STEAMBOAT SPRINGS, COLO. – Make lidocaine, epinephrine, and tetracaine gel your choice for pain control when repairing lacerations in children, Dr. Steven M. Selbst said.

Adoption of LET gel for routine use in wound repair may be the single most important change in practice that physicians can make in terms of analgesia for children, said Dr. Steven M. Selbst, professor and vice chair of pediatrics at Jefferson Medical College, Philadelphia.

©Andrew Penner/iStockphoto.com

"Even if you don’t suture wounds in your office, I think it’s key to try to make sure that the emergency department near your office uses LET in wound repair for children. It’s an incredible agent. I’ve been using it for 20 years, and I know it has been around for longer than that. I’ve seen so many anxious kids who are scared to death of having a wound repair with suturing that have had a completely painless repair with LET without any injection whatsoever. To me it’s amazing that some hospitals still don’t use LET," said Dr. Selbst, who is chair of the executive committee of the American Academy of Pediatrics Section on Pediatric Emergency Medicine.

The advantages of pharmacist-compounded LET gel over commercially available anesthetic creams, such as eutectic mixture of local anesthetics (EMLA) and lidocaine 4% (LMX-4), include much lower cost and a good anesthetic response within 20-30 minutes after LET is applied. In contrast, EMLA requires 60 minutes of contact, making it less practical for laceration repair. LET is as effective as tetracaine, adrenaline, and cocaine (TAC) solution, but it costs less and has less morbidity, he said at the meeting.

Once the treated site shows blanching due to LET’s vasoconstrictive activity, the physician can proceed with pain-free suturing, even on the face and scalp.

The gel formulation of LET contains 10 mL of injectable lidocaine 20%, 5 mL of racemic epinephrine, 12.5 mL of tetracaine hydrochloride 2%, 31.5 mg of sodium metabisulfite, and methylcellulose gel 5% added in sufficient quantity to bring the total volume to 50 mL. The ingredients are stirred or shaken until completely mixed, which takes about 2-3 minutes.

The LET gel remains stable for 4 weeks at room temperature or for 6 months if refrigerated.

"You can apply the gel directly to the wound or put it on cotton gauze and tape it to the wound. Use a generous amount," Dr. Selbst said.

Numerous studies have documented that inadequate pain control is far more common in children with painful conditions than in adults. Children with lower-extremity fractures, serious burns, or sickle cell crises were less than half as likely to get analgesics in the emergency department, compared with adults with the same conditions, according to an earlier study done by Dr. Selbst and a colleague. They also found that kids younger than 2 years got analgesics less frequently than older children (Ann. Emerg. Med. 1990;19:1010-3).

Recent studies indicate this gap has narrowed somewhat, although inadequate dosing of analgesics in children continues to be a problem. Possible explanations include the inability of infants and young children to verbalize, the disproved myth that babies don’t feel or remember pain, and fear of causing respiratory depression or addiction, although there is no evidence that giving a single dose of a narcotic for an acute painful condition is associated with an increased risk of addiction, Dr. Selbst emphasized.

He reported having no financial conflicts.

STEAMBOAT SPRINGS, COLO. – Make lidocaine, epinephrine, and tetracaine gel your choice for pain control when repairing lacerations in children, Dr. Steven M. Selbst said.

Adoption of LET gel for routine use in wound repair may be the single most important change in practice that physicians can make in terms of analgesia for children, said Dr. Steven M. Selbst, professor and vice chair of pediatrics at Jefferson Medical College, Philadelphia.

©Andrew Penner/iStockphoto.com

"Even if you don’t suture wounds in your office, I think it’s key to try to make sure that the emergency department near your office uses LET in wound repair for children. It’s an incredible agent. I’ve been using it for 20 years, and I know it has been around for longer than that. I’ve seen so many anxious kids who are scared to death of having a wound repair with suturing that have had a completely painless repair with LET without any injection whatsoever. To me it’s amazing that some hospitals still don’t use LET," said Dr. Selbst, who is chair of the executive committee of the American Academy of Pediatrics Section on Pediatric Emergency Medicine.

The advantages of pharmacist-compounded LET gel over commercially available anesthetic creams, such as eutectic mixture of local anesthetics (EMLA) and lidocaine 4% (LMX-4), include much lower cost and a good anesthetic response within 20-30 minutes after LET is applied. In contrast, EMLA requires 60 minutes of contact, making it less practical for laceration repair. LET is as effective as tetracaine, adrenaline, and cocaine (TAC) solution, but it costs less and has less morbidity, he said at the meeting.

Once the treated site shows blanching due to LET’s vasoconstrictive activity, the physician can proceed with pain-free suturing, even on the face and scalp.

The gel formulation of LET contains 10 mL of injectable lidocaine 20%, 5 mL of racemic epinephrine, 12.5 mL of tetracaine hydrochloride 2%, 31.5 mg of sodium metabisulfite, and methylcellulose gel 5% added in sufficient quantity to bring the total volume to 50 mL. The ingredients are stirred or shaken until completely mixed, which takes about 2-3 minutes.

The LET gel remains stable for 4 weeks at room temperature or for 6 months if refrigerated.

"You can apply the gel directly to the wound or put it on cotton gauze and tape it to the wound. Use a generous amount," Dr. Selbst said.

Numerous studies have documented that inadequate pain control is far more common in children with painful conditions than in adults. Children with lower-extremity fractures, serious burns, or sickle cell crises were less than half as likely to get analgesics in the emergency department, compared with adults with the same conditions, according to an earlier study done by Dr. Selbst and a colleague. They also found that kids younger than 2 years got analgesics less frequently than older children (Ann. Emerg. Med. 1990;19:1010-3).

Recent studies indicate this gap has narrowed somewhat, although inadequate dosing of analgesics in children continues to be a problem. Possible explanations include the inability of infants and young children to verbalize, the disproved myth that babies don’t feel or remember pain, and fear of causing respiratory depression or addiction, although there is no evidence that giving a single dose of a narcotic for an acute painful condition is associated with an increased risk of addiction, Dr. Selbst emphasized.

He reported having no financial conflicts.

STEAMBOAT SPRINGS, COLO. – Make lidocaine, epinephrine, and tetracaine gel your choice for pain control when repairing lacerations in children, Dr. Steven M. Selbst said.

Adoption of LET gel for routine use in wound repair may be the single most important change in practice that physicians can make in terms of analgesia for children, said Dr. Steven M. Selbst, professor and vice chair of pediatrics at Jefferson Medical College, Philadelphia.

©Andrew Penner/iStockphoto.com

"Even if you don’t suture wounds in your office, I think it’s key to try to make sure that the emergency department near your office uses LET in wound repair for children. It’s an incredible agent. I’ve been using it for 20 years, and I know it has been around for longer than that. I’ve seen so many anxious kids who are scared to death of having a wound repair with suturing that have had a completely painless repair with LET without any injection whatsoever. To me it’s amazing that some hospitals still don’t use LET," said Dr. Selbst, who is chair of the executive committee of the American Academy of Pediatrics Section on Pediatric Emergency Medicine.

The advantages of pharmacist-compounded LET gel over commercially available anesthetic creams, such as eutectic mixture of local anesthetics (EMLA) and lidocaine 4% (LMX-4), include much lower cost and a good anesthetic response within 20-30 minutes after LET is applied. In contrast, EMLA requires 60 minutes of contact, making it less practical for laceration repair. LET is as effective as tetracaine, adrenaline, and cocaine (TAC) solution, but it costs less and has less morbidity, he said at the meeting.

Once the treated site shows blanching due to LET’s vasoconstrictive activity, the physician can proceed with pain-free suturing, even on the face and scalp.

The gel formulation of LET contains 10 mL of injectable lidocaine 20%, 5 mL of racemic epinephrine, 12.5 mL of tetracaine hydrochloride 2%, 31.5 mg of sodium metabisulfite, and methylcellulose gel 5% added in sufficient quantity to bring the total volume to 50 mL. The ingredients are stirred or shaken until completely mixed, which takes about 2-3 minutes.

The LET gel remains stable for 4 weeks at room temperature or for 6 months if refrigerated.

"You can apply the gel directly to the wound or put it on cotton gauze and tape it to the wound. Use a generous amount," Dr. Selbst said.

Numerous studies have documented that inadequate pain control is far more common in children with painful conditions than in adults. Children with lower-extremity fractures, serious burns, or sickle cell crises were less than half as likely to get analgesics in the emergency department, compared with adults with the same conditions, according to an earlier study done by Dr. Selbst and a colleague. They also found that kids younger than 2 years got analgesics less frequently than older children (Ann. Emerg. Med. 1990;19:1010-3).

Recent studies indicate this gap has narrowed somewhat, although inadequate dosing of analgesics in children continues to be a problem. Possible explanations include the inability of infants and young children to verbalize, the disproved myth that babies don’t feel or remember pain, and fear of causing respiratory depression or addiction, although there is no evidence that giving a single dose of a narcotic for an acute painful condition is associated with an increased risk of addiction, Dr. Selbst emphasized.

He reported having no financial conflicts.

 

Anas Younes, MD

 

SAN FRANCISCO—The US currently has 284 open clinical trials enrolling patients with T-cell lymphomas, a fact that is actually detrimental to this patient population, according to an expert in the field.  

Anas Younes, MD, of MD Anderson Cancer Center in Houston, presented this perspective at the 4th Annual T-cell Lymphoma Forum, which took place January 26-28.

Dr Younes noted that there are 361 clinical trials worldwide that are currently accruing patients with T-cell lymphomas. Of those, 284 are taking place in the US. Less than half of the US trials are new; 124 of them have been submitted since January 2010.

The new trials are divided pretty evenly between phase 1 and phase 2—66 and 61 trials, respectively. But only 1 of the studies is a phase 3, which suggests that having such a large number of trials may be hindering drug development as well as patient treatment.

“[W]e have too many clinical trials available for a small pool of patients,” Dr Younes said. “I think it’s not a good idea to have that. We’re diluting our efforts, major trials are not able to enroll in a timely manner, and most of them will close before they even enroll [an] adequate [number of] patients.”

As an example, Dr Younes cited lymphoma trials developed at MD Anderson that were open between 2004 and 2011. The center’s accrual of follicular lymphoma patients during this period ranged from roughly 40 to 160 patients. The number of Hodgkin lymphoma patients enrolled ranged from about 25 to 110, and the number of mantle cell lymphoma patients ranged from about 30 to 70.

But the largest number of T-cell lymphoma patients enrolled was about 50 in 2007. And on the whole, the center has not enrolled more than 10 to 15 patients per year.

“And the reason is there are so many competing trials in the United States,” Dr Younes said. “By the time [patients are] referred to us, they’re either not eligible or too sick to be treated . . . . So I think it’s becoming unhealthy competition with such a large number of protocols available for these patients.”

As of right now, MD Anderson is running 5 trials for T-cell lymphoma patients (and planning to open 3 more trials soon), but patient accrual has been slow.

For instance, a trial of vorinostat plus CHOP for untreated T-cell lymphoma has been open since 2008. It has accrued 12 patients but still has 40 slots open.

And a trial of MK-2206 in relapsed or refractory T-cell lymphoma has been open since 2010. It has accrued 1 patient and has 15 slots still open.

“We’re really unable to enroll enough patients in a timely manner anymore,” Dr Younes said. “So we need to prioritize [our trials]. We need to collaborate more.”

 

Anas Younes, MD

 

SAN FRANCISCO—The US currently has 284 open clinical trials enrolling patients with T-cell lymphomas, a fact that is actually detrimental to this patient population, according to an expert in the field.  

Anas Younes, MD, of MD Anderson Cancer Center in Houston, presented this perspective at the 4th Annual T-cell Lymphoma Forum, which took place January 26-28.

Dr Younes noted that there are 361 clinical trials worldwide that are currently accruing patients with T-cell lymphomas. Of those, 284 are taking place in the US. Less than half of the US trials are new; 124 of them have been submitted since January 2010.

The new trials are divided pretty evenly between phase 1 and phase 2—66 and 61 trials, respectively. But only 1 of the studies is a phase 3, which suggests that having such a large number of trials may be hindering drug development as well as patient treatment.

“[W]e have too many clinical trials available for a small pool of patients,” Dr Younes said. “I think it’s not a good idea to have that. We’re diluting our efforts, major trials are not able to enroll in a timely manner, and most of them will close before they even enroll [an] adequate [number of] patients.”

As an example, Dr Younes cited lymphoma trials developed at MD Anderson that were open between 2004 and 2011. The center’s accrual of follicular lymphoma patients during this period ranged from roughly 40 to 160 patients. The number of Hodgkin lymphoma patients enrolled ranged from about 25 to 110, and the number of mantle cell lymphoma patients ranged from about 30 to 70.

But the largest number of T-cell lymphoma patients enrolled was about 50 in 2007. And on the whole, the center has not enrolled more than 10 to 15 patients per year.

“And the reason is there are so many competing trials in the United States,” Dr Younes said. “By the time [patients are] referred to us, they’re either not eligible or too sick to be treated . . . . So I think it’s becoming unhealthy competition with such a large number of protocols available for these patients.”

As of right now, MD Anderson is running 5 trials for T-cell lymphoma patients (and planning to open 3 more trials soon), but patient accrual has been slow.

For instance, a trial of vorinostat plus CHOP for untreated T-cell lymphoma has been open since 2008. It has accrued 12 patients but still has 40 slots open.

And a trial of MK-2206 in relapsed or refractory T-cell lymphoma has been open since 2010. It has accrued 1 patient and has 15 slots still open.

“We’re really unable to enroll enough patients in a timely manner anymore,” Dr Younes said. “So we need to prioritize [our trials]. We need to collaborate more.”

 

Anas Younes, MD

 

SAN FRANCISCO—The US currently has 284 open clinical trials enrolling patients with T-cell lymphomas, a fact that is actually detrimental to this patient population, according to an expert in the field.  

Anas Younes, MD, of MD Anderson Cancer Center in Houston, presented this perspective at the 4th Annual T-cell Lymphoma Forum, which took place January 26-28.

Dr Younes noted that there are 361 clinical trials worldwide that are currently accruing patients with T-cell lymphomas. Of those, 284 are taking place in the US. Less than half of the US trials are new; 124 of them have been submitted since January 2010.

The new trials are divided pretty evenly between phase 1 and phase 2—66 and 61 trials, respectively. But only 1 of the studies is a phase 3, which suggests that having such a large number of trials may be hindering drug development as well as patient treatment.

“[W]e have too many clinical trials available for a small pool of patients,” Dr Younes said. “I think it’s not a good idea to have that. We’re diluting our efforts, major trials are not able to enroll in a timely manner, and most of them will close before they even enroll [an] adequate [number of] patients.”

As an example, Dr Younes cited lymphoma trials developed at MD Anderson that were open between 2004 and 2011. The center’s accrual of follicular lymphoma patients during this period ranged from roughly 40 to 160 patients. The number of Hodgkin lymphoma patients enrolled ranged from about 25 to 110, and the number of mantle cell lymphoma patients ranged from about 30 to 70.

But the largest number of T-cell lymphoma patients enrolled was about 50 in 2007. And on the whole, the center has not enrolled more than 10 to 15 patients per year.

“And the reason is there are so many competing trials in the United States,” Dr Younes said. “By the time [patients are] referred to us, they’re either not eligible or too sick to be treated . . . . So I think it’s becoming unhealthy competition with such a large number of protocols available for these patients.”

As of right now, MD Anderson is running 5 trials for T-cell lymphoma patients (and planning to open 3 more trials soon), but patient accrual has been slow.

For instance, a trial of vorinostat plus CHOP for untreated T-cell lymphoma has been open since 2008. It has accrued 12 patients but still has 40 slots open.

And a trial of MK-2206 in relapsed or refractory T-cell lymphoma has been open since 2010. It has accrued 1 patient and has 15 slots still open.

“We’re really unable to enroll enough patients in a timely manner anymore,” Dr Younes said. “So we need to prioritize [our trials]. We need to collaborate more.”

Antigen therapy with glutamic acid decarboxylase 65 formulated with alum failed to induce immunologic tolerance and stem the loss of stimulated serum C-peptide in a phase III clinical trial of new-onset type 1 diabetes, according to a report in the Feb. 2 issue of the New England Journal of Medicine.

The treatment also failed to improve clinical outcomes during the 15-month study, said Dr. Johnny L. Ludvigsson of the department of clinical and experimental medicine, division of pediatrics, Linkoping (Sweden) University, and his associates.

In a previous phase II study, treatment with the 65-kD isoform of glutamic acid decarboxylase (GAD65) formulated with alum (GAD-alum) had preserved stimulated C-peptide levels and fasting C-peptide levels for 4 years in a subgroup of patients who were treated immediately after diagnosis (Diabetologia 2011;54:634-40). However, a more recent phase II trial of GAD-alum did not show any clinical benefit, the investigators noted.

Dr. Ludvigsson and his colleagues performed their phase III clinical trial at 63 clinics in Finland, France, Germany, Italy, the Netherlands, Slovenia, Spain, Sweden, and the United Kingdom. The 327 study subjects were aged 10-20 years and had been diagnosed as having type 1 diabetes within the preceding 3 months.

The patients were randomly assigned in double-blind fashion to receive one of three regimens of subcutaneous injections: four doses of GAD-alum (on days 1, 30, 90, and 270), two doses of GAD-alum (on days 1 and 30), or four doses of placebo.

The primary outcome was preservation of the stimulated serum C-peptide level after 15 months. Stimulated C-peptide levels showed progressive declines in all three groups throughout the study. The declines were not significantly different among the three groups at any time point, including at the conclusion of the study, the investigators said (N. Engl. J. Med. 2012;366:433-42).

Moreover, there were no differences among the three groups in mean daily insulin dose, glycated hemoglobin levels, or several other clinical outcomes.

The rates of adverse events also were similar among the three study groups.

"Much as treatments for diseases such as childhood cancer and immunotherapy of allergy have developed in a stepwise, gradual manner through the combination of existing therapies, treatment for type 1 diabetes will most likely be based on the knowledge gained from this and other studies, as well as future studies, of single agents or combination therapies for both intervention and prevention," Dr. Ludvigsson and his associates said.

They added that patients who develop stiff person syndrome have been shown in previous studies to carry elevated levels of GAD65 autoantibodies. In this study, all the subjects underwent periodic neurologic assessments, and no symptoms suggestive of stiff person syndrome were seen.

This study was supported by Diamyd Medical and the Swedish Child Diabetes Foundation. Dr. Ludvigsson reported ties to Johnson & Johnson, GlaxoSmithKline, Sanofi-Aventis, and Novo Nordisk; his associates reported ties to Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly, Medtronic, Tolerx, and Andromeda Biotech.

Antigen therapy with glutamic acid decarboxylase 65 formulated with alum failed to induce immunologic tolerance and stem the loss of stimulated serum C-peptide in a phase III clinical trial of new-onset type 1 diabetes, according to a report in the Feb. 2 issue of the New England Journal of Medicine.

The treatment also failed to improve clinical outcomes during the 15-month study, said Dr. Johnny L. Ludvigsson of the department of clinical and experimental medicine, division of pediatrics, Linkoping (Sweden) University, and his associates.

In a previous phase II study, treatment with the 65-kD isoform of glutamic acid decarboxylase (GAD65) formulated with alum (GAD-alum) had preserved stimulated C-peptide levels and fasting C-peptide levels for 4 years in a subgroup of patients who were treated immediately after diagnosis (Diabetologia 2011;54:634-40). However, a more recent phase II trial of GAD-alum did not show any clinical benefit, the investigators noted.

Dr. Ludvigsson and his colleagues performed their phase III clinical trial at 63 clinics in Finland, France, Germany, Italy, the Netherlands, Slovenia, Spain, Sweden, and the United Kingdom. The 327 study subjects were aged 10-20 years and had been diagnosed as having type 1 diabetes within the preceding 3 months.

The patients were randomly assigned in double-blind fashion to receive one of three regimens of subcutaneous injections: four doses of GAD-alum (on days 1, 30, 90, and 270), two doses of GAD-alum (on days 1 and 30), or four doses of placebo.

The primary outcome was preservation of the stimulated serum C-peptide level after 15 months. Stimulated C-peptide levels showed progressive declines in all three groups throughout the study. The declines were not significantly different among the three groups at any time point, including at the conclusion of the study, the investigators said (N. Engl. J. Med. 2012;366:433-42).

Moreover, there were no differences among the three groups in mean daily insulin dose, glycated hemoglobin levels, or several other clinical outcomes.

The rates of adverse events also were similar among the three study groups.

"Much as treatments for diseases such as childhood cancer and immunotherapy of allergy have developed in a stepwise, gradual manner through the combination of existing therapies, treatment for type 1 diabetes will most likely be based on the knowledge gained from this and other studies, as well as future studies, of single agents or combination therapies for both intervention and prevention," Dr. Ludvigsson and his associates said.

They added that patients who develop stiff person syndrome have been shown in previous studies to carry elevated levels of GAD65 autoantibodies. In this study, all the subjects underwent periodic neurologic assessments, and no symptoms suggestive of stiff person syndrome were seen.

This study was supported by Diamyd Medical and the Swedish Child Diabetes Foundation. Dr. Ludvigsson reported ties to Johnson & Johnson, GlaxoSmithKline, Sanofi-Aventis, and Novo Nordisk; his associates reported ties to Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly, Medtronic, Tolerx, and Andromeda Biotech.

Antigen therapy with glutamic acid decarboxylase 65 formulated with alum failed to induce immunologic tolerance and stem the loss of stimulated serum C-peptide in a phase III clinical trial of new-onset type 1 diabetes, according to a report in the Feb. 2 issue of the New England Journal of Medicine.

The treatment also failed to improve clinical outcomes during the 15-month study, said Dr. Johnny L. Ludvigsson of the department of clinical and experimental medicine, division of pediatrics, Linkoping (Sweden) University, and his associates.

In a previous phase II study, treatment with the 65-kD isoform of glutamic acid decarboxylase (GAD65) formulated with alum (GAD-alum) had preserved stimulated C-peptide levels and fasting C-peptide levels for 4 years in a subgroup of patients who were treated immediately after diagnosis (Diabetologia 2011;54:634-40). However, a more recent phase II trial of GAD-alum did not show any clinical benefit, the investigators noted.

Dr. Ludvigsson and his colleagues performed their phase III clinical trial at 63 clinics in Finland, France, Germany, Italy, the Netherlands, Slovenia, Spain, Sweden, and the United Kingdom. The 327 study subjects were aged 10-20 years and had been diagnosed as having type 1 diabetes within the preceding 3 months.

The patients were randomly assigned in double-blind fashion to receive one of three regimens of subcutaneous injections: four doses of GAD-alum (on days 1, 30, 90, and 270), two doses of GAD-alum (on days 1 and 30), or four doses of placebo.

The primary outcome was preservation of the stimulated serum C-peptide level after 15 months. Stimulated C-peptide levels showed progressive declines in all three groups throughout the study. The declines were not significantly different among the three groups at any time point, including at the conclusion of the study, the investigators said (N. Engl. J. Med. 2012;366:433-42).

Moreover, there were no differences among the three groups in mean daily insulin dose, glycated hemoglobin levels, or several other clinical outcomes.

The rates of adverse events also were similar among the three study groups.

"Much as treatments for diseases such as childhood cancer and immunotherapy of allergy have developed in a stepwise, gradual manner through the combination of existing therapies, treatment for type 1 diabetes will most likely be based on the knowledge gained from this and other studies, as well as future studies, of single agents or combination therapies for both intervention and prevention," Dr. Ludvigsson and his associates said.

They added that patients who develop stiff person syndrome have been shown in previous studies to carry elevated levels of GAD65 autoantibodies. In this study, all the subjects underwent periodic neurologic assessments, and no symptoms suggestive of stiff person syndrome were seen.

This study was supported by Diamyd Medical and the Swedish Child Diabetes Foundation. Dr. Ludvigsson reported ties to Johnson & Johnson, GlaxoSmithKline, Sanofi-Aventis, and Novo Nordisk; his associates reported ties to Merck Sharp and Dohme, Bristol-Myers Squibb, Eli Lilly, Medtronic, Tolerx, and Andromeda Biotech.

MIAMI BEACH – Cardiac and respiratory comorbidities were "common culprits" and present in more than half of thyroidectomy patients who died in the hospital, according to analysis of a large inpatient database.

Although overall mortality is less than 1% for thyroidectomy patients nationwide, researcher Rishi Vashishta said, "Patient comorbidities can often contribute to perioperative death and should really be considered when discussing treatment options with patients."

Mr. Vashishta and his associates identified 11,862 patients who underwent thyroidectomy using ICD-9 codes from the Healthcare Cost Utilization Project Nationwide Inpatient Sample (NIS) database for 2009. Two-thirds of patients were white and three-fourths were female A total of 73 of these patients died during their hospitalization that year.

