout, the symptoms of CPPD joint disease may overlap with other inflammatory conditions. “The disease may present as pseudorheumatoid arthritis, pseudo-osteoarthritis with or without pseudogout, or pseudoneuropathic arthritis,” said Dr. Robinson. “In many patients, the condition is actually asymptomatic.”

CPPD disease develops idiopathically in individuals older than age 50. In younger patients, “it's more likely to be a complication of osteoarthritis, a late consequence of joint trauma or knee meniscectomy, or related to an underlying metabolic disease, such as hyperparathyroidism, dialysis-dependent renal failure, hemochromatosis, and hypomagnesemia,” said Dr. Robinson, noting that there also may be a familial component.

Although the exact mechanism for the development of CPPD deposition disease is uncertain, an overactivity of enzymes that break down nucleoside triphosphates has been implicated, as have genetic defects, specifically mutations in the human homologue of the murine ANK gene. “Several mutations in the [human homologue] may be responsible for human disease, including CPPD arthropath,” said Dr. Robinson.

There currently are no proven prophylactic therapies for pseudogout, but acute attacks can be treated effectively with, primarily, nonsteroidal anti-inflammatory drugs, said Dr. Robinson. Given the risks of gastrointestinal and renal toxicities associated with NSAIDs, particularly in elderly patients, intra-articular corticosteroid injection into the affected joint is a reasonable treatment option, he said, as is a short course of systemic corticosteroids for polyarticular pseudogout attacks. Oral or intravenous colchicine should be considered only as a treatment of last resort because of the associated risks of gastrointestinal and other toxicities.

BOSTON— To differentiate definitively between acute gout and pseudogout, look at the crystals.

On UV light microscopy, fluid aspirated from the inflamed joint of a patient with pseudogout will be teeming with rhomboid-shaped calcium pyrophosphate dihydrate (CPPD) crystals, which are morphologically different from the needle-shaped monosodium urate (MSU) crystals implicated in the pain and swelling of acute gout, Dr. Dwight R. Robinson said at a meeting on rheumatology sponsored by Harvard Medical School. “Calcium pyrophosphate dihydrate crystals are less well formed and show more variation in size and shape than monosodium urate crystals. In that way, they are a little more difficult to identify.”

Like MSU crystals in the joints of gout patients, the deposition of CPPD crystals in pseudogout causes acute pain and swelling in one or multiple joints. The acute attacks can last anywhere from 1 day to 4 weeks and sometimes are accompanied by fever, leukocytosis, and elevated acute-phase reactants said Dr. Robinson, a rheumatologist and professor of medicine at Harvard Medical School, Boston. Because the latter signs also may be indicative of septic arthritis, sepsis first must be excluded by gram stain and culture of synovial fluid.

In general, CPPD crystals have a predilection for depositing in articular and fibrocartilage, said Dr. Robinson. In pseudogout, this process commonly involves the knee or wrist joint but also may involve the first metatarsophalangeal joint, as occurs in gout, or almost any other joint, he said. Radiographically, the diagnosis of pseudogout often can be confirmed by evidence of chondrocalcinosis in the affected joint space.

In addition to mimicking the clinical patterns of gout, the symptoms of CPPD joint disease may overlap with other inflammatory conditions. “The disease may present as pseudorheumatoid arthritis, pseudo-osteoarthritis with or without pseudogout, or pseudoneuropathic arthritis,” said Dr. Robinson. “In many patients, the condition is actually asymptomatic.”

CPPD disease develops idiopathically in individuals older than age 50. In younger patients, “it's more likely to be a complication of osteoarthritis, a late consequence of joint trauma or knee meniscectomy, or related to an underlying metabolic disease, such as hyperparathyroidism, dialysis-dependent renal failure, hemochromatosis, and hypomagnesemia,” said Dr. Robinson, noting that there also may be a familial component.

Although the exact mechanism for the development of CPPD deposition disease is uncertain, an overactivity of enzymes that break down nucleoside triphosphates has been implicated, as have genetic defects, specifically mutations in the human homologue of the murine ANK gene. “Several mutations in the [human homologue] may be responsible for human disease, including CPPD arthropath,” said Dr. Robinson.

There currently are no proven prophylactic therapies for pseudogout, but acute attacks can be treated effectively with, primarily, nonsteroidal anti-inflammatory drugs, said Dr. Robinson. Given the risks of gastrointestinal and renal toxicities associated with NSAIDs, particularly in elderly patients, intra-articular corticosteroid injection into the affected joint is a reasonable treatment option, he said, as is a short course of systemic corticosteroids for polyarticular pseudogout attacks. Oral or intravenous colchicine should be considered only as a treatment of last resort because of the associated risks of gastrointestinal and other toxicities.

In the absence of pathologic gastroesophageal reflux disease, young children with esophageal symptoms or feeding problems and older children and adults with dysphagia or esophageal food impaction should be evaluated for eosinophilic esophagitis, particularly if their symptoms are unresponsive or only partially responsive to acid blockade, according to a new consensus report on the inflammatory gastroesophageal disorder. The report appears in the October 2007 issue of Gastroenterology.

Characterized by a range of gastrointestinal symptoms including abdominal pain, nausea, regurgitation, and/or vomiting along with severely elevated levels of eosinophils, eosinophilic esophagitis (EE) is an “enigmatic” disease that is frequently mistaken for gastroesophageal reflux disease (GERD), said Dr. Glenn T. Furuta, cochair of the First International Gastrointestinal Eosinophilic Research Symposium (FIGERS), from which the consensus report was generated.

Because EE and GERD require different treatment strategies and are associated with different long-term consequences, distinguishing between the two is critical, but doing so has been hindered by the absence of definitive diagnostic and treatment guidelines for EE, said Dr. Furuta of Children's Hospital of Denver. “The consensus report is the best first step in providing outstanding care to children and adults who are affected by this newly recognized disease,” he said in an interview.

Developed through the collaboration of 32 physicians from multiple disciplines, including pediatric and adult gastroenterology, allergy, and pathology, the consensus report is based on a systematic review of data from 80 studies published between 1977 and 2006 including 754 children and 323 adults, as well as expert opinion.

Among the most important features of the report are its diagnostic guidelines, Dr. Furuta said. In this regard, “the report states that affected patients should have symptoms referable to the esophagus that occur in combination with greater than or equal to 15 eosinophils per high-powered field in the esophageal mucosa with normal gastric and duodenal mucosa,” he said. “Most importantly, GERD must have been ruled out as a cause of these findings.”

The available data on the natural history of the disease suggest that EE is a chronic condition with persistent or relapsing symptoms. “To date, esophageal strictures and small caliber esophagus, often resulting in food impaction, have been the major complications identified,” the authors wrote in the report. “When these findings are encountered, either radiologically or at endoscopy, a high index of suspicion should be raised for EE and mucosal biopsies should be obtained.”

Importantly, mucosal pinch biopsies are recommended for all patients in whom eosinophilic esophagitis is in the differential diagnosis, regardless of the gross appearance of the mucosa, the authors wrote. Additionally, multiple biopsies should be obtained from different esophageal locations along the length of the esophagus, and they should be obtained from the stomach and duodenum to rule out other gastrointestinal diseases, they stated.

When endoscopy and biopsy do not provide sufficient information to distinguish between GERD and eosinophilic esophagitis, “intraesophageal pH monitoring may be of use in excluding pathologic reflux as either the primary or a concomitant cause for esophageal eosinophilia,” according to the report. “Alternatively, an upper endoscopy after 6–8 weeks of high-dose proton pump inhibitor treatment can help determine the etiology of esophageal eosinophilia.”

Regarding diagnostic histopathology, based on the available data and the panel's collective clinical experience, “we conclude that a peak count of 15 intraepithelial eosinophils per high-powered field is an absolute minimum number to make the diagnosis of EE in the proper clinical context,” they wrote. For research purposes, it may be useful to use a higher threshold of peak eosinophils in order to increase the specificity of the diagnosis, they noted.

Additional histopathologic features that, while not pathognomonic, may be helpful in establishing a diagnosis, are eosinophil microabscesses, surface layering of eosinophils, basal layer hyperplasia, papillary lengthening, degranulating eosino- phils, and lamina propria fibrosis and inflammation, according to the report.

