Nosocomial Bacterial Meningitis

Diederik van de Beek, M.D., Ph.D., James M. Drake, M.B., B.Ch., and Allan R. Tunkel, M.D., Ph.D.

Nosocomial bacterial meningitis may result from invasive procedures (e.g., craniotomy, placement of internal or external ventricular catheters, lumbar puncture, intrathecal infusions of medications, or spinal anesthesia), complicated head trauma, or in rare cases, metastatic infection in patients with hospital-acquired bacteremia. These cases of meningitis are caused by a different spectrum of microorganisms than cases acquired in the community setting, and illness is the result of diverse pathogenetic mechanisms (Figure 1).

Figure 1. Pathogenetic Mechanisms at the Most Common Sites of Nosocomial Bacterial Meningitis.

Bacteria may enter the meninges and subarachnoid space from contiguous sites of colonization or foci of suppuration after craniotomy (Panel A). Cerebrospinal fluid (CSF) catheters (Panel B) have a proximal portion that enters the cerebrospinal fluid space and a distal portion that may also be internal, terminating in the peritoneal, pleural, or vascular space, or that may be external, when the need for the catheter is temporary. Cerebrospinal fluid catheters may become infected by retrograde infection from the distal end of the shunt, wound or skin breakdown overlying the catheter, metastatic infection in patients with bacteremia, or colonization of the catheter at the time of surgery. Concentrations of leukocytes, antibodies, and complement components in the subarachnoid space are low, facilitating multiplication of bacteria (Panel C). After head trauma, microorganisms may enter the subarachnoid space through direct invasion as a result of the trauma or, in the case of a basilar skull fracture, through a dural tear, which may provide an avenue for invasion of the central nervous system by bacteria located in the auditory canal, nose, or nasopharynx (Panel D). Bacteria may also be introduced by lumbar puncture (Panel E).

Epidemiology and Pathogenesis

The central nervous system is protected against microbial entry from the bloodstream by the blood–brain barrier and by an external barrier that is formed by the skull and leptomeninges. Consequently, pathogens may enter the central nervous system by direct invasion through the external barrier or through the bloodstream in association with a breakdown of the blood–brain barrier. The following sections review the predisposing conditions and risk factors for the development of nosocomial meningitis.

Craniotomy

Bacterial meningitis is a serious complication of craniotomy; it occurs in 0.8 to 1.5% of patients who undergo craniotomy.^1,2 Among cases of meningitis that develop in patients after craniotomy, approximately one third occur in the first week after surgery, one third in the second week, and one third after the second week, with some cases occurring years after the initial surgery.¹ The risk of postoperative meningitis can be minimized by the practice of careful surgical techniques, especially those that decrease the likelihood of cerebrospinal fluid leakage.¹ Other factors that are associated with the development of meningitis after craniotomy are concomitant infection at the site of the incision and a duration of surgery of more than 4 hours. Specific neurosurgical techniques that may minimize the risk of postoperative meningitis are listed in Table 1

Internal Ventricular Catheters

The case incidence of meningitis associated with internal ventricular catheters (i.e., cerebrospinal fluid shunts), which are commonly used for the treatment of hydrocephalus, ranges from 4 to 17%.^3,4 The most important causal factor is colonization of the catheter at the time of surgery, since the majority of infections are manifested within 1 month after surgery.^3,4 One prospective, observational study identified holes in the surgical gloves, combined with direct handling of the shunt catheter by the surgical team, as a possible risk factor⁵; double gloving led to a reduction in the rates of catheter infections as compared with the rates among historical controls.⁶ One study suggested that changing the outer pair of gloves before handling catheter material during surgery may further decrease the rates of infection.⁷

External Ventricular Catheters

External ventricular catheters are used for the monitoring of intracranial pressure or the temporary diversion of cerebrospinal fluid from an obstructed ventricular system, or as part of the treatment approach for infected internal catheters. The rate of infection associated with external catheters is approximately 8%.⁸ The risk of infection is reported to be increased with an increased duration of drainage, but the extent of increase per unit of time is uncertain. Although one study showed a sharp increase in the risk of infection after 5 days of external drainage,⁸ a prospective, randomized trial showed that removing external catheters within 5 days is unnecessary and that catheters can be left in place for longer periods with no obvious increase in the daily risk of infection.⁹ Since infection may be acquired by the introduction of bacteria after the insertion of a new catheter, changing uninfected catheters might actually increase the risk of infection. Other risk factors for infection are the routine sampling of cerebrospinal fluid, leakage of cerebrospinal fluid at the site, blockage of the drain, and intraventricular hemorrhage.