"We calculated the mortality rate during hospitalization to be 0.61%," Mr. Vashishta, a medical student at George Washington University, Washington, said at the Triological Society Combined Sections meeting.

Other aims of the study were to assess thyroid surgery complications, length of stay, and total hospital charges. "There are a large number of institutional studies, but there remains a relative paucity of studies examining this procedure on a more macro and socioeconomic level," said Mr. Vashishta.

Among the nearly 12,000 admissions, mean length of stay was 2.97 days and mean total hospital charges accrued was $39,236.

In contrast, a subgroup analysis revealed mean length of stay was 13.8 days and mean increase in total hospital charges was nearly $218,855 among patients who died during hospitalization. "Interestingly, the respiratory status in these patients was markedly worse, with a tracheostomy required in 28%, prolonged mechanical ventilation required in 43%, and endotracheal intubation in 55%," Mr. Vashishta said at the meeting, which was jointly sponsored by the Triological Society and the American College of Surgeons.

Acute cerebrovascular disease was involved in 62% of deaths, he reported.

The mean age of patients who died was 65 years, compared with a mean of 53 years for all thyroidectomy patients in the study.

Approximately 80% of all surgeries in the study were elective. The majority of patients, 55%, underwent total thyroidectomy, 32% underwent unilateral lobectomy, and the remainder had partial thyroidectomy.

When Mr. Vashishta and his colleagues assessed complications, they found hypocalcemia present in 6%, vocal cord paresis in 1.4%, and hypoparathyroidism in 0.77% of patients using bivariate analyses. The incidence of hematoma and hemorrhage were low at 1.43% and 0.67%, respectively. "Our complication rates were generally consistent with those from institutional studies published in the literature."

"We found strong predictors of [these] complications during hospitalization included female gender; hospital location and teaching status; and type of thyroid diagnosis," he said. "Although the majority of cases were conducted at large teaching hospitals in urban centers, no socioeconomic or regional differences were observed," the investigators noted in their abstract but did not offer further explanation.

Admissions data showed that nontoxic nodular goiter was a diagnosis code for 36% of patients. In addition, malignant neoplasm was a code for 31% and benign neoplasm for 11%, "Graves’ disease, which we classified under acquired hypothyroidism, was much less common, around 8%," Mr. Vashishta said. ICD-9 codes for thyrotoxicosis and thyroiditis each were noted on 8% of records.

Errors in coding and sampling are a potential limitation of this and any study based on a large administrative database, Mr. Vashishta said. For example, use of ICD-9 codes "inevitably included patients in our stratified sample admitted for some other problem who underwent incidental thyroidectomies during their hospitalization." Furthermore, thyroidectomy is increasingly being performed as an outpatient procedure and the NIS is an inpatient database. "This effectively skewed our mean total charges and mean length of stay in the hospital upwards."

The study was not funded by industry. Mr. Vashishta said that he had no relevant financial disclosures.

MIAMI BEACH – Cardiac and respiratory comorbidities were "common culprits" and present in more than half of thyroidectomy patients who died in the hospital, according to analysis of a large inpatient database.

Although overall mortality is less than 1% for thyroidectomy patients nationwide, researcher Rishi Vashishta said, "Patient comorbidities can often contribute to perioperative death and should really be considered when discussing treatment options with patients."

Mr. Vashishta and his associates identified 11,862 patients who underwent thyroidectomy using ICD-9 codes from the Healthcare Cost Utilization Project Nationwide Inpatient Sample (NIS) database for 2009. Two-thirds of patients were white and three-fourths were female A total of 73 of these patients died during their hospitalization that year.

"We calculated the mortality rate during hospitalization to be 0.61%," Mr. Vashishta, a medical student at George Washington University, Washington, said at the Triological Society Combined Sections meeting.

Other aims of the study were to assess thyroid surgery complications, length of stay, and total hospital charges. "There are a large number of institutional studies, but there remains a relative paucity of studies examining this procedure on a more macro and socioeconomic level," said Mr. Vashishta.

Among the nearly 12,000 admissions, mean length of stay was 2.97 days and mean total hospital charges accrued was $39,236.

In contrast, a subgroup analysis revealed mean length of stay was 13.8 days and mean increase in total hospital charges was nearly $218,855 among patients who died during hospitalization. "Interestingly, the respiratory status in these patients was markedly worse, with a tracheostomy required in 28%, prolonged mechanical ventilation required in 43%, and endotracheal intubation in 55%," Mr. Vashishta said at the meeting, which was jointly sponsored by the Triological Society and the American College of Surgeons.

Acute cerebrovascular disease was involved in 62% of deaths, he reported.

The mean age of patients who died was 65 years, compared with a mean of 53 years for all thyroidectomy patients in the study.

Approximately 80% of all surgeries in the study were elective. The majority of patients, 55%, underwent total thyroidectomy, 32% underwent unilateral lobectomy, and the remainder had partial thyroidectomy.

When Mr. Vashishta and his colleagues assessed complications, they found hypocalcemia present in 6%, vocal cord paresis in 1.4%, and hypoparathyroidism in 0.77% of patients using bivariate analyses. The incidence of hematoma and hemorrhage were low at 1.43% and 0.67%, respectively. "Our complication rates were generally consistent with those from institutional studies published in the literature."

"We found strong predictors of [these] complications during hospitalization included female gender; hospital location and teaching status; and type of thyroid diagnosis," he said. "Although the majority of cases were conducted at large teaching hospitals in urban centers, no socioeconomic or regional differences were observed," the investigators noted in their abstract but did not offer further explanation.

Admissions data showed that nontoxic nodular goiter was a diagnosis code for 36% of patients. In addition, malignant neoplasm was a code for 31% and benign neoplasm for 11%, "Graves’ disease, which we classified under acquired hypothyroidism, was much less common, around 8%," Mr. Vashishta said. ICD-9 codes for thyrotoxicosis and thyroiditis each were noted on 8% of records.

Errors in coding and sampling are a potential limitation of this and any study based on a large administrative database, Mr. Vashishta said. For example, use of ICD-9 codes "inevitably included patients in our stratified sample admitted for some other problem who underwent incidental thyroidectomies during their hospitalization." Furthermore, thyroidectomy is increasingly being performed as an outpatient procedure and the NIS is an inpatient database. "This effectively skewed our mean total charges and mean length of stay in the hospital upwards."

The study was not funded by industry. Mr. Vashishta said that he had no relevant financial disclosures.

MIAMI BEACH – Cardiac and respiratory comorbidities were "common culprits" and present in more than half of thyroidectomy patients who died in the hospital, according to analysis of a large inpatient database.

Although overall mortality is less than 1% for thyroidectomy patients nationwide, researcher Rishi Vashishta said, "Patient comorbidities can often contribute to perioperative death and should really be considered when discussing treatment options with patients."

Mr. Vashishta and his associates identified 11,862 patients who underwent thyroidectomy using ICD-9 codes from the Healthcare Cost Utilization Project Nationwide Inpatient Sample (NIS) database for 2009. Two-thirds of patients were white and three-fourths were female A total of 73 of these patients died during their hospitalization that year.

"We calculated the mortality rate during hospitalization to be 0.61%," Mr. Vashishta, a medical student at George Washington University, Washington, said at the Triological Society Combined Sections meeting.

Other aims of the study were to assess thyroid surgery complications, length of stay, and total hospital charges. "There are a large number of institutional studies, but there remains a relative paucity of studies examining this procedure on a more macro and socioeconomic level," said Mr. Vashishta.

Among the nearly 12,000 admissions, mean length of stay was 2.97 days and mean total hospital charges accrued was $39,236.

In contrast, a subgroup analysis revealed mean length of stay was 13.8 days and mean increase in total hospital charges was nearly $218,855 among patients who died during hospitalization. "Interestingly, the respiratory status in these patients was markedly worse, with a tracheostomy required in 28%, prolonged mechanical ventilation required in 43%, and endotracheal intubation in 55%," Mr. Vashishta said at the meeting, which was jointly sponsored by the Triological Society and the American College of Surgeons.

Acute cerebrovascular disease was involved in 62% of deaths, he reported.

The mean age of patients who died was 65 years, compared with a mean of 53 years for all thyroidectomy patients in the study.

Approximately 80% of all surgeries in the study were elective. The majority of patients, 55%, underwent total thyroidectomy, 32% underwent unilateral lobectomy, and the remainder had partial thyroidectomy.

When Mr. Vashishta and his colleagues assessed complications, they found hypocalcemia present in 6%, vocal cord paresis in 1.4%, and hypoparathyroidism in 0.77% of patients using bivariate analyses. The incidence of hematoma and hemorrhage were low at 1.43% and 0.67%, respectively. "Our complication rates were generally consistent with those from institutional studies published in the literature."

"We found strong predictors of [these] complications during hospitalization included female gender; hospital location and teaching status; and type of thyroid diagnosis," he said. "Although the majority of cases were conducted at large teaching hospitals in urban centers, no socioeconomic or regional differences were observed," the investigators noted in their abstract but did not offer further explanation.

Admissions data showed that nontoxic nodular goiter was a diagnosis code for 36% of patients. In addition, malignant neoplasm was a code for 31% and benign neoplasm for 11%, "Graves’ disease, which we classified under acquired hypothyroidism, was much less common, around 8%," Mr. Vashishta said. ICD-9 codes for thyrotoxicosis and thyroiditis each were noted on 8% of records.

Errors in coding and sampling are a potential limitation of this and any study based on a large administrative database, Mr. Vashishta said. For example, use of ICD-9 codes "inevitably included patients in our stratified sample admitted for some other problem who underwent incidental thyroidectomies during their hospitalization." Furthermore, thyroidectomy is increasingly being performed as an outpatient procedure and the NIS is an inpatient database. "This effectively skewed our mean total charges and mean length of stay in the hospital upwards."

The study was not funded by industry. Mr. Vashishta said that he had no relevant financial disclosures.

STEAMBOAT SPRINGS, COLO. – In discussing a child’s weight problem with the parents, it’s best for physicians to refrain from using the terms "fat," "extremely obese," and even "obese."

"Parents find those terms undesirable. They’re stigmatizing, blaming, nonmotivating, and condescending," Dr. Paul R. Stricker said at a meeting on practical pediatrics sponsored by the American Academy of Pediatrics.

©Tom Reese/Seattle Times/Newscom

And that’s not just his personal opinion, either. He cited a recent groundbreaking study in which investigators at Yale University in New Haven, Conn., conducted a national online survey of the parents of 455 children aged 2-18 years. The purpose was to examine parental perceptions of language related to weight in order to improve the quality of physician-parent discussions about their child’s obesity. The underlying idea is that the likelihood of successful long-term weight loss is enhanced if the parents are committed to the proposed lifestyle modifications.

On a 5-point rating scale, most parents ranked "weight" and "unhealthy weight" as terms they preferred physicians to use in describing their child’s extra pounds. Moreover, the parents indicated they found the terms "unhealthy weight," "overweight," and "weight problem" to be the most motivating to lose weight, noted Dr. Stricker, a youth sports medicine specialist at the Scripps Clinic in San Diego.

On the other hand, parents perceived the terms "chubby," "fat," "obese," and "extremely obese" quite negatively, rating them as the least motivating to encourage weight loss (Pediatrics 2011;128:e786-93).

These data cast doubt on the wisdom of the British public health minister's 2010 declaration that U.K. health providers should call their obese patients "fat" to motivate them to lose weight.

As a pediatric sports medicine specialist, Dr. Stricker’s goal is to help overweight kids have a positive sports and exercise experience. He wants it to be "something they’ll want to pass along to their own children." He combines his exercise guidance with dietary instruction in weight loss, with an emphasis placed on eating multiple small meals to keep the metabolic rate revved so more calories are burned.

But lifestyle interventions don’t always work, and Dr. Stricker highlighted a recent German study that’s eye-opening as to why.

The prospective study included 111 overweight and obese 7- to 15-year-olds and their parents. The youths were referred to a 1-year-long best-practice lifestyle intervention program.

Treatment success was defined as at least a 5% weight reduction at follow-up 1 year after completing the year-long intervention. The investigators found – consistent with their study hypothesis – that psychosocial familial characteristics were significantly predictive of long-term success or failure. This was true even after the researchers controlled for familial obesity in order to cancel out the impact of genetic factors.

The strongest predictor of long-term failure for the lifestyle intervention was maternal depression. Maternal attachment insecurity and family adversity also predicted long-term treatment failure (Pediatrics 2011;128: e779-85).

These findings point to the need for further research aimed at developing lifestyle interventions for pediatric weight loss that are tailored to a family’s psychosocial dynamics, Dr. Stricker observed.

He reported having no financial conflicts.

STEAMBOAT SPRINGS, COLO. – In discussing a child’s weight problem with the parents, it’s best for physicians to refrain from using the terms "fat," "extremely obese," and even "obese."

"Parents find those terms undesirable. They’re stigmatizing, blaming, nonmotivating, and condescending," Dr. Paul R. Stricker said at a meeting on practical pediatrics sponsored by the American Academy of Pediatrics.

©Tom Reese/Seattle Times/Newscom

And that’s not just his personal opinion, either. He cited a recent groundbreaking study in which investigators at Yale University in New Haven, Conn., conducted a national online survey of the parents of 455 children aged 2-18 years. The purpose was to examine parental perceptions of language related to weight in order to improve the quality of physician-parent discussions about their child’s obesity. The underlying idea is that the likelihood of successful long-term weight loss is enhanced if the parents are committed to the proposed lifestyle modifications.

On a 5-point rating scale, most parents ranked "weight" and "unhealthy weight" as terms they preferred physicians to use in describing their child’s extra pounds. Moreover, the parents indicated they found the terms "unhealthy weight," "overweight," and "weight problem" to be the most motivating to lose weight, noted Dr. Stricker, a youth sports medicine specialist at the Scripps Clinic in San Diego.

On the other hand, parents perceived the terms "chubby," "fat," "obese," and "extremely obese" quite negatively, rating them as the least motivating to encourage weight loss (Pediatrics 2011;128:e786-93).

These data cast doubt on the wisdom of the British public health minister's 2010 declaration that U.K. health providers should call their obese patients "fat" to motivate them to lose weight.

As a pediatric sports medicine specialist, Dr. Stricker’s goal is to help overweight kids have a positive sports and exercise experience. He wants it to be "something they’ll want to pass along to their own children." He combines his exercise guidance with dietary instruction in weight loss, with an emphasis placed on eating multiple small meals to keep the metabolic rate revved so more calories are burned.

But lifestyle interventions don’t always work, and Dr. Stricker highlighted a recent German study that’s eye-opening as to why.

The prospective study included 111 overweight and obese 7- to 15-year-olds and their parents. The youths were referred to a 1-year-long best-practice lifestyle intervention program.

Treatment success was defined as at least a 5% weight reduction at follow-up 1 year after completing the year-long intervention. The investigators found – consistent with their study hypothesis – that psychosocial familial characteristics were significantly predictive of long-term success or failure. This was true even after the researchers controlled for familial obesity in order to cancel out the impact of genetic factors.

The strongest predictor of long-term failure for the lifestyle intervention was maternal depression. Maternal attachment insecurity and family adversity also predicted long-term treatment failure (Pediatrics 2011;128: e779-85).

These findings point to the need for further research aimed at developing lifestyle interventions for pediatric weight loss that are tailored to a family’s psychosocial dynamics, Dr. Stricker observed.

He reported having no financial conflicts.

STEAMBOAT SPRINGS, COLO. – In discussing a child’s weight problem with the parents, it’s best for physicians to refrain from using the terms "fat," "extremely obese," and even "obese."

"Parents find those terms undesirable. They’re stigmatizing, blaming, nonmotivating, and condescending," Dr. Paul R. Stricker said at a meeting on practical pediatrics sponsored by the American Academy of Pediatrics.

©Tom Reese/Seattle Times/Newscom

And that’s not just his personal opinion, either. He cited a recent groundbreaking study in which investigators at Yale University in New Haven, Conn., conducted a national online survey of the parents of 455 children aged 2-18 years. The purpose was to examine parental perceptions of language related to weight in order to improve the quality of physician-parent discussions about their child’s obesity. The underlying idea is that the likelihood of successful long-term weight loss is enhanced if the parents are committed to the proposed lifestyle modifications.

On a 5-point rating scale, most parents ranked "weight" and "unhealthy weight" as terms they preferred physicians to use in describing their child’s extra pounds. Moreover, the parents indicated they found the terms "unhealthy weight," "overweight," and "weight problem" to be the most motivating to lose weight, noted Dr. Stricker, a youth sports medicine specialist at the Scripps Clinic in San Diego.

On the other hand, parents perceived the terms "chubby," "fat," "obese," and "extremely obese" quite negatively, rating them as the least motivating to encourage weight loss (Pediatrics 2011;128:e786-93).

These data cast doubt on the wisdom of the British public health minister's 2010 declaration that U.K. health providers should call their obese patients "fat" to motivate them to lose weight.

As a pediatric sports medicine specialist, Dr. Stricker’s goal is to help overweight kids have a positive sports and exercise experience. He wants it to be "something they’ll want to pass along to their own children." He combines his exercise guidance with dietary instruction in weight loss, with an emphasis placed on eating multiple small meals to keep the metabolic rate revved so more calories are burned.

But lifestyle interventions don’t always work, and Dr. Stricker highlighted a recent German study that’s eye-opening as to why.

The prospective study included 111 overweight and obese 7- to 15-year-olds and their parents. The youths were referred to a 1-year-long best-practice lifestyle intervention program.

Treatment success was defined as at least a 5% weight reduction at follow-up 1 year after completing the year-long intervention. The investigators found – consistent with their study hypothesis – that psychosocial familial characteristics were significantly predictive of long-term success or failure. This was true even after the researchers controlled for familial obesity in order to cancel out the impact of genetic factors.

The strongest predictor of long-term failure for the lifestyle intervention was maternal depression. Maternal attachment insecurity and family adversity also predicted long-term treatment failure (Pediatrics 2011;128: e779-85).

These findings point to the need for further research aimed at developing lifestyle interventions for pediatric weight loss that are tailored to a family’s psychosocial dynamics, Dr. Stricker observed.

He reported having no financial conflicts.

Transfusion therapy is an essential part of hematology practice, allowing for curative therapy of diseases such as leukemia, aplastic anemia, and aggressive lymphomas. Nonetheless, transfusions are associated with significant risks, including transfusion-transmitted infections and transfusion-related reactions, and controversy remains about key issues in transfusion therapy, such as triggers for red cell transfusions. This article reviews the available blood products and indications for transfusion along with the associated risks and also discusses specific clinical situations, such as massive transfusion.

To read the full article in PDF:

Click here

Transfusion therapy is an essential part of hematology practice, allowing for curative therapy of diseases such as leukemia, aplastic anemia, and aggressive lymphomas. Nonetheless, transfusions are associated with significant risks, including transfusion-transmitted infections and transfusion-related reactions, and controversy remains about key issues in transfusion therapy, such as triggers for red cell transfusions. This article reviews the available blood products and indications for transfusion along with the associated risks and also discusses specific clinical situations, such as massive transfusion.

To read the full article in PDF:

Click here

Transfusion therapy is an essential part of hematology practice, allowing for curative therapy of diseases such as leukemia, aplastic anemia, and aggressive lymphomas. Nonetheless, transfusions are associated with significant risks, including transfusion-transmitted infections and transfusion-related reactions, and controversy remains about key issues in transfusion therapy, such as triggers for red cell transfusions. This article reviews the available blood products and indications for transfusion along with the associated risks and also discusses specific clinical situations, such as massive transfusion.

To read the full article in PDF:

Click here

A 37-year-old man presented to the emergency department with an 8-week history of a mildly productive cough and shortness of breath accompanied by high fevers, chills, and night sweats. He also had some nausea but no vomiting.

Four days earlier, he had been evaluated by his primary care physician, who prescribed a 14-day course of one double-strength trimethoprim-sulfamethoxazole tablet (Bactrim DS) every 12 hours for presumed acute bronchitis, but his symptoms did not improve.

He was unemployed, living in Arizona, married with children. He denied any use of tobacco, alcohol, or injection drugs. On further questioning, he disclosed that he had unintentionally lost 30 pounds over the past 2 to 3 months and had been feeling tired.

When asked about his medical history, he revealed that he had been diagnosed with human immunodeficiency virus (HIV) infection in 2008 and that recently he had not been taking his antiretroviral medication, a once-daily combination pill containing efavirenz, emtricitabine, and tenofovir (Atripla). He had no other significant medical history, and the only medication he was currently taking was the trimethoprim-sulfamethoxazole.

On examination, his temperature was 38.7°C (101.7°F), blood pressure 109/68 mm Hg, heart rate 60 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 100% while breathing supplemental oxygen via nasal cannula at 2 L/min. He did not appear seriously ill.

Initial blood tests (Table 1) showed a normal white blood cell count, normal results on a complete metabolic panel, and a lactate dehydrogenase level of 539 IU/L (reference range 313–618). His serum lactate level was within normal limits.

HIV-specific tests performed on the second day of hospitalization showed extreme immunosuppression, with a CD4 count of 5 cells/μL (normal 326–1,404 cells/μL).

WHICH ORGANISM IS CAUSING HIS LUNG INFECTION?

1. Which of the following organisms is the least likely to be associated with this patient’s condition?

• Mycobacterium tuberculosis
• Pneumocystis jirovecii
• Coccidioides immitis
• Candida albicans
• Streptococcus pneumoniae
• Cytomegalovirus

Bacterial, fungal, and viral lung infections are common in HIV-infected patients, especially if they are not on antiretroviral therapy and their CD4 lymphocyte counts are low. Clues to the cause can be derived from the history, physical examination, and general laboratory studies. For instance, knowing where the patient lives and where he has travelled recently provides insight into exposure to endemic infectious agents.

The complete blood cell count with differential white blood cell count can help narrow the differential diagnosis but rarely helps exclude a possibility. Neutrophilia is common in bacterial infections. Lymphocytosis can be seen in tuberculosis, in fungal and viral infections, and, rarely, in hematologic malignancies. Eosinophilia can be seen in acute retroviral syndrome, fungal and helminthic infections, adrenal insufficiency, autoimmune disease, and lymphoma.

A caveat to these clues is that in severely immunocompromised hosts, like this man, diagnoses should not be excluded without firm evidence. This patient has severe, active immunosuppression, and only one of the six answer choices above is not a possible causative agent: C albicans rarely causes lung infection, even in immunocompromised people.

Mycobacterium tuberculosis

Tuberculosis can be the first manifestation of HIV infection. It can occur at any CD4 count, but as the count decreases, the risk of dissemination increases.¹ Classic symptoms are fever, night sweats, hemoptysis, and weight loss.

The CD4 count also affects the radiographic presentation. If the count is higher than 350 cells/μL, then infiltration of the upper lobe is likely; if it is lower than 200 cells/μL, then middle, lower, miliary, and extrapulmonary manifestations are likely.^1,2 Cavitation is less common in HIV-infected patients, but mediastinal adenopathy is more common.¹

Definitive diagnosis is via sputum examination, blood culture, nucleic acid amplification, or microscopic study of biopsy specimens of affected tissues to look for acid-fast bacilli.¹

Interferon-gamma-release assays such as the QuantiFERON test (Cellestis, Valencia, CA) or a tuberculin skin test can be used to check for latent tuberculosis infection. These tests can also provide evidence of active infection in the appropriate clinical context.³

Interferon-gamma-release assays have several advantages over skin testing: they are more sensitive (76% to 80%) and specific (97%); they do not give false-positive results in people who previously received bacille Calmette-Guérin vaccine; they react only minimally to previous exposure to nontuberculous mycobacteria; and interpretation is not subject to interreader variability.^4,5 However, concordance between skin testing and interferon-gamma-release assays is low. Therefore, either or both tests can be used if tuberculosis is strongly suspected, and a positive result on either test should prompt further workup.^6,7

Of note, both tests may be affected by immunosuppression, making both susceptible to false-negative results as the CD4 count declines.³

In any case, a positive acid-fast bacillus smear, radiographic evidence of latent infection, or pulmonary symptoms should be presumed to represent active tuberculosis. In such a situation, directly observed treatment with the typical four-drug regimen—rifampin (Rifadin), isoniazid, pyrazinamide, and ethambutol (Myambutol)—is recommended while awaiting definitive results from culture or polymerase chain reaction (PCR) testing.¹

P jirovecii was previously known as P carinii, and P jirovecii pneumonia is an AIDS-defining illness. Most cases occur when the CD4 count falls below 200 cells/μL.¹ Symptoms, including a nonproductive cough, develop insidiously over days to weeks.

Physical examination may reveal inspiratory crackles; however, half of the time the physical examination is nondiagnostic. Oral candidiasis is a common coinfection. The lactate dehydrogenase level may be elevated.^1,8 Radiographs show bilateral interstitial infiltrates, and in 10% to 20% of patients lung cysts develop—hence the name of the organism.¹ Pneumothorax in a patient with HIV should prompt a workup for P jirovecii pneumonia.^9,10

No consensus exists for the diagnosis. However, if sputum examination is unrevealing but suspicion is high, then bronchoalveolar lavage can help.^11–13

Trimethoprim-sulfamethoxazole for 21 days is the first-line treatment, with glucocorticoids added if the Pao₂ is less than 70 mm Hg or if the alveolar-arterial oxygen gradient is greater than 35 mm Hg.¹

Coccidioides species

Coccidioides infection is typically due to either C immitis or C posadasii.¹⁴ People living in or travelling to areas where it is endemic, such as the southwestern United States, Mexico, and Central and South America, are at higher risk.¹⁴

Typical signs and symptoms of this fungal infection include an influenza-like illness with fever, cough, adenopathy, and wasting, and when combined with erythema nodosum, erythema multiforme, arthralgia, or ocular involvement, this constellation is colloquially termed “valley fever.”¹⁵ Most HIV-infected patients who have CD4 counts higher than 250 cells/μL present with focal pneumonia, while lower counts predispose to disseminated disease.^1,2,16

Findings on examination are nonspecific and depend on the various pulmonary manifestations, which include acute, chronic progressive, or diffuse pneumonia, nodules, or cavities.¹⁴ Eosinophilia may accompany the infection.¹⁵

The diagnosis can be made by finding the organisms on direct microscopic examination of involved tissues or secretions or on culture of clinical specimens.^1,2,14 Serologic tests, antigen detection tests, or culture can be helpful if positive, but negative results do not rule out the diagnosis.^1,2,14

A caveat about testing: if the pretest probability of infection is low, positive tests for immunoglobulin M (IgM) do not necessarily equal infection, and the IgM test should be followed up with confirmatory testing. Along the same lines, a high pretest probability should not be ignored if initial tests are negative, and patients in this situation should also undergo further evaluation.¹⁷

Therapy with an azole drug such as fluconazole (Diflucan) or one of the amphotericin B preparations should be started, depending on the severity of the disease.^1,2,14,18

Candida albicans

C albicans is a rare cause of lung infection.^19,20 It is, however, a common inhabitant of the upper airway tract, and pulmonary infection is usually the result of aspiration or hematogenous spread from either the gastrointestinal tract or an infected central venous catheter.²⁰

The presentation is relatively nonspecific. Fever despite broad-spectrum antibacterial therapy is a major clue. Radiographic abnormalities usually are due to other causes, such as superimposed infections or pulmonary hemorrhage.²¹ Sputum culture is unreliable because of colonization. The definitive diagnosis is based on lung biopsy demonstrating organisms within the tissue.^19,20,22

Therapy with a systemic antifungal agent is recommended.

Streptococcus pneumoniae

S pneumoniae is one of the most common bacterial causes of community-acquired pneumonia in people with or without HIV.^23–25 Moreover, two or more episodes of bacterial pneumonia in 12 months can be an AIDS-defining condition in patients with a positive serologic test for HIV.¹⁶ Therefore, in patients with fever, cough, and pulmonary infiltrates on chest radiography, S pneumoniae must always be considered.

Urinary antigen testing has a relatively high positive predictive value (> 89%) and specificity (96%) for diagnosing S pneumoniae pneumonia.²⁶ Blood and sputum cultures should be done not only to confirm the diagnosis, but also because the rates of bacteremia and drug resistance are higher with S pneumoniae infection in the HIV-infected.¹

A combination of a beta-lactam and a macrolide or respiratory fluoroquinolone is the treatment of choice.¹

Cytomegalovirus

Although influenza is the most common cause of viral pneumonia in HIV-infected people, cytomegalovirus is an opportunistic cause.² This is usually a reactivation of latent infection rather than new infection.²⁷ Typically, infections occur at CD4 counts lower than 50 cells/μL, with cough, dyspnea, and fever that last for 2 to 4 weeks.²

Crackles may be heard on lung examination. The lactate dehydrogenase level can be elevated, as in P jirovecii pneumonia.² Radiography can show a wide range of nonspecific findings, from reticular and ground-glass opacities to alveolar or interstitial infiltrates to nodules.

The diagnosis of cytomegalovirus pneumonia is not always clear. Since HIV-infected patients typically shed the virus in their airways, bronchoalveolar lavage is not adequate because a positive finding does not necessarily mean the patient has active viral pneumonitis.²⁷ For this reason, infection should be confirmed by biopsy demonstrating characteristic cytomegalovirus inclusions in lung tissue.²

Importantly, once cytomegalovirus pneumonia is confirmed, the patient should be screened for cytomegalovirus retinitis even if he or she has no visual symptoms, as cytomegalovirus pneumonitis is typically a part of a disseminated infection.¹

Treatment with intravenous ganciclovir (Cytovene) is required.¹

CASE CONTINUED: POSITIVE TESTS FOR COCCIDIOIDES

Our patient began empiric treatment for community-acquired pneumonia with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax).

On the basis of these findings, the patient was immediately placed in negative pressure respiratory isolation and underwent induced sputum examinations for tuberculosis. Further tests for S pneumoniae, S aureus, Mycoplasma, Legionella, influenza, Pneumocystis, Cryptococcus, Histoplasma, and Coccidioides species were performed.

QuantiFERON testing was negative, and blood cultures were sterile. The first induced sputum examination was negative for acid-fast bacilli. PCR testing for mycobacterial DNA in the sputum was also negative.

Both silver and direct fluorescent antibody staining of the sputum were negative for Pneumocystis. On the basis of these findings and the patient’s lack of clinical improvement with trimethoprim-sulfamethoxazole, Pneumocystis infection was excluded.

THE PATIENT BEGINS TREATMENT

2. Which treatment is most appropriate for this patient?

• Posaconazole (Noxafil)
• Caspofungin (Cancidas) and surgery
• Fluconazole
• Voriconazole (Vfend) and surgery
• Amphotericin B

Solitary pulmonary cavities tend to be asymptomatic and do not require treatment, even if coccidioidal infection is microbiologically confirmed.

However, if there is pain, hemoptysis, or bacterial superinfection, antifungal therapy may result in improvement but not closure of the cavity.¹⁸ Therefore, in all cases of symptomatic coccidioidal pulmonary cavities, surgical resection is the only definitive treatment.

Coccidioidal cavities may rupture and cause pyopneumothorax, but this is an infrequent complication, and antifungal therapy combined with surgical decortication is the treatment of choice.¹⁸

Commonly prescribed antifungals include fluconazole and amphotericin B, the latter usually reserved for patients with significant hypoxia or rapid clinical deterioration.¹⁸ At this time, there are not enough clinical data to show that voriconazole or posaconazole is effective, and thus neither is approved for the treatment of coccidioidomycosis. Likewise, there have been no human trials of the efficacy of caspofungin against Coccidioides infection, although it has been shown to be active in mouse models.¹⁸

Our patient was started on oral fluconazole and observed for clinical improvement or, conversely, for signs of dissemination. After 2 days, he had markedly improved, and within 1 week he was almost back to his baseline level of health. Testing for all other infectious etiologies was unrevealing, and he was removed from negative pressure isolation.

However, as we mentioned above, his CD4 count was 5 cells/μL. We discussed the issue with the patient, and he said he was willing to comply with his treatment for both his Coccidioides and his HIV infection. After much deliberation, he said he was also willing to start and comply with prophylactic treatment for opportunistic infections.

PREVENTING OPPORTUNISTIC INFECTIONS IN HIV PATIENTS

3. Which of the following prophylactic regimens is most appropriate for this patient?

• Trimethoprim-sulfamethoxazole, atovaquone (Mepron), and azithromycin
• Trimethoprim-sulfamethoxazole and azithromycin
• Pentamidine (Nebupent), dapsone, and clarithromycin (Biaxin)
• Dapsone and clarithromycin
• Trimethoprim-sulfamethoxazole by itself

According to guidelines for the prevention of opportunistic diseases in patients with HIV, he needs primary prophylaxis against the following organisms: P jirovecii, Toxoplasma gondii, and Mycobacterium avium complex.¹

The CD4 count dictates the appropriate time to start therapy. If the count is lower than 200 cells/μL or if the patient has oropharyngeal candidiasis regardless of the CD4 count, trimethoprim-sulfamethoxazole is indicated to prevent P jirovecii pneumonia. In those who cannot tolerate trimethoprim-sulfamethoxazole or who are allergic to it, dapsone, pentamidine, or atovaquone can be substituted.¹

In patients seropositive for T gondii, a CD4 count lower than 100/μL indicates the need for prophylaxis.¹ Prophylactic measures are similar to those for Pneumocystis. However, if the patient cannot tolerate trimethoprim-sulfamethoxazole, the recommended alternative is dapsone-pyrimethamine with leucovorin, which is also effective against Pneumocystis.¹

Finally, if the CD4 count is lower than 50 cells/μL, prophylaxis against M avium complex is mandatory, with either azithromycin weekly or clarithromycin daily.¹

Given our patient’s degree of immunosuppression, trimethoprim-sulfamethoxazole plus azithromycin is his most appropriate option.

Trimethoprim-sulfamethoxazole and azithromycin were added to his antimicrobial regimen before he was discharged. Two weeks later, he noted no side effects from any of the medications, he had no new symptoms, he was feeling well, and his cough had improved greatly. He did not have any signs of dissemination of his coccidioidal infection, and we concluded that the primary and only infection was located in the lungs.

DISSEMINATED COCCIDIOIDOMYCOSIS

4. Which of the following extrapulmonary sites is Coccidioides least likely to infect?

• Brain
• Skin
• Meninges
• Lymph nodes
• Bones
• Joints

Extrapulmonary coccidioidomycosis can involve almost any site. However, the most common sites of dissemination are the skin, lymph nodes, bones, and joints.¹⁴ The least likely site is the brain.

Central nervous system involvement

In the central nervous system, involvement is typically with the meninges, rather than frank involvement of the brain parenchyma.^18,28,29 Although patients with HIV or those who are otherwise severely immunocompromised are at higher risk for coccidioidal meningitis, it is rare even in this population.^30,31 Meningitis most commonly presents as headache, vomiting, meningismus, confusion, or diplopia.^32,33

If neurologic findings are absent, experts do not generally recommend lumbar puncture because the incidence of meningeal involvement is low. When cerebrospinal fluid is obtained in an active case of coccidioidal meningitis, fluid analysis typically finds elevated protein, low glucose, and lymphocytic pleocytosis.^1,32

Meningeal enhancement on CT or magnetic resonance imaging is common.³⁴ The diagnosis is established by culture or serologic testing of cerebrospinal fluid (IgM titer, IgG titer, immunodiffusion, or complement fixation).¹⁴

Of note, cerebral infarction and hydrocephalus are feared complications and pose a serious risk of death in any patient.^32,35 In these cases, treatment with antifungals is lifelong, regardless of immune system status.¹⁸

Skin involvement

Skin involvement is variable, consisting of nodules, verrucae, abscesses, or ulcerations.^15,16 Hemorrhage from the skin is relatively common.³⁶ From the skin, the infection can spread to the lymph nodes, leading to regional lymphadenopathy.^14,15 Nodes can ulcerate, drain, or even become necrotic.

Bone and joint involvement

Once integrity of the blood vessels is disrupted, Coccidioides can spread via the blood to the bones or joints,^14,15 causing osteomyelitis, septic arthritis, or synovitis. Subcutaneous abscesses or sinus tracts may subsequently develop.^14,15

HOW LONG MUST HE BE TREATED?

On follow-up, the patient asked how long he needed to continue his antifungal regimen and if any other testing for his coccidioidal infection was necessary, since he was feeling better.

5. Which is the most appropriate response to the patient’s question?

• He can discontinue his antifungal drugs; no further testing is necessary
• He needs 14 more days of antifungal therapy and periodic serologic tests
• He needs 2.5 more months of antifungal therapy and monthly blood cultures
• He needs lifelong antifungal therapy and periodic urinary antigen levels
• He needs 5.5 more months of antifungal therapy; bronchoscopy with bronchoalveolar lavage at 1 year

How long to treat and how to monitor for coccidioidomycosis vary by patient.

Duration of therapy depends on symptoms and immune status

The severity of infection (Table 2) and the immune status are important factors that must be considered when tailoring a therapeutic regimen.

Immunocompetent patients without symptoms or with mild symptoms usually do not need therapy and are followed periodically for signs of improvement.^14,18,29

Immunocompetent patients with severe symptoms typically receive 3 to 6 months of antifungal therapy.¹⁸

Immunocompromised patients (especially HIV-infected patients with CD4 counts < 250 cells/μL) need antifungal treatment, regardless of the severity of infection.^14,18,29 In many cases, the type of infection will dictate the duration of therapy.

Diffuse pneumonia or extrapulmonary dissemination typically requires treatment for at least 1 year regardless of immune status.^14,18 For those with HIV and diffuse pneumonia, dissemination, or meningitis, guidelines dictate that secondary prophylaxis be started after at least 1 year of therapy and improvement in clinical status; it should be continued indefinitely to prevent reactivation of latent infection.¹⁸

The guidelines say that in patients with higher CD4 counts (presumably > 250 cells/μL) and nonmeningeal coccidioidomycosis, providers may consider discontinuing secondary prophylaxis, as long as there is clinical evidence of improvement and control of the primary infection.¹⁸ However, many experts advocate continuing secondary prophylaxis regardless of the CD4 count, as the rates of relapse and dissemination are high.^1,16,37

Monitoring

Regardless of the therapy chosen, disease monitoring every 2 to 4 months with clinical history and examination, radiography, and coccidioidal-specific testing is recommended for at least 1 year, and perhaps longer, to ensure complete resolution and to monitor for signs of dissemination.^14,18

Which test to use is not clear. Serologic testing identifies antibodies (IgM or IgG) to coccidioidal antigens. IgM appears during the acute infection, and tests include immunodiffusion, latex agglutination, and enzymelinked immunoassays. The last two are highly sensitive but have a significant false-positive rate, and should be confirmed with the former if found to be positive.^17,18 IgG appears weeks after the acute infection and can be evaluated with immunodiffusion or enzyme-linked immunoassay as well.

Keep in mind that these tests provide only qualitative results on the presence of these antibodies, not quantitative information. Furthermore, enzyme-linked immunoassay is not as accurate as immunodiffusion, which has a sensitivity in immunocompromised patients of only approximately 50%.^38,39

For that reason, complement fixation titers are extremely helpful because they reflect the severity of infection, can be used to monitor the response to treatment, and can even provide insight into the prognosis.¹⁸ The sensitivity of this test in immunocompromised hosts is 60% to 70%.³⁸ Titers can be checked to confirm the diagnosis and can be periodically monitored throughout the treatment course to ensure efficacy of therapy and to watch for reactivation of the infection.¹ In fact, an initial complement fixation titer of 1:2 or 1:4 is associated with favorable outcomes, while a titer greater than 1:16 portends dissemination.¹⁸

The caveat to any serologic test (immunodiffusion, enzyme-linked immunoassay, and complement fixation) is that severely immunocompromised patients (as in our case) may not mount an immune response and may have falsely low titers even in the face of a severe infection, and therefore these tests may not be reliable.³⁸ In these situations, urinary coccidioidal antigen detection assay (sensitivity 71%) or nucleic acid amplification of coccidioidal DNA (sensitivity 75%) may be of more help.^40,41

Therefore, in the setting of HIV infection, an asymptomatic pulmonary cavity, and diffuse pulmonary involvement secondary to coccidioidal infection, lifelong antibiotics (treatment plus secondary prophylaxis) with periodic testing of urinary coccidioidal antigen levels is the best response to the patient’s question, given that his complement fixation titers were initially negative and antigen levels were positive.

CASE CONCLUDED

The patient continues to be followed for his HIV infection. He is undergoing serologic and urinary antigen testing for Coccidioides infection every 3 months in addition to his maintenance HIV testing. He is on chronic suppressive therapy with fluconazole. He has not had a recurrence of his Coccidioides infection, nor have there been any signs of dissemination.

CAVITARY LUNG LESIONS IN HIV PATIENTS

In patients with HIV, cavitary lung lesions on chest radiography can be due to a wide variety of etiologies that range from infection to malignancy. Historical clues, including environmental exposure, occupation, geographic residence, sick contacts, travel, or animal contact can be helpful in ordering subsequent confirmatory testing, especially in the case of infection.

Tuberculosis should be suspected, and appropriate isolation precautions should be taken until it is ruled out.

Laboratory testing, including the complete blood cell count with differential and CD4 count, provide ancillary data to narrow the differential diagnosis. For example, if the CD4 count is greater than 200 cells/μL, mycobacterial infection should be strongly suspected; however, lower CD4 counts should also prompt a search for opportunistic infections. In the appropriate clinical scenario, malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and bronchogenic carcinoma can be seen and should also be considered.

Nevertheless, the evaluation hinges on the sputum examination and CT scan of the chest to further characterize the cavity, surrounding lung parenchyma, lymph nodes, and potential fluid collections. Usually, further serologic tests and even bronchoscopy with bronchoalveolar lavage and transbronchial biopsy are required. Treatment should begin once the most likely diagnosis is established.

Coccidioidal pneumonia should be considered in all patients with immunodeficiency, including HIV patients, transplant recipients, those undergoing chemotherapy, and those with intrinsic immune system defects, especially if they have a history of exposure or if they are from an endemic region. Antifungal therapy should be initiated early, and dissemination must be ruled out. Suppressive therapy is mandatory for those with a severely compromised immune system, and serologic testing to ensure remission of the infection is needed. Patients who were previously exposed to Coccidioides or who vacationed or live in the southwestern United States (where it is prevalent) are at risk and may present with any number of symptoms.

A 37-year-old man presented to the emergency department with an 8-week history of a mildly productive cough and shortness of breath accompanied by high fevers, chills, and night sweats. He also had some nausea but no vomiting.

Four days earlier, he had been evaluated by his primary care physician, who prescribed a 14-day course of one double-strength trimethoprim-sulfamethoxazole tablet (Bactrim DS) every 12 hours for presumed acute bronchitis, but his symptoms did not improve.

He was unemployed, living in Arizona, married with children. He denied any use of tobacco, alcohol, or injection drugs. On further questioning, he disclosed that he had unintentionally lost 30 pounds over the past 2 to 3 months and had been feeling tired.

When asked about his medical history, he revealed that he had been diagnosed with human immunodeficiency virus (HIV) infection in 2008 and that recently he had not been taking his antiretroviral medication, a once-daily combination pill containing efavirenz, emtricitabine, and tenofovir (Atripla). He had no other significant medical history, and the only medication he was currently taking was the trimethoprim-sulfamethoxazole.

On examination, his temperature was 38.7°C (101.7°F), blood pressure 109/68 mm Hg, heart rate 60 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 100% while breathing supplemental oxygen via nasal cannula at 2 L/min. He did not appear seriously ill.

Initial blood tests (Table 1) showed a normal white blood cell count, normal results on a complete metabolic panel, and a lactate dehydrogenase level of 539 IU/L (reference range 313–618). His serum lactate level was within normal limits.

HIV-specific tests performed on the second day of hospitalization showed extreme immunosuppression, with a CD4 count of 5 cells/μL (normal 326–1,404 cells/μL).

WHICH ORGANISM IS CAUSING HIS LUNG INFECTION?

1. Which of the following organisms is the least likely to be associated with this patient’s condition?

• Mycobacterium tuberculosis
• Pneumocystis jirovecii
• Coccidioides immitis
• Candida albicans
• Streptococcus pneumoniae
• Cytomegalovirus

Bacterial, fungal, and viral lung infections are common in HIV-infected patients, especially if they are not on antiretroviral therapy and their CD4 lymphocyte counts are low. Clues to the cause can be derived from the history, physical examination, and general laboratory studies. For instance, knowing where the patient lives and where he has travelled recently provides insight into exposure to endemic infectious agents.

The complete blood cell count with differential white blood cell count can help narrow the differential diagnosis but rarely helps exclude a possibility. Neutrophilia is common in bacterial infections. Lymphocytosis can be seen in tuberculosis, in fungal and viral infections, and, rarely, in hematologic malignancies. Eosinophilia can be seen in acute retroviral syndrome, fungal and helminthic infections, adrenal insufficiency, autoimmune disease, and lymphoma.

A caveat to these clues is that in severely immunocompromised hosts, like this man, diagnoses should not be excluded without firm evidence. This patient has severe, active immunosuppression, and only one of the six answer choices above is not a possible causative agent: C albicans rarely causes lung infection, even in immunocompromised people.

Mycobacterium tuberculosis

Tuberculosis can be the first manifestation of HIV infection. It can occur at any CD4 count, but as the count decreases, the risk of dissemination increases.¹ Classic symptoms are fever, night sweats, hemoptysis, and weight loss.

The CD4 count also affects the radiographic presentation. If the count is higher than 350 cells/μL, then infiltration of the upper lobe is likely; if it is lower than 200 cells/μL, then middle, lower, miliary, and extrapulmonary manifestations are likely.^1,2 Cavitation is less common in HIV-infected patients, but mediastinal adenopathy is more common.¹

Definitive diagnosis is via sputum examination, blood culture, nucleic acid amplification, or microscopic study of biopsy specimens of affected tissues to look for acid-fast bacilli.¹

Interferon-gamma-release assays such as the QuantiFERON test (Cellestis, Valencia, CA) or a tuberculin skin test can be used to check for latent tuberculosis infection. These tests can also provide evidence of active infection in the appropriate clinical context.³

Interferon-gamma-release assays have several advantages over skin testing: they are more sensitive (76% to 80%) and specific (97%); they do not give false-positive results in people who previously received bacille Calmette-Guérin vaccine; they react only minimally to previous exposure to nontuberculous mycobacteria; and interpretation is not subject to interreader variability.^4,5 However, concordance between skin testing and interferon-gamma-release assays is low. Therefore, either or both tests can be used if tuberculosis is strongly suspected, and a positive result on either test should prompt further workup.^6,7

Of note, both tests may be affected by immunosuppression, making both susceptible to false-negative results as the CD4 count declines.³

In any case, a positive acid-fast bacillus smear, radiographic evidence of latent infection, or pulmonary symptoms should be presumed to represent active tuberculosis. In such a situation, directly observed treatment with the typical four-drug regimen—rifampin (Rifadin), isoniazid, pyrazinamide, and ethambutol (Myambutol)—is recommended while awaiting definitive results from culture or polymerase chain reaction (PCR) testing.¹

P jirovecii was previously known as P carinii, and P jirovecii pneumonia is an AIDS-defining illness. Most cases occur when the CD4 count falls below 200 cells/μL.¹ Symptoms, including a nonproductive cough, develop insidiously over days to weeks.

Physical examination may reveal inspiratory crackles; however, half of the time the physical examination is nondiagnostic. Oral candidiasis is a common coinfection. The lactate dehydrogenase level may be elevated.^1,8 Radiographs show bilateral interstitial infiltrates, and in 10% to 20% of patients lung cysts develop—hence the name of the organism.¹ Pneumothorax in a patient with HIV should prompt a workup for P jirovecii pneumonia.^9,10

No consensus exists for the diagnosis. However, if sputum examination is unrevealing but suspicion is high, then bronchoalveolar lavage can help.^11–13

Trimethoprim-sulfamethoxazole for 21 days is the first-line treatment, with glucocorticoids added if the Pao₂ is less than 70 mm Hg or if the alveolar-arterial oxygen gradient is greater than 35 mm Hg.¹

Coccidioides species

Coccidioides infection is typically due to either C immitis or C posadasii.¹⁴ People living in or travelling to areas where it is endemic, such as the southwestern United States, Mexico, and Central and South America, are at higher risk.¹⁴

Typical signs and symptoms of this fungal infection include an influenza-like illness with fever, cough, adenopathy, and wasting, and when combined with erythema nodosum, erythema multiforme, arthralgia, or ocular involvement, this constellation is colloquially termed “valley fever.”¹⁵ Most HIV-infected patients who have CD4 counts higher than 250 cells/μL present with focal pneumonia, while lower counts predispose to disseminated disease.^1,2,16

Findings on examination are nonspecific and depend on the various pulmonary manifestations, which include acute, chronic progressive, or diffuse pneumonia, nodules, or cavities.¹⁴ Eosinophilia may accompany the infection.¹⁵

The diagnosis can be made by finding the organisms on direct microscopic examination of involved tissues or secretions or on culture of clinical specimens.^1,2,14 Serologic tests, antigen detection tests, or culture can be helpful if positive, but negative results do not rule out the diagnosis.^1,2,14

A caveat about testing: if the pretest probability of infection is low, positive tests for immunoglobulin M (IgM) do not necessarily equal infection, and the IgM test should be followed up with confirmatory testing. Along the same lines, a high pretest probability should not be ignored if initial tests are negative, and patients in this situation should also undergo further evaluation.¹⁷

Therapy with an azole drug such as fluconazole (Diflucan) or one of the amphotericin B preparations should be started, depending on the severity of the disease.^1,2,14,18

Candida albicans

C albicans is a rare cause of lung infection.^19,20 It is, however, a common inhabitant of the upper airway tract, and pulmonary infection is usually the result of aspiration or hematogenous spread from either the gastrointestinal tract or an infected central venous catheter.²⁰

The presentation is relatively nonspecific. Fever despite broad-spectrum antibacterial therapy is a major clue. Radiographic abnormalities usually are due to other causes, such as superimposed infections or pulmonary hemorrhage.²¹ Sputum culture is unreliable because of colonization. The definitive diagnosis is based on lung biopsy demonstrating organisms within the tissue.^19,20,22

Therapy with a systemic antifungal agent is recommended.

Streptococcus pneumoniae

S pneumoniae is one of the most common bacterial causes of community-acquired pneumonia in people with or without HIV.^23–25 Moreover, two or more episodes of bacterial pneumonia in 12 months can be an AIDS-defining condition in patients with a positive serologic test for HIV.¹⁶ Therefore, in patients with fever, cough, and pulmonary infiltrates on chest radiography, S pneumoniae must always be considered.

Urinary antigen testing has a relatively high positive predictive value (> 89%) and specificity (96%) for diagnosing S pneumoniae pneumonia.²⁶ Blood and sputum cultures should be done not only to confirm the diagnosis, but also because the rates of bacteremia and drug resistance are higher with S pneumoniae infection in the HIV-infected.¹

A combination of a beta-lactam and a macrolide or respiratory fluoroquinolone is the treatment of choice.¹

Cytomegalovirus

Although influenza is the most common cause of viral pneumonia in HIV-infected people, cytomegalovirus is an opportunistic cause.² This is usually a reactivation of latent infection rather than new infection.²⁷ Typically, infections occur at CD4 counts lower than 50 cells/μL, with cough, dyspnea, and fever that last for 2 to 4 weeks.²

Crackles may be heard on lung examination. The lactate dehydrogenase level can be elevated, as in P jirovecii pneumonia.² Radiography can show a wide range of nonspecific findings, from reticular and ground-glass opacities to alveolar or interstitial infiltrates to nodules.

The diagnosis of cytomegalovirus pneumonia is not always clear. Since HIV-infected patients typically shed the virus in their airways, bronchoalveolar lavage is not adequate because a positive finding does not necessarily mean the patient has active viral pneumonitis.²⁷ For this reason, infection should be confirmed by biopsy demonstrating characteristic cytomegalovirus inclusions in lung tissue.²

Importantly, once cytomegalovirus pneumonia is confirmed, the patient should be screened for cytomegalovirus retinitis even if he or she has no visual symptoms, as cytomegalovirus pneumonitis is typically a part of a disseminated infection.¹

Treatment with intravenous ganciclovir (Cytovene) is required.¹

CASE CONTINUED: POSITIVE TESTS FOR COCCIDIOIDES

Our patient began empiric treatment for community-acquired pneumonia with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax).

On the basis of these findings, the patient was immediately placed in negative pressure respiratory isolation and underwent induced sputum examinations for tuberculosis. Further tests for S pneumoniae, S aureus, Mycoplasma, Legionella, influenza, Pneumocystis, Cryptococcus, Histoplasma, and Coccidioides species were performed.

QuantiFERON testing was negative, and blood cultures were sterile. The first induced sputum examination was negative for acid-fast bacilli. PCR testing for mycobacterial DNA in the sputum was also negative.

Both silver and direct fluorescent antibody staining of the sputum were negative for Pneumocystis. On the basis of these findings and the patient’s lack of clinical improvement with trimethoprim-sulfamethoxazole, Pneumocystis infection was excluded.

THE PATIENT BEGINS TREATMENT

2. Which treatment is most appropriate for this patient?

• Posaconazole (Noxafil)
• Caspofungin (Cancidas) and surgery
• Fluconazole
• Voriconazole (Vfend) and surgery
• Amphotericin B

Solitary pulmonary cavities tend to be asymptomatic and do not require treatment, even if coccidioidal infection is microbiologically confirmed.

However, if there is pain, hemoptysis, or bacterial superinfection, antifungal therapy may result in improvement but not closure of the cavity.¹⁸ Therefore, in all cases of symptomatic coccidioidal pulmonary cavities, surgical resection is the only definitive treatment.

Coccidioidal cavities may rupture and cause pyopneumothorax, but this is an infrequent complication, and antifungal therapy combined with surgical decortication is the treatment of choice.¹⁸

Commonly prescribed antifungals include fluconazole and amphotericin B, the latter usually reserved for patients with significant hypoxia or rapid clinical deterioration.¹⁸ At this time, there are not enough clinical data to show that voriconazole or posaconazole is effective, and thus neither is approved for the treatment of coccidioidomycosis. Likewise, there have been no human trials of the efficacy of caspofungin against Coccidioides infection, although it has been shown to be active in mouse models.¹⁸

Our patient was started on oral fluconazole and observed for clinical improvement or, conversely, for signs of dissemination. After 2 days, he had markedly improved, and within 1 week he was almost back to his baseline level of health. Testing for all other infectious etiologies was unrevealing, and he was removed from negative pressure isolation.

However, as we mentioned above, his CD4 count was 5 cells/μL. We discussed the issue with the patient, and he said he was willing to comply with his treatment for both his Coccidioides and his HIV infection. After much deliberation, he said he was also willing to start and comply with prophylactic treatment for opportunistic infections.

PREVENTING OPPORTUNISTIC INFECTIONS IN HIV PATIENTS

3. Which of the following prophylactic regimens is most appropriate for this patient?

• Trimethoprim-sulfamethoxazole, atovaquone (Mepron), and azithromycin
• Trimethoprim-sulfamethoxazole and azithromycin
• Pentamidine (Nebupent), dapsone, and clarithromycin (Biaxin)
• Dapsone and clarithromycin
• Trimethoprim-sulfamethoxazole by itself

According to guidelines for the prevention of opportunistic diseases in patients with HIV, he needs primary prophylaxis against the following organisms: P jirovecii, Toxoplasma gondii, and Mycobacterium avium complex.¹

The CD4 count dictates the appropriate time to start therapy. If the count is lower than 200 cells/μL or if the patient has oropharyngeal candidiasis regardless of the CD4 count, trimethoprim-sulfamethoxazole is indicated to prevent P jirovecii pneumonia. In those who cannot tolerate trimethoprim-sulfamethoxazole or who are allergic to it, dapsone, pentamidine, or atovaquone can be substituted.¹

In patients seropositive for T gondii, a CD4 count lower than 100/μL indicates the need for prophylaxis.¹ Prophylactic measures are similar to those for Pneumocystis. However, if the patient cannot tolerate trimethoprim-sulfamethoxazole, the recommended alternative is dapsone-pyrimethamine with leucovorin, which is also effective against Pneumocystis.¹

Finally, if the CD4 count is lower than 50 cells/μL, prophylaxis against M avium complex is mandatory, with either azithromycin weekly or clarithromycin daily.¹

Given our patient’s degree of immunosuppression, trimethoprim-sulfamethoxazole plus azithromycin is his most appropriate option.

Trimethoprim-sulfamethoxazole and azithromycin were added to his antimicrobial regimen before he was discharged. Two weeks later, he noted no side effects from any of the medications, he had no new symptoms, he was feeling well, and his cough had improved greatly. He did not have any signs of dissemination of his coccidioidal infection, and we concluded that the primary and only infection was located in the lungs.

DISSEMINATED COCCIDIOIDOMYCOSIS

4. Which of the following extrapulmonary sites is Coccidioides least likely to infect?

• Brain
• Skin
• Meninges
• Lymph nodes
• Bones
• Joints

Extrapulmonary coccidioidomycosis can involve almost any site. However, the most common sites of dissemination are the skin, lymph nodes, bones, and joints.¹⁴ The least likely site is the brain.

Central nervous system involvement

In the central nervous system, involvement is typically with the meninges, rather than frank involvement of the brain parenchyma.^18,28,29 Although patients with HIV or those who are otherwise severely immunocompromised are at higher risk for coccidioidal meningitis, it is rare even in this population.^30,31 Meningitis most commonly presents as headache, vomiting, meningismus, confusion, or diplopia.^32,33

If neurologic findings are absent, experts do not generally recommend lumbar puncture because the incidence of meningeal involvement is low. When cerebrospinal fluid is obtained in an active case of coccidioidal meningitis, fluid analysis typically finds elevated protein, low glucose, and lymphocytic pleocytosis.^1,32

Meningeal enhancement on CT or magnetic resonance imaging is common.³⁴ The diagnosis is established by culture or serologic testing of cerebrospinal fluid (IgM titer, IgG titer, immunodiffusion, or complement fixation).¹⁴

Of note, cerebral infarction and hydrocephalus are feared complications and pose a serious risk of death in any patient.^32,35 In these cases, treatment with antifungals is lifelong, regardless of immune system status.¹⁸

Skin involvement

Skin involvement is variable, consisting of nodules, verrucae, abscesses, or ulcerations.^15,16 Hemorrhage from the skin is relatively common.³⁶ From the skin, the infection can spread to the lymph nodes, leading to regional lymphadenopathy.^14,15 Nodes can ulcerate, drain, or even become necrotic.

Bone and joint involvement

Once integrity of the blood vessels is disrupted, Coccidioides can spread via the blood to the bones or joints,^14,15 causing osteomyelitis, septic arthritis, or synovitis. Subcutaneous abscesses or sinus tracts may subsequently develop.^14,15

HOW LONG MUST HE BE TREATED?

On follow-up, the patient asked how long he needed to continue his antifungal regimen and if any other testing for his coccidioidal infection was necessary, since he was feeling better.

5. Which is the most appropriate response to the patient’s question?

• He can discontinue his antifungal drugs; no further testing is necessary
• He needs 14 more days of antifungal therapy and periodic serologic tests
• He needs 2.5 more months of antifungal therapy and monthly blood cultures
• He needs lifelong antifungal therapy and periodic urinary antigen levels
• He needs 5.5 more months of antifungal therapy; bronchoscopy with bronchoalveolar lavage at 1 year

How long to treat and how to monitor for coccidioidomycosis vary by patient.

Duration of therapy depends on symptoms and immune status

The severity of infection (Table 2) and the immune status are important factors that must be considered when tailoring a therapeutic regimen.

Immunocompetent patients without symptoms or with mild symptoms usually do not need therapy and are followed periodically for signs of improvement.^14,18,29

Immunocompetent patients with severe symptoms typically receive 3 to 6 months of antifungal therapy.¹⁸

Immunocompromised patients (especially HIV-infected patients with CD4 counts < 250 cells/μL) need antifungal treatment, regardless of the severity of infection.^14,18,29 In many cases, the type of infection will dictate the duration of therapy.

Diffuse pneumonia or extrapulmonary dissemination typically requires treatment for at least 1 year regardless of immune status.^14,18 For those with HIV and diffuse pneumonia, dissemination, or meningitis, guidelines dictate that secondary prophylaxis be started after at least 1 year of therapy and improvement in clinical status; it should be continued indefinitely to prevent reactivation of latent infection.¹⁸

The guidelines say that in patients with higher CD4 counts (presumably > 250 cells/μL) and nonmeningeal coccidioidomycosis, providers may consider discontinuing secondary prophylaxis, as long as there is clinical evidence of improvement and control of the primary infection.¹⁸ However, many experts advocate continuing secondary prophylaxis regardless of the CD4 count, as the rates of relapse and dissemination are high.^1,16,37

Monitoring

Regardless of the therapy chosen, disease monitoring every 2 to 4 months with clinical history and examination, radiography, and coccidioidal-specific testing is recommended for at least 1 year, and perhaps longer, to ensure complete resolution and to monitor for signs of dissemination.^14,18

Which test to use is not clear. Serologic testing identifies antibodies (IgM or IgG) to coccidioidal antigens. IgM appears during the acute infection, and tests include immunodiffusion, latex agglutination, and enzymelinked immunoassays. The last two are highly sensitive but have a significant false-positive rate, and should be confirmed with the former if found to be positive.^17,18 IgG appears weeks after the acute infection and can be evaluated with immunodiffusion or enzyme-linked immunoassay as well.

Keep in mind that these tests provide only qualitative results on the presence of these antibodies, not quantitative information. Furthermore, enzyme-linked immunoassay is not as accurate as immunodiffusion, which has a sensitivity in immunocompromised patients of only approximately 50%.^38,39

For that reason, complement fixation titers are extremely helpful because they reflect the severity of infection, can be used to monitor the response to treatment, and can even provide insight into the prognosis.¹⁸ The sensitivity of this test in immunocompromised hosts is 60% to 70%.³⁸ Titers can be checked to confirm the diagnosis and can be periodically monitored throughout the treatment course to ensure efficacy of therapy and to watch for reactivation of the infection.¹ In fact, an initial complement fixation titer of 1:2 or 1:4 is associated with favorable outcomes, while a titer greater than 1:16 portends dissemination.¹⁸

The caveat to any serologic test (immunodiffusion, enzyme-linked immunoassay, and complement fixation) is that severely immunocompromised patients (as in our case) may not mount an immune response and may have falsely low titers even in the face of a severe infection, and therefore these tests may not be reliable.³⁸ In these situations, urinary coccidioidal antigen detection assay (sensitivity 71%) or nucleic acid amplification of coccidioidal DNA (sensitivity 75%) may be of more help.^40,41

Therefore, in the setting of HIV infection, an asymptomatic pulmonary cavity, and diffuse pulmonary involvement secondary to coccidioidal infection, lifelong antibiotics (treatment plus secondary prophylaxis) with periodic testing of urinary coccidioidal antigen levels is the best response to the patient’s question, given that his complement fixation titers were initially negative and antigen levels were positive.

CASE CONCLUDED

The patient continues to be followed for his HIV infection. He is undergoing serologic and urinary antigen testing for Coccidioides infection every 3 months in addition to his maintenance HIV testing. He is on chronic suppressive therapy with fluconazole. He has not had a recurrence of his Coccidioides infection, nor have there been any signs of dissemination.

CAVITARY LUNG LESIONS IN HIV PATIENTS

In patients with HIV, cavitary lung lesions on chest radiography can be due to a wide variety of etiologies that range from infection to malignancy. Historical clues, including environmental exposure, occupation, geographic residence, sick contacts, travel, or animal contact can be helpful in ordering subsequent confirmatory testing, especially in the case of infection.

Tuberculosis should be suspected, and appropriate isolation precautions should be taken until it is ruled out.

Laboratory testing, including the complete blood cell count with differential and CD4 count, provide ancillary data to narrow the differential diagnosis. For example, if the CD4 count is greater than 200 cells/μL, mycobacterial infection should be strongly suspected; however, lower CD4 counts should also prompt a search for opportunistic infections. In the appropriate clinical scenario, malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and bronchogenic carcinoma can be seen and should also be considered.

Nevertheless, the evaluation hinges on the sputum examination and CT scan of the chest to further characterize the cavity, surrounding lung parenchyma, lymph nodes, and potential fluid collections. Usually, further serologic tests and even bronchoscopy with bronchoalveolar lavage and transbronchial biopsy are required. Treatment should begin once the most likely diagnosis is established.

Coccidioidal pneumonia should be considered in all patients with immunodeficiency, including HIV patients, transplant recipients, those undergoing chemotherapy, and those with intrinsic immune system defects, especially if they have a history of exposure or if they are from an endemic region. Antifungal therapy should be initiated early, and dissemination must be ruled out. Suppressive therapy is mandatory for those with a severely compromised immune system, and serologic testing to ensure remission of the infection is needed. Patients who were previously exposed to Coccidioides or who vacationed or live in the southwestern United States (where it is prevalent) are at risk and may present with any number of symptoms.

A 37-year-old man presented to the emergency department with an 8-week history of a mildly productive cough and shortness of breath accompanied by high fevers, chills, and night sweats. He also had some nausea but no vomiting.

Four days earlier, he had been evaluated by his primary care physician, who prescribed a 14-day course of one double-strength trimethoprim-sulfamethoxazole tablet (Bactrim DS) every 12 hours for presumed acute bronchitis, but his symptoms did not improve.

He was unemployed, living in Arizona, married with children. He denied any use of tobacco, alcohol, or injection drugs. On further questioning, he disclosed that he had unintentionally lost 30 pounds over the past 2 to 3 months and had been feeling tired.

When asked about his medical history, he revealed that he had been diagnosed with human immunodeficiency virus (HIV) infection in 2008 and that recently he had not been taking his antiretroviral medication, a once-daily combination pill containing efavirenz, emtricitabine, and tenofovir (Atripla). He had no other significant medical history, and the only medication he was currently taking was the trimethoprim-sulfamethoxazole.

On examination, his temperature was 38.7°C (101.7°F), blood pressure 109/68 mm Hg, heart rate 60 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 100% while breathing supplemental oxygen via nasal cannula at 2 L/min. He did not appear seriously ill.

Initial blood tests (Table 1) showed a normal white blood cell count, normal results on a complete metabolic panel, and a lactate dehydrogenase level of 539 IU/L (reference range 313–618). His serum lactate level was within normal limits.

HIV-specific tests performed on the second day of hospitalization showed extreme immunosuppression, with a CD4 count of 5 cells/μL (normal 326–1,404 cells/μL).

WHICH ORGANISM IS CAUSING HIS LUNG INFECTION?

1. Which of the following organisms is the least likely to be associated with this patient’s condition?

• Mycobacterium tuberculosis
• Pneumocystis jirovecii
• Coccidioides immitis
• Candida albicans
• Streptococcus pneumoniae
• Cytomegalovirus

Bacterial, fungal, and viral lung infections are common in HIV-infected patients, especially if they are not on antiretroviral therapy and their CD4 lymphocyte counts are low. Clues to the cause can be derived from the history, physical examination, and general laboratory studies. For instance, knowing where the patient lives and where he has travelled recently provides insight into exposure to endemic infectious agents.

The complete blood cell count with differential white blood cell count can help narrow the differential diagnosis but rarely helps exclude a possibility. Neutrophilia is common in bacterial infections. Lymphocytosis can be seen in tuberculosis, in fungal and viral infections, and, rarely, in hematologic malignancies. Eosinophilia can be seen in acute retroviral syndrome, fungal and helminthic infections, adrenal insufficiency, autoimmune disease, and lymphoma.

A caveat to these clues is that in severely immunocompromised hosts, like this man, diagnoses should not be excluded without firm evidence. This patient has severe, active immunosuppression, and only one of the six answer choices above is not a possible causative agent: C albicans rarely causes lung infection, even in immunocompromised people.

Mycobacterium tuberculosis

Tuberculosis can be the first manifestation of HIV infection. It can occur at any CD4 count, but as the count decreases, the risk of dissemination increases.¹ Classic symptoms are fever, night sweats, hemoptysis, and weight loss.

The CD4 count also affects the radiographic presentation. If the count is higher than 350 cells/μL, then infiltration of the upper lobe is likely; if it is lower than 200 cells/μL, then middle, lower, miliary, and extrapulmonary manifestations are likely.^1,2 Cavitation is less common in HIV-infected patients, but mediastinal adenopathy is more common.¹

Definitive diagnosis is via sputum examination, blood culture, nucleic acid amplification, or microscopic study of biopsy specimens of affected tissues to look for acid-fast bacilli.¹

Interferon-gamma-release assays such as the QuantiFERON test (Cellestis, Valencia, CA) or a tuberculin skin test can be used to check for latent tuberculosis infection. These tests can also provide evidence of active infection in the appropriate clinical context.³

Interferon-gamma-release assays have several advantages over skin testing: they are more sensitive (76% to 80%) and specific (97%); they do not give false-positive results in people who previously received bacille Calmette-Guérin vaccine; they react only minimally to previous exposure to nontuberculous mycobacteria; and interpretation is not subject to interreader variability.^4,5 However, concordance between skin testing and interferon-gamma-release assays is low. Therefore, either or both tests can be used if tuberculosis is strongly suspected, and a positive result on either test should prompt further workup.^6,7

Of note, both tests may be affected by immunosuppression, making both susceptible to false-negative results as the CD4 count declines.³

In any case, a positive acid-fast bacillus smear, radiographic evidence of latent infection, or pulmonary symptoms should be presumed to represent active tuberculosis. In such a situation, directly observed treatment with the typical four-drug regimen—rifampin (Rifadin), isoniazid, pyrazinamide, and ethambutol (Myambutol)—is recommended while awaiting definitive results from culture or polymerase chain reaction (PCR) testing.¹

P jirovecii was previously known as P carinii, and P jirovecii pneumonia is an AIDS-defining illness. Most cases occur when the CD4 count falls below 200 cells/μL.¹ Symptoms, including a nonproductive cough, develop insidiously over days to weeks.

Physical examination may reveal inspiratory crackles; however, half of the time the physical examination is nondiagnostic. Oral candidiasis is a common coinfection. The lactate dehydrogenase level may be elevated.^1,8 Radiographs show bilateral interstitial infiltrates, and in 10% to 20% of patients lung cysts develop—hence the name of the organism.¹ Pneumothorax in a patient with HIV should prompt a workup for P jirovecii pneumonia.^9,10

No consensus exists for the diagnosis. However, if sputum examination is unrevealing but suspicion is high, then bronchoalveolar lavage can help.^11–13

Trimethoprim-sulfamethoxazole for 21 days is the first-line treatment, with glucocorticoids added if the Pao₂ is less than 70 mm Hg or if the alveolar-arterial oxygen gradient is greater than 35 mm Hg.¹

Coccidioides species

Coccidioides infection is typically due to either C immitis or C posadasii.¹⁴ People living in or travelling to areas where it is endemic, such as the southwestern United States, Mexico, and Central and South America, are at higher risk.¹⁴

Typical signs and symptoms of this fungal infection include an influenza-like illness with fever, cough, adenopathy, and wasting, and when combined with erythema nodosum, erythema multiforme, arthralgia, or ocular involvement, this constellation is colloquially termed “valley fever.”¹⁵ Most HIV-infected patients who have CD4 counts higher than 250 cells/μL present with focal pneumonia, while lower counts predispose to disseminated disease.^1,2,16

Findings on examination are nonspecific and depend on the various pulmonary manifestations, which include acute, chronic progressive, or diffuse pneumonia, nodules, or cavities.¹⁴ Eosinophilia may accompany the infection.¹⁵

The diagnosis can be made by finding the organisms on direct microscopic examination of involved tissues or secretions or on culture of clinical specimens.^1,2,14 Serologic tests, antigen detection tests, or culture can be helpful if positive, but negative results do not rule out the diagnosis.^1,2,14

A caveat about testing: if the pretest probability of infection is low, positive tests for immunoglobulin M (IgM) do not necessarily equal infection, and the IgM test should be followed up with confirmatory testing. Along the same lines, a high pretest probability should not be ignored if initial tests are negative, and patients in this situation should also undergo further evaluation.¹⁷

Therapy with an azole drug such as fluconazole (Diflucan) or one of the amphotericin B preparations should be started, depending on the severity of the disease.^1,2,14,18

Candida albicans

C albicans is a rare cause of lung infection.^19,20 It is, however, a common inhabitant of the upper airway tract, and pulmonary infection is usually the result of aspiration or hematogenous spread from either the gastrointestinal tract or an infected central venous catheter.²⁰

The presentation is relatively nonspecific. Fever despite broad-spectrum antibacterial therapy is a major clue. Radiographic abnormalities usually are due to other causes, such as superimposed infections or pulmonary hemorrhage.²¹ Sputum culture is unreliable because of colonization. The definitive diagnosis is based on lung biopsy demonstrating organisms within the tissue.^19,20,22

Therapy with a systemic antifungal agent is recommended.

Streptococcus pneumoniae

S pneumoniae is one of the most common bacterial causes of community-acquired pneumonia in people with or without HIV.^23–25 Moreover, two or more episodes of bacterial pneumonia in 12 months can be an AIDS-defining condition in patients with a positive serologic test for HIV.¹⁶ Therefore, in patients with fever, cough, and pulmonary infiltrates on chest radiography, S pneumoniae must always be considered.

Urinary antigen testing has a relatively high positive predictive value (> 89%) and specificity (96%) for diagnosing S pneumoniae pneumonia.²⁶ Blood and sputum cultures should be done not only to confirm the diagnosis, but also because the rates of bacteremia and drug resistance are higher with S pneumoniae infection in the HIV-infected.¹

A combination of a beta-lactam and a macrolide or respiratory fluoroquinolone is the treatment of choice.¹

Cytomegalovirus

Although influenza is the most common cause of viral pneumonia in HIV-infected people, cytomegalovirus is an opportunistic cause.² This is usually a reactivation of latent infection rather than new infection.²⁷ Typically, infections occur at CD4 counts lower than 50 cells/μL, with cough, dyspnea, and fever that last for 2 to 4 weeks.²

Crackles may be heard on lung examination. The lactate dehydrogenase level can be elevated, as in P jirovecii pneumonia.² Radiography can show a wide range of nonspecific findings, from reticular and ground-glass opacities to alveolar or interstitial infiltrates to nodules.

The diagnosis of cytomegalovirus pneumonia is not always clear. Since HIV-infected patients typically shed the virus in their airways, bronchoalveolar lavage is not adequate because a positive finding does not necessarily mean the patient has active viral pneumonitis.²⁷ For this reason, infection should be confirmed by biopsy demonstrating characteristic cytomegalovirus inclusions in lung tissue.²

Importantly, once cytomegalovirus pneumonia is confirmed, the patient should be screened for cytomegalovirus retinitis even if he or she has no visual symptoms, as cytomegalovirus pneumonitis is typically a part of a disseminated infection.¹

Treatment with intravenous ganciclovir (Cytovene) is required.¹

CASE CONTINUED: POSITIVE TESTS FOR COCCIDIOIDES

Our patient began empiric treatment for community-acquired pneumonia with intravenous ceftriaxone (Rocephin) and azithromycin (Zithromax).

On the basis of these findings, the patient was immediately placed in negative pressure respiratory isolation and underwent induced sputum examinations for tuberculosis. Further tests for S pneumoniae, S aureus, Mycoplasma, Legionella, influenza, Pneumocystis, Cryptococcus, Histoplasma, and Coccidioides species were performed.

QuantiFERON testing was negative, and blood cultures were sterile. The first induced sputum examination was negative for acid-fast bacilli. PCR testing for mycobacterial DNA in the sputum was also negative.

Both silver and direct fluorescent antibody staining of the sputum were negative for Pneumocystis. On the basis of these findings and the patient’s lack of clinical improvement with trimethoprim-sulfamethoxazole, Pneumocystis infection was excluded.

THE PATIENT BEGINS TREATMENT

2. Which treatment is most appropriate for this patient?

• Posaconazole (Noxafil)
• Caspofungin (Cancidas) and surgery
• Fluconazole
• Voriconazole (Vfend) and surgery
• Amphotericin B

Solitary pulmonary cavities tend to be asymptomatic and do not require treatment, even if coccidioidal infection is microbiologically confirmed.

However, if there is pain, hemoptysis, or bacterial superinfection, antifungal therapy may result in improvement but not closure of the cavity.¹⁸ Therefore, in all cases of symptomatic coccidioidal pulmonary cavities, surgical resection is the only definitive treatment.

Coccidioidal cavities may rupture and cause pyopneumothorax, but this is an infrequent complication, and antifungal therapy combined with surgical decortication is the treatment of choice.¹⁸

Commonly prescribed antifungals include fluconazole and amphotericin B, the latter usually reserved for patients with significant hypoxia or rapid clinical deterioration.¹⁸ At this time, there are not enough clinical data to show that voriconazole or posaconazole is effective, and thus neither is approved for the treatment of coccidioidomycosis. Likewise, there have been no human trials of the efficacy of caspofungin against Coccidioides infection, although it has been shown to be active in mouse models.¹⁸

Our patient was started on oral fluconazole and observed for clinical improvement or, conversely, for signs of dissemination. After 2 days, he had markedly improved, and within 1 week he was almost back to his baseline level of health. Testing for all other infectious etiologies was unrevealing, and he was removed from negative pressure isolation.

However, as we mentioned above, his CD4 count was 5 cells/μL. We discussed the issue with the patient, and he said he was willing to comply with his treatment for both his Coccidioides and his HIV infection. After much deliberation, he said he was also willing to start and comply with prophylactic treatment for opportunistic infections.

PREVENTING OPPORTUNISTIC INFECTIONS IN HIV PATIENTS

3. Which of the following prophylactic regimens is most appropriate for this patient?

• Trimethoprim-sulfamethoxazole, atovaquone (Mepron), and azithromycin
• Trimethoprim-sulfamethoxazole and azithromycin
• Pentamidine (Nebupent), dapsone, and clarithromycin (Biaxin)
• Dapsone and clarithromycin
• Trimethoprim-sulfamethoxazole by itself

According to guidelines for the prevention of opportunistic diseases in patients with HIV, he needs primary prophylaxis against the following organisms: P jirovecii, Toxoplasma gondii, and Mycobacterium avium complex.¹

The CD4 count dictates the appropriate time to start therapy. If the count is lower than 200 cells/μL or if the patient has oropharyngeal candidiasis regardless of the CD4 count, trimethoprim-sulfamethoxazole is indicated to prevent P jirovecii pneumonia. In those who cannot tolerate trimethoprim-sulfamethoxazole or who are allergic to it, dapsone, pentamidine, or atovaquone can be substituted.¹

In patients seropositive for T gondii, a CD4 count lower than 100/μL indicates the need for prophylaxis.¹ Prophylactic measures are similar to those for Pneumocystis. However, if the patient cannot tolerate trimethoprim-sulfamethoxazole, the recommended alternative is dapsone-pyrimethamine with leucovorin, which is also effective against Pneumocystis.¹

Finally, if the CD4 count is lower than 50 cells/μL, prophylaxis against M avium complex is mandatory, with either azithromycin weekly or clarithromycin daily.¹

Given our patient’s degree of immunosuppression, trimethoprim-sulfamethoxazole plus azithromycin is his most appropriate option.

Trimethoprim-sulfamethoxazole and azithromycin were added to his antimicrobial regimen before he was discharged. Two weeks later, he noted no side effects from any of the medications, he had no new symptoms, he was feeling well, and his cough had improved greatly. He did not have any signs of dissemination of his coccidioidal infection, and we concluded that the primary and only infection was located in the lungs.

DISSEMINATED COCCIDIOIDOMYCOSIS

4. Which of the following extrapulmonary sites is Coccidioides least likely to infect?

• Brain
• Skin
• Meninges
• Lymph nodes
• Bones
• Joints

Extrapulmonary coccidioidomycosis can involve almost any site. However, the most common sites of dissemination are the skin, lymph nodes, bones, and joints.¹⁴ The least likely site is the brain.

Central nervous system involvement

In the central nervous system, involvement is typically with the meninges, rather than frank involvement of the brain parenchyma.^18,28,29 Although patients with HIV or those who are otherwise severely immunocompromised are at higher risk for coccidioidal meningitis, it is rare even in this population.^30,31 Meningitis most commonly presents as headache, vomiting, meningismus, confusion, or diplopia.^32,33

If neurologic findings are absent, experts do not generally recommend lumbar puncture because the incidence of meningeal involvement is low. When cerebrospinal fluid is obtained in an active case of coccidioidal meningitis, fluid analysis typically finds elevated protein, low glucose, and lymphocytic pleocytosis.^1,32

Meningeal enhancement on CT or magnetic resonance imaging is common.³⁴ The diagnosis is established by culture or serologic testing of cerebrospinal fluid (IgM titer, IgG titer, immunodiffusion, or complement fixation).¹⁴

Of note, cerebral infarction and hydrocephalus are feared complications and pose a serious risk of death in any patient.^32,35 In these cases, treatment with antifungals is lifelong, regardless of immune system status.¹⁸

Skin involvement

Skin involvement is variable, consisting of nodules, verrucae, abscesses, or ulcerations.^15,16 Hemorrhage from the skin is relatively common.³⁶ From the skin, the infection can spread to the lymph nodes, leading to regional lymphadenopathy.^14,15 Nodes can ulcerate, drain, or even become necrotic.

Bone and joint involvement

Once integrity of the blood vessels is disrupted, Coccidioides can spread via the blood to the bones or joints,^14,15 causing osteomyelitis, septic arthritis, or synovitis. Subcutaneous abscesses or sinus tracts may subsequently develop.^14,15

HOW LONG MUST HE BE TREATED?

On follow-up, the patient asked how long he needed to continue his antifungal regimen and if any other testing for his coccidioidal infection was necessary, since he was feeling better.

5. Which is the most appropriate response to the patient’s question?

• He can discontinue his antifungal drugs; no further testing is necessary
• He needs 14 more days of antifungal therapy and periodic serologic tests
• He needs 2.5 more months of antifungal therapy and monthly blood cultures
• He needs lifelong antifungal therapy and periodic urinary antigen levels
• He needs 5.5 more months of antifungal therapy; bronchoscopy with bronchoalveolar lavage at 1 year

How long to treat and how to monitor for coccidioidomycosis vary by patient.

Duration of therapy depends on symptoms and immune status

The severity of infection (Table 2) and the immune status are important factors that must be considered when tailoring a therapeutic regimen.

Immunocompetent patients without symptoms or with mild symptoms usually do not need therapy and are followed periodically for signs of improvement.^14,18,29

Immunocompetent patients with severe symptoms typically receive 3 to 6 months of antifungal therapy.¹⁸

Immunocompromised patients (especially HIV-infected patients with CD4 counts < 250 cells/μL) need antifungal treatment, regardless of the severity of infection.^14,18,29 In many cases, the type of infection will dictate the duration of therapy.

Diffuse pneumonia or extrapulmonary dissemination typically requires treatment for at least 1 year regardless of immune status.^14,18 For those with HIV and diffuse pneumonia, dissemination, or meningitis, guidelines dictate that secondary prophylaxis be started after at least 1 year of therapy and improvement in clinical status; it should be continued indefinitely to prevent reactivation of latent infection.¹⁸

The guidelines say that in patients with higher CD4 counts (presumably > 250 cells/μL) and nonmeningeal coccidioidomycosis, providers may consider discontinuing secondary prophylaxis, as long as there is clinical evidence of improvement and control of the primary infection.¹⁸ However, many experts advocate continuing secondary prophylaxis regardless of the CD4 count, as the rates of relapse and dissemination are high.^1,16,37

Monitoring

Regardless of the therapy chosen, disease monitoring every 2 to 4 months with clinical history and examination, radiography, and coccidioidal-specific testing is recommended for at least 1 year, and perhaps longer, to ensure complete resolution and to monitor for signs of dissemination.^14,18

Which test to use is not clear. Serologic testing identifies antibodies (IgM or IgG) to coccidioidal antigens. IgM appears during the acute infection, and tests include immunodiffusion, latex agglutination, and enzymelinked immunoassays. The last two are highly sensitive but have a significant false-positive rate, and should be confirmed with the former if found to be positive.^17,18 IgG appears weeks after the acute infection and can be evaluated with immunodiffusion or enzyme-linked immunoassay as well.

Keep in mind that these tests provide only qualitative results on the presence of these antibodies, not quantitative information. Furthermore, enzyme-linked immunoassay is not as accurate as immunodiffusion, which has a sensitivity in immunocompromised patients of only approximately 50%.^38,39

For that reason, complement fixation titers are extremely helpful because they reflect the severity of infection, can be used to monitor the response to treatment, and can even provide insight into the prognosis.¹⁸ The sensitivity of this test in immunocompromised hosts is 60% to 70%.³⁸ Titers can be checked to confirm the diagnosis and can be periodically monitored throughout the treatment course to ensure efficacy of therapy and to watch for reactivation of the infection.¹ In fact, an initial complement fixation titer of 1:2 or 1:4 is associated with favorable outcomes, while a titer greater than 1:16 portends dissemination.¹⁸

The caveat to any serologic test (immunodiffusion, enzyme-linked immunoassay, and complement fixation) is that severely immunocompromised patients (as in our case) may not mount an immune response and may have falsely low titers even in the face of a severe infection, and therefore these tests may not be reliable.³⁸ In these situations, urinary coccidioidal antigen detection assay (sensitivity 71%) or nucleic acid amplification of coccidioidal DNA (sensitivity 75%) may be of more help.^40,41

Therefore, in the setting of HIV infection, an asymptomatic pulmonary cavity, and diffuse pulmonary involvement secondary to coccidioidal infection, lifelong antibiotics (treatment plus secondary prophylaxis) with periodic testing of urinary coccidioidal antigen levels is the best response to the patient’s question, given that his complement fixation titers were initially negative and antigen levels were positive.

CASE CONCLUDED

The patient continues to be followed for his HIV infection. He is undergoing serologic and urinary antigen testing for Coccidioides infection every 3 months in addition to his maintenance HIV testing. He is on chronic suppressive therapy with fluconazole. He has not had a recurrence of his Coccidioides infection, nor have there been any signs of dissemination.

CAVITARY LUNG LESIONS IN HIV PATIENTS

In patients with HIV, cavitary lung lesions on chest radiography can be due to a wide variety of etiologies that range from infection to malignancy. Historical clues, including environmental exposure, occupation, geographic residence, sick contacts, travel, or animal contact can be helpful in ordering subsequent confirmatory testing, especially in the case of infection.

Tuberculosis should be suspected, and appropriate isolation precautions should be taken until it is ruled out.

Laboratory testing, including the complete blood cell count with differential and CD4 count, provide ancillary data to narrow the differential diagnosis. For example, if the CD4 count is greater than 200 cells/μL, mycobacterial infection should be strongly suspected; however, lower CD4 counts should also prompt a search for opportunistic infections. In the appropriate clinical scenario, malignancies including Kaposi sarcoma, non-Hodgkin lymphoma, and bronchogenic carcinoma can be seen and should also be considered.

Nevertheless, the evaluation hinges on the sputum examination and CT scan of the chest to further characterize the cavity, surrounding lung parenchyma, lymph nodes, and potential fluid collections. Usually, further serologic tests and even bronchoscopy with bronchoalveolar lavage and transbronchial biopsy are required. Treatment should begin once the most likely diagnosis is established.

Coccidioidal pneumonia should be considered in all patients with immunodeficiency, including HIV patients, transplant recipients, those undergoing chemotherapy, and those with intrinsic immune system defects, especially if they have a history of exposure or if they are from an endemic region. Antifungal therapy should be initiated early, and dissemination must be ruled out. Suppressive therapy is mandatory for those with a severely compromised immune system, and serologic testing to ensure remission of the infection is needed. Patients who were previously exposed to Coccidioides or who vacationed or live in the southwestern United States (where it is prevalent) are at risk and may present with any number of symptoms.

Treatment for lupus nephritis has changed dramatically in recent years. Only 10 years ago, rheumatologists and nephrologists, whether specializing in adult or pediatric medicine, treated lupus nephritis with a similar regimen of monthly intravenous cyclophosphamide (Cytoxan) and glucocorticoids. Although the regimen is effective, side effects such as infection, hair loss, and infertility were extremely common.

Effective but very toxic therapy is common in autoimmune diseases. In the last decade, clinical trials have shown that less toxic drugs are as effective for treating lupus nephritis. This article will review new developments in therapy for lupus nephritis, which can be viewed as a prototype for other fields of medicine.

DEMOGRAPHICS ARE IMPORTANT

Although numerous factors have prognostic value in lupus nephritis (eg, serum creatinine, proteinuria, renal biopsy findings), the most important to consider when designing and interpreting studies are race and socioeconomic variables.

A retrospective study in Miami, FL,¹ evaluated 213 patients with lupus nephritis, of whom 47% were Hispanic, 44% African American, and 20% white. At baseline, African Americans had higher blood pressure, higher serum creatinine levels, and lower household income. After 6 years, African Americans fared the worst in terms of doubling of serum creatinine, developing end-stage renal disease, and death; whites had the best outcomes, and Hispanics were in between. Low income was found to be a significant risk factor, independent of racial background.

In a similar retrospective study in New York City in 128 patients (43% white, 40% Hispanic, and 17% African American) with proliferative lupus nephritis,² disease was much more likely to progress to renal failure over 10 years in patients living in a poor neighborhood, even after adjustment for race.

We need to keep in mind that racial and socioeconomic factors correlate with disease severity when we design and interpret studies of lupus nephritis. Study groups must be carefully balanced with patients of similar racial and socioeconomic profiles. Study findings must be interpreted with caution; for example, whether results from a study from China are applicable to an African American with lupus nephritis in New York City is unclear.

OLDER STANDARD THERAPY: EFFECTIVE BUT TOXIC

The last large National Institutes of Health study that involved only cyclophosphamide and a glucocorticoid was published in 2001,³ with 21 patients receiving cyclophosphamide alone and 20 patients receiving cyclophosphamide plus methylprednisolone. Although lupus nephritis improved, serious side effects occurred in one-third to one-half of patients in each group and included hypertension, hyperlipidemia, valvular heart disease, avascular necrosis, premature menopause, and major infections, including herpes zoster.

Less cyclophosphamide works just as well

The multicenter, prospective Euro-Lupus Nephritis Trial⁴ randomized 90 patients with proliferative lupus nephritis to receive either standard high-dose intravenous (IV) cyclophosphamide therapy (six monthly pulses and two quarterly pulses, with doses increasing according to the white blood cell count) or low-dose IV cyclophosphamide therapy (six pulses every 2 weeks at a fixed dose of 500 mg). Both regimens were followed by azathioprine (Imuran).

At 4 years, the two treatment groups were not significantly different in terms of treatment failure, remission rates, serum creatinine levels, 24-hour proteinuria, and freedom from renal flares. However, the rates of side effects were significantly different, with more patients in the low-dosage group free of severe infection.

One problem with this study is whether it is applicable to an American lupus nephritis population, since 84% of the patients were white. Since this study, others indicate that this regimen is probably also safe and effective for different racial groups in the United States.

At 10-year follow-up,⁵ both treatment groups still had identical excellent rates of freedom from end-stage renal disease. Serum creatinine and 24-hour proteinuria were also at excellent levels and identical in both groups. Nearly three quarters of patients still needed glucocorticoid therapy and more than half still needed immunosuppressive therapy, but the rates were not statistically significantly different between the treatment groups.

The cumulative dose of cyclophosphamide was 9.5 g in the standard-treatment group and 5.5 g in the low-dose group. This difference in exposure could make a tremendous difference to patients, not only for immediate side effects such as early menopause and infections, but for the risk of cancer in later decades.

This study showed clearly that low-dose cyclophosphamide is an option for induction therapy. Drawbacks of the study were that the population was mostly white and that patients had only moderately severe disease.

Low-dose cyclophosphamide has largely replaced the older National Institutes of Health regimen, although during the last decade drug therapy has undergone more changes.

MYCOPHENOLATE AND AZATHIOPRINE: ALTERNATIVES TO CYCLOPHOSPHAMIDE

In a Chinese study, mycophenolate was better than cyclophosphamide for induction

In a study in Hong Kong, Chan et al⁶ randomized 42 patients with severe lupus nephritis to receive either mycophenolate mofetil (available in the United States as CellCept; 2 g/day for 6 months, then 1 g/day for 6 months) or oral cyclophosphamide (2.5 mg/kg per day for 6 months) followed by azathioprine (1.5–2.0 mg/kg per day) for 6 months. Both groups also received prednisolone during the year.

At the end of the first year, the two groups were not significantly different in their rates of complete remission, partial remission, and relapse. The rate of infection, although not significantly different, was higher in the cyclophosphamide group (33% vs 19%). Two patients (10%) died in the cyclophosphamide group, but the difference in mortality rates was not statistically significant.

Nearly 5 years later,⁷ rates of chronic renal failure and relapse were still statistically the same in the two groups. Infections were fewer in the mycophenolate group (13% vs 40%, P = .013). The rate of amenorrhea was 36% in the cyclophosphamide group and only 4% in the mycophenolate group (P = .004). Four patients in the cyclophosphamide group and none in the mycophenolate group reached the composite end point of end-stage renal failure or death (P = .062).

This study appeared to offer a new option with equal efficacy and fewer side effects than standard therapy. However, its applicability to non-Chinese populations remained to be shown.

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.

RITUXIMAB: PROMISING BUT UNPROVEN

Rituximab (Rituxan) was originally approved to treat tumors, then rheumatoid arthritis, and most recently vasculitis. Evidence thus far is mixed regarding its use as a treatment for lupus nephritis. Although randomized clinical trials have not found it to be superior to standard regimens, there are many signs that it may be effective.

Rituximab in uncontrolled studies

Terrier et al¹³ analyzed prospective data from 136 patients with systemic lupus erythematosus, most of whom had renal disease, from the French Autoimmunity and Rituximab registry. Response occurred in 71% of patients using rituximab, with no difference found between patients receiving rituximab monotherapy and those concomitantly receiving immunosuppressive agents.

Melander et al¹⁴ retrospectively studied 19 women and 1 man who had been treated with rituximab for severe lupus nephritis and followed for at least 1 year. Three patients had concurrent therapy with cyclophosphamide, and 10 patients continued rituximab as maintenance therapy; 12 patients had lupus nephritis that had been refractory to standard treatment, and 6 had relapsing disease.

At a median follow-up of 22 months, 12 patients (60%) had achieved complete or partial renal remission.

Condon et al¹⁵ treated 21 patients who had severe lupus nephritis with two doses of rituximab and IV methylprednisolone 2 weeks apart, then maintenance therapy with mycophenolate without any oral steroids. At a mean follow-up of 35 months ( ± 14 months), 16 (76%) were in complete remission, with a mean time to remission of 12 months. Two (9.5%) achieved partial remission. The rate of toxicity was low.

Thus, rituximab appears promising in uncontrolled studies.

Placebo-controlled trials fail to prove rituximab effective

LUNAR trial. On the other hand, the largest placebo-controlled trial to evaluate rituximab in patients with proliferative lupus nephritis, the Lupus Nephritis Assessment With Rituximab (LUNAR) trial¹⁶ found differences in favor of rituximab, but none reached statistical significance. The trial randomized 140 patients to receive either mycophenolate plus periodic rituximab infusions or mycophenolate plus placebo infusions for 1 year. All patients received the same dosage of glucocorticoids, which was tapered over the year.

At the end of 1 year, the groups were not statistically different in terms of complete renal response and partial renal response. Rituximab appeared less likely to produce no response, but the difference was not statistically significant.

African Americans appeared to have a higher response rate to rituximab (70% in the rituximab group achieved a response vs 45% in the control group), but again, the difference did not reach statistical significance, and the total study population of African Americans was only 40.

Rituximab did have a statistically significant positive effect on two serologic markers at 1 year: levels of anti-dsDNA fell faster and complement rose faster. In addition, rates of adverse and serious adverse events were similar between the two groups, with no new or unexpected “safety signals.”

This study can be interpreted in a number of ways. The number of patients may have been too small to show significance and the follow-up may have been too short. On the other hand, it may simply not be effective to add rituximab to a full dose of mycophenolate and steroids, an already good treatment.

EXPLORER trial. Similarly, for patients with lupus without nephritis, the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial¹⁷ also tested rituximab against a background of an effective therapeutic regimen and found no additional benefit. This study had design problems similar to those of the LUNAR trial.

Rituximab as rescue therapy

The evidence so far indicates that rituximab may have a role as rescue therapy for refractory or relapsing disease. Rituximab must be used with other therapies, but maintenance corticosteroid therapy is not necessary. Its role as a first-line agent in induction therapy for lupus nephritis remains unclear, although it may have an important role for nonwhites. In general, it has been well tolerated. Until a large randomized trial indicates otherwise, it should not be used as a first-line therapy.

The US Food and Drug Administration (FDA) sent out a warning about the danger of progressive multifocal leukoencephalopathy as an adverse effect of rituximab and of mycophenolate, but this does not appear to be a major concern for most patients and is only likely to occur in those who have been over-immunosuppressed for many years.

MULTITARGET THERAPY

The concept of using multiple drugs simultaneously—such as mycophenolate, steroids, and rituximab—is increasingly being tried. Multi-target therapy appears to offer the advantages of combining different modes of action with better results, and it offers fewer side effects because dosages of each individual drug can be lower when combined with other immunosuppressives.

Bao et al¹⁸ in China randomly assigned 40 patients with diffuse proliferative and membranous nephritis to 6 to 9 months of induction treatment with either multitarget therapy (mycophenolate, tacrolimus [Prograf], and glucocorticoids) or IV cyclophosphamide. More complete remissions occurred in the multitarget therapy group, both at 6 months (50% vs 5%) and at 9 months (65% vs 15%). Most adverse events were less frequent in the multitarget therapy group, although three patients (15%) in the multitarget therapy group developed new-onset hypertension vs none in the cyclophosphamide group.

NEW MEDICATIONS

Entirely new classes of drugs are being developed with immunomodulatory effects, including tolerance molecules, cytokine blockers, inhibitors of human B lymphocyte stimulator, and costimulatory blockers.

Belimumab offers small improvement for lupus

Belimumab (Benlysta) is a human monoclonal antibody that inhibits the biologic activity of human B lymphocyte stimulator; it has recently been approved by the FDA for lupus nephritis. In a worldwide study,¹⁹ 867 patients with systemic lupus erythematosus were randomized to receive either belimumab (1 mg/kg or 10 mg/kg) or placebo.

The primary end point was the reduction of disease activity by a scoring system (SELENA-SLEDAI) that incorporated multiple features of lupus, including arthritis, vasculitis, proteinuria, rash, and others. Patients in the belimumab group had better outcomes, but the results were not dramatic. Because the drug is so expensive (about $25,000 per year) and the improvement offered is only incremental, this drug will not likely change the treatment of lupus very much.

Moreover, patients with lupus nephritis were not included in the study, but a new study is being planned to do so. Improvement is harder to demonstrate in lupus nephritis than in rheumatoid arthritis and systemic lupus erythematosus: significant changes in creatinine levels and 24-hour urinary protein must be achieved, rather than more qualitative signs and symptoms of joint pain, rash, and feeling better. Although belimumab is still unproven for lupus nephritis, it might be worth trying for patients failing other therapy.

Laquinimod: A promising experimental drug

Laquinimod is an oral immunomodulatory drug with a number of effects, including down-regulating major histocompatability complex II, chemokines, and adhesion-related molecules related to inflammation. It has been studied in more than 2,500 patients with multiple sclerosis. Pilot studies are now being done for its use for lupus nephritis. If it shows promise, a large randomized, controlled trial will be conducted.

Abatacept is in clinical trials

Abatacept (Orencia), a costimulation blocker, is undergoing clinical trials in lupus nephritis. Results should be available shortly.

INDIVIDUALIZE THERAPY

This past decade has seen such an increase in options to treat lupus nephritis that therapy can now be individualized.

Choosing IV cyclophosphamide vs mycophenolate

As a result of recent trials, doctors in the United States are increasingly using mycophenolate as the first-line drug for lupus nephritis. In Europe, however, many are choosing the shorter regimen of IV cyclophosphamide because of the results of the Euro-Lupus study.

Nowadays, I tend to use IV cyclophosphamide as the first-line drug only for patients with severe crescenteric glomerulonephritis or a very high serum creatinine level. In such cases, there is more experience with cyclophosphamide, and such severe disease does not lend itself to the luxury of trying out different therapies sequentially. If such a severely ill patient insists that a future pregnancy is very important, an alternative therapy of mycophenolate plus rituximab should be considered. I prefer mycophenolate for induction and maintenance therapy in most patients.

Dosing and formulation considerations for mycophenolate

Large dosages of mycophenolate are much better tolerated when broken up throughout the day. A patient who cannot tolerate 1 g twice daily may be able to tolerate 500 mg four times a day. The formulation can also make a difference. Some patients tolerate sustained-release mycophenolate (Myfortic) better than CellCept, and vice versa.

For patients who cannot tolerate mycophenolate, azathioprine is an acceptable alternative. In addition, for a patient who is already doing well on azathioprine, there is no need to change to mycophenolate.

Long maintenance therapy now acceptable

The ALMS Maintenance Trial¹² found 3 years of maintenance therapy to be safe and effective. Such a long maintenance period is increasingly viewed as important, especially for patients in their teens and 20s, as it allows them to live a normal life, ie, to finish their education, get married, and become settled socially. Whether 5 years of maintenance therapy or even 10 years is advisable is still unknown.

Treatment during pregnancy

Neither mycophenolate nor azathioprine is recommended during pregnancy, although their effects are unknown. Because we have much more renal transplant experience with azathioprine during pregnancy, I recommend either switching from mycophenolate to azathioprine or trying to stop medication altogether if the patient has been well controlled.

Treatment for lupus nephritis has changed dramatically in recent years. Only 10 years ago, rheumatologists and nephrologists, whether specializing in adult or pediatric medicine, treated lupus nephritis with a similar regimen of monthly intravenous cyclophosphamide (Cytoxan) and glucocorticoids. Although the regimen is effective, side effects such as infection, hair loss, and infertility were extremely common.

Effective but very toxic therapy is common in autoimmune diseases. In the last decade, clinical trials have shown that less toxic drugs are as effective for treating lupus nephritis. This article will review new developments in therapy for lupus nephritis, which can be viewed as a prototype for other fields of medicine.

DEMOGRAPHICS ARE IMPORTANT

Although numerous factors have prognostic value in lupus nephritis (eg, serum creatinine, proteinuria, renal biopsy findings), the most important to consider when designing and interpreting studies are race and socioeconomic variables.

A retrospective study in Miami, FL,¹ evaluated 213 patients with lupus nephritis, of whom 47% were Hispanic, 44% African American, and 20% white. At baseline, African Americans had higher blood pressure, higher serum creatinine levels, and lower household income. After 6 years, African Americans fared the worst in terms of doubling of serum creatinine, developing end-stage renal disease, and death; whites had the best outcomes, and Hispanics were in between. Low income was found to be a significant risk factor, independent of racial background.

In a similar retrospective study in New York City in 128 patients (43% white, 40% Hispanic, and 17% African American) with proliferative lupus nephritis,² disease was much more likely to progress to renal failure over 10 years in patients living in a poor neighborhood, even after adjustment for race.

We need to keep in mind that racial and socioeconomic factors correlate with disease severity when we design and interpret studies of lupus nephritis. Study groups must be carefully balanced with patients of similar racial and socioeconomic profiles. Study findings must be interpreted with caution; for example, whether results from a study from China are applicable to an African American with lupus nephritis in New York City is unclear.

OLDER STANDARD THERAPY: EFFECTIVE BUT TOXIC

The last large National Institutes of Health study that involved only cyclophosphamide and a glucocorticoid was published in 2001,³ with 21 patients receiving cyclophosphamide alone and 20 patients receiving cyclophosphamide plus methylprednisolone. Although lupus nephritis improved, serious side effects occurred in one-third to one-half of patients in each group and included hypertension, hyperlipidemia, valvular heart disease, avascular necrosis, premature menopause, and major infections, including herpes zoster.

Less cyclophosphamide works just as well

The multicenter, prospective Euro-Lupus Nephritis Trial⁴ randomized 90 patients with proliferative lupus nephritis to receive either standard high-dose intravenous (IV) cyclophosphamide therapy (six monthly pulses and two quarterly pulses, with doses increasing according to the white blood cell count) or low-dose IV cyclophosphamide therapy (six pulses every 2 weeks at a fixed dose of 500 mg). Both regimens were followed by azathioprine (Imuran).

At 4 years, the two treatment groups were not significantly different in terms of treatment failure, remission rates, serum creatinine levels, 24-hour proteinuria, and freedom from renal flares. However, the rates of side effects were significantly different, with more patients in the low-dosage group free of severe infection.

One problem with this study is whether it is applicable to an American lupus nephritis population, since 84% of the patients were white. Since this study, others indicate that this regimen is probably also safe and effective for different racial groups in the United States.

At 10-year follow-up,⁵ both treatment groups still had identical excellent rates of freedom from end-stage renal disease. Serum creatinine and 24-hour proteinuria were also at excellent levels and identical in both groups. Nearly three quarters of patients still needed glucocorticoid therapy and more than half still needed immunosuppressive therapy, but the rates were not statistically significantly different between the treatment groups.

The cumulative dose of cyclophosphamide was 9.5 g in the standard-treatment group and 5.5 g in the low-dose group. This difference in exposure could make a tremendous difference to patients, not only for immediate side effects such as early menopause and infections, but for the risk of cancer in later decades.

This study showed clearly that low-dose cyclophosphamide is an option for induction therapy. Drawbacks of the study were that the population was mostly white and that patients had only moderately severe disease.

Low-dose cyclophosphamide has largely replaced the older National Institutes of Health regimen, although during the last decade drug therapy has undergone more changes.

MYCOPHENOLATE AND AZATHIOPRINE: ALTERNATIVES TO CYCLOPHOSPHAMIDE

In a Chinese study, mycophenolate was better than cyclophosphamide for induction

In a study in Hong Kong, Chan et al⁶ randomized 42 patients with severe lupus nephritis to receive either mycophenolate mofetil (available in the United States as CellCept; 2 g/day for 6 months, then 1 g/day for 6 months) or oral cyclophosphamide (2.5 mg/kg per day for 6 months) followed by azathioprine (1.5–2.0 mg/kg per day) for 6 months. Both groups also received prednisolone during the year.

At the end of the first year, the two groups were not significantly different in their rates of complete remission, partial remission, and relapse. The rate of infection, although not significantly different, was higher in the cyclophosphamide group (33% vs 19%). Two patients (10%) died in the cyclophosphamide group, but the difference in mortality rates was not statistically significant.

Nearly 5 years later,⁷ rates of chronic renal failure and relapse were still statistically the same in the two groups. Infections were fewer in the mycophenolate group (13% vs 40%, P = .013). The rate of amenorrhea was 36% in the cyclophosphamide group and only 4% in the mycophenolate group (P = .004). Four patients in the cyclophosphamide group and none in the mycophenolate group reached the composite end point of end-stage renal failure or death (P = .062).

This study appeared to offer a new option with equal efficacy and fewer side effects than standard therapy. However, its applicability to non-Chinese populations remained to be shown.

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.

RITUXIMAB: PROMISING BUT UNPROVEN

Rituximab (Rituxan) was originally approved to treat tumors, then rheumatoid arthritis, and most recently vasculitis. Evidence thus far is mixed regarding its use as a treatment for lupus nephritis. Although randomized clinical trials have not found it to be superior to standard regimens, there are many signs that it may be effective.

Rituximab in uncontrolled studies

Terrier et al¹³ analyzed prospective data from 136 patients with systemic lupus erythematosus, most of whom had renal disease, from the French Autoimmunity and Rituximab registry. Response occurred in 71% of patients using rituximab, with no difference found between patients receiving rituximab monotherapy and those concomitantly receiving immunosuppressive agents.

Melander et al¹⁴ retrospectively studied 19 women and 1 man who had been treated with rituximab for severe lupus nephritis and followed for at least 1 year. Three patients had concurrent therapy with cyclophosphamide, and 10 patients continued rituximab as maintenance therapy; 12 patients had lupus nephritis that had been refractory to standard treatment, and 6 had relapsing disease.

At a median follow-up of 22 months, 12 patients (60%) had achieved complete or partial renal remission.

Condon et al¹⁵ treated 21 patients who had severe lupus nephritis with two doses of rituximab and IV methylprednisolone 2 weeks apart, then maintenance therapy with mycophenolate without any oral steroids. At a mean follow-up of 35 months ( ± 14 months), 16 (76%) were in complete remission, with a mean time to remission of 12 months. Two (9.5%) achieved partial remission. The rate of toxicity was low.

Thus, rituximab appears promising in uncontrolled studies.

Placebo-controlled trials fail to prove rituximab effective

LUNAR trial. On the other hand, the largest placebo-controlled trial to evaluate rituximab in patients with proliferative lupus nephritis, the Lupus Nephritis Assessment With Rituximab (LUNAR) trial¹⁶ found differences in favor of rituximab, but none reached statistical significance. The trial randomized 140 patients to receive either mycophenolate plus periodic rituximab infusions or mycophenolate plus placebo infusions for 1 year. All patients received the same dosage of glucocorticoids, which was tapered over the year.

At the end of 1 year, the groups were not statistically different in terms of complete renal response and partial renal response. Rituximab appeared less likely to produce no response, but the difference was not statistically significant.

African Americans appeared to have a higher response rate to rituximab (70% in the rituximab group achieved a response vs 45% in the control group), but again, the difference did not reach statistical significance, and the total study population of African Americans was only 40.

Rituximab did have a statistically significant positive effect on two serologic markers at 1 year: levels of anti-dsDNA fell faster and complement rose faster. In addition, rates of adverse and serious adverse events were similar between the two groups, with no new or unexpected “safety signals.”

This study can be interpreted in a number of ways. The number of patients may have been too small to show significance and the follow-up may have been too short. On the other hand, it may simply not be effective to add rituximab to a full dose of mycophenolate and steroids, an already good treatment.

EXPLORER trial. Similarly, for patients with lupus without nephritis, the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial¹⁷ also tested rituximab against a background of an effective therapeutic regimen and found no additional benefit. This study had design problems similar to those of the LUNAR trial.

Rituximab as rescue therapy

The evidence so far indicates that rituximab may have a role as rescue therapy for refractory or relapsing disease. Rituximab must be used with other therapies, but maintenance corticosteroid therapy is not necessary. Its role as a first-line agent in induction therapy for lupus nephritis remains unclear, although it may have an important role for nonwhites. In general, it has been well tolerated. Until a large randomized trial indicates otherwise, it should not be used as a first-line therapy.

The US Food and Drug Administration (FDA) sent out a warning about the danger of progressive multifocal leukoencephalopathy as an adverse effect of rituximab and of mycophenolate, but this does not appear to be a major concern for most patients and is only likely to occur in those who have been over-immunosuppressed for many years.

MULTITARGET THERAPY

The concept of using multiple drugs simultaneously—such as mycophenolate, steroids, and rituximab—is increasingly being tried. Multi-target therapy appears to offer the advantages of combining different modes of action with better results, and it offers fewer side effects because dosages of each individual drug can be lower when combined with other immunosuppressives.

Bao et al¹⁸ in China randomly assigned 40 patients with diffuse proliferative and membranous nephritis to 6 to 9 months of induction treatment with either multitarget therapy (mycophenolate, tacrolimus [Prograf], and glucocorticoids) or IV cyclophosphamide. More complete remissions occurred in the multitarget therapy group, both at 6 months (50% vs 5%) and at 9 months (65% vs 15%). Most adverse events were less frequent in the multitarget therapy group, although three patients (15%) in the multitarget therapy group developed new-onset hypertension vs none in the cyclophosphamide group.

NEW MEDICATIONS

Entirely new classes of drugs are being developed with immunomodulatory effects, including tolerance molecules, cytokine blockers, inhibitors of human B lymphocyte stimulator, and costimulatory blockers.

Belimumab offers small improvement for lupus

Belimumab (Benlysta) is a human monoclonal antibody that inhibits the biologic activity of human B lymphocyte stimulator; it has recently been approved by the FDA for lupus nephritis. In a worldwide study,¹⁹ 867 patients with systemic lupus erythematosus were randomized to receive either belimumab (1 mg/kg or 10 mg/kg) or placebo.

The primary end point was the reduction of disease activity by a scoring system (SELENA-SLEDAI) that incorporated multiple features of lupus, including arthritis, vasculitis, proteinuria, rash, and others. Patients in the belimumab group had better outcomes, but the results were not dramatic. Because the drug is so expensive (about $25,000 per year) and the improvement offered is only incremental, this drug will not likely change the treatment of lupus very much.

Moreover, patients with lupus nephritis were not included in the study, but a new study is being planned to do so. Improvement is harder to demonstrate in lupus nephritis than in rheumatoid arthritis and systemic lupus erythematosus: significant changes in creatinine levels and 24-hour urinary protein must be achieved, rather than more qualitative signs and symptoms of joint pain, rash, and feeling better. Although belimumab is still unproven for lupus nephritis, it might be worth trying for patients failing other therapy.

Laquinimod: A promising experimental drug

Laquinimod is an oral immunomodulatory drug with a number of effects, including down-regulating major histocompatability complex II, chemokines, and adhesion-related molecules related to inflammation. It has been studied in more than 2,500 patients with multiple sclerosis. Pilot studies are now being done for its use for lupus nephritis. If it shows promise, a large randomized, controlled trial will be conducted.

Abatacept is in clinical trials

Abatacept (Orencia), a costimulation blocker, is undergoing clinical trials in lupus nephritis. Results should be available shortly.

INDIVIDUALIZE THERAPY

This past decade has seen such an increase in options to treat lupus nephritis that therapy can now be individualized.

Choosing IV cyclophosphamide vs mycophenolate

As a result of recent trials, doctors in the United States are increasingly using mycophenolate as the first-line drug for lupus nephritis. In Europe, however, many are choosing the shorter regimen of IV cyclophosphamide because of the results of the Euro-Lupus study.

Nowadays, I tend to use IV cyclophosphamide as the first-line drug only for patients with severe crescenteric glomerulonephritis or a very high serum creatinine level. In such cases, there is more experience with cyclophosphamide, and such severe disease does not lend itself to the luxury of trying out different therapies sequentially. If such a severely ill patient insists that a future pregnancy is very important, an alternative therapy of mycophenolate plus rituximab should be considered. I prefer mycophenolate for induction and maintenance therapy in most patients.

Dosing and formulation considerations for mycophenolate

Large dosages of mycophenolate are much better tolerated when broken up throughout the day. A patient who cannot tolerate 1 g twice daily may be able to tolerate 500 mg four times a day. The formulation can also make a difference. Some patients tolerate sustained-release mycophenolate (Myfortic) better than CellCept, and vice versa.

For patients who cannot tolerate mycophenolate, azathioprine is an acceptable alternative. In addition, for a patient who is already doing well on azathioprine, there is no need to change to mycophenolate.

Long maintenance therapy now acceptable

The ALMS Maintenance Trial¹² found 3 years of maintenance therapy to be safe and effective. Such a long maintenance period is increasingly viewed as important, especially for patients in their teens and 20s, as it allows them to live a normal life, ie, to finish their education, get married, and become settled socially. Whether 5 years of maintenance therapy or even 10 years is advisable is still unknown.

Treatment during pregnancy

Neither mycophenolate nor azathioprine is recommended during pregnancy, although their effects are unknown. Because we have much more renal transplant experience with azathioprine during pregnancy, I recommend either switching from mycophenolate to azathioprine or trying to stop medication altogether if the patient has been well controlled.

Treatment for lupus nephritis has changed dramatically in recent years. Only 10 years ago, rheumatologists and nephrologists, whether specializing in adult or pediatric medicine, treated lupus nephritis with a similar regimen of monthly intravenous cyclophosphamide (Cytoxan) and glucocorticoids. Although the regimen is effective, side effects such as infection, hair loss, and infertility were extremely common.

Effective but very toxic therapy is common in autoimmune diseases. In the last decade, clinical trials have shown that less toxic drugs are as effective for treating lupus nephritis. This article will review new developments in therapy for lupus nephritis, which can be viewed as a prototype for other fields of medicine.

DEMOGRAPHICS ARE IMPORTANT

Although numerous factors have prognostic value in lupus nephritis (eg, serum creatinine, proteinuria, renal biopsy findings), the most important to consider when designing and interpreting studies are race and socioeconomic variables.

A retrospective study in Miami, FL,¹ evaluated 213 patients with lupus nephritis, of whom 47% were Hispanic, 44% African American, and 20% white. At baseline, African Americans had higher blood pressure, higher serum creatinine levels, and lower household income. After 6 years, African Americans fared the worst in terms of doubling of serum creatinine, developing end-stage renal disease, and death; whites had the best outcomes, and Hispanics were in between. Low income was found to be a significant risk factor, independent of racial background.

In a similar retrospective study in New York City in 128 patients (43% white, 40% Hispanic, and 17% African American) with proliferative lupus nephritis,² disease was much more likely to progress to renal failure over 10 years in patients living in a poor neighborhood, even after adjustment for race.

We need to keep in mind that racial and socioeconomic factors correlate with disease severity when we design and interpret studies of lupus nephritis. Study groups must be carefully balanced with patients of similar racial and socioeconomic profiles. Study findings must be interpreted with caution; for example, whether results from a study from China are applicable to an African American with lupus nephritis in New York City is unclear.

OLDER STANDARD THERAPY: EFFECTIVE BUT TOXIC

The last large National Institutes of Health study that involved only cyclophosphamide and a glucocorticoid was published in 2001,³ with 21 patients receiving cyclophosphamide alone and 20 patients receiving cyclophosphamide plus methylprednisolone. Although lupus nephritis improved, serious side effects occurred in one-third to one-half of patients in each group and included hypertension, hyperlipidemia, valvular heart disease, avascular necrosis, premature menopause, and major infections, including herpes zoster.

Less cyclophosphamide works just as well

The multicenter, prospective Euro-Lupus Nephritis Trial⁴ randomized 90 patients with proliferative lupus nephritis to receive either standard high-dose intravenous (IV) cyclophosphamide therapy (six monthly pulses and two quarterly pulses, with doses increasing according to the white blood cell count) or low-dose IV cyclophosphamide therapy (six pulses every 2 weeks at a fixed dose of 500 mg). Both regimens were followed by azathioprine (Imuran).

At 4 years, the two treatment groups were not significantly different in terms of treatment failure, remission rates, serum creatinine levels, 24-hour proteinuria, and freedom from renal flares. However, the rates of side effects were significantly different, with more patients in the low-dosage group free of severe infection.

One problem with this study is whether it is applicable to an American lupus nephritis population, since 84% of the patients were white. Since this study, others indicate that this regimen is probably also safe and effective for different racial groups in the United States.

At 10-year follow-up,⁵ both treatment groups still had identical excellent rates of freedom from end-stage renal disease. Serum creatinine and 24-hour proteinuria were also at excellent levels and identical in both groups. Nearly three quarters of patients still needed glucocorticoid therapy and more than half still needed immunosuppressive therapy, but the rates were not statistically significantly different between the treatment groups.

The cumulative dose of cyclophosphamide was 9.5 g in the standard-treatment group and 5.5 g in the low-dose group. This difference in exposure could make a tremendous difference to patients, not only for immediate side effects such as early menopause and infections, but for the risk of cancer in later decades.

This study showed clearly that low-dose cyclophosphamide is an option for induction therapy. Drawbacks of the study were that the population was mostly white and that patients had only moderately severe disease.

Low-dose cyclophosphamide has largely replaced the older National Institutes of Health regimen, although during the last decade drug therapy has undergone more changes.

MYCOPHENOLATE AND AZATHIOPRINE: ALTERNATIVES TO CYCLOPHOSPHAMIDE

In a Chinese study, mycophenolate was better than cyclophosphamide for induction

In a study in Hong Kong, Chan et al⁶ randomized 42 patients with severe lupus nephritis to receive either mycophenolate mofetil (available in the United States as CellCept; 2 g/day for 6 months, then 1 g/day for 6 months) or oral cyclophosphamide (2.5 mg/kg per day for 6 months) followed by azathioprine (1.5–2.0 mg/kg per day) for 6 months. Both groups also received prednisolone during the year.

At the end of the first year, the two groups were not significantly different in their rates of complete remission, partial remission, and relapse. The rate of infection, although not significantly different, was higher in the cyclophosphamide group (33% vs 19%). Two patients (10%) died in the cyclophosphamide group, but the difference in mortality rates was not statistically significant.

Nearly 5 years later,⁷ rates of chronic renal failure and relapse were still statistically the same in the two groups. Infections were fewer in the mycophenolate group (13% vs 40%, P = .013). The rate of amenorrhea was 36% in the cyclophosphamide group and only 4% in the mycophenolate group (P = .004). Four patients in the cyclophosphamide group and none in the mycophenolate group reached the composite end point of end-stage renal failure or death (P = .062).

This study appeared to offer a new option with equal efficacy and fewer side effects than standard therapy. However, its applicability to non-Chinese populations remained to be shown.

In a study in Miami,⁸ 59 patients with lupus nephritis were given standard induction therapy with IV cyclophosphamide plus glucocorticoids for 6 months, then randomly assigned to one of three maintenance therapies for 1 to 3 years: IV injections of cyclophosphamide every 3 months (standard therapy), oral azathioprine, or oral mycophenolate. The population was 93% female, their average age was 33 years, and nearly half were African American, with many of the others being Hispanic. Patients tended to have severe disease, with nearly two-thirds having nephrotic syndrome.

After 6 years, there had been more deaths in the cyclophosphamide group than in the azathioprine group (P = .02) and in the mycophenolate group, although the latter difference was not statistically significant (P = .11). The combined rate of death and chronic renal failure was significantly higher with cyclophosphamide than with either of the oral agents. The cyclophosphamide group also had the highest relapse rate during the maintenance phase.

The differences in side effects were even more dramatic. Amenorrhea affected 32% of patients in the cyclophosphamide group, and only 7% and 6% in the azathioprine and mycophenolate groups, respectively. Rates of infections were 68% in the cyclophosphamide group and 28% and 21% in the azathioprine and mycophenolate groups, respectively. Patients given cyclophosphamide had 13 hospital days per patient per year, while the other groups each had only 1.

This study showed that maintenance therapy with oral azathioprine or mycophenolate was more effective and had fewer adverse effects than standard IV cyclophosphamide therapy. As a result of this study, oral agents for maintenance therapy became the new standard, but the question remained whether oral agents could safely be used for induction.

In a US study, mycophenolate was better than cyclophosphamide for induction

In a noninferiority study, Ginzler et al⁹ randomized 140 patients with severe lupus nephritis to receive either monthly IV cyclophosphamide or oral mycophenolate as induction therapy for 6 months. Adjunctive care with glucocorticoids was given in both groups. The study population was from 18 US academic centers and was predominantly female, and more than half were African American.

After 24 weeks, 22.5% of the mycophenolate patients were in complete remission by very strict criteria vs only 4% of those given cyclophosphamide (P = .005). The trend for partial remissions was also in favor of mycophenolate, although the difference was not statistically significant. The rate of complete and partial remissions, a prespecified end point, was significantly higher in the mycophenolate group. Although the study was trying to evaluate equivalency, it actually showed superiority for mycophenolate induction therapy.

Serum creatinine levels declined in both groups, but more in the mycophenolate group by 24 weeks. Urinary protein levels fell the same amount in both groups. At 3 years, the groups were statistically equivalent in terms of renal flares, renal failures, and deaths. However, the study groups were small, and the mycophenolate group did have a better trend for both renal failure (N = 4 vs 7) and deaths (N = 4 vs 8).

Mycophenolate also had fewer side effects, including infection, although again the numbers were too small to show statistical significance. The exception was diarrhea (N = 15 in the mycophenolate group vs 2 in the cyclophosphamide group).

A drawback of the study is that it was designed as a crossover study: a patient for whom therapy was failing after 3 months could switch to the other group, introducing potential confounding. Other problems involved the small population size and the question of whether results from patients in the United States were applicable to others worldwide.

In a worldwide study, mycophenolate was at least equivalent to cyclophosphamide for induction

The Aspreva Lupus Management Study (ALMS)¹⁰ used a similar design with 370 patients worldwide (United States, China, South America, and Europe) in one of the largest trials ever conducted in lupus nephritis. Patients were randomized to 6 months of induction therapy with either IV cyclophosphamide or oral mycophenolate but could not cross over.

At 6 months, response rates were identical between the two groups, with response defined as a combination of specific improvement in proteinuria, serum creatinine, and hematuria (50%–55%). In terms of individual renal and nonrenal variables, both groups appeared identical.

However, the side effect profiles differed between the two groups. As expected for mycophenolate, diarrhea was the most common side effect (occurring in 28% vs 12% in the cyclophosphamide group). Nausea and vomiting were more common with cyclophosphamide (45% and 37% respectively vs 14% and 13% in the mycophenolate group). Cyclophosphamide also caused hair loss in 35%, vs 10% in the mycophenolate group.

There were 14 deaths overall, which is a very low number considering the patients’ severity of illness, and it indicates the better results now achieved with therapy. The mortality rate was higher in the mycophenolate group (5% vs 3%), but the difference was not statistically significant. Six of the nine deaths with mycophenolate were from the same center in China, and none were from Europe or the United States. In summary, the study did not show that mycophenolate was superior to IV cyclophosphamide for induction therapy, but that they were equivalent in efficacy with different side effect profiles.

Membranous nephropathy: Mycophenolate vs cyclophosphamide

Less evidence is available about treatment for membranous disease, which is characterized by heavy proteinuria and the nephrotic syndrome but usually does not progress to renal failure. Radhakrishnan et al¹¹ combined data from the trial by Ginzler et al⁹ and the ALMS trial¹⁰ and found 84 patients with pure membranous lupus, who were equally divided between the treatment groups receiving IV cyclophosphamide and mycophenolate. Consistent with the larger group’s data, mycophenolate and cyclophosphamide performed similarly in terms of efficacy, but there was a slightly higher rate of side effects with cyclophosphamide.

Maintenance therapy: Mycophenolate superior to azathioprine

The ALMS Maintenance Trial¹² evaluated maintenance therapy in the same worldwide population that was studied for induction therapy. Of the 370 patients involved in the induction phase that compared IV cyclophosphamide and oral mycophenolate, 227 responded sufficiently to be rerandomized in a controlled, double-blinded trial of 36 months of maintenance therapy with corticosteroids and either mycophenolate (1 g twice daily) or azathioprine (2 mg/kg per day).

In intention-to-treat analysis, the time to treatment failure (ie, doubling of the serum creatinine level, progressing to renal failure, or death) was significantly shorter in the azathioprine group (P = .003). Every individual end point—end-stage renal disease, renal flares, doubling of serum creatinine, rescue immunosuppression required—was in favor of mycophenolate maintenance. At 3 years, the completion rate was 63% with mycophenolate and 49% with azathioprine. Serious adverse events and withdrawals because of adverse events were more common in the azathioprine group.

In summary, mycophenolate was superior to azathioprine in maintaining renal response and in preventing relapse in patients with active lupus nephritis who responded to induction therapy with either mycophenolate or IV cyclophosphamide. Mycophenolate was found to be superior regardless of initial induction treatment, race, or region and was confirmed by all key secondary end points.

Only one of the 227 patients died during the 3 years—from an auto accident. Again, this indicates the dramatically improved survival today compared with a decade ago.

RITUXIMAB: PROMISING BUT UNPROVEN

Rituximab (Rituxan) was originally approved to treat tumors, then rheumatoid arthritis, and most recently vasculitis. Evidence thus far is mixed regarding its use as a treatment for lupus nephritis. Although randomized clinical trials have not found it to be superior to standard regimens, there are many signs that it may be effective.

Rituximab in uncontrolled studies

Terrier et al¹³ analyzed prospective data from 136 patients with systemic lupus erythematosus, most of whom had renal disease, from the French Autoimmunity and Rituximab registry. Response occurred in 71% of patients using rituximab, with no difference found between patients receiving rituximab monotherapy and those concomitantly receiving immunosuppressive agents.

Melander et al¹⁴ retrospectively studied 19 women and 1 man who had been treated with rituximab for severe lupus nephritis and followed for at least 1 year. Three patients had concurrent therapy with cyclophosphamide, and 10 patients continued rituximab as maintenance therapy; 12 patients had lupus nephritis that had been refractory to standard treatment, and 6 had relapsing disease.

At a median follow-up of 22 months, 12 patients (60%) had achieved complete or partial renal remission.

Condon et al¹⁵ treated 21 patients who had severe lupus nephritis with two doses of rituximab and IV methylprednisolone 2 weeks apart, then maintenance therapy with mycophenolate without any oral steroids. At a mean follow-up of 35 months ( ± 14 months), 16 (76%) were in complete remission, with a mean time to remission of 12 months. Two (9.5%) achieved partial remission. The rate of toxicity was low.

Thus, rituximab appears promising in uncontrolled studies.

Placebo-controlled trials fail to prove rituximab effective

LUNAR trial. On the other hand, the largest placebo-controlled trial to evaluate rituximab in patients with proliferative lupus nephritis, the Lupus Nephritis Assessment With Rituximab (LUNAR) trial¹⁶ found differences in favor of rituximab, but none reached statistical significance. The trial randomized 140 patients to receive either mycophenolate plus periodic rituximab infusions or mycophenolate plus placebo infusions for 1 year. All patients received the same dosage of glucocorticoids, which was tapered over the year.

At the end of 1 year, the groups were not statistically different in terms of complete renal response and partial renal response. Rituximab appeared less likely to produce no response, but the difference was not statistically significant.

African Americans appeared to have a higher response rate to rituximab (70% in the rituximab group achieved a response vs 45% in the control group), but again, the difference did not reach statistical significance, and the total study population of African Americans was only 40.

Rituximab did have a statistically significant positive effect on two serologic markers at 1 year: levels of anti-dsDNA fell faster and complement rose faster. In addition, rates of adverse and serious adverse events were similar between the two groups, with no new or unexpected “safety signals.”

This study can be interpreted in a number of ways. The number of patients may have been too small to show significance and the follow-up may have been too short. On the other hand, it may simply not be effective to add rituximab to a full dose of mycophenolate and steroids, an already good treatment.

EXPLORER trial. Similarly, for patients with lupus without nephritis, the Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial¹⁷ also tested rituximab against a background of an effective therapeutic regimen and found no additional benefit. This study had design problems similar to those of the LUNAR trial.

Rituximab as rescue therapy

The evidence so far indicates that rituximab may have a role as rescue therapy for refractory or relapsing disease. Rituximab must be used with other therapies, but maintenance corticosteroid therapy is not necessary. Its role as a first-line agent in induction therapy for lupus nephritis remains unclear, although it may have an important role for nonwhites. In general, it has been well tolerated. Until a large randomized trial indicates otherwise, it should not be used as a first-line therapy.

The US Food and Drug Administration (FDA) sent out a warning about the danger of progressive multifocal leukoencephalopathy as an adverse effect of rituximab and of mycophenolate, but this does not appear to be a major concern for most patients and is only likely to occur in those who have been over-immunosuppressed for many years.

MULTITARGET THERAPY

The concept of using multiple drugs simultaneously—such as mycophenolate, steroids, and rituximab—is increasingly being tried. Multi-target therapy appears to offer the advantages of combining different modes of action with better results, and it offers fewer side effects because dosages of each individual drug can be lower when combined with other immunosuppressives.

Bao et al¹⁸ in China randomly assigned 40 patients with diffuse proliferative and membranous nephritis to 6 to 9 months of induction treatment with either multitarget therapy (mycophenolate, tacrolimus [Prograf], and glucocorticoids) or IV cyclophosphamide. More complete remissions occurred in the multitarget therapy group, both at 6 months (50% vs 5%) and at 9 months (65% vs 15%). Most adverse events were less frequent in the multitarget therapy group, although three patients (15%) in the multitarget therapy group developed new-onset hypertension vs none in the cyclophosphamide group.

NEW MEDICATIONS

Entirely new classes of drugs are being developed with immunomodulatory effects, including tolerance molecules, cytokine blockers, inhibitors of human B lymphocyte stimulator, and costimulatory blockers.

Belimumab offers small improvement for lupus

Belimumab (Benlysta) is a human monoclonal antibody that inhibits the biologic activity of human B lymphocyte stimulator; it has recently been approved by the FDA for lupus nephritis. In a worldwide study,¹⁹ 867 patients with systemic lupus erythematosus were randomized to receive either belimumab (1 mg/kg or 10 mg/kg) or placebo.

The primary end point was the reduction of disease activity by a scoring system (SELENA-SLEDAI) that incorporated multiple features of lupus, including arthritis, vasculitis, proteinuria, rash, and others. Patients in the belimumab group had better outcomes, but the results were not dramatic. Because the drug is so expensive (about $25,000 per year) and the improvement offered is only incremental, this drug will not likely change the treatment of lupus very much.

Moreover, patients with lupus nephritis were not included in the study, but a new study is being planned to do so. Improvement is harder to demonstrate in lupus nephritis than in rheumatoid arthritis and systemic lupus erythematosus: significant changes in creatinine levels and 24-hour urinary protein must be achieved, rather than more qualitative signs and symptoms of joint pain, rash, and feeling better. Although belimumab is still unproven for lupus nephritis, it might be worth trying for patients failing other therapy.

Laquinimod: A promising experimental drug

Laquinimod is an oral immunomodulatory drug with a number of effects, including down-regulating major histocompatability complex II, chemokines, and adhesion-related molecules related to inflammation. It has been studied in more than 2,500 patients with multiple sclerosis. Pilot studies are now being done for its use for lupus nephritis. If it shows promise, a large randomized, controlled trial will be conducted.

Abatacept is in clinical trials

Abatacept (Orencia), a costimulation blocker, is undergoing clinical trials in lupus nephritis. Results should be available shortly.

INDIVIDUALIZE THERAPY

This past decade has seen such an increase in options to treat lupus nephritis that therapy can now be individualized.

Choosing IV cyclophosphamide vs mycophenolate

As a result of recent trials, doctors in the United States are increasingly using mycophenolate as the first-line drug for lupus nephritis. In Europe, however, many are choosing the shorter regimen of IV cyclophosphamide because of the results of the Euro-Lupus study.

Nowadays, I tend to use IV cyclophosphamide as the first-line drug only for patients with severe crescenteric glomerulonephritis or a very high serum creatinine level. In such cases, there is more experience with cyclophosphamide, and such severe disease does not lend itself to the luxury of trying out different therapies sequentially. If such a severely ill patient insists that a future pregnancy is very important, an alternative therapy of mycophenolate plus rituximab should be considered. I prefer mycophenolate for induction and maintenance therapy in most patients.

Dosing and formulation considerations for mycophenolate

Large dosages of mycophenolate are much better tolerated when broken up throughout the day. A patient who cannot tolerate 1 g twice daily may be able to tolerate 500 mg four times a day. The formulation can also make a difference. Some patients tolerate sustained-release mycophenolate (Myfortic) better than CellCept, and vice versa.

For patients who cannot tolerate mycophenolate, azathioprine is an acceptable alternative. In addition, for a patient who is already doing well on azathioprine, there is no need to change to mycophenolate.

Long maintenance therapy now acceptable

The ALMS Maintenance Trial¹² found 3 years of maintenance therapy to be safe and effective. Such a long maintenance period is increasingly viewed as important, especially for patients in their teens and 20s, as it allows them to live a normal life, ie, to finish their education, get married, and become settled socially. Whether 5 years of maintenance therapy or even 10 years is advisable is still unknown.

Treatment during pregnancy

Neither mycophenolate nor azathioprine is recommended during pregnancy, although their effects are unknown. Because we have much more renal transplant experience with azathioprine during pregnancy, I recommend either switching from mycophenolate to azathioprine or trying to stop medication altogether if the patient has been well controlled.

An acute kidney injury can result from a myriad of causes and pathogenic pathways. Of these, the two main categories are prerenal causes (eg, heart failure, volume depletion) and causes that are intrinsic to the kidney (eg, acute tubular necrosis). Together, these categories account for more than 70% of all cases.^1–3

While early intervention improves outcomes in both of these categories, the physician in the acute care setting must quickly distinguish between them, as their treatments differ. Similar clinical presentations along with confounding laboratory values make this distinction difficult. Furthermore, prolonged prerenal azotemia can eventually lead to acute tubular necrosis.

Therefore, several methods for distinguishing prerenal from intrinsic causes of acute kidney injury have been developed, including urinalysis, response to fluid challenge, the blood urea nitrogen-to-plasma creatinine ratio, levels of various urine electrolytes and biomarkers, and, the topics of our discussion here, the fractional excretion of sodium (FENa) and the fractional excretion of urea (FEU).⁴ While each method offers a unique picture of renal function, the validity of each may be affected by specific clinical factors.

In light of the frequent use of diuretics in inpatients and outpatients, a review of the utility of the FEU test is warranted. We will therefore present the theory behind the use of the FENa and the FEU for distinguishing intrinsic from prerenal causes of acute kidney injury, the relevant literature comparing the utility of these investigations, and our suggestions for clinical practice.

ACUTE KIDNEY INJURY DEFINED

Acute kidney injury (formerly called acute renal failure) describes an abrupt decline in renal function. Consensus definitions of it have been published and are gaining more widespread acceptance and use.^9,10 The current definition is¹⁰:

• An absolute increase in serum creatinine ≥ 0.3 mg/dL (26.4 μmol/L) in 48 hours, or
• A percentage increase in serum creatinine ≥ 50% in 48 hours, or
• Urine output < 0.5 mL/kg/hour for > 6 hours.

These clear criteria allow for earlier recognition and treatment of this condition.

Acute kidney injury is fairly common in hospitalized patients, with 172 to 620 cases per million patients per year.^11–14 Furthermore, hospitalized patients with acute kidney injury continue to have high rates of morbidity and death, especially those with more severe cases, in which the mortality rate remains as high as 40%.¹⁵

FRACTIONAL EXCRETION OF SODIUM

The FENa is a measure of the extraction of sodium and water from the glomerular filtrate. It is the ratio of the rate of sodium filtration (the urinary sodium concentration times the urinary flow rate, divided by the plasma sodium concentration) to the overall glomerular filtration rate, estimated by the renal filtration of creatinine. It can be calculated as the ratio of plasma creatinine to urine creatinine divided by the ratio of plasma sodium to urine sodium:

A euvolemic person with normal renal function and moderate salt intake in a steady state will have an FENa of approximately 1%.¹⁶

In 1976, Espinel¹⁷ originally showed that the FENa could be used during the oliguric phase in patients in acute renal failure to differentiate between prerenal acute kidney injury and acute tubular necrosis. Given the kidney’s ability to reabsorb more sodium during times of volume depletion, Espinel suggested that an FENa of less than 1% reflected normal sodium retention, indicating a prerenal cause, ie, diminished effective circulating volume. A value greater than 3% likely represented tubular damage, indicating that the nephrons were unable to properly reabsorb sodium.

The clinical utility of this index was apparent, as the management of prerenal azotemia and acute tubular necrosis differ.¹⁸ While both require fluid repletion, the risk of volume overload in acute tubular necrosis is high. Furthermore, acute tubular necrosis secondary to nephrotoxins could require hemodialysis to facilitate clearance of the offending agent.

The FENa test was subsequently validated in a number of studies in different populations and is still widely used.^19–21

Limitations to the use of the FENa have been noted in various clinical settings. Notably, it can be falsely depressed in a number of intrinsic renal conditions, such as contrast-induced nephropathy, rhabdomyolysis, and acute glomerulonephritis. Conversely, patients with prerenal acute kidney injury who take diuretics can have a falsely elevated value due to the pharmacologically induced renal excretion of sodium independent of volume status. This is commonly seen in patients on diuretic therapy with baseline low effective circulating volumes, such those with congestive heart failure and hepatic cirrhosis.

FRACTIONAL EXCRETION OF UREA

Urea is continuously produced in the liver as the end product of protein metabolism. It is a small, water-soluble molecule that freely passes across cell membranes and is therefore continuously filtered and excreted by the kidneys. Not merely a waste product, urea is also important in water balance and constitutes approximately half of the normal solute content of urine.²²

Urea’s excretion mechanisms are well characterized.^22,23 It is absorbed in the proximal tubule, the medullary loop of Henle, and the medullary collecting ducts via facilitated diffusion through specific urea transporters.²⁴ After being absorbed in the loop of Henle, urea is resecreted, a process that creates an osmotic gradient along the medulla that ultimately regulates urea excretion and reabsorption in the medullary collecting duct. Low-volume states are associated with decreased urea excretion due to a physiologic increase in antidiuretic hormone secretion, and the reverse is true for high-volume states.

The FEU has been recognized as a clinically useful tool. The correlation between serum and urine urea concentrations was investigated as early as 1904.²⁵ However, most studies during the ensuing century focused on the serum urea concentration or the creatinine-to-urea ratio as a measure of glomerular failure.^26–28 In 1992, Kaplan and Kohn²⁹ proposed that the FEU could be a useful measure for assessing renal dysfunction in acute kidney injury. Conceptually similar to the FENa, the FEU is calculated as:

An FEU less than 35% suggests a prerenal cause of acute kidney injury, while a value greater than 50% suggests an intrinsic one.

FRACTIONAL EXCRETION OF UREA VS FRACTIONAL EXCRETION OF SODIUM

Kaplan and Kohn (1992)

Kaplan and Kohn,²⁹ in their 1992 study, retrospectively analyzed 87 urine samples from 40 patients with renal dysfunction (not specifically acute kidney injury) thought to be secondary to volume depletion in which the FENa was discordant with the FEU.

Findings. Thirty-nine of the 40 patients treated with diuretics had a high FENa value. However, the FEU was low in all of these patients, leading the authors to conclude that the latter may be the more useful of the two indices in evaluating patients receiving diuretics who present with symptoms that suggest prerenal azotemia.

Limitations of the study. On closer inspection, these findings were not generalizable, for several reasons. First, the time that elapsed between administration of diuretics and evaluation of urinary electrolytes varied widely. Additionally, the study was a retrospective analysis of isolated urine specimens without clear correlation to a clinical patient or context. For these reasons, prospective analyses to investigate the utility of the fractional excretion of urea needed to be conducted.

Carvounis et al (2002)

Carvounis et al³⁰ prospectively evaluated the FENa and the FEU in 102 consecutive intensive care patients with acute kidney injury (defined as a serum creatinine concentration > 1.5 mg/dL or an increase of more than 0.5 mg/dL in less than 48 hours). Oliguria was not an inclusion criterion for the study, but patients with acute glomerulonephritis and obstructive nephropathy were excluded. The study grouped subjects into those with prerenal azotemia, prerenal azotemia plus diuretic use, or acute tubular necrosis on the basis of the clinical diagnosis of the attending nephrologist.

Findings. The FEU was more sensitive than the FENa in detecting prerenal azotemia, especially in those with prerenal azotemia who were receiving diuretics. Overall, the FEU had higher sensitivity and specificity for prerenal azotemia regardless of diuretic usage, and more importantly, the best overall positive and negative predictive value for detecting it (99% and 75% respectively).

These results indicate that, in patients given diuretics, the FENa fails to discriminate between prerenal azotemia and acute tubular necrosis. Conversely, the FEU was excellent in discriminating between all cases of prerenal azotemia and acute tubular necrosis irrespective of the use of diuretics. This has significant practical application, given the frequency of diuretic use in the hospital, particularly in intensive care patients.

Limitations of the study. While the findings supported the utility of the FEU, the study population was limited to intensive care patients. Furthermore, the authors did not report the statistical significance of their findings.³⁰

Pépin et al (2007)

Pépin et al⁸ performed a similar study, investigating the diagnostic utility of the FENa and the FEU in patients with acute kidney injury, with or without diuretic therapy.

The authors prospectively studied 99 consecutive patients confirmed by an independent nephrologist to have acute kidney injury (defined as an increase in serum creatinine of more than 30% over baseline values within less than 1 week) due to either volume depletion or ischemia. They excluded patients with less common causes of acute kidney injury, such as rhabdomyolysis, obstructive nephropathy, adrenal insufficiency, acute glomerulonephritis, and nephrotoxic acute kidney injury, as well as patients with chronic kidney disease.

Patients were grouped into those with transient acute kidney injury (from decreased kidney perfusion) and persistent acute kidney injury (attributed to acute tubular necrosis), with or without diuretic therapy, according to predefined clinical criteria. They were considered to have diuretic exposure if they had received furosemide (Lasix) within 24 hours or a thiazide within 48 hours of sampling.

Findings. The FENa proved superior to the FEU in patients not taking diuretics and, contrary to the findings of Carvounis et al,³⁰ exhibited diagnostic utility in patients taking diuretics as well. Neither index discriminated between the different etiologies exceptionally well, however.

Of note, the study population was more inclusive than in previous studies, with only 63 intensive care patients, thus making the results more generalizable to all cases of inpatient acute kidney injury. Furthermore, the study included patients with and without oliguria, and the sensitivity and specificity of both the FENa and the FEU were higher in the nonoliguric group (n = 25).

Limitations of the study. The authors admit that a long time may have elapsed between diuretic administration and urine measurements, thereby mitigating the diuretic’s natriuretic effect independent of the patient’s volume status. While this variable may account for the better performance of the FENa than in the other studies, it does not account for the poor performance of the FEU.

Additionally, few of the findings reached statistical significance.

Lastly, a high percentage (30%) of patients had sepsis. The FEU is less effective in patients with infection, as cytokines interfere with the urea transporters in the kidney and colon.³¹

Lim et al (2009)

Lim et al³² conducted a study similar in design to that of Pépin et al.⁸

Findings. The FEU was as clinically useful as the FENa at distinguishing transient from persistent acute kidney injury in patients on diuretics. Using a cutoff FEU of less than 30% and a cutoff FENa of less than 1.5% for transient acute kidney injury (based on calculated receiver operating characteristic curves), FENa was more sensitive and specific than FEU in the nondiuretic groups. In patients exposed to diuretics, FEU was more sensitive but less specific than FENa.

FRACTIONAL EXCRETION OF UREA IN OLIGURIA

Diskin et al (2010)

In 2010, Diskin et al³³ published a prospective, observational study of 100 consecutive patients with oliguric azotemia referred to a nephrology service. They defined acute kidney injury as serum creatinine concentration greater than 1.9 mg/dL and urine output less than 100 mL in 24 hours. They used a higher FEU cutoff for prerenal azotemia of less than 40% to reflect the known urea secretion rate in oliguric patients (600 mL/24 hours). They used an FENa of less than 1% and greater than 3% to distinguish prerenal azotemia from acute tubular necrosis.

Findings. The FEU was more accurate than the FENa, giving the right diagnosis in 95% vs 54% of cases (P < .0001). The difference was exclusively due to the FEU’s greater utility in the 67 patients who had received diuretics (98% vs 49%, P < .0001). Both the FEU and the FENa accurately detected acute tubular necrosis. As expected, the FENa outperformed FEU in the setting of infection, in which cytokine stimulation interferes with urea excretion.

Limitations of the study. Approximately 80% of the patients had prerenal azotemia, potentially biasing the results toward a test geared toward detecting this condition. However, since prerenal causes are more common than intrinsic causes, the authors argued that their cohort more accurately reflected the population encountered in clinical practice.

Additionally, only patients with oliguria and more advanced kidney injury (serum creatinine > 1.9 mg/dL) were included in the study, potentially limiting the applicability of these results in patients with preserved urine output in the early stages of renal failure.

Table 2 summarizes the findings of the studies discussed above.^{8,15,30,32,33}

FRACTIONAL EXCRETION OF UREA IN CHILDREN AND THE ELDERLY

The FEU has also been validated in populations at the extremes of age.

In children, Fahimi et al³⁴ performed a cross-sectional study in 43 patients referred to a nephrology service because of acute kidney injury.

An FEU less than 35% had greater sensitivity and specificity than an FENa less than 1% for differentiating prerenal from intrinsic causes in pediatric populations. An FEU of less than 30% had an even greater power of distinguishing between the two. Interestingly, 15 of the 26 patients in the group with prerenal azotemia had an FENa greater than 1%, 8 of whom had an obvious cause (diuretic therapy in 5, salt-losing congenital adrenal hyperplasia in 2, and metabolic alkalosis in 1).

In elderly people, urinary indices are less reliable because of reduced sodium and urea reabsorption and urinary concentrating capability. Thus, the FENa and FEU are increased, making the standard cutoff values unreliable and unpredictable for distinguishing prerenal from intrinsic causes of acute kidney injury.³⁵

WHICH TEST SHOULD BE USED?

Both the FENa and the FEU have been validated in prospective trials as useful clinical indices in identifying prerenal azotemia. Results of these studies vary as to which index is superior and when. This may be attributable to the various definitions of acute kidney injury and diagnostic criteria used in the studies as well as the heterogeneity of patients in each study.

However, the preponderance of evidence indicates that the FEU is more useful than the FENa in patients on diuretics. Since diuretics are widely used, particularly in acute care settings in which acute kidney injury is prevalent, the FEU is a useful clinical tool and should be utilized in this context accordingly. Specifically, when there is a history of recent diuretic use, the evidence supports ordering the FEU alone, or at least in conjunction with the FENa. If the two indices yield disparate results, the physician should look for circumstances that would alter each one of them, such as sepsis or an unrecognized dose of diuretic.

In managing acute kidney injury, distinguishing prerenal from intrinsic causes is a difficult task, particularly because prolonged prerenal azotemia can develop into acute tubular necrosis. Therefore, a single index, calculated at a specific time, often is insufficient to properly characterize the pathogenesis of acute kidney injury, and a combination of both of these indices may increase diagnostic sensitivity and specificity.³⁶ Moreover, urine samples collected after acute changes in volume or osmolarity, such as blood loss, administration of intravenous fluids or parenteral nutrition, or dialysis may compromise their diagnostic utility, and care must be taken to interpret the results in the appropriate clinical context.

The clinician must be aware of both the respective applications and limitations of these indices when using them to guide management and navigate the differential diagnosis in the appropriate clinical settings.

An acute kidney injury can result from a myriad of causes and pathogenic pathways. Of these, the two main categories are prerenal causes (eg, heart failure, volume depletion) and causes that are intrinsic to the kidney (eg, acute tubular necrosis). Together, these categories account for more than 70% of all cases.^1–3

While early intervention improves outcomes in both of these categories, the physician in the acute care setting must quickly distinguish between them, as their treatments differ. Similar clinical presentations along with confounding laboratory values make this distinction difficult. Furthermore, prolonged prerenal azotemia can eventually lead to acute tubular necrosis.

Therefore, several methods for distinguishing prerenal from intrinsic causes of acute kidney injury have been developed, including urinalysis, response to fluid challenge, the blood urea nitrogen-to-plasma creatinine ratio, levels of various urine electrolytes and biomarkers, and, the topics of our discussion here, the fractional excretion of sodium (FENa) and the fractional excretion of urea (FEU).⁴ While each method offers a unique picture of renal function, the validity of each may be affected by specific clinical factors.

In light of the frequent use of diuretics in inpatients and outpatients, a review of the utility of the FEU test is warranted. We will therefore present the theory behind the use of the FENa and the FEU for distinguishing intrinsic from prerenal causes of acute kidney injury, the relevant literature comparing the utility of these investigations, and our suggestions for clinical practice.

ACUTE KIDNEY INJURY DEFINED

Acute kidney injury (formerly called acute renal failure) describes an abrupt decline in renal function. Consensus definitions of it have been published and are gaining more widespread acceptance and use.^9,10 The current definition is¹⁰:

• An absolute increase in serum creatinine ≥ 0.3 mg/dL (26.4 μmol/L) in 48 hours, or
• A percentage increase in serum creatinine ≥ 50% in 48 hours, or
• Urine output < 0.5 mL/kg/hour for > 6 hours.

These clear criteria allow for earlier recognition and treatment of this condition.

Acute kidney injury is fairly common in hospitalized patients, with 172 to 620 cases per million patients per year.^11–14 Furthermore, hospitalized patients with acute kidney injury continue to have high rates of morbidity and death, especially those with more severe cases, in which the mortality rate remains as high as 40%.¹⁵

FRACTIONAL EXCRETION OF SODIUM

The FENa is a measure of the extraction of sodium and water from the glomerular filtrate. It is the ratio of the rate of sodium filtration (the urinary sodium concentration times the urinary flow rate, divided by the plasma sodium concentration) to the overall glomerular filtration rate, estimated by the renal filtration of creatinine. It can be calculated as the ratio of plasma creatinine to urine creatinine divided by the ratio of plasma sodium to urine sodium:

A euvolemic person with normal renal function and moderate salt intake in a steady state will have an FENa of approximately 1%.¹⁶

In 1976, Espinel¹⁷ originally showed that the FENa could be used during the oliguric phase in patients in acute renal failure to differentiate between prerenal acute kidney injury and acute tubular necrosis. Given the kidney’s ability to reabsorb more sodium during times of volume depletion, Espinel suggested that an FENa of less than 1% reflected normal sodium retention, indicating a prerenal cause, ie, diminished effective circulating volume. A value greater than 3% likely represented tubular damage, indicating that the nephrons were unable to properly reabsorb sodium.

The clinical utility of this index was apparent, as the management of prerenal azotemia and acute tubular necrosis differ.¹⁸ While both require fluid repletion, the risk of volume overload in acute tubular necrosis is high. Furthermore, acute tubular necrosis secondary to nephrotoxins could require hemodialysis to facilitate clearance of the offending agent.

The FENa test was subsequently validated in a number of studies in different populations and is still widely used.^19–21

Limitations to the use of the FENa have been noted in various clinical settings. Notably, it can be falsely depressed in a number of intrinsic renal conditions, such as contrast-induced nephropathy, rhabdomyolysis, and acute glomerulonephritis. Conversely, patients with prerenal acute kidney injury who take diuretics can have a falsely elevated value due to the pharmacologically induced renal excretion of sodium independent of volume status. This is commonly seen in patients on diuretic therapy with baseline low effective circulating volumes, such those with congestive heart failure and hepatic cirrhosis.

FRACTIONAL EXCRETION OF UREA

Urea is continuously produced in the liver as the end product of protein metabolism. It is a small, water-soluble molecule that freely passes across cell membranes and is therefore continuously filtered and excreted by the kidneys. Not merely a waste product, urea is also important in water balance and constitutes approximately half of the normal solute content of urine.²²

Urea’s excretion mechanisms are well characterized.^22,23 It is absorbed in the proximal tubule, the medullary loop of Henle, and the medullary collecting ducts via facilitated diffusion through specific urea transporters.²⁴ After being absorbed in the loop of Henle, urea is resecreted, a process that creates an osmotic gradient along the medulla that ultimately regulates urea excretion and reabsorption in the medullary collecting duct. Low-volume states are associated with decreased urea excretion due to a physiologic increase in antidiuretic hormone secretion, and the reverse is true for high-volume states.

The FEU has been recognized as a clinically useful tool. The correlation between serum and urine urea concentrations was investigated as early as 1904.²⁵ However, most studies during the ensuing century focused on the serum urea concentration or the creatinine-to-urea ratio as a measure of glomerular failure.^26–28 In 1992, Kaplan and Kohn²⁹ proposed that the FEU could be a useful measure for assessing renal dysfunction in acute kidney injury. Conceptually similar to the FENa, the FEU is calculated as:

An FEU less than 35% suggests a prerenal cause of acute kidney injury, while a value greater than 50% suggests an intrinsic one.

FRACTIONAL EXCRETION OF UREA VS FRACTIONAL EXCRETION OF SODIUM

Kaplan and Kohn (1992)

Kaplan and Kohn,²⁹ in their 1992 study, retrospectively analyzed 87 urine samples from 40 patients with renal dysfunction (not specifically acute kidney injury) thought to be secondary to volume depletion in which the FENa was discordant with the FEU.

Findings. Thirty-nine of the 40 patients treated with diuretics had a high FENa value. However, the FEU was low in all of these patients, leading the authors to conclude that the latter may be the more useful of the two indices in evaluating patients receiving diuretics who present with symptoms that suggest prerenal azotemia.

Limitations of the study. On closer inspection, these findings were not generalizable, for several reasons. First, the time that elapsed between administration of diuretics and evaluation of urinary electrolytes varied widely. Additionally, the study was a retrospective analysis of isolated urine specimens without clear correlation to a clinical patient or context. For these reasons, prospective analyses to investigate the utility of the fractional excretion of urea needed to be conducted.

Carvounis et al (2002)

Carvounis et al³⁰ prospectively evaluated the FENa and the FEU in 102 consecutive intensive care patients with acute kidney injury (defined as a serum creatinine concentration > 1.5 mg/dL or an increase of more than 0.5 mg/dL in less than 48 hours). Oliguria was not an inclusion criterion for the study, but patients with acute glomerulonephritis and obstructive nephropathy were excluded. The study grouped subjects into those with prerenal azotemia, prerenal azotemia plus diuretic use, or acute tubular necrosis on the basis of the clinical diagnosis of the attending nephrologist.

Findings. The FEU was more sensitive than the FENa in detecting prerenal azotemia, especially in those with prerenal azotemia who were receiving diuretics. Overall, the FEU had higher sensitivity and specificity for prerenal azotemia regardless of diuretic usage, and more importantly, the best overall positive and negative predictive value for detecting it (99% and 75% respectively).

These results indicate that, in patients given diuretics, the FENa fails to discriminate between prerenal azotemia and acute tubular necrosis. Conversely, the FEU was excellent in discriminating between all cases of prerenal azotemia and acute tubular necrosis irrespective of the use of diuretics. This has significant practical application, given the frequency of diuretic use in the hospital, particularly in intensive care patients.

Limitations of the study. While the findings supported the utility of the FEU, the study population was limited to intensive care patients. Furthermore, the authors did not report the statistical significance of their findings.³⁰

Pépin et al (2007)

Pépin et al⁸ performed a similar study, investigating the diagnostic utility of the FENa and the FEU in patients with acute kidney injury, with or without diuretic therapy.

The authors prospectively studied 99 consecutive patients confirmed by an independent nephrologist to have acute kidney injury (defined as an increase in serum creatinine of more than 30% over baseline values within less than 1 week) due to either volume depletion or ischemia. They excluded patients with less common causes of acute kidney injury, such as rhabdomyolysis, obstructive nephropathy, adrenal insufficiency, acute glomerulonephritis, and nephrotoxic acute kidney injury, as well as patients with chronic kidney disease.

Patients were grouped into those with transient acute kidney injury (from decreased kidney perfusion) and persistent acute kidney injury (attributed to acute tubular necrosis), with or without diuretic therapy, according to predefined clinical criteria. They were considered to have diuretic exposure if they had received furosemide (Lasix) within 24 hours or a thiazide within 48 hours of sampling.

Findings. The FENa proved superior to the FEU in patients not taking diuretics and, contrary to the findings of Carvounis et al,³⁰ exhibited diagnostic utility in patients taking diuretics as well. Neither index discriminated between the different etiologies exceptionally well, however.

Of note, the study population was more inclusive than in previous studies, with only 63 intensive care patients, thus making the results more generalizable to all cases of inpatient acute kidney injury. Furthermore, the study included patients with and without oliguria, and the sensitivity and specificity of both the FENa and the FEU were higher in the nonoliguric group (n = 25).

Limitations of the study. The authors admit that a long time may have elapsed between diuretic administration and urine measurements, thereby mitigating the diuretic’s natriuretic effect independent of the patient’s volume status. While this variable may account for the better performance of the FENa than in the other studies, it does not account for the poor performance of the FEU.

Additionally, few of the findings reached statistical significance.

Lastly, a high percentage (30%) of patients had sepsis. The FEU is less effective in patients with infection, as cytokines interfere with the urea transporters in the kidney and colon.³¹

Lim et al (2009)

Lim et al³² conducted a study similar in design to that of Pépin et al.⁸

Findings. The FEU was as clinically useful as the FENa at distinguishing transient from persistent acute kidney injury in patients on diuretics. Using a cutoff FEU of less than 30% and a cutoff FENa of less than 1.5% for transient acute kidney injury (based on calculated receiver operating characteristic curves), FENa was more sensitive and specific than FEU in the nondiuretic groups. In patients exposed to diuretics, FEU was more sensitive but less specific than FENa.

FRACTIONAL EXCRETION OF UREA IN OLIGURIA

Diskin et al (2010)

In 2010, Diskin et al³³ published a prospective, observational study of 100 consecutive patients with oliguric azotemia referred to a nephrology service. They defined acute kidney injury as serum creatinine concentration greater than 1.9 mg/dL and urine output less than 100 mL in 24 hours. They used a higher FEU cutoff for prerenal azotemia of less than 40% to reflect the known urea secretion rate in oliguric patients (600 mL/24 hours). They used an FENa of less than 1% and greater than 3% to distinguish prerenal azotemia from acute tubular necrosis.

Findings. The FEU was more accurate than the FENa, giving the right diagnosis in 95% vs 54% of cases (P < .0001). The difference was exclusively due to the FEU’s greater utility in the 67 patients who had received diuretics (98% vs 49%, P < .0001). Both the FEU and the FENa accurately detected acute tubular necrosis. As expected, the FENa outperformed FEU in the setting of infection, in which cytokine stimulation interferes with urea excretion.

Limitations of the study. Approximately 80% of the patients had prerenal azotemia, potentially biasing the results toward a test geared toward detecting this condition. However, since prerenal causes are more common than intrinsic causes, the authors argued that their cohort more accurately reflected the population encountered in clinical practice.

Additionally, only patients with oliguria and more advanced kidney injury (serum creatinine > 1.9 mg/dL) were included in the study, potentially limiting the applicability of these results in patients with preserved urine output in the early stages of renal failure.

Table 2 summarizes the findings of the studies discussed above.^{8,15,30,32,33}

FRACTIONAL EXCRETION OF UREA IN CHILDREN AND THE ELDERLY

The FEU has also been validated in populations at the extremes of age.

In children, Fahimi et al³⁴ performed a cross-sectional study in 43 patients referred to a nephrology service because of acute kidney injury.

An FEU less than 35% had greater sensitivity and specificity than an FENa less than 1% for differentiating prerenal from intrinsic causes in pediatric populations. An FEU of less than 30% had an even greater power of distinguishing between the two. Interestingly, 15 of the 26 patients in the group with prerenal azotemia had an FENa greater than 1%, 8 of whom had an obvious cause (diuretic therapy in 5, salt-losing congenital adrenal hyperplasia in 2, and metabolic alkalosis in 1).

In elderly people, urinary indices are less reliable because of reduced sodium and urea reabsorption and urinary concentrating capability. Thus, the FENa and FEU are increased, making the standard cutoff values unreliable and unpredictable for distinguishing prerenal from intrinsic causes of acute kidney injury.³⁵

WHICH TEST SHOULD BE USED?

Both the FENa and the FEU have been validated in prospective trials as useful clinical indices in identifying prerenal azotemia. Results of these studies vary as to which index is superior and when. This may be attributable to the various definitions of acute kidney injury and diagnostic criteria used in the studies as well as the heterogeneity of patients in each study.

However, the preponderance of evidence indicates that the FEU is more useful than the FENa in patients on diuretics. Since diuretics are widely used, particularly in acute care settings in which acute kidney injury is prevalent, the FEU is a useful clinical tool and should be utilized in this context accordingly. Specifically, when there is a history of recent diuretic use, the evidence supports ordering the FEU alone, or at least in conjunction with the FENa. If the two indices yield disparate results, the physician should look for circumstances that would alter each one of them, such as sepsis or an unrecognized dose of diuretic.

In managing acute kidney injury, distinguishing prerenal from intrinsic causes is a difficult task, particularly because prolonged prerenal azotemia can develop into acute tubular necrosis. Therefore, a single index, calculated at a specific time, often is insufficient to properly characterize the pathogenesis of acute kidney injury, and a combination of both of these indices may increase diagnostic sensitivity and specificity.³⁶ Moreover, urine samples collected after acute changes in volume or osmolarity, such as blood loss, administration of intravenous fluids or parenteral nutrition, or dialysis may compromise their diagnostic utility, and care must be taken to interpret the results in the appropriate clinical context.

The clinician must be aware of both the respective applications and limitations of these indices when using them to guide management and navigate the differential diagnosis in the appropriate clinical settings.

An acute kidney injury can result from a myriad of causes and pathogenic pathways. Of these, the two main categories are prerenal causes (eg, heart failure, volume depletion) and causes that are intrinsic to the kidney (eg, acute tubular necrosis). Together, these categories account for more than 70% of all cases.^1–3

While early intervention improves outcomes in both of these categories, the physician in the acute care setting must quickly distinguish between them, as their treatments differ. Similar clinical presentations along with confounding laboratory values make this distinction difficult. Furthermore, prolonged prerenal azotemia can eventually lead to acute tubular necrosis.

Therefore, several methods for distinguishing prerenal from intrinsic causes of acute kidney injury have been developed, including urinalysis, response to fluid challenge, the blood urea nitrogen-to-plasma creatinine ratio, levels of various urine electrolytes and biomarkers, and, the topics of our discussion here, the fractional excretion of sodium (FENa) and the fractional excretion of urea (FEU).⁴ While each method offers a unique picture of renal function, the validity of each may be affected by specific clinical factors.

In light of the frequent use of diuretics in inpatients and outpatients, a review of the utility of the FEU test is warranted. We will therefore present the theory behind the use of the FENa and the FEU for distinguishing intrinsic from prerenal causes of acute kidney injury, the relevant literature comparing the utility of these investigations, and our suggestions for clinical practice.

ACUTE KIDNEY INJURY DEFINED

Acute kidney injury (formerly called acute renal failure) describes an abrupt decline in renal function. Consensus definitions of it have been published and are gaining more widespread acceptance and use.^9,10 The current definition is¹⁰:

• An absolute increase in serum creatinine ≥ 0.3 mg/dL (26.4 μmol/L) in 48 hours, or
• A percentage increase in serum creatinine ≥ 50% in 48 hours, or
• Urine output < 0.5 mL/kg/hour for > 6 hours.

These clear criteria allow for earlier recognition and treatment of this condition.

Acute kidney injury is fairly common in hospitalized patients, with 172 to 620 cases per million patients per year.^11–14 Furthermore, hospitalized patients with acute kidney injury continue to have high rates of morbidity and death, especially those with more severe cases, in which the mortality rate remains as high as 40%.¹⁵

FRACTIONAL EXCRETION OF SODIUM

The FENa is a measure of the extraction of sodium and water from the glomerular filtrate. It is the ratio of the rate of sodium filtration (the urinary sodium concentration times the urinary flow rate, divided by the plasma sodium concentration) to the overall glomerular filtration rate, estimated by the renal filtration of creatinine. It can be calculated as the ratio of plasma creatinine to urine creatinine divided by the ratio of plasma sodium to urine sodium:

A euvolemic person with normal renal function and moderate salt intake in a steady state will have an FENa of approximately 1%.¹⁶

In 1976, Espinel¹⁷ originally showed that the FENa could be used during the oliguric phase in patients in acute renal failure to differentiate between prerenal acute kidney injury and acute tubular necrosis. Given the kidney’s ability to reabsorb more sodium during times of volume depletion, Espinel suggested that an FENa of less than 1% reflected normal sodium retention, indicating a prerenal cause, ie, diminished effective circulating volume. A value greater than 3% likely represented tubular damage, indicating that the nephrons were unable to properly reabsorb sodium.

The clinical utility of this index was apparent, as the management of prerenal azotemia and acute tubular necrosis differ.¹⁸ While both require fluid repletion, the risk of volume overload in acute tubular necrosis is high. Furthermore, acute tubular necrosis secondary to nephrotoxins could require hemodialysis to facilitate clearance of the offending agent.

The FENa test was subsequently validated in a number of studies in different populations and is still widely used.^19–21

Limitations to the use of the FENa have been noted in various clinical settings. Notably, it can be falsely depressed in a number of intrinsic renal conditions, such as contrast-induced nephropathy, rhabdomyolysis, and acute glomerulonephritis. Conversely, patients with prerenal acute kidney injury who take diuretics can have a falsely elevated value due to the pharmacologically induced renal excretion of sodium independent of volume status. This is commonly seen in patients on diuretic therapy with baseline low effective circulating volumes, such those with congestive heart failure and hepatic cirrhosis.

FRACTIONAL EXCRETION OF UREA

Urea is continuously produced in the liver as the end product of protein metabolism. It is a small, water-soluble molecule that freely passes across cell membranes and is therefore continuously filtered and excreted by the kidneys. Not merely a waste product, urea is also important in water balance and constitutes approximately half of the normal solute content of urine.²²

Urea’s excretion mechanisms are well characterized.^22,23 It is absorbed in the proximal tubule, the medullary loop of Henle, and the medullary collecting ducts via facilitated diffusion through specific urea transporters.²⁴ After being absorbed in the loop of Henle, urea is resecreted, a process that creates an osmotic gradient along the medulla that ultimately regulates urea excretion and reabsorption in the medullary collecting duct. Low-volume states are associated with decreased urea excretion due to a physiologic increase in antidiuretic hormone secretion, and the reverse is true for high-volume states.

The FEU has been recognized as a clinically useful tool. The correlation between serum and urine urea concentrations was investigated as early as 1904.²⁵ However, most studies during the ensuing century focused on the serum urea concentration or the creatinine-to-urea ratio as a measure of glomerular failure.^26–28 In 1992, Kaplan and Kohn²⁹ proposed that the FEU could be a useful measure for assessing renal dysfunction in acute kidney injury. Conceptually similar to the FENa, the FEU is calculated as:

An FEU less than 35% suggests a prerenal cause of acute kidney injury, while a value greater than 50% suggests an intrinsic one.

FRACTIONAL EXCRETION OF UREA VS FRACTIONAL EXCRETION OF SODIUM

Kaplan and Kohn (1992)

Kaplan and Kohn,²⁹ in their 1992 study, retrospectively analyzed 87 urine samples from 40 patients with renal dysfunction (not specifically acute kidney injury) thought to be secondary to volume depletion in which the FENa was discordant with the FEU.

Findings. Thirty-nine of the 40 patients treated with diuretics had a high FENa value. However, the FEU was low in all of these patients, leading the authors to conclude that the latter may be the more useful of the two indices in evaluating patients receiving diuretics who present with symptoms that suggest prerenal azotemia.

Limitations of the study. On closer inspection, these findings were not generalizable, for several reasons. First, the time that elapsed between administration of diuretics and evaluation of urinary electrolytes varied widely. Additionally, the study was a retrospective analysis of isolated urine specimens without clear correlation to a clinical patient or context. For these reasons, prospective analyses to investigate the utility of the fractional excretion of urea needed to be conducted.

Carvounis et al (2002)

Carvounis et al³⁰ prospectively evaluated the FENa and the FEU in 102 consecutive intensive care patients with acute kidney injury (defined as a serum creatinine concentration > 1.5 mg/dL or an increase of more than 0.5 mg/dL in less than 48 hours). Oliguria was not an inclusion criterion for the study, but patients with acute glomerulonephritis and obstructive nephropathy were excluded. The study grouped subjects into those with prerenal azotemia, prerenal azotemia plus diuretic use, or acute tubular necrosis on the basis of the clinical diagnosis of the attending nephrologist.

Findings. The FEU was more sensitive than the FENa in detecting prerenal azotemia, especially in those with prerenal azotemia who were receiving diuretics. Overall, the FEU had higher sensitivity and specificity for prerenal azotemia regardless of diuretic usage, and more importantly, the best overall positive and negative predictive value for detecting it (99% and 75% respectively).

These results indicate that, in patients given diuretics, the FENa fails to discriminate between prerenal azotemia and acute tubular necrosis. Conversely, the FEU was excellent in discriminating between all cases of prerenal azotemia and acute tubular necrosis irrespective of the use of diuretics. This has significant practical application, given the frequency of diuretic use in the hospital, particularly in intensive care patients.

Limitations of the study. While the findings supported the utility of the FEU, the study population was limited to intensive care patients. Furthermore, the authors did not report the statistical significance of their findings.³⁰