The last several years have seen increased debate over the appropriate hemoglobin target range when using erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease and kidney failure. But several recent studies have raised alarms, and in November 2006 the US Food and Drug Administration (FDA) issued a new warning regarding the use of ESAs in renal disease.

For a perspective on the use of erythropoiesis-stimulating agents in cancer patients, see the related editorial.

This article will discuss the history of ESAs and the current guidelines for their use. ESAs are also indicated to treat anemia in patients undergoing cancer chemotherapy or surgery, but those uses will not be discussed in this article.

THE BENEFITS OF ESAs

The first ESA, Epogen, was approved by the FDA in 1989 to treat anemia associated with kidney disease.

Since then, ESAs have made a revolutionary change in the care of patients with kidney failure by allowing them to avoid blood transfusions, which were the norm, and by improving the quality of life, although the evidence for the latter is less compelling.¹ The benefits of avoiding the use of blood products include a lower risk of reactions, lower cost, and avoiding sensitization of the human lymphocyte antigen (HLA) system in kidney transplant candidates.

To date, however, no randomized, placebo-controlled clinical trial with adequate power to detect a reduction in adverse clinical outcomes (hospitalizations, nonfatal cardiovascular events, or deaths) has assessed the effect of raising hemoglobin levels with ESAs in patients with chronic kidney disease or end-stage renal disease. Nevertheless, several small studies have shown ESAs to have favorable effects on surrogate end points, and an impressive amount of observational data have shown higher survival rates with higher hemoglobin levels.^2–6

HOW HIGH SHOULD THE HEMOGLOBIN BE RAISED?

During ESA treatment, the FDA first approved a target hemoglobin range of 10 to 11 g/dL, and subsequently changed it to 10 to 12 g/dL in 1994. The National Kidney Foundation, in its 1997 practice guidelines, endorsed a target range of 11 to 12 g/dL.

US Renal Data System. USRDS 2006 annual data report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2006.

The US Normal Hematocrit Study (1998) struck a sour note. In this study, 1,233 dialysis patients with cardiovascular disease were randomized to either a low hematocrit target (33%) or a normal hematocrit target (42%). The trial was stopped early when the investigators recognized that more patients in the normal-hematocrit group had died, that the difference was nearing statistical significance, and that continuing the study was unlikely to reveal a benefit in the normal-hematocrit group. Also of note, the incidence of vascular access thrombosis was higher in the normal-hematocrit group.⁸

In 2006 the National Kidney Foundation modified its 1997 guidelines, suggesting an upper hemoglobin boundary of 13 g/dL. But in early 2007 it retreated to a hemoglobin target range of 11–12 g/dL,⁹ after the simultaneous publication of two randomized controlled trials that found no improved outcomes with hemoglobin normalization, and some evidence of harm.^10,11

The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial randomized predialysis patients to a hemoglobin goal of either 11.3 g/dL or 13.5 g/dL. The trial was terminated early because the likelihood of benefit with the high hemoglobin goal was low. In fact, the higher-hemoglobin group had a higher incidence of the primary end point, ie, the composite of death, stroke, myocardial infarction, and hospitalization for congestive heart failure. Death and hospitalization for congestive heart failure were the main drivers of the difference in the composite end point between the groups. Quality of life was no better with the higher goal than with the lower goal.¹⁰

The Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin Beta (CREATE) trial¹¹ found that the risk of cardiovascular events in predialysis patients was no lower when anemia was completely corrected (target hemoglobin range 13.0–15.0 g/dL) than with a goal of 10.5 to 11.5 g/dL. Moreover, renal function declined faster in the higher-goal group than in the lower-goal group. However, this study did show higher quality-of-life scores in the group with the higher hemoglobin goal.¹¹

AN FDA ALERT

On November 16, 2006, the FDA issued an alert and required that ESA product labeling include a new boxed warning with the following information¹²:

• Use the lowest dose of an ESA (Procrit, Epogen, or Aranesp) that will gradually raise the hemoglobin concentration to the lowest level sufficient to avoid the need for blood transfusion.
• ESAs should not be given to treat symptoms of anemia or poor quality of life.
• Maintain the hemoglobin level in the target range of 10 to 12 g/dL.
• Decrease the dose if the hemoglobin level increases by more than 1 g/dL in any 2-week period.

ANOTHER LOOK AT THE DATA

In post hoc analyses, data from the US Normal Hematocrit and CHOIR studies were analyzed on an “as-treated” basis instead of on an intention-to-treat basis as originally reported.^13,14 Although the original studies found no survival advantage (and perhaps harm) with higher hemoglobin targets (ie, by intention-to-treat analysis), when the investigators looked at the actual hemoglobin levels achieved, they found that event rates were higher with low hemoglobin levels.

Such discordant findings highlight the importance of randomized experimental designs to avoid bias due to confounding factors (measured and unmeasured) linked to both hemoglobin level and outcome. To reconcile the above findings, we offer the following observations:

• In each treatment group, event rates were higher among those who responded poorly to ESAs (hyporesponders). This finding undermines the intuitive assumption that higher achieved hemoglobin levels were causing volume-related events (congestive heart failure or pulmonary edema) and thrombotic events. Of note, rapid changes in hemoglobin levels in either direction further increased the frequency of events among hyporesponders (which might be associated with the more aggressive algorithm needed in the higher target group).
• Within each treatment group, the difference in event rates is unlikely to be explained by the variation in hemoglobin within its narrow range. Rather, it was mostly due to a higher burden of disease among the hyporesponders. This problem—called targeting bias—is peculiar to therapies that are adjusted according to a target level, eg, of serum hemoglobin.¹⁵ Therefore, any association of mortality with achieved hemoglobin within the individual target hemoglobin group is more likely due to other factors such as patient comorbidities.
• Patients assigned to the higher hemoglobin targets received more than just higher doses of ESAs: they also got more of other interventions such as intravenous iron supplementation. Therefore, the results of the trials reflect not only the target level achieved but also the independent effects of the study drug, the co-interventions, and the treatment algorithm.

TAKE-HOME POINTS

Partial correction of the anemia associated with kidney disease reduces transfusion requirements, but normalizing the hemoglobin level does not confer survival benefit and may be harmful. In accordance with the FDA recommendations and the available evidence, we agree that the goal for treating anemia associated with kidney disease should be partial correction: the upper boundary of hemoglobin should be 12 g/dL. However, transient trespasses beyond the upper boundary in day-to-day clinical practice should not trigger a panic response in the health care provider (as seen with hyperkalemia, for instance). Rather, they should result in appropriate and timely treatment adjustments.

Further efforts should explore the merits of treatment algorithms that minimize rapid changes in hemoglobin levels, as well as dose limitation of ESAs and co-interventions among hyporesponders.

The last several years have seen increased debate over the appropriate hemoglobin target range when using erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease and kidney failure. But several recent studies have raised alarms, and in November 2006 the US Food and Drug Administration (FDA) issued a new warning regarding the use of ESAs in renal disease.

For a perspective on the use of erythropoiesis-stimulating agents in cancer patients, see the related editorial.

This article will discuss the history of ESAs and the current guidelines for their use. ESAs are also indicated to treat anemia in patients undergoing cancer chemotherapy or surgery, but those uses will not be discussed in this article.

THE BENEFITS OF ESAs

The first ESA, Epogen, was approved by the FDA in 1989 to treat anemia associated with kidney disease.

Since then, ESAs have made a revolutionary change in the care of patients with kidney failure by allowing them to avoid blood transfusions, which were the norm, and by improving the quality of life, although the evidence for the latter is less compelling.¹ The benefits of avoiding the use of blood products include a lower risk of reactions, lower cost, and avoiding sensitization of the human lymphocyte antigen (HLA) system in kidney transplant candidates.

To date, however, no randomized, placebo-controlled clinical trial with adequate power to detect a reduction in adverse clinical outcomes (hospitalizations, nonfatal cardiovascular events, or deaths) has assessed the effect of raising hemoglobin levels with ESAs in patients with chronic kidney disease or end-stage renal disease. Nevertheless, several small studies have shown ESAs to have favorable effects on surrogate end points, and an impressive amount of observational data have shown higher survival rates with higher hemoglobin levels.^2–6

HOW HIGH SHOULD THE HEMOGLOBIN BE RAISED?

During ESA treatment, the FDA first approved a target hemoglobin range of 10 to 11 g/dL, and subsequently changed it to 10 to 12 g/dL in 1994. The National Kidney Foundation, in its 1997 practice guidelines, endorsed a target range of 11 to 12 g/dL.

US Renal Data System. USRDS 2006 annual data report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2006.

The US Normal Hematocrit Study (1998) struck a sour note. In this study, 1,233 dialysis patients with cardiovascular disease were randomized to either a low hematocrit target (33%) or a normal hematocrit target (42%). The trial was stopped early when the investigators recognized that more patients in the normal-hematocrit group had died, that the difference was nearing statistical significance, and that continuing the study was unlikely to reveal a benefit in the normal-hematocrit group. Also of note, the incidence of vascular access thrombosis was higher in the normal-hematocrit group.⁸

In 2006 the National Kidney Foundation modified its 1997 guidelines, suggesting an upper hemoglobin boundary of 13 g/dL. But in early 2007 it retreated to a hemoglobin target range of 11–12 g/dL,⁹ after the simultaneous publication of two randomized controlled trials that found no improved outcomes with hemoglobin normalization, and some evidence of harm.^10,11

The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial randomized predialysis patients to a hemoglobin goal of either 11.3 g/dL or 13.5 g/dL. The trial was terminated early because the likelihood of benefit with the high hemoglobin goal was low. In fact, the higher-hemoglobin group had a higher incidence of the primary end point, ie, the composite of death, stroke, myocardial infarction, and hospitalization for congestive heart failure. Death and hospitalization for congestive heart failure were the main drivers of the difference in the composite end point between the groups. Quality of life was no better with the higher goal than with the lower goal.¹⁰

The Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin Beta (CREATE) trial¹¹ found that the risk of cardiovascular events in predialysis patients was no lower when anemia was completely corrected (target hemoglobin range 13.0–15.0 g/dL) than with a goal of 10.5 to 11.5 g/dL. Moreover, renal function declined faster in the higher-goal group than in the lower-goal group. However, this study did show higher quality-of-life scores in the group with the higher hemoglobin goal.¹¹

AN FDA ALERT

On November 16, 2006, the FDA issued an alert and required that ESA product labeling include a new boxed warning with the following information¹²:

• Use the lowest dose of an ESA (Procrit, Epogen, or Aranesp) that will gradually raise the hemoglobin concentration to the lowest level sufficient to avoid the need for blood transfusion.
• ESAs should not be given to treat symptoms of anemia or poor quality of life.
• Maintain the hemoglobin level in the target range of 10 to 12 g/dL.
• Decrease the dose if the hemoglobin level increases by more than 1 g/dL in any 2-week period.

ANOTHER LOOK AT THE DATA

In post hoc analyses, data from the US Normal Hematocrit and CHOIR studies were analyzed on an “as-treated” basis instead of on an intention-to-treat basis as originally reported.^13,14 Although the original studies found no survival advantage (and perhaps harm) with higher hemoglobin targets (ie, by intention-to-treat analysis), when the investigators looked at the actual hemoglobin levels achieved, they found that event rates were higher with low hemoglobin levels.

Such discordant findings highlight the importance of randomized experimental designs to avoid bias due to confounding factors (measured and unmeasured) linked to both hemoglobin level and outcome. To reconcile the above findings, we offer the following observations:

• In each treatment group, event rates were higher among those who responded poorly to ESAs (hyporesponders). This finding undermines the intuitive assumption that higher achieved hemoglobin levels were causing volume-related events (congestive heart failure or pulmonary edema) and thrombotic events. Of note, rapid changes in hemoglobin levels in either direction further increased the frequency of events among hyporesponders (which might be associated with the more aggressive algorithm needed in the higher target group).
• Within each treatment group, the difference in event rates is unlikely to be explained by the variation in hemoglobin within its narrow range. Rather, it was mostly due to a higher burden of disease among the hyporesponders. This problem—called targeting bias—is peculiar to therapies that are adjusted according to a target level, eg, of serum hemoglobin.¹⁵ Therefore, any association of mortality with achieved hemoglobin within the individual target hemoglobin group is more likely due to other factors such as patient comorbidities.
• Patients assigned to the higher hemoglobin targets received more than just higher doses of ESAs: they also got more of other interventions such as intravenous iron supplementation. Therefore, the results of the trials reflect not only the target level achieved but also the independent effects of the study drug, the co-interventions, and the treatment algorithm.

TAKE-HOME POINTS

Partial correction of the anemia associated with kidney disease reduces transfusion requirements, but normalizing the hemoglobin level does not confer survival benefit and may be harmful. In accordance with the FDA recommendations and the available evidence, we agree that the goal for treating anemia associated with kidney disease should be partial correction: the upper boundary of hemoglobin should be 12 g/dL. However, transient trespasses beyond the upper boundary in day-to-day clinical practice should not trigger a panic response in the health care provider (as seen with hyperkalemia, for instance). Rather, they should result in appropriate and timely treatment adjustments.

Further efforts should explore the merits of treatment algorithms that minimize rapid changes in hemoglobin levels, as well as dose limitation of ESAs and co-interventions among hyporesponders.

The last several years have seen increased debate over the appropriate hemoglobin target range when using erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease and kidney failure. But several recent studies have raised alarms, and in November 2006 the US Food and Drug Administration (FDA) issued a new warning regarding the use of ESAs in renal disease.

For a perspective on the use of erythropoiesis-stimulating agents in cancer patients, see the related editorial.

This article will discuss the history of ESAs and the current guidelines for their use. ESAs are also indicated to treat anemia in patients undergoing cancer chemotherapy or surgery, but those uses will not be discussed in this article.

THE BENEFITS OF ESAs

The first ESA, Epogen, was approved by the FDA in 1989 to treat anemia associated with kidney disease.

Since then, ESAs have made a revolutionary change in the care of patients with kidney failure by allowing them to avoid blood transfusions, which were the norm, and by improving the quality of life, although the evidence for the latter is less compelling.¹ The benefits of avoiding the use of blood products include a lower risk of reactions, lower cost, and avoiding sensitization of the human lymphocyte antigen (HLA) system in kidney transplant candidates.

To date, however, no randomized, placebo-controlled clinical trial with adequate power to detect a reduction in adverse clinical outcomes (hospitalizations, nonfatal cardiovascular events, or deaths) has assessed the effect of raising hemoglobin levels with ESAs in patients with chronic kidney disease or end-stage renal disease. Nevertheless, several small studies have shown ESAs to have favorable effects on surrogate end points, and an impressive amount of observational data have shown higher survival rates with higher hemoglobin levels.^2–6

HOW HIGH SHOULD THE HEMOGLOBIN BE RAISED?

During ESA treatment, the FDA first approved a target hemoglobin range of 10 to 11 g/dL, and subsequently changed it to 10 to 12 g/dL in 1994. The National Kidney Foundation, in its 1997 practice guidelines, endorsed a target range of 11 to 12 g/dL.

US Renal Data System. USRDS 2006 annual data report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2006.

The US Normal Hematocrit Study (1998) struck a sour note. In this study, 1,233 dialysis patients with cardiovascular disease were randomized to either a low hematocrit target (33%) or a normal hematocrit target (42%). The trial was stopped early when the investigators recognized that more patients in the normal-hematocrit group had died, that the difference was nearing statistical significance, and that continuing the study was unlikely to reveal a benefit in the normal-hematocrit group. Also of note, the incidence of vascular access thrombosis was higher in the normal-hematocrit group.⁸

In 2006 the National Kidney Foundation modified its 1997 guidelines, suggesting an upper hemoglobin boundary of 13 g/dL. But in early 2007 it retreated to a hemoglobin target range of 11–12 g/dL,⁹ after the simultaneous publication of two randomized controlled trials that found no improved outcomes with hemoglobin normalization, and some evidence of harm.^10,11

The Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial randomized predialysis patients to a hemoglobin goal of either 11.3 g/dL or 13.5 g/dL. The trial was terminated early because the likelihood of benefit with the high hemoglobin goal was low. In fact, the higher-hemoglobin group had a higher incidence of the primary end point, ie, the composite of death, stroke, myocardial infarction, and hospitalization for congestive heart failure. Death and hospitalization for congestive heart failure were the main drivers of the difference in the composite end point between the groups. Quality of life was no better with the higher goal than with the lower goal.¹⁰

The Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin Beta (CREATE) trial¹¹ found that the risk of cardiovascular events in predialysis patients was no lower when anemia was completely corrected (target hemoglobin range 13.0–15.0 g/dL) than with a goal of 10.5 to 11.5 g/dL. Moreover, renal function declined faster in the higher-goal group than in the lower-goal group. However, this study did show higher quality-of-life scores in the group with the higher hemoglobin goal.¹¹

AN FDA ALERT

On November 16, 2006, the FDA issued an alert and required that ESA product labeling include a new boxed warning with the following information¹²:

• Use the lowest dose of an ESA (Procrit, Epogen, or Aranesp) that will gradually raise the hemoglobin concentration to the lowest level sufficient to avoid the need for blood transfusion.
• ESAs should not be given to treat symptoms of anemia or poor quality of life.
• Maintain the hemoglobin level in the target range of 10 to 12 g/dL.
• Decrease the dose if the hemoglobin level increases by more than 1 g/dL in any 2-week period.

ANOTHER LOOK AT THE DATA

In post hoc analyses, data from the US Normal Hematocrit and CHOIR studies were analyzed on an “as-treated” basis instead of on an intention-to-treat basis as originally reported.^13,14 Although the original studies found no survival advantage (and perhaps harm) with higher hemoglobin targets (ie, by intention-to-treat analysis), when the investigators looked at the actual hemoglobin levels achieved, they found that event rates were higher with low hemoglobin levels.

Such discordant findings highlight the importance of randomized experimental designs to avoid bias due to confounding factors (measured and unmeasured) linked to both hemoglobin level and outcome. To reconcile the above findings, we offer the following observations:

• In each treatment group, event rates were higher among those who responded poorly to ESAs (hyporesponders). This finding undermines the intuitive assumption that higher achieved hemoglobin levels were causing volume-related events (congestive heart failure or pulmonary edema) and thrombotic events. Of note, rapid changes in hemoglobin levels in either direction further increased the frequency of events among hyporesponders (which might be associated with the more aggressive algorithm needed in the higher target group).
• Within each treatment group, the difference in event rates is unlikely to be explained by the variation in hemoglobin within its narrow range. Rather, it was mostly due to a higher burden of disease among the hyporesponders. This problem—called targeting bias—is peculiar to therapies that are adjusted according to a target level, eg, of serum hemoglobin.¹⁵ Therefore, any association of mortality with achieved hemoglobin within the individual target hemoglobin group is more likely due to other factors such as patient comorbidities.
• Patients assigned to the higher hemoglobin targets received more than just higher doses of ESAs: they also got more of other interventions such as intravenous iron supplementation. Therefore, the results of the trials reflect not only the target level achieved but also the independent effects of the study drug, the co-interventions, and the treatment algorithm.

TAKE-HOME POINTS

Partial correction of the anemia associated with kidney disease reduces transfusion requirements, but normalizing the hemoglobin level does not confer survival benefit and may be harmful. In accordance with the FDA recommendations and the available evidence, we agree that the goal for treating anemia associated with kidney disease should be partial correction: the upper boundary of hemoglobin should be 12 g/dL. However, transient trespasses beyond the upper boundary in day-to-day clinical practice should not trigger a panic response in the health care provider (as seen with hyperkalemia, for instance). Rather, they should result in appropriate and timely treatment adjustments.

Further efforts should explore the merits of treatment algorithms that minimize rapid changes in hemoglobin levels, as well as dose limitation of ESAs and co-interventions among hyporesponders.

Case Report

A 54-year-old woman with polycystic disease of kidneys was scheduled for renal transplant and presented with a 2-week history of an extremely pruritic rash that primarily affected her torso, buttocks, shoulders, and thighs. She described the lesions as red, raised, and linear, typically lasting less than 24 hours at a time. She had been previously treated with a 5-day course of prednisone by another physician, without improvement. Her only new medication was glucosamine and chondroitin sulfate, which she had started one week prior to the eruption. Raloxifene hydrochloride and cetirizine hydrochloride were long-term medications.

The patient reported one similar episode many years ago. She denied any recent changes in her health and reported no gastrointestinal tract or pulmonary symptoms. She was raised in Panama and had visited there in the past year. She specifically denied walking without shoes.

On physical examination, the patient had a pink, serpiginous, urticarial plaque on the right side of the trunk that was surrounded by a few red serpiginous patches (Figure). Her white blood cell count was 6.5X103/µL (reference range, 3.5–10.5X103/µL), with 19.2% eosinophils (reference, 2.7%). Her absolute eosinophil count was elevated at 1200/µL (reference range, 0–450/µL). A review of prior laboratory test results indicated that her absolute eosinophil count also had been elevated 6 months prior to presentation. Serologic evaluation by enzyme-linked immunosorbent assay was positive for Strongyloides. Results of stool studies did not reveal ova and parasites.

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

The patient was treated with oral thiabendazole 1500 mg twice daily for 2 days and her transplant was postponed. Her rash resolved, but 2 weeks later, her white blood cell count was 5.6X103/µL, with 11.6% eosinophils. She was subsequently treated with a single dose of 200 µg/kg of ivermectin. Results of a complete blood count obtained 2 weeks later demonstrated that her eosinophil count was within reference range and she was able to proceed with the transplant. The patient's sister (the donor) also was born in Panama and had negative serologic evaluation results for Strongyloides. The patient did well following the transplant and the results of repeat serologic evaluations performed 4 months after the transplant were negative for Strongyloides.

Comment

Strongyloides stercoralis is an intestinal nematode primarily found in tropical or subtropical countries. Humans are infected by filariform larvae that dwell in the soil. Larvae penetrate intact skin, gain access to the venous system, pass through the heart to the lungs, enter the pulmonary alveoli, migrate up the tracheobronchial tree, and are swallowed, thereby entering the gastrointestinal tract.¹ The larvae mature into adult females that penetrate the mucosa of the small intestine and deposit eggs. The eggs hatch into rhabditiform larvae that are passed in the stool to the soil where transformation into the infective form (filariform) occurs. Autoinfection may take place when this transformation to the infective-stage larvae occurs within the gastrointestinal tract, enabling the infective larvae to invade the lower large bowel or perianal skin and begin the migratory pathway. Autoinfection can allow the persistence of infection for long periods of time and also can allow chronic infections to persist in climates where free-living larvae cannot survive.²

Uncomplicated infection with S stercoralis can cause cutaneous, gastrointestinal tract, and pulmonary symptoms corresponding to the involvement of organs during the parasite's life cycle. Rash is uncommon in acute infection, though it is common in chronic disease. Maculopapular eruptions and chronic urticaria have been reported in up to two-thirds of patients.³ Larva currens is a migratory, rapidly extending, serpiginous, urticarial lesion that is pathognomonic for chronic strongyloidiasis. The rash typically lasts from several hours to several days. It most commonly affects the buttocks, perineum, and thighs, and is secondary to invasion of perianal skin by filariform larvae from the patient's intestine. Arthur and Shelley⁴ proposed the term larva currens (running larva) because the larvae and subsequent rash can move up to 10 cm per hour.

In a healthy host, the cellular immune system seems to limit parasite invasion of mucosal tissues.⁵ If immunosuppression occurs, individuals with strongyloidiasis can develop a hyperinfective syndrome and massive numbers of larvae can invade any organ of the body, with a mortality rate of 70% to 90%.^6,7 The cutaneous manifestation of disseminated strongyloidiasis is the rapid onset of a petechial and purpuric eruption that typically involves the proximal extremities and trunk and results from massive invasion of the skin by filariform larvae. The "thumbprint sign" refers to a pattern of periumbilical ecchymoses resembling multiple thumbprints that can occur in hyperinfection.⁸

Gastrointestinal tract symptoms predominate in acute infection. Diarrhea and midepigastric pain that may mimic peptic ulcer disease are common. Diarrhea also can alternate with constipation. Other gastrointestinal tract symptoms include nausea, vomiting, anorexia, pruritus ani, and bloating.¹ Some severe cases can have malabsorption and evidence of a protein-losing enteropathy.^9,10

Pulmonary symptoms in acute infection can occur and include wheezing, coughing, and shortness of breath.1 Larval migration through the lungs also can lead to transient pulmonary infiltrates. Some patients have presented with asthma.¹¹ Patients with chronic disease may have gastrointestinal tract and pulmonary symptoms, though chronic infection tends to be indolent and patients may be asymptomatic.

Diagnosis can be difficult, as results from stool samples often are negative and multiple samples may be required. Results of biopsies performed on larva currens specimens usually do not reveal larvae, though biopsy results of the petechial and purpuric eruptions of disseminated disease will reveal larvae. Serologic testing with enzyme-linked immunosorbent assay has a sensitivity of approximately 90%.^12,13

Traditionally, thiabendazole has been used to treat this infection, though in approximately 30% of cases, the parasite is not eradicated from the feces. Ivermectin has been found to be more effective for treating uncomplicated chronic disease.¹⁴

In most cases of disseminated disease, patients were receiving corticosteroids or other immunosuppressive drugs or had an underlying illness, such as malignancy or AIDS.^1,2,15,16 Our patient was scheduled to undergo a renal transplant and fatal disseminated strongyloidiasis has been reported in patients undergoing renal transplant.^2,16 Morgan et al² reviewed 29 cases of strongyloidiasis complicating renal transplants; 15 patients died.

Infection in the immunocompromised patient can be complicated by the fact that invasive larvae can transport gram-negative bacilli from the intestine to sites of migration, such as the pulmonary and central nervous systems.⁵ Gram-negative sepsis, meningitis, or pneumonia can result. Diagnosis can be difficult because eosinophilia often is absent in immunocompromised patients with disseminated disease.⁵

Although common in tropical and subtropical countries, other geographic regions of endemic Strongyloides are recognized. The climate and soil of the southeastern United States favor the survival of the organism,⁵ and the parasite was reported in 3% (N=561) of a group of rural Kentucky schoolchildren¹⁷; similar findings were reported in another study conducted in Kentucky.¹⁸Strongyloides also was the most commonly detected parasite in a review of stool samples examined at the University of Kentucky Medical Center.¹⁹ Ex–prisoners of war who served in Southeast Asia during World War II also constitute an at-risk group in the United States.^20-22

It is imperative to rule out the presence of this parasite prior to transplant in patients with a geographic history predisposing them to infection, a history of eosinophilia, or symptoms of chronic strongyloidiasis.¹ Many transplantation centers routinely screen for this parasite as part of the pretransplant evaluation. Although uncommon in acute infections, cutaneous involvement often is present in chronic strongyloidiasis.¹ It also is important to follow patients already treated for larva currens closely posttransplant, as therapeutic failures occur.

Case Report

A 54-year-old woman with polycystic disease of kidneys was scheduled for renal transplant and presented with a 2-week history of an extremely pruritic rash that primarily affected her torso, buttocks, shoulders, and thighs. She described the lesions as red, raised, and linear, typically lasting less than 24 hours at a time. She had been previously treated with a 5-day course of prednisone by another physician, without improvement. Her only new medication was glucosamine and chondroitin sulfate, which she had started one week prior to the eruption. Raloxifene hydrochloride and cetirizine hydrochloride were long-term medications.

The patient reported one similar episode many years ago. She denied any recent changes in her health and reported no gastrointestinal tract or pulmonary symptoms. She was raised in Panama and had visited there in the past year. She specifically denied walking without shoes.

On physical examination, the patient had a pink, serpiginous, urticarial plaque on the right side of the trunk that was surrounded by a few red serpiginous patches (Figure). Her white blood cell count was 6.5X103/µL (reference range, 3.5–10.5X103/µL), with 19.2% eosinophils (reference, 2.7%). Her absolute eosinophil count was elevated at 1200/µL (reference range, 0–450/µL). A review of prior laboratory test results indicated that her absolute eosinophil count also had been elevated 6 months prior to presentation. Serologic evaluation by enzyme-linked immunosorbent assay was positive for Strongyloides. Results of stool studies did not reveal ova and parasites.

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

The patient was treated with oral thiabendazole 1500 mg twice daily for 2 days and her transplant was postponed. Her rash resolved, but 2 weeks later, her white blood cell count was 5.6X103/µL, with 11.6% eosinophils. She was subsequently treated with a single dose of 200 µg/kg of ivermectin. Results of a complete blood count obtained 2 weeks later demonstrated that her eosinophil count was within reference range and she was able to proceed with the transplant. The patient's sister (the donor) also was born in Panama and had negative serologic evaluation results for Strongyloides. The patient did well following the transplant and the results of repeat serologic evaluations performed 4 months after the transplant were negative for Strongyloides.

Comment

Strongyloides stercoralis is an intestinal nematode primarily found in tropical or subtropical countries. Humans are infected by filariform larvae that dwell in the soil. Larvae penetrate intact skin, gain access to the venous system, pass through the heart to the lungs, enter the pulmonary alveoli, migrate up the tracheobronchial tree, and are swallowed, thereby entering the gastrointestinal tract.¹ The larvae mature into adult females that penetrate the mucosa of the small intestine and deposit eggs. The eggs hatch into rhabditiform larvae that are passed in the stool to the soil where transformation into the infective form (filariform) occurs. Autoinfection may take place when this transformation to the infective-stage larvae occurs within the gastrointestinal tract, enabling the infective larvae to invade the lower large bowel or perianal skin and begin the migratory pathway. Autoinfection can allow the persistence of infection for long periods of time and also can allow chronic infections to persist in climates where free-living larvae cannot survive.²

Uncomplicated infection with S stercoralis can cause cutaneous, gastrointestinal tract, and pulmonary symptoms corresponding to the involvement of organs during the parasite's life cycle. Rash is uncommon in acute infection, though it is common in chronic disease. Maculopapular eruptions and chronic urticaria have been reported in up to two-thirds of patients.³ Larva currens is a migratory, rapidly extending, serpiginous, urticarial lesion that is pathognomonic for chronic strongyloidiasis. The rash typically lasts from several hours to several days. It most commonly affects the buttocks, perineum, and thighs, and is secondary to invasion of perianal skin by filariform larvae from the patient's intestine. Arthur and Shelley⁴ proposed the term larva currens (running larva) because the larvae and subsequent rash can move up to 10 cm per hour.

In a healthy host, the cellular immune system seems to limit parasite invasion of mucosal tissues.⁵ If immunosuppression occurs, individuals with strongyloidiasis can develop a hyperinfective syndrome and massive numbers of larvae can invade any organ of the body, with a mortality rate of 70% to 90%.^6,7 The cutaneous manifestation of disseminated strongyloidiasis is the rapid onset of a petechial and purpuric eruption that typically involves the proximal extremities and trunk and results from massive invasion of the skin by filariform larvae. The "thumbprint sign" refers to a pattern of periumbilical ecchymoses resembling multiple thumbprints that can occur in hyperinfection.⁸

Gastrointestinal tract symptoms predominate in acute infection. Diarrhea and midepigastric pain that may mimic peptic ulcer disease are common. Diarrhea also can alternate with constipation. Other gastrointestinal tract symptoms include nausea, vomiting, anorexia, pruritus ani, and bloating.¹ Some severe cases can have malabsorption and evidence of a protein-losing enteropathy.^9,10

Pulmonary symptoms in acute infection can occur and include wheezing, coughing, and shortness of breath.1 Larval migration through the lungs also can lead to transient pulmonary infiltrates. Some patients have presented with asthma.¹¹ Patients with chronic disease may have gastrointestinal tract and pulmonary symptoms, though chronic infection tends to be indolent and patients may be asymptomatic.

Diagnosis can be difficult, as results from stool samples often are negative and multiple samples may be required. Results of biopsies performed on larva currens specimens usually do not reveal larvae, though biopsy results of the petechial and purpuric eruptions of disseminated disease will reveal larvae. Serologic testing with enzyme-linked immunosorbent assay has a sensitivity of approximately 90%.^12,13

Traditionally, thiabendazole has been used to treat this infection, though in approximately 30% of cases, the parasite is not eradicated from the feces. Ivermectin has been found to be more effective for treating uncomplicated chronic disease.¹⁴

In most cases of disseminated disease, patients were receiving corticosteroids or other immunosuppressive drugs or had an underlying illness, such as malignancy or AIDS.^1,2,15,16 Our patient was scheduled to undergo a renal transplant and fatal disseminated strongyloidiasis has been reported in patients undergoing renal transplant.^2,16 Morgan et al² reviewed 29 cases of strongyloidiasis complicating renal transplants; 15 patients died.

Infection in the immunocompromised patient can be complicated by the fact that invasive larvae can transport gram-negative bacilli from the intestine to sites of migration, such as the pulmonary and central nervous systems.⁵ Gram-negative sepsis, meningitis, or pneumonia can result. Diagnosis can be difficult because eosinophilia often is absent in immunocompromised patients with disseminated disease.⁵

Although common in tropical and subtropical countries, other geographic regions of endemic Strongyloides are recognized. The climate and soil of the southeastern United States favor the survival of the organism,⁵ and the parasite was reported in 3% (N=561) of a group of rural Kentucky schoolchildren¹⁷; similar findings were reported in another study conducted in Kentucky.¹⁸Strongyloides also was the most commonly detected parasite in a review of stool samples examined at the University of Kentucky Medical Center.¹⁹ Ex–prisoners of war who served in Southeast Asia during World War II also constitute an at-risk group in the United States.^20-22

It is imperative to rule out the presence of this parasite prior to transplant in patients with a geographic history predisposing them to infection, a history of eosinophilia, or symptoms of chronic strongyloidiasis.¹ Many transplantation centers routinely screen for this parasite as part of the pretransplant evaluation. Although uncommon in acute infections, cutaneous involvement often is present in chronic strongyloidiasis.¹ It also is important to follow patients already treated for larva currens closely posttransplant, as therapeutic failures occur.

Case Report

A 54-year-old woman with polycystic disease of kidneys was scheduled for renal transplant and presented with a 2-week history of an extremely pruritic rash that primarily affected her torso, buttocks, shoulders, and thighs. She described the lesions as red, raised, and linear, typically lasting less than 24 hours at a time. She had been previously treated with a 5-day course of prednisone by another physician, without improvement. Her only new medication was glucosamine and chondroitin sulfate, which she had started one week prior to the eruption. Raloxifene hydrochloride and cetirizine hydrochloride were long-term medications.

The patient reported one similar episode many years ago. She denied any recent changes in her health and reported no gastrointestinal tract or pulmonary symptoms. She was raised in Panama and had visited there in the past year. She specifically denied walking without shoes.

On physical examination, the patient had a pink, serpiginous, urticarial plaque on the right side of the trunk that was surrounded by a few red serpiginous patches (Figure). Her white blood cell count was 6.5X103/µL (reference range, 3.5–10.5X103/µL), with 19.2% eosinophils (reference, 2.7%). Her absolute eosinophil count was elevated at 1200/µL (reference range, 0–450/µL). A review of prior laboratory test results indicated that her absolute eosinophil count also had been elevated 6 months prior to presentation. Serologic evaluation by enzyme-linked immunosorbent assay was positive for Strongyloides. Results of stool studies did not reveal ova and parasites.

PLEASE REFER TO THE PDF TO VIEW THE FIGURE

The patient was treated with oral thiabendazole 1500 mg twice daily for 2 days and her transplant was postponed. Her rash resolved, but 2 weeks later, her white blood cell count was 5.6X103/µL, with 11.6% eosinophils. She was subsequently treated with a single dose of 200 µg/kg of ivermectin. Results of a complete blood count obtained 2 weeks later demonstrated that her eosinophil count was within reference range and she was able to proceed with the transplant. The patient's sister (the donor) also was born in Panama and had negative serologic evaluation results for Strongyloides. The patient did well following the transplant and the results of repeat serologic evaluations performed 4 months after the transplant were negative for Strongyloides.

Comment

Strongyloides stercoralis is an intestinal nematode primarily found in tropical or subtropical countries. Humans are infected by filariform larvae that dwell in the soil. Larvae penetrate intact skin, gain access to the venous system, pass through the heart to the lungs, enter the pulmonary alveoli, migrate up the tracheobronchial tree, and are swallowed, thereby entering the gastrointestinal tract.¹ The larvae mature into adult females that penetrate the mucosa of the small intestine and deposit eggs. The eggs hatch into rhabditiform larvae that are passed in the stool to the soil where transformation into the infective form (filariform) occurs. Autoinfection may take place when this transformation to the infective-stage larvae occurs within the gastrointestinal tract, enabling the infective larvae to invade the lower large bowel or perianal skin and begin the migratory pathway. Autoinfection can allow the persistence of infection for long periods of time and also can allow chronic infections to persist in climates where free-living larvae cannot survive.²

Uncomplicated infection with S stercoralis can cause cutaneous, gastrointestinal tract, and pulmonary symptoms corresponding to the involvement of organs during the parasite's life cycle. Rash is uncommon in acute infection, though it is common in chronic disease. Maculopapular eruptions and chronic urticaria have been reported in up to two-thirds of patients.³ Larva currens is a migratory, rapidly extending, serpiginous, urticarial lesion that is pathognomonic for chronic strongyloidiasis. The rash typically lasts from several hours to several days. It most commonly affects the buttocks, perineum, and thighs, and is secondary to invasion of perianal skin by filariform larvae from the patient's intestine. Arthur and Shelley⁴ proposed the term larva currens (running larva) because the larvae and subsequent rash can move up to 10 cm per hour.

In a healthy host, the cellular immune system seems to limit parasite invasion of mucosal tissues.⁵ If immunosuppression occurs, individuals with strongyloidiasis can develop a hyperinfective syndrome and massive numbers of larvae can invade any organ of the body, with a mortality rate of 70% to 90%.^6,7 The cutaneous manifestation of disseminated strongyloidiasis is the rapid onset of a petechial and purpuric eruption that typically involves the proximal extremities and trunk and results from massive invasion of the skin by filariform larvae. The "thumbprint sign" refers to a pattern of periumbilical ecchymoses resembling multiple thumbprints that can occur in hyperinfection.⁸

Gastrointestinal tract symptoms predominate in acute infection. Diarrhea and midepigastric pain that may mimic peptic ulcer disease are common. Diarrhea also can alternate with constipation. Other gastrointestinal tract symptoms include nausea, vomiting, anorexia, pruritus ani, and bloating.¹ Some severe cases can have malabsorption and evidence of a protein-losing enteropathy.^9,10

Pulmonary symptoms in acute infection can occur and include wheezing, coughing, and shortness of breath.1 Larval migration through the lungs also can lead to transient pulmonary infiltrates. Some patients have presented with asthma.¹¹ Patients with chronic disease may have gastrointestinal tract and pulmonary symptoms, though chronic infection tends to be indolent and patients may be asymptomatic.

Diagnosis can be difficult, as results from stool samples often are negative and multiple samples may be required. Results of biopsies performed on larva currens specimens usually do not reveal larvae, though biopsy results of the petechial and purpuric eruptions of disseminated disease will reveal larvae. Serologic testing with enzyme-linked immunosorbent assay has a sensitivity of approximately 90%.^12,13

Traditionally, thiabendazole has been used to treat this infection, though in approximately 30% of cases, the parasite is not eradicated from the feces. Ivermectin has been found to be more effective for treating uncomplicated chronic disease.¹⁴

In most cases of disseminated disease, patients were receiving corticosteroids or other immunosuppressive drugs or had an underlying illness, such as malignancy or AIDS.^1,2,15,16 Our patient was scheduled to undergo a renal transplant and fatal disseminated strongyloidiasis has been reported in patients undergoing renal transplant.^2,16 Morgan et al² reviewed 29 cases of strongyloidiasis complicating renal transplants; 15 patients died.

Infection in the immunocompromised patient can be complicated by the fact that invasive larvae can transport gram-negative bacilli from the intestine to sites of migration, such as the pulmonary and central nervous systems.⁵ Gram-negative sepsis, meningitis, or pneumonia can result. Diagnosis can be difficult because eosinophilia often is absent in immunocompromised patients with disseminated disease.⁵

Although common in tropical and subtropical countries, other geographic regions of endemic Strongyloides are recognized. The climate and soil of the southeastern United States favor the survival of the organism,⁵ and the parasite was reported in 3% (N=561) of a group of rural Kentucky schoolchildren¹⁷; similar findings were reported in another study conducted in Kentucky.¹⁸Strongyloides also was the most commonly detected parasite in a review of stool samples examined at the University of Kentucky Medical Center.¹⁹ Ex–prisoners of war who served in Southeast Asia during World War II also constitute an at-risk group in the United States.^20-22

It is imperative to rule out the presence of this parasite prior to transplant in patients with a geographic history predisposing them to infection, a history of eosinophilia, or symptoms of chronic strongyloidiasis.¹ Many transplantation centers routinely screen for this parasite as part of the pretransplant evaluation. Although uncommon in acute infections, cutaneous involvement often is present in chronic strongyloidiasis.¹ It also is important to follow patients already treated for larva currens closely posttransplant, as therapeutic failures occur.

Q When we manage a patient in the hospital for premature rupture of membranes (PROM), we might decide to treat her medically or, depending on fetal age, progress to delivery at admission. Can we legitimately bill for these inpatient services outside of the global obstetric package?

A As with most issues dealing with obstetric care, the payer has the final word on what can and cannot be billed outside of global care. In the situation you describe or, for that matter, admission for any complication of pregnancy, payers generally reimburse for hospital care that occurs before the date of delivery. That includes admission and subsequent care. If you admit the patient for PROM and she goes on to deliver that day, your chances of being reimbursed for the admission diminish considerably—unless your documentation shows considerable work on your part to stop contractions and labor.

BSO for breast Ca patient—OK to code as CIS surgery?

Q I am planning to perform a laparoscopic bilateral salpingo-oophorectomy for a patient who has breast cancer. She is having surgery because she is unable to tolerate anti-estrogens. I plan on indicating the diagnosis as 233.0 and V50.42. Would these codes be correct for this surgery?

A The answer depends on whether 1) she has breast cancer now or 2) she already had treatment and you are planning the surgery to remove structures that are causing the estrogen risk. Reporting 233.0 (carcinoma in situ of the breast) signifies she has breast cancer now, and is still in treatment. If that is not the case—if treatment for in situ cancer has been completed—she instead has a history of the condition (V10.3). This coding rule can be found in the ICD-9-CM official guidelines.

In any case, your primary diagnosis would be V50.42 (prophylactic organ removal, ovary), followed by V10.3, then followed by V86.1 because she is probably estrogen-receptor positive (meaning that taking anti-estrogens will not prevent the return of cancer).

If she is still being treated for cancer in situ, then 233.0 is correct but V50.42 needs to be the primary diagnosis because, otherwise, you get a mismatch between the diagnosis and the surgery (i.e., it appears that you are performing an oophorectomy because of breast cancer).

Q When we manage a patient in the hospital for premature rupture of membranes (PROM), we might decide to treat her medically or, depending on fetal age, progress to delivery at admission. Can we legitimately bill for these inpatient services outside of the global obstetric package?

A As with most issues dealing with obstetric care, the payer has the final word on what can and cannot be billed outside of global care. In the situation you describe or, for that matter, admission for any complication of pregnancy, payers generally reimburse for hospital care that occurs before the date of delivery. That includes admission and subsequent care. If you admit the patient for PROM and she goes on to deliver that day, your chances of being reimbursed for the admission diminish considerably—unless your documentation shows considerable work on your part to stop contractions and labor.

BSO for breast Ca patient—OK to code as CIS surgery?

Q I am planning to perform a laparoscopic bilateral salpingo-oophorectomy for a patient who has breast cancer. She is having surgery because she is unable to tolerate anti-estrogens. I plan on indicating the diagnosis as 233.0 and V50.42. Would these codes be correct for this surgery?

A The answer depends on whether 1) she has breast cancer now or 2) she already had treatment and you are planning the surgery to remove structures that are causing the estrogen risk. Reporting 233.0 (carcinoma in situ of the breast) signifies she has breast cancer now, and is still in treatment. If that is not the case—if treatment for in situ cancer has been completed—she instead has a history of the condition (V10.3). This coding rule can be found in the ICD-9-CM official guidelines.

In any case, your primary diagnosis would be V50.42 (prophylactic organ removal, ovary), followed by V10.3, then followed by V86.1 because she is probably estrogen-receptor positive (meaning that taking anti-estrogens will not prevent the return of cancer).

If she is still being treated for cancer in situ, then 233.0 is correct but V50.42 needs to be the primary diagnosis because, otherwise, you get a mismatch between the diagnosis and the surgery (i.e., it appears that you are performing an oophorectomy because of breast cancer).

Q When we manage a patient in the hospital for premature rupture of membranes (PROM), we might decide to treat her medically or, depending on fetal age, progress to delivery at admission. Can we legitimately bill for these inpatient services outside of the global obstetric package?

A As with most issues dealing with obstetric care, the payer has the final word on what can and cannot be billed outside of global care. In the situation you describe or, for that matter, admission for any complication of pregnancy, payers generally reimburse for hospital care that occurs before the date of delivery. That includes admission and subsequent care. If you admit the patient for PROM and she goes on to deliver that day, your chances of being reimbursed for the admission diminish considerably—unless your documentation shows considerable work on your part to stop contractions and labor.

BSO for breast Ca patient—OK to code as CIS surgery?

Q I am planning to perform a laparoscopic bilateral salpingo-oophorectomy for a patient who has breast cancer. She is having surgery because she is unable to tolerate anti-estrogens. I plan on indicating the diagnosis as 233.0 and V50.42. Would these codes be correct for this surgery?

A The answer depends on whether 1) she has breast cancer now or 2) she already had treatment and you are planning the surgery to remove structures that are causing the estrogen risk. Reporting 233.0 (carcinoma in situ of the breast) signifies she has breast cancer now, and is still in treatment. If that is not the case—if treatment for in situ cancer has been completed—she instead has a history of the condition (V10.3). This coding rule can be found in the ICD-9-CM official guidelines.

In any case, your primary diagnosis would be V50.42 (prophylactic organ removal, ovary), followed by V10.3, then followed by V86.1 because she is probably estrogen-receptor positive (meaning that taking anti-estrogens will not prevent the return of cancer).

If she is still being treated for cancer in situ, then 233.0 is correct but V50.42 needs to be the primary diagnosis because, otherwise, you get a mismatch between the diagnosis and the surgery (i.e., it appears that you are performing an oophorectomy because of breast cancer).

Q We often are denied for ultrasonography (US) scans performed for pelvic pain (625.9). This is one of the symptoms that may indicate a problem with the uterus or ovaries, so why isn’t the payer allowing this diagnosis?

A For many payers, a diagnosis of 625.9 represents an unspecific symptom that can turn out to be something—or nothing at all. In the absence of additional diagnosis codes that more strongly indicate the need for US, many believe that medical necessity is not established.

If the patient can pinpoint which quadrant the pain is in, a better option is to report 789.0X (abdominal pain; the fifth [X] digit reports the site, such as left lower-quadrant or right upper-quadrant, etc.). Using this code more specifically identifies the complaint and location; I have found that fewer payers deny a US scan when this code is reported.

Problem with -52 modifier for US follicle evaluation

Q Our infertility practice often performs transvaginal US scans to check for follicles. We have been billing 76830 (ultrasound, transvaginal) with a -52 modifier (reduced service) instead of 76857 (ultrasound, pelvic [nonobstetric], real time with image documentation; limited or follow-up [e.g., for follicles]) and, so far, have had no problems getting paid. We also perform 76817 (ultrasound, pregnant uterus, real time with image documentation, transvaginal) with a modifier -52 for cervical checks or 76830 for endometrial thickness checks.

Can you comment on our coding strategies for these services?

A You say you are being reimbursed with “no problems”—but have you checked to see if you are being reimbursed at a reduced level? Not all payer systems do anything with a modifier -52, by way of reducing the allowed amount; if you are not being asked for additional information about the amount of work you did perform, I suspect you are being paid for the full service. This constitutes an overpayment to you for a service you did not document, according to CPT requirements.

Among payers that recognize -52, almost all put the claim into manual review before payment. If you are being paid a reduced amount, have you compared it with the reimbursement you might be getting by reporting 76857 instead? Note that neither code 76857 (which specifies checking for follicles) nor code 76815 (which specifies a limited exam such as you would perform for a quick cervical check on a pregnant patient) specifies the approach—in other words, the word “pelvic” does not imply strictly a transabdominal approach. These codes can therefore be used to report either an abdominal or transvaginal scan. In my opinion, either code more accurately describes the procedures that you are performing.

Dx/procedure mismatch when checking for fibroids

Q For an obstetric patient with fibroids, we just performed a Doppler ultrasound scan to check the vascularity of the fibroid. Can we use code 93975 (duplex scan of arterial inflow and venous outflow of abdominal, pelvic, scrotal contents and/or retroperitoneal organs; complete study) with an obstetric US code?

A Yes. You may report a duplex-Doppler scan with an obstetric US procedure because there are no bundles within the National Correct Coding Initiative that preclude your doing so. But your diagnosis code will be taken from the obstetric complications chapter (e.g., 654.13, tumors of body of uterus), which may create a mismatch in the diagnosis/procedure check in the payer’s computer. This doesn’t mean you won’t be paid for the nonobstetric sonogram being linked to an obstetric complication, but you might have to submit additional information with the claim.

Also, understand that the duplex procedures are only reported when you are trying to characterize the pattern and direction of blood flow in arteries or veins. This year, CPT clarified that, although evaluation of vascular structures using both color and spectral Doppler is reportable separately, color Doppler alone, when performed for identification of anatomic structures in conjunction with a real-time US exam, cannot be reported separately.

Last, the code you are billing, 93975, represents a complete study. Examination of a single fibroid within the uterus constitutes a limited study, billed using 93976.

Q We often are denied for ultrasonography (US) scans performed for pelvic pain (625.9). This is one of the symptoms that may indicate a problem with the uterus or ovaries, so why isn’t the payer allowing this diagnosis?

A For many payers, a diagnosis of 625.9 represents an unspecific symptom that can turn out to be something—or nothing at all. In the absence of additional diagnosis codes that more strongly indicate the need for US, many believe that medical necessity is not established.

If the patient can pinpoint which quadrant the pain is in, a better option is to report 789.0X (abdominal pain; the fifth [X] digit reports the site, such as left lower-quadrant or right upper-quadrant, etc.). Using this code more specifically identifies the complaint and location; I have found that fewer payers deny a US scan when this code is reported.

Problem with -52 modifier for US follicle evaluation

Q Our infertility practice often performs transvaginal US scans to check for follicles. We have been billing 76830 (ultrasound, transvaginal) with a -52 modifier (reduced service) instead of 76857 (ultrasound, pelvic [nonobstetric], real time with image documentation; limited or follow-up [e.g., for follicles]) and, so far, have had no problems getting paid. We also perform 76817 (ultrasound, pregnant uterus, real time with image documentation, transvaginal) with a modifier -52 for cervical checks or 76830 for endometrial thickness checks.

Can you comment on our coding strategies for these services?

A You say you are being reimbursed with “no problems”—but have you checked to see if you are being reimbursed at a reduced level? Not all payer systems do anything with a modifier -52, by way of reducing the allowed amount; if you are not being asked for additional information about the amount of work you did perform, I suspect you are being paid for the full service. This constitutes an overpayment to you for a service you did not document, according to CPT requirements.

Among payers that recognize -52, almost all put the claim into manual review before payment. If you are being paid a reduced amount, have you compared it with the reimbursement you might be getting by reporting 76857 instead? Note that neither code 76857 (which specifies checking for follicles) nor code 76815 (which specifies a limited exam such as you would perform for a quick cervical check on a pregnant patient) specifies the approach—in other words, the word “pelvic” does not imply strictly a transabdominal approach. These codes can therefore be used to report either an abdominal or transvaginal scan. In my opinion, either code more accurately describes the procedures that you are performing.

Dx/procedure mismatch when checking for fibroids

Q For an obstetric patient with fibroids, we just performed a Doppler ultrasound scan to check the vascularity of the fibroid. Can we use code 93975 (duplex scan of arterial inflow and venous outflow of abdominal, pelvic, scrotal contents and/or retroperitoneal organs; complete study) with an obstetric US code?

A Yes. You may report a duplex-Doppler scan with an obstetric US procedure because there are no bundles within the National Correct Coding Initiative that preclude your doing so. But your diagnosis code will be taken from the obstetric complications chapter (e.g., 654.13, tumors of body of uterus), which may create a mismatch in the diagnosis/procedure check in the payer’s computer. This doesn’t mean you won’t be paid for the nonobstetric sonogram being linked to an obstetric complication, but you might have to submit additional information with the claim.

Also, understand that the duplex procedures are only reported when you are trying to characterize the pattern and direction of blood flow in arteries or veins. This year, CPT clarified that, although evaluation of vascular structures using both color and spectral Doppler is reportable separately, color Doppler alone, when performed for identification of anatomic structures in conjunction with a real-time US exam, cannot be reported separately.

Last, the code you are billing, 93975, represents a complete study. Examination of a single fibroid within the uterus constitutes a limited study, billed using 93976.

Q We often are denied for ultrasonography (US) scans performed for pelvic pain (625.9). This is one of the symptoms that may indicate a problem with the uterus or ovaries, so why isn’t the payer allowing this diagnosis?

A For many payers, a diagnosis of 625.9 represents an unspecific symptom that can turn out to be something—or nothing at all. In the absence of additional diagnosis codes that more strongly indicate the need for US, many believe that medical necessity is not established.

If the patient can pinpoint which quadrant the pain is in, a better option is to report 789.0X (abdominal pain; the fifth [X] digit reports the site, such as left lower-quadrant or right upper-quadrant, etc.). Using this code more specifically identifies the complaint and location; I have found that fewer payers deny a US scan when this code is reported.

Problem with -52 modifier for US follicle evaluation

Q Our infertility practice often performs transvaginal US scans to check for follicles. We have been billing 76830 (ultrasound, transvaginal) with a -52 modifier (reduced service) instead of 76857 (ultrasound, pelvic [nonobstetric], real time with image documentation; limited or follow-up [e.g., for follicles]) and, so far, have had no problems getting paid. We also perform 76817 (ultrasound, pregnant uterus, real time with image documentation, transvaginal) with a modifier -52 for cervical checks or 76830 for endometrial thickness checks.

Can you comment on our coding strategies for these services?

A You say you are being reimbursed with “no problems”—but have you checked to see if you are being reimbursed at a reduced level? Not all payer systems do anything with a modifier -52, by way of reducing the allowed amount; if you are not being asked for additional information about the amount of work you did perform, I suspect you are being paid for the full service. This constitutes an overpayment to you for a service you did not document, according to CPT requirements.

Among payers that recognize -52, almost all put the claim into manual review before payment. If you are being paid a reduced amount, have you compared it with the reimbursement you might be getting by reporting 76857 instead? Note that neither code 76857 (which specifies checking for follicles) nor code 76815 (which specifies a limited exam such as you would perform for a quick cervical check on a pregnant patient) specifies the approach—in other words, the word “pelvic” does not imply strictly a transabdominal approach. These codes can therefore be used to report either an abdominal or transvaginal scan. In my opinion, either code more accurately describes the procedures that you are performing.

Dx/procedure mismatch when checking for fibroids

Q For an obstetric patient with fibroids, we just performed a Doppler ultrasound scan to check the vascularity of the fibroid. Can we use code 93975 (duplex scan of arterial inflow and venous outflow of abdominal, pelvic, scrotal contents and/or retroperitoneal organs; complete study) with an obstetric US code?

A Yes. You may report a duplex-Doppler scan with an obstetric US procedure because there are no bundles within the National Correct Coding Initiative that preclude your doing so. But your diagnosis code will be taken from the obstetric complications chapter (e.g., 654.13, tumors of body of uterus), which may create a mismatch in the diagnosis/procedure check in the payer’s computer. This doesn’t mean you won’t be paid for the nonobstetric sonogram being linked to an obstetric complication, but you might have to submit additional information with the claim.

Also, understand that the duplex procedures are only reported when you are trying to characterize the pattern and direction of blood flow in arteries or veins. This year, CPT clarified that, although evaluation of vascular structures using both color and spectral Doppler is reportable separately, color Doppler alone, when performed for identification of anatomic structures in conjunction with a real-time US exam, cannot be reported separately.

Last, the code you are billing, 93975, represents a complete study. Examination of a single fibroid within the uterus constitutes a limited study, billed using 93976.

Researchers have discovered the mechanism behind the deaths and adverse events that occurred in patients receiving contaminated heparin.

In March, a team led by Ram Sasisekharan, PhD, of Massachusetts Institute of Technology in Cambridge, identified the contaminant responsible for the numerous adverse events and 81 deaths that have occurred since November 2007 in patients receiving heparin.

Now, Dr Sasisekharan and colleagues have identified the mechanism by which the contaminant, oversulfated chondroitin sulfate (OSCS), works. This finding was published in New England Journal of Medicine April 24.

The researchers found that OSCS activated the kinin-kallikrein pathway in human plasma, which can lead to the generation of the potent vasoactive mediator bradykinin. In addition, OSCS induced generation of C3a and C5a, which are potent anaphylatoxins derived from complement proteins.

Dr Sasisekharan’s team arrived at these conclusions by testing 29 lots of heparin obtained from the FDA. Thirteen of these lots had been associated with adverse events. A laboratory lot was also included to serve as a control.

In a blinded fashion, the researchers screened the heparin for the existence of OSCS. They then tested the effects heparin contaminated with 19.3% wt/wt OSCS had on human plasma.

At 2.5 µg/mL and 25 µg/mL, contaminated heparin showed activation of kallikrein, while the same doses of uncontaminated heparin did not.

At 250 µg/mL, the contaminated heparin did not demonstrate activation of kallikrein. Dr Sasisekharan and colleagues said this suggests that, at a high concentration, heparin may inhibit or cause the depletion of factor XII.

The researchers next examined the contaminated heparin for its ability to generate C3a and C5a. At 5 µg/mL and 50 µg/mL, contaminated heparin generated C5a, whereas the same doses of uncontaminated heparin did not. At 500 µg/mL, the contaminated heparin did not generate significant amounts of C5a.

Dr Sasisekharan and colleagues also found that activation of C3a and C5a were linked and dependent upon fluid-phase activation of factor XII.

To ensure the accuracy of these results, the researchers created synthetic OSCS via chemical sulfonation of chondroitin sulfate. This synthetic OSCS behaved in the same manner as the OSCS found in the contaminated lots of heparin— demonstrating activation of kallikrein and generating C3a and C5a.

In an attempt to better understand the effects of OSCS, the team tested their results on swine. Swine were chosen because their reactions to contaminated heparin were similar to those observed in humans.

Each pig received an infusion of 5mg of one of the following substances: control heparin, contaminated heparin, chondroitin sulfate A, or synthetic OSCS. The researchers monitored the pigs’ vital signs for an hour before the animals were euthanized. The team collected blood samples at baseline and 5, 10, 20, 40, and 60 minutes.

Six pigs received contaminated heparin. Of these, 2 experienced at least a 30% drop in blood pressure within the first 30 minutes after infusion. One pig experienced hypotension for more than 15 minutes.

In the pigs that received synthetic OSCS, adverse events were more severe. This was expected, as the dose of OSCS in this group was higher than that in the group of pigs receiving contaminated heparin. All pigs given synthetic OSCS experienced a profound drop in blood pressure and an increased heart rate. One pig had difficulty breathing.

None of the pigs given control heparin or chondroitin sulfate A experienced any adverse events.

Dr Sasisekharan and colleagues said the results of this study suggest that a simple in vitro bioassay could complement the tests currently used in the screening of heparin. This bioassay would uncover the presence of OSCS and other polysulfated contaminants that might cause patients harm.

Researchers have discovered the mechanism behind the deaths and adverse events that occurred in patients receiving contaminated heparin.

In March, a team led by Ram Sasisekharan, PhD, of Massachusetts Institute of Technology in Cambridge, identified the contaminant responsible for the numerous adverse events and 81 deaths that have occurred since November 2007 in patients receiving heparin.

Now, Dr Sasisekharan and colleagues have identified the mechanism by which the contaminant, oversulfated chondroitin sulfate (OSCS), works. This finding was published in New England Journal of Medicine April 24.

The researchers found that OSCS activated the kinin-kallikrein pathway in human plasma, which can lead to the generation of the potent vasoactive mediator bradykinin. In addition, OSCS induced generation of C3a and C5a, which are potent anaphylatoxins derived from complement proteins.

Dr Sasisekharan’s team arrived at these conclusions by testing 29 lots of heparin obtained from the FDA. Thirteen of these lots had been associated with adverse events. A laboratory lot was also included to serve as a control.

In a blinded fashion, the researchers screened the heparin for the existence of OSCS. They then tested the effects heparin contaminated with 19.3% wt/wt OSCS had on human plasma.

At 2.5 µg/mL and 25 µg/mL, contaminated heparin showed activation of kallikrein, while the same doses of uncontaminated heparin did not.

At 250 µg/mL, the contaminated heparin did not demonstrate activation of kallikrein. Dr Sasisekharan and colleagues said this suggests that, at a high concentration, heparin may inhibit or cause the depletion of factor XII.

The researchers next examined the contaminated heparin for its ability to generate C3a and C5a. At 5 µg/mL and 50 µg/mL, contaminated heparin generated C5a, whereas the same doses of uncontaminated heparin did not. At 500 µg/mL, the contaminated heparin did not generate significant amounts of C5a.

Dr Sasisekharan and colleagues also found that activation of C3a and C5a were linked and dependent upon fluid-phase activation of factor XII.

To ensure the accuracy of these results, the researchers created synthetic OSCS via chemical sulfonation of chondroitin sulfate. This synthetic OSCS behaved in the same manner as the OSCS found in the contaminated lots of heparin— demonstrating activation of kallikrein and generating C3a and C5a.

In an attempt to better understand the effects of OSCS, the team tested their results on swine. Swine were chosen because their reactions to contaminated heparin were similar to those observed in humans.

Each pig received an infusion of 5mg of one of the following substances: control heparin, contaminated heparin, chondroitin sulfate A, or synthetic OSCS. The researchers monitored the pigs’ vital signs for an hour before the animals were euthanized. The team collected blood samples at baseline and 5, 10, 20, 40, and 60 minutes.

Six pigs received contaminated heparin. Of these, 2 experienced at least a 30% drop in blood pressure within the first 30 minutes after infusion. One pig experienced hypotension for more than 15 minutes.

In the pigs that received synthetic OSCS, adverse events were more severe. This was expected, as the dose of OSCS in this group was higher than that in the group of pigs receiving contaminated heparin. All pigs given synthetic OSCS experienced a profound drop in blood pressure and an increased heart rate. One pig had difficulty breathing.

None of the pigs given control heparin or chondroitin sulfate A experienced any adverse events.

Dr Sasisekharan and colleagues said the results of this study suggest that a simple in vitro bioassay could complement the tests currently used in the screening of heparin. This bioassay would uncover the presence of OSCS and other polysulfated contaminants that might cause patients harm.

Researchers have discovered the mechanism behind the deaths and adverse events that occurred in patients receiving contaminated heparin.

In March, a team led by Ram Sasisekharan, PhD, of Massachusetts Institute of Technology in Cambridge, identified the contaminant responsible for the numerous adverse events and 81 deaths that have occurred since November 2007 in patients receiving heparin.

Now, Dr Sasisekharan and colleagues have identified the mechanism by which the contaminant, oversulfated chondroitin sulfate (OSCS), works. This finding was published in New England Journal of Medicine April 24.

The researchers found that OSCS activated the kinin-kallikrein pathway in human plasma, which can lead to the generation of the potent vasoactive mediator bradykinin. In addition, OSCS induced generation of C3a and C5a, which are potent anaphylatoxins derived from complement proteins.

Dr Sasisekharan’s team arrived at these conclusions by testing 29 lots of heparin obtained from the FDA. Thirteen of these lots had been associated with adverse events. A laboratory lot was also included to serve as a control.

In a blinded fashion, the researchers screened the heparin for the existence of OSCS. They then tested the effects heparin contaminated with 19.3% wt/wt OSCS had on human plasma.

At 2.5 µg/mL and 25 µg/mL, contaminated heparin showed activation of kallikrein, while the same doses of uncontaminated heparin did not.

At 250 µg/mL, the contaminated heparin did not demonstrate activation of kallikrein. Dr Sasisekharan and colleagues said this suggests that, at a high concentration, heparin may inhibit or cause the depletion of factor XII.

The researchers next examined the contaminated heparin for its ability to generate C3a and C5a. At 5 µg/mL and 50 µg/mL, contaminated heparin generated C5a, whereas the same doses of uncontaminated heparin did not. At 500 µg/mL, the contaminated heparin did not generate significant amounts of C5a.

Dr Sasisekharan and colleagues also found that activation of C3a and C5a were linked and dependent upon fluid-phase activation of factor XII.

To ensure the accuracy of these results, the researchers created synthetic OSCS via chemical sulfonation of chondroitin sulfate. This synthetic OSCS behaved in the same manner as the OSCS found in the contaminated lots of heparin— demonstrating activation of kallikrein and generating C3a and C5a.

In an attempt to better understand the effects of OSCS, the team tested their results on swine. Swine were chosen because their reactions to contaminated heparin were similar to those observed in humans.

Each pig received an infusion of 5mg of one of the following substances: control heparin, contaminated heparin, chondroitin sulfate A, or synthetic OSCS. The researchers monitored the pigs’ vital signs for an hour before the animals were euthanized. The team collected blood samples at baseline and 5, 10, 20, 40, and 60 minutes.

Six pigs received contaminated heparin. Of these, 2 experienced at least a 30% drop in blood pressure within the first 30 minutes after infusion. One pig experienced hypotension for more than 15 minutes.

In the pigs that received synthetic OSCS, adverse events were more severe. This was expected, as the dose of OSCS in this group was higher than that in the group of pigs receiving contaminated heparin. All pigs given synthetic OSCS experienced a profound drop in blood pressure and an increased heart rate. One pig had difficulty breathing.

None of the pigs given control heparin or chondroitin sulfate A experienced any adverse events.

Dr Sasisekharan and colleagues said the results of this study suggest that a simple in vitro bioassay could complement the tests currently used in the screening of heparin. This bioassay would uncover the presence of OSCS and other polysulfated contaminants that might cause patients harm.