In terms of treating the disease, dietary therapy in particular should be considered in all children diagnosed with the condition, as there is strong circumstantial evidence that food allergens contribute to the pathogenesis of the disease in children. In fact, “the removal of food antigens has clearly been demonstrated to successfully treat both the symptoms and the underlying histopathology in the majority of patients with EE,” the authors wrote. Toward this end, allergy testing and clinical history can help guide specific food elimination, they stated, adding that consultation with a registered dietitian is advisable to ensure that proper nutrition is maintained.

Corticosteroids can effectively resolve acute clinicopathologic features of EE, but the disease typically recurs when the steroids are stopped. And while systemic corticosteroids have a role in emergent cases, including dysphagia requiring hospitalization, dehydration because of swallowing difficulties, and weight loss, the potential for significant toxicity over time should preclude their long-term use, the authors stated. Topical corticosteroids have also shown some efficacy and are associated with fewer side effects, they noted.

Although gastric acid is not thought to be the primary mediator of EE, acid suppression may be considered as cotherapy in patients with established disease who have symptoms secondary to GERD.

For patients who present with symptomatic esophageal narrowing secondary to fixed strictures causing food impaction, esophageal dilatation may be a useful treatment option, the authors wrote. To minimize the risk of mucosal tearing and perforation, however, “a diagnostic endoscopy with biopsy followed by medical or dietary therapy for EE should be attempted prior to performing esophageal dilatation,” they stressed. And the esophagus should be inspected, either radiographically or by gentle endoscopic examination, after dilation to assess for laceration injury before performing larger caliber dilation.

Biologic agents that specifically target eosinophil activity may present a unique treatment opportunity for some patients with EE; however, they cannot yet be recommended for routine use given the lack of clinical trial data to date, according to the authors.

“The motivating factor for treating all patients should be symptom relief and prevention of complications of esophageal strictures and long-segment narrowing,” said Dr. Furuta.

In the absence of pathologic gastroesophageal reflux disease, young children with esophageal symptoms or feeding problems and older children and adults with dysphagia or esophageal food impaction should be evaluated for eosinophilic esophagitis, particularly if their symptoms are unresponsive or only partially responsive to acid blockade, according to a new consensus report on the inflammatory gastroesophageal disorder. The report appears in the October 2007 issue of Gastroenterology.

Characterized by a range of gastrointestinal symptoms including abdominal pain, nausea, regurgitation, and/or vomiting along with severely elevated levels of eosinophils, eosinophilic esophagitis (EE) is an “enigmatic” disease that is frequently mistaken for gastroesophageal reflux disease (GERD), said Dr. Glenn T. Furuta, cochair of the First International Gastrointestinal Eosinophilic Research Symposium (FIGERS), from which the consensus report was generated.

Because EE and GERD require different treatment strategies and are associated with different long-term consequences, distinguishing between the two is critical, but doing so has been hindered by the absence of definitive diagnostic and treatment guidelines for EE, said Dr. Furuta of Children's Hospital of Denver. “The consensus report is the best first step in providing outstanding care to children and adults who are affected by this newly recognized disease,” he said in an interview.

Developed through the collaboration of 32 physicians from multiple disciplines, including pediatric and adult gastroenterology, allergy, and pathology, the consensus report is based on a systematic review of data from 80 studies published between 1977 and 2006 including 754 children and 323 adults, as well as expert opinion.

Among the most important features of the report are its diagnostic guidelines, Dr. Furuta said. In this regard, “the report states that affected patients should have symptoms referable to the esophagus that occur in combination with greater than or equal to 15 eosinophils per high-powered field in the esophageal mucosa with normal gastric and duodenal mucosa,” he said. “Most importantly, GERD must have been ruled out as a cause of these findings.”

The available data on the natural history of the disease suggest that EE is a chronic condition with persistent or relapsing symptoms. “To date, esophageal strictures and small caliber esophagus, often resulting in food impaction, have been the major complications identified,” the authors wrote in the report. “When these findings are encountered, either radiologically or at endoscopy, a high index of suspicion should be raised for EE and mucosal biopsies should be obtained.”

Importantly, mucosal pinch biopsies are recommended for all patients in whom eosinophilic esophagitis is in the differential diagnosis, regardless of the gross appearance of the mucosa, the authors wrote. Additionally, multiple biopsies should be obtained from different esophageal locations along the length of the esophagus, and they should be obtained from the stomach and duodenum to rule out other gastrointestinal diseases, they stated.

When endoscopy and biopsy do not provide sufficient information to distinguish between GERD and eosinophilic esophagitis, “intraesophageal pH monitoring may be of use in excluding pathologic reflux as either the primary or a concomitant cause for esophageal eosinophilia,” according to the report. “Alternatively, an upper endoscopy after 6–8 weeks of high-dose proton pump inhibitor treatment can help determine the etiology of esophageal eosinophilia.”

Regarding diagnostic histopathology, based on the available data and the panel's collective clinical experience, “we conclude that a peak count of 15 intraepithelial eosinophils per high-powered field is an absolute minimum number to make the diagnosis of EE in the proper clinical context,” they wrote. For research purposes, it may be useful to use a higher threshold of peak eosinophils in order to increase the specificity of the diagnosis, they noted.

Additional histopathologic features that, while not pathognomonic, may be helpful in establishing a diagnosis, are eosinophil microabscesses, surface layering of eosinophils, basal layer hyperplasia, papillary lengthening, degranulating eosino- phils, and lamina propria fibrosis and inflammation, according to the report.

In terms of treating the disease, dietary therapy in particular should be considered in all children diagnosed with the condition, as there is strong circumstantial evidence that food allergens contribute to the pathogenesis of the disease in children. In fact, “the removal of food antigens has clearly been demonstrated to successfully treat both the symptoms and the underlying histopathology in the majority of patients with EE,” the authors wrote. Toward this end, allergy testing and clinical history can help guide specific food elimination, they stated, adding that consultation with a registered dietitian is advisable to ensure that proper nutrition is maintained.

Corticosteroids can effectively resolve acute clinicopathologic features of EE, but the disease typically recurs when the steroids are stopped. And while systemic corticosteroids have a role in emergent cases, including dysphagia requiring hospitalization, dehydration because of swallowing difficulties, and weight loss, the potential for significant toxicity over time should preclude their long-term use, the authors stated. Topical corticosteroids have also shown some efficacy and are associated with fewer side effects, they noted.

Although gastric acid is not thought to be the primary mediator of EE, acid suppression may be considered as cotherapy in patients with established disease who have symptoms secondary to GERD.

For patients who present with symptomatic esophageal narrowing secondary to fixed strictures causing food impaction, esophageal dilatation may be a useful treatment option, the authors wrote. To minimize the risk of mucosal tearing and perforation, however, “a diagnostic endoscopy with biopsy followed by medical or dietary therapy for EE should be attempted prior to performing esophageal dilatation,” they stressed. And the esophagus should be inspected, either radiographically or by gentle endoscopic examination, after dilation to assess for laceration injury before performing larger caliber dilation.

Biologic agents that specifically target eosinophil activity may present a unique treatment opportunity for some patients with EE; however, they cannot yet be recommended for routine use given the lack of clinical trial data to date, according to the authors.

“The motivating factor for treating all patients should be symptom relief and prevention of complications of esophageal strictures and long-segment narrowing,” said Dr. Furuta.

In the absence of pathologic gastroesophageal reflux disease, young children with esophageal symptoms or feeding problems and older children and adults with dysphagia or esophageal food impaction should be evaluated for eosinophilic esophagitis, particularly if their symptoms are unresponsive or only partially responsive to acid blockade, according to a new consensus report on the inflammatory gastroesophageal disorder. The report appears in the October 2007 issue of Gastroenterology.

Characterized by a range of gastrointestinal symptoms including abdominal pain, nausea, regurgitation, and/or vomiting along with severely elevated levels of eosinophils, eosinophilic esophagitis (EE) is an “enigmatic” disease that is frequently mistaken for gastroesophageal reflux disease (GERD), said Dr. Glenn T. Furuta, cochair of the First International Gastrointestinal Eosinophilic Research Symposium (FIGERS), from which the consensus report was generated.

Because EE and GERD require different treatment strategies and are associated with different long-term consequences, distinguishing between the two is critical, but doing so has been hindered by the absence of definitive diagnostic and treatment guidelines for EE, said Dr. Furuta of Children's Hospital of Denver. “The consensus report is the best first step in providing outstanding care to children and adults who are affected by this newly recognized disease,” he said in an interview.

Developed through the collaboration of 32 physicians from multiple disciplines, including pediatric and adult gastroenterology, allergy, and pathology, the consensus report is based on a systematic review of data from 80 studies published between 1977 and 2006 including 754 children and 323 adults, as well as expert opinion.

Among the most important features of the report are its diagnostic guidelines, Dr. Furuta said. In this regard, “the report states that affected patients should have symptoms referable to the esophagus that occur in combination with greater than or equal to 15 eosinophils per high-powered field in the esophageal mucosa with normal gastric and duodenal mucosa,” he said. “Most importantly, GERD must have been ruled out as a cause of these findings.”

The available data on the natural history of the disease suggest that EE is a chronic condition with persistent or relapsing symptoms. “To date, esophageal strictures and small caliber esophagus, often resulting in food impaction, have been the major complications identified,” the authors wrote in the report. “When these findings are encountered, either radiologically or at endoscopy, a high index of suspicion should be raised for EE and mucosal biopsies should be obtained.”

Importantly, mucosal pinch biopsies are recommended for all patients in whom eosinophilic esophagitis is in the differential diagnosis, regardless of the gross appearance of the mucosa, the authors wrote. Additionally, multiple biopsies should be obtained from different esophageal locations along the length of the esophagus, and they should be obtained from the stomach and duodenum to rule out other gastrointestinal diseases, they stated.

When endoscopy and biopsy do not provide sufficient information to distinguish between GERD and eosinophilic esophagitis, “intraesophageal pH monitoring may be of use in excluding pathologic reflux as either the primary or a concomitant cause for esophageal eosinophilia,” according to the report. “Alternatively, an upper endoscopy after 6–8 weeks of high-dose proton pump inhibitor treatment can help determine the etiology of esophageal eosinophilia.”

Regarding diagnostic histopathology, based on the available data and the panel's collective clinical experience, “we conclude that a peak count of 15 intraepithelial eosinophils per high-powered field is an absolute minimum number to make the diagnosis of EE in the proper clinical context,” they wrote. For research purposes, it may be useful to use a higher threshold of peak eosinophils in order to increase the specificity of the diagnosis, they noted.

Additional histopathologic features that, while not pathognomonic, may be helpful in establishing a diagnosis, are eosinophil microabscesses, surface layering of eosinophils, basal layer hyperplasia, papillary lengthening, degranulating eosino- phils, and lamina propria fibrosis and inflammation, according to the report.

In terms of treating the disease, dietary therapy in particular should be considered in all children diagnosed with the condition, as there is strong circumstantial evidence that food allergens contribute to the pathogenesis of the disease in children. In fact, “the removal of food antigens has clearly been demonstrated to successfully treat both the symptoms and the underlying histopathology in the majority of patients with EE,” the authors wrote. Toward this end, allergy testing and clinical history can help guide specific food elimination, they stated, adding that consultation with a registered dietitian is advisable to ensure that proper nutrition is maintained.

Corticosteroids can effectively resolve acute clinicopathologic features of EE, but the disease typically recurs when the steroids are stopped. And while systemic corticosteroids have a role in emergent cases, including dysphagia requiring hospitalization, dehydration because of swallowing difficulties, and weight loss, the potential for significant toxicity over time should preclude their long-term use, the authors stated. Topical corticosteroids have also shown some efficacy and are associated with fewer side effects, they noted.

Although gastric acid is not thought to be the primary mediator of EE, acid suppression may be considered as cotherapy in patients with established disease who have symptoms secondary to GERD.

For patients who present with symptomatic esophageal narrowing secondary to fixed strictures causing food impaction, esophageal dilatation may be a useful treatment option, the authors wrote. To minimize the risk of mucosal tearing and perforation, however, “a diagnostic endoscopy with biopsy followed by medical or dietary therapy for EE should be attempted prior to performing esophageal dilatation,” they stressed. And the esophagus should be inspected, either radiographically or by gentle endoscopic examination, after dilation to assess for laceration injury before performing larger caliber dilation.

Biologic agents that specifically target eosinophil activity may present a unique treatment opportunity for some patients with EE; however, they cannot yet be recommended for routine use given the lack of clinical trial data to date, according to the authors.

“The motivating factor for treating all patients should be symptom relief and prevention of complications of esophageal strictures and long-segment narrowing,” said Dr. Furuta.