External Lumbar Catheters

External lumbar catheters, which are placed mainly to aid in the diagnosis of normal-pressure hydrocephalus, have been associated with meningitis rates of up to 5%.¹⁰ The risk factors associated with these catheters include disconnection of the external drainage system and the presence of other infections. In a recent study involving 233 consecutive patients who underwent placement of an external lumbar catheter, the rate of meningitis was low (0.8%)¹⁰; the investigators in that study used a strict protocol that called for no surveillance testing of cerebrospinal fluid, drainage of cerebrospinal fluid for a maximum of 5 days, sterile reconnection after disconnection or fracture of the drain, and permanent removal of the catheter after a second disconnection or fracture — protocols that minimized the risk of infection.

Head Trauma

The incidence of meningitis after moderate or severe head trauma is estimated to be 1.4%.¹¹ Open compound cranial fractures are complications of up to 5% of head injuries and have been associated with rates of meningitis that range from 2 to 11%.¹² In patients with compound fractures in which the skull is depressed deeper than the thickness of the cranium, the wound should be carefully examined and débrided, and preventive antimicrobial therapy should be administered (Table 1). Nonoperative management is an option if there is no clinical or radiographic evidence of the following: dural penetration, large intracranial hematoma, depression that is deeper than 1 cm, involvement of the frontal sinuses, gross cosmetic deformity, wound infection, pneumocephalus, or gross contamination of the wound.¹²

The majority of patients in whom meningitis develops as a complication of closed head trauma have a basilar skull fracture,¹¹ which causes the subarachnoid space to be connected to the sinus cavity and is associated with an increased risk of infection; rates of infection are reported to be as high as 25%, with a median time between injury and the onset of meningitis of 11 days.^11,13 Leakage of cerebrospinal fluid is the major risk factor for the development of meningitis, although most leaks that occur after trauma are unrecognized.^11,13 Most leaks resolve spontaneously within 7 days, but surgical intervention is indicated if leakage persists. Head trauma is the most common cause of recurrent bacterial meningitis.¹⁴

Lumbar Puncture

Meningitis develops after lumbar puncture in approximately 1 in 50,000 cases, with about 80 cases reported annually in the United States.¹⁵ The majority of cases occur after spinal anesthesia or myelography. The risk of meningitis after lumbar puncture may be substantially decreased if aseptic conditions are met (i.e., hand disinfection and the use of sterile gloves) and if operators wear face masks and operating caps when performing spinal anesthesia or myelography.

Pathogens

The specific bacteria that cause nosocomial meningitis vary according to the pathogenesis and timing of the infection after the predisposing event.^{1,2,11,13,15,16,17} Meningitis that develops after neurosurgery or in patients who are hospitalized for a prolonged period after penetrating trauma or basilar skull fracture can be caused by staphylococci or by facultative or aerobic gram-negative bacilli. In patients in whom foreign bodies (e.g., internal ventricular drains) have been placed, meningitis is often caused by cutaneous organisms such as coagulase-negative staphylococci or Propionibacterium acnes. The majority of meningitis cases that occur after basilar skull fracture or early after otorhinologic surgery are caused by microorganisms that colonize the nasopharynx (especially Streptococcus pneumoniae). These infecting microorganisms are important to consider in the approach to empirical antimicrobial therapy (see below).

Clinical Findings and Diagnosis

A clinical suspicion of nosocomial bacterial meningitis should prompt a diagnostic workup and antimicrobial therapy. Fever and a decreased level of consciousness are the most consistent clinical features,^{3,4,11,14,15,16} although they are nonspecific and difficult to recognize in patients who are sedated, who have just undergone neurosurgery, or who have an underlying disease that may mask the symptoms.¹⁸ Infections associated with cerebrospinal fluid shunts may cause nonspecific symptoms such as low-grade fever or general malaise³; signs of meningeal irritation are seen in less than 50% of patients. Symptoms and signs of infection may also be associated with the distal portion of the shunt (i.e., peritonitis or bacteremia).

The diagnostic workup consists of neuroimaging, cerebrospinal fluid analysis (cell counts, Gram’s staining, biochemical tests for glucose and protein, and cultures), and cultures of blood. Neuroimaging is indicated in most patients with suspected nosocomial bacterial meningitis, since it allows for an evaluation of ventricular size and provides information on whether there is a malfunction of the shunt or whether potentially contaminated catheters retained from previous surgical procedures are present. Multislice computed tomographic (CT) scanners with multiplanar reformatting capabilities may be helpful in localizing leaks of cerebrospinal fluid (Figure 2). Neuroimaging may also show expanding masses (i.e., hemorrhage, subdural empyema, or hydrocephalus) and brain shift, which should be identified before lumbar puncture is performed. Cerebrospinal fluid can be obtained through the catheter in patients with internal or external ventricular catheters; otherwise, a lumbar puncture is necessary. However, in patients with obstructive hydrocephalus, lumbar cerebrospinal fluid may not be reflective of ventricular infection because of the lack of communication between ventricular and lumbar cerebrospinal fluid.

Figure 2. Cranial CT Scans in a 51-Year-Old Woman with Pneumococcal Meningitis 1 Week after Nasal Septum Surgery.

The scan in Panel A shows bilateral subdural air collections, a finding referred to as “Mount Fuji sign.” The scan in Panel B shows a bony defect of the lamina cribrosa on the right (arrow). The patient underwent neurosurgical closure of the defect.

The diagnosis of nosocomial bacterial meningitis is made on the basis of the results of a cerebrospinal fluid culture; aerobic and anaerobic culturing techniques are obligatory. However, cultures require prolonged incubation before being confirmed as negative, and results may be negative in patients who have received previous antimicrobial therapy. Cerebrospinal fluid should be analyzed to determine cell counts, including differential counts, and biochemical tests for glucose and protein, as well as Gram’s staining, should be performed. One study that compared Gram’s staining with cerebrospinal fluid cultures for the diagnosis of bacterial meningitis showed that Gram’s staining had a high specificity but a low sensitivity.¹⁹

Cell counts in cerebrospinal fluid may be helpful but have low sensitivity and specificity in clinical subgroups of patients.^17,19 In a prospective study involving 172 patients with external ventricular catheters, cell counts in cerebrospinal fluid were normal in 4 of 18 patients in whom meningitis was confirmed by culture (22%)¹⁷; a similar proportion of patients without positive cultures had pleocytosis. The interpretation of the numbers of white cells in cerebrospinal fluid is especially problematic in patients who have meningitis that develops after intraventricular hemorrhage; although a formula has been proposed for interpretation,²⁰ the diagnostic accuracy is unknown.²¹ Among patients assessed for postoperative meningitis, aseptic meningitis as a result of the local inflammatory reaction to blood breakdown products may account for up to 70% of cases.²²

Additional tests to establish the diagnosis of bacterial meningitis have been evaluated. In patients who had undergone neurosurgery, a lactate concentration of 4 mmol per liter or more in the cerebrospinal fluid was shown to have a sensitivity of 88%, a specificity of 98%, a positive predictive value of 96%, and a negative predictive value of 94% for the diagnosis of bacterial meningitis.²³ However, a retrospective review of cases of bacterial meningitis associated with a cerebrospinal fluid shunt showed that with the use of that cutoff value for lactate, almost half of the infections would have been missed.³ Concentrations of C-reactive protein in serum or cerebrospinal fluid, and serum concentrations of procalcitonin, have been evaluated for their usefulness in determining the diagnosis²⁴; although elevated concentrations are suggestive of bacterial infection, they do not establish the diagnosis, and further studies are needed to determine the usefulness of these markers in the diagnosis of nosocomial bacterial meningitis.

Nucleic acid–amplification tests, such as polymerase-chain-reaction (PCR) assays, have been evaluated for their effectiveness in detecting the presence of bacterial DNA in cerebrospinal fluid from patients with ventricular catheters. In one study that used PCR to detect gram-positive bacteria in 86 specimens, 42 were negative as assessed by culture but positive as assessed by PCR; there were no positive culture results in patients with negative PCR results, suggesting that a negative PCR result is predictive of the absence of infection.²⁵ More studies are needed, however, before routine use of PCR assays is recommended for the diagnosis of bacterial meningitis, especially because contaminating bacteria may lead to false positive results.

Antimicrobial Therapy

The choice of empirical antimicrobial therapy for nosocomial bacterial meningitis depends on the pathogenesis of the infection (Table 2). The therapy for patients in whom meningitis develops after neurosurgery or for patients who are hospitalized for a prolonged period after penetrating head trauma or basilar skull fracture should consist of vancomycin in combination with cefepime, ceftazidime, or meropenem²⁶; the choice of the second agent should be based on the antimicrobial-susceptibility profiles of the local gram-negative bacilli. Meropenem is the agent of choice if one of the carbapenems is used, given the lower risk of seizure with meropenem than with imipenem, and given the clinical studies that have shown its usefulness in the treatment of bacterial meningitis.²⁶ Empirical therapy after basilar skull fracture or early after otorhinologic surgery should consist of vancomycin plus a third-generation cephalosporin (either cefotaxime or ceftriaxone).^11,13,14 Once a specific pathogen has been isolated, antimicrobial therapy can be modified for optimal management.

Concerns have been raised regarding the adequacy of the penetration of vancomycin into the cerebrospinal fluid in patients with nosocomial meningitis, as well as the potential for side effects when the elimination of vancomycin is hampered in patients with multiorgan system dysfunction.²⁷ Linezolid and daptomycin have been shown to have efficacy in some cases of staphylococcal meningitis^28,29; linezolid has also been shown to have favorable pharmacokinetic characteristics (i.e., cerebrospinal fluid penetration of approximately 80% at steady state) in neurosurgical patients in critical care units.³⁰ However, vancomycin is recommended as the first-line therapy and is administered at dosages aimed at achieving a serum trough concentration of 15 to 20 µg per milliliter.²⁶ Alternative agents may be used in patients in whom an adequate response is not seen.

The British Society for Antimicrobial Chemotherapy recommends empirical therapy for all patients who have signs of postoperative meningitis; treatment should be withdrawn after 72 hours if the results of cerebrospinal fluid cultures are negative.³¹ When this recommendation was evaluated in a prospective study, complications were shown to be rare after treatment was withdrawn, if Gram’s staining of cerebrospinal fluid and cerebrospinal fluid cultures were negative for bacterial meningitis after 72 hours.²² However, the therapeutic approach to nosocomial bacterial meningitis must be individualized, and some patients, especially those who have received previous or concurrent antimicrobial therapy, may require treatment with an appropriate antimicrobial agent despite negative culture results.

Direct infusion of antimicrobial agents into the ventricles through a catheter is occasionally necessary, when infections that develop after neurosurgical procedures or in association with cerebrospinal fluid catheters are difficult to eradicate with parenteral antimicrobial therapy alone.^{26,27,32,33,34} However, no antimicrobial agent has been approved by the Food and Drug Administration for intraventricular use, and the indications for this mode of administration are not well defined. Vancomycin and gentamicin are the antimicrobial agents that have been used most often.^{27,31,32,33,34} Dosages have been determined empirically (Table 3), with adjustments made on the basis of the concentration of the agent in the cerebrospinal fluid. The drain is usually closed for 1 hour after the administration of the first intraventricular dose. Subsequent doses can be determined by measuring the trough concentration in a sample of cerebrospinal fluid obtained immediately before the infusion of the next dose. The trough concentration divided by the minimal inhibitory concentration of the agent for the isolated bacterial pathogen should generally exceed 10 to 20 for consistent sterilization of the cerebrospinal fluid. Although this procedure is not standardized, it is a reasonable approach to adopt when agents whose concentrations can be routinely measured are used. At some centers, peak and trough antimicrobial concentrations in cerebrospinal fluid are monitored by the placement of a separate ventricular access device,³⁶ although it is unclear whether the peak level that is reached above the minimal inhibitory concentration or the length of time that the level remains above the minimal inhibitory concentration is a better predictor of the outcome.³³

Multidrug-Resistant Gram-Negative Bacilli

Given the emergence of multidrug-resistant gram-negative bacilli, the approach to antimicrobial therapy in patients with nosocomial meningitis that is caused by these pathogens has become problematic.³⁷ In particular, acinetobacter species have become more common in patients with nosocomial meningitis,³⁴ and these bacteria are frequently resistant to third-generation and fourth-generation cephalosporins; resistance to carbapenems has also been reported. Therefore, adequate concentrations of these agents in the cerebrospinal fluid may not be achieved after parenteral administration. For empirical treatment of acinetobacter meningitis, intravenous meropenem, with or without an aminoglycoside administered by the intraventricular or intrathecal route, has been recommended³⁴; if the organism is subsequently found to be resistant to carbapenems, colistin (usually formulated as colistimethate sodium) or polymyxin B should be substituted for meropenem and may also need to be administered by the intraventricular or intrathecal route.³⁷ In a review of 14 patients with multidrug-resistant Acinetobacter baumannii meningitis or ventriculitis who were treated with colistin administered either intravenously or by the intraventricular or intrathecal route, cerebrospinal fluid sterilization was achieved in all cases, and 13 patients were cured.³⁸ In a retrospective review of 51 cases of acinetobacter meningitis, all 8 patients who were treated with intravenous and intrathecal colistin survived.³⁵

Removal of Catheters

If bacterial meningitis develops in a patient who has an external ventricular catheter, the catheter should be removed to increase the likelihood that the infection can be cured. In the case of internal ventricular catheters, antimicrobial therapy, removal of all components of the infected catheter, and placement of an external drain appear to be the most effective treatment, with success in more than 85% of patients; external drainage leads to more rapid resolution of the ventriculitis, allows monitoring of cerebrospinal fluid findings and cultures, and allows continued treatment of the underlying hydrocephalus. The optimal timing for reimplantation of the shunt is not clearly defined, although general guidelines can be suggested. In patients with shunt infections that are caused by a coagulase-negative staphylococcus or P. acnes in association with abnormalities of the cerebrospinal fluid (e.g., pleocytosis), antimicrobial therapy for 7 days is commonly recommended before placement of a new shunt; if repeat cultures are positive, antimicrobial therapy should generally be continued until cerebrospinal fluid cultures have been negative for 10 consecutive days before a new shunt is placed. In the case of shunt infections caused by Staphylococcus aureus or gram-negative bacilli, 10 days of antimicrobial therapy after repeated negative cultures are recommended before placement of a new shunt, although some authorities recommend an even longer duration of therapy when gram-negative bacilli are isolated. Some experts have recommended a 3-day observation period after the completion of antimicrobial therapy before a new shunt is placed to confirm that the infection has been cleared, although this is not uniformly recommended.

Removal of the catheter hardware, followed by immediate replacement and intravenous antimicrobial therapy, cures approximately 65% of patients with catheter-related infections.³⁹ Conservative management (i.e., leaving the internal catheter in place and administering intravenous or intraventricular antimicrobial therapy) has generally been associated with a low success rate (approximately 35%)^39,40 but has been successfully used in selected patients with infections from cerebrospinal fluid catheters that were caused by less virulent microorganisms such as coagulase-negative staphylococci. In an observational study of 43 patients, 84% were cured with systemic and intraventricular antimicrobial agents (infused through a separate ventricular access device), with a 92% success rate in the case of infections caused by bacteria other than S. aureus.³⁵ Regardless of the manner of treatment, infections from cerebrospinal fluid shunts can recur. In one study, the recurrence rate was 26%, with two thirds of the cases caused by the same microorganism.⁴¹

Future Directions

The prevention and management of nosocomial bacterial meningitis pose a substantial challenge, especially with the emergence of disease caused by multidrug-resistant pathogens. Protocols must be developed to standardize surgical techniques in order to minimize the risk of infection. Clinical trials of simple interventions, such as changing the outer pairs of gloves before handling the catheter material during surgery, should be initiated. Early recognition and aggressive treatment may improve the outcome for patients with nosocomial bacterial meningitis.

Supported by grants from the Netherlands Organization for Health Research and Development (NWO-Veni grant 2006 [916.76.023]) and the Academic Medical Center (AMC Fellowship 2008), both to Dr. van de Beek.

No potential conflict of interest relevant to this article was reported.
Source Information

From the Department of Neurology, Center of Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam (D.B.); the Division of Neurosurgery, Department of Surgery, Hospital for Sick Children, University of Toronto, Toronto (J.M.D.); and the Department of Medicine, Monmouth Medical Center, Long Branch, NJ (A.R.T.).

Address reprint requests to Dr. van de Beek at the Department of Neurology, Center of Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, P.O. Box 22660, 1100 DD Amsterdam, the Netherlands, or at d.vandebeek@amc.uva.nl// <![CDATA[// <![CDATA[
var u = "d.vandebeek", d = "amc.uva.nl"; document.getElementById("em0").innerHTML = '' + u + '@' + d + ''
// ]]>.

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A Step Forward in Therapy for Hepatitis C

A Step Forward in Therapy for Hepatitis C

Jay H. Hoofnagle, M.D.

The therapy of hepatitis C began almost 25 years ago with a small trial of recombinant human interferon alfa.¹ The rationale for using interferon was its broad antiviral effects and the suspicion that it might be active against the still-undiscovered agent of non-A, non-B hepatitis. Indeed, interferon had striking effects, lowering serum aminotransferase levels and, in a proportion of patients, inducing a lasting improvement in serum enzyme levels. Not until the discovery of the hepatitis C virus (HCV) were the effects of interferon understood; treatment resulted in a decrease in HCV RNA levels, which led to a sustained absence of virus in a proportion of patients.² The difficulty was that interferon required parenteral injections, had multiple adverse effects, and resulted in a poor overall response rate. Nevertheless, interferon was approved for use for hepatitis C treatment in the United States in 1992.

The second important advance in hepatitis C therapy came with the use of ribavirin. Ribavirin is a nucleoside analogue known to have activity against several flaviviruses. When HCV was identified as a flavivirus, ribavirin was an obvious treatment choice. Ribavirin had little effect on serum HCV RNA levels but led to improvements in aminotransferase levels and histologic characteristics of the liver.³ More importantly, when combined with interferon, ribavirin increased the rate of sustained virologic response.⁴ Interferon and ribavirin given in combination for 48 weeks yielded rates of sustained virologic response of 40 to 50%, two to three times those obtained with interferon alone.³ Ribavirin was approved for use as an adjunct to interferon therapy of hepatitis C in 1998.

A third advance in therapy of hepatitis C came soon thereafter, with the introduction of pegylated forms of interferon that allowed for once-weekly (rather than thrice-weekly) injections. Peginterferon yielded higher rates of sustained virologic response than standard interferon: 45 to 55% after a 48-week course of peginterferon and ribavirin.⁵ The response rates varied according to HCV genotype. Among patients infected with genotypes 2 and 3 (approximately 25% of patients in the United States), rates of sustained virologic response were 70 to 80% and were achieved with a 24-week course and reduced doses of ribavirin.⁶ In contrast, rates of sustained virologic response among patients infected with genotype 1 (approximately 70% of patients in the United States) were less satisfactory, ranging from 40 to 50% and requiring 48 weeks of full doses of ribavirin. In some populations, response rates were even lower, with rates of approximately 25 to 30% among blacks.⁷ Higher doses and longer courses of therapy increased rates of sustained virologic response minimally and usually were associated with increased side effects.³ Peginterferon was approved in the United States in 2001.

Almost 10 years later, a fourth advance in hepatitis C therapy is still awaited but now may be close at hand. Two articles in this issue of the Journal describe results of phase 2 trials involving telaprevir (formerly known as VX-950).^8,9 Telaprevir is a specific inhibitor of the HCV protease and is one of several molecules developed according to a rational drug design based on the molecular structure of HCV.¹⁰ Telaprevir is peptidomimetic, meaning that it resembles the HCV polypeptide that is cleaved by the viral protease, a necessary step in replication. However, telaprevir has an electrophilic “serine-trap warhead” that forms a covalent bond with the catalytic serine residue of the protease, blocking its activity. Telaprevir, an agent developed specifically to target HCV, represents a new era of therapy for hepatitis C.

Telaprevir has profound effects on HCV replication in cell culture and in animal models.¹⁰ In phase 1 studies of chronic hepatitis C, a 1-to-2-week course of telaprevir lowered HCV RNA levels by 2 to 5 log₁₀ IU per milliliter.¹¹ As expected, this short-term therapy was followed by a rebound in viral levels after the drug was stopped. Furthermore, telaprevir resistance appeared rapidly, and viral levels trended upward during the last days of treatment. The combination of telaprevir and peginterferon appeared to provide more profound viral suppression and less viral resistance.^12,13 Some patients treated with peginterferon and ribavirin for a full 48 weeks after the short course of therapy with telaprevir, peginterferon, and ribavirin had a sustained virologic response.

These phase 1 studies led to the design of the two trials reported here, by McHutchison et al. in the United States (ClinicalTrials.gov number, NCT00336479 [ClinicalTrials.gov] )⁸ and Hézode et al. in Europe (NCT00372385 [ClinicalTrials.gov] ).⁹ The trial designs were somewhat complex. Telaprevir was given for 12 weeks only, in combination with peginterferon alfa-2a with or without ribavirin, which were given for either for the same 12 weeks or for a total of 24 or 48 weeks. The control group received the standard therapy of peginterferon and ribavirin for 48 weeks. Standard therapy yielded rates of sustained virologic response of 41% and 46%, respectively. In comparison, telaprevir given for 12 weeks combined with peginterferon and ribavirin given for 24 weeks yielded response rates of 61% and 69%, both significant increases over the responses to standard therapy.

The other regimens tested had less satisfactory results. The stopping of all therapy at 12 weeks yielded lower rates of sustained virologic response than seen with continuation of therapy through 24 weeks, and the use of peginterferon and telaprevir without ribavirin was associated with high rates of relapse. Finally, in the study by McHutchison et al., the continuation of peginterferon and ribavirin for a total of 48 weeks, including the initial 12-week course of all three agents, was no more effective than the 24-week regimen (rate of sustained virologic response, 67% and 61%, respectively). These phase 2 trials suggest that the addition of telaprevir to the combination of peginterferon and ribavirin will increase rates of sustained virologic response in patients with chronic hepatitis C due to infection with HCV genotype 1 from approximately 45% to as high as 65% and will permit therapy to be limited to 24 weeks, thus avoiding the expense and side effects of prolonged therapy.

An obvious question is why telaprevir was given for only 12 weeks and not continued with the peginterferon and ribavirin for a total of 24 or 48 weeks. The reason was the side effects. In both studies, telaprevir was associated with an increased rate of anemia, nausea, diarrhea, pruritus, and rash. The rashes tended to be severe, to arise after 8 weeks of treatment, and to increase in frequency thereafter. The nature and cause of the rashes were not elucidated.

A second question is why the rate of sustained virologic response to the combination of telaprevir, peginterferon, and ribavirin was not higher. In preliminary studies, this combination led to decreases of the HCV RNA to undetectable levels within a few weeks in almost all patients.^11,12,13 Nevertheless, at the end of the treatment period in these two trials, only 57% and 70% of patients had undetectable HCV RNA levels, end-of-treatment response rates that can be achieved with the use of peginterferon and ribavirin alone.^5,6,7 Because the relapse rates were lower among patients receiving telaprevir than among those receiving standard therapy, the sustained virologic response rates were higher with telaprevir. Therefore, the enhanced response rates with telaprevir may be due to the prevention of viral breakthrough and relapse and may occur only in patients who have at least a partial response to peginterferon.

Telaprevir appears to be a material advance in the therapy of hepatitis C, beginning a new era of treatment — an era of antiviral agents developed specifically to target this virus. Other HCV-specific agents, including other protease inhibitors,¹⁴ helicase and polymerase inhibitors, and molecular agents that interfere with viral replication,¹⁵ are likely to follow. Combinations of these new agents with drugs currently in use may ultimately provide effective therapy for all patients with hepatitis C, the promised goal of decades of research.

No potential conflict of interest relevant to this article was reported.
Source Information

From the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

References

1. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon: a preliminary report. N Engl J Med 1986;315:1575-1578. [Abstract]
2. Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic hepatitis C. N Engl J Med 2006;355:2444-2451. [Free Full Text]
3. Di Bisceglie AM, Conjeevaram HS, Fried MW, et al. Ribavirin as therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:897-903. [Free Full Text]
4. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-1492. [Free Full Text]
5. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975-982. [Free Full Text]
6. Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004;140:346-355. [Free Full Text]
7. Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology 2006;131:470-477. [CrossRef][ISI][Medline]
8. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827-1838. [Free Full Text]
9. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839-1850. [Free Full Text]
10. Lin K, Perni RB, Kwong AD, Lin C. VX-950, a novel hepatitis C virus (HCV) NS3-4A protease inhibitor, exhibits potent antiviral activities in HCV replicon cells. Antimicrob Agents Chemother 2006;50:1813-1822. [Free Full Text]
11. Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 2006;131:997-1002. [CrossRef][ISI][Medline]
12. Forestier N, Reesink HW, Weegink CJ, et al. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology 2007;46:640-648. [CrossRef][ISI][Medline]
13. Lawitz E, Rodriguez-Torres, Muir AJ, et al. Antiviral effects and safety of telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in hepatitis C patients. J Hepatol 2008;49:163-169. [CrossRef][ISI][Medline]
14. Sarrazin C, Rouzier R, Wagner F, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology 2007;132:1270-1278. [CrossRef][ISI][Medline]
15. McHutchison JG, Bartenschlager R, Patel K, Pawlotsky J-M. The face of future hepatitis C antiviral drug development: recent biological and virologic advances and their translation to drug development and clinical practice. J Hepatol 2006;44:411-421. [CrossRef][ISI][Medline]

When to Start Antiretroviral Therapy — Ready When You

When to Start Antiretroviral Therapy — Ready When You

Paul E. Sax, M.D., and Lindsey R. Baden, M.D.

The optimal time to start antiretroviral therapy in asymptomatic patients has been one of the central controversies in the care of patients with the human immunodeficiency virus (HIV) since the introduction of the first antiretroviral agent, zidovudine, more than two decades ago.¹ Since then, periods of enthusiasm for aggressive early intervention² have been followed by a more cautious approach.³ This slowly swinging pendulum has been pushed back and forth by the extraordinary benefits of antiretroviral therapy on one side⁴ and emerging data on its adverse effects on the other.⁵

The absence of a controlled, prospective study comparing early and deferred therapy has forced treatment guidelines to rely largely on data from observational cohort studies.^6,7 Currently, these guidelines state that the optimal time to start therapy for an asymptomatic patient with a CD4+ count of more than 350 cells per cubic millimeter is unknown.

In this issue of the Journal, Kitahata and colleagues present data from the one of the largest of these observational cohorts, the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD).⁸ The combined effort of 22 North American prospective research groups, NA-ACCORD evaluated patients with HIV infection who had not undergone previous therapy and who were stratified according to their CD4+ count at baseline: 351 to 500 cells per cubic millimeter or more than 500 cells per cubic millimeter. The investigators compared survival between patients who started antiretroviral therapy within the given CD4+ stratum with those who waited until after the CD4+ count fell below the stratum.

The results are striking. Among the 8362 patients with a CD4+ count of 351 to 500 cells per cubic millimeter, deferral of therapy until the CD4+ count had fallen to 350 cells or less was associated with an increase of 69% in the risk of death, as compared with patients who initiated therapy when their CD4+ count was within the designated range. Similarly, among the 9155 patients with a CD4+ count of more than 500 cells per cubic millimeter, deferral of therapy until the CD4+ count fell below 500 cells was associated with a significantly increased risk of death of 94%.

The strengths of this study included its relatively large size, the use of advanced statistical methods that attempted to analyze the data in a fashion similar to that of a randomized trial, and the use of survival (rather than AIDS progression or death) as the end point. The use of death from any cause is important in evaluating patients who have higher CD4+ counts, since HIV-related opportunistic infections and cancers develop relatively infrequently in such patients.⁹ Indeed, in the NA-ACCORD study, the majority of deaths for which cause was available were from “non–AIDS-defining” causes. An additional strength of the study was its ability to minimize lead-time bias by having access to data for patients before antiretroviral therapy was started. In many other cohort studies, such events are either not accounted for¹⁰ or must be estimated with the use of historical data.¹¹

The strengths of the study notwithstanding, the results of the NA-ACCORD study cannot be considered definitive evidence that everyone with HIV should start receiving antiretroviral therapy. This was not a randomized trial, and the patients who chose to begin therapy early might have differed in other important ways from those who chose to defer therapy — ways that improved survival but were not measured. Although NA-ACCORD investigators tried to account for this potential bias by controlling for known associations with an increased risk of death in patients with HIV infection (e.g., increased rates of coinfection with hepatitis C virus and of injection-drug use), some unmeasured factors inevitably remain. For example, in many ways, patients who were offered and began potent combination antiretroviral therapy with a high CD4+ count in the late 1990s were the ideal patients: highly adherent, committed to doing whatever they could to prevent AIDS, and willing to push through the sometimes punishing side effects and drug-regimen burdens of the early therapies. This sort of “health-seeking” behavior cannot be measured in the NA-ACCORD study yet could still substantially influence outcomes; its effects can be accounted for only in a randomized, prospective study. In addition to differences in baseline factors, such as HCV infection and injection-drug use, the rates of virologic suppression after 12 months of therapy differed between the two groups among patients with a CD4+ count of more than 500 cells per cubic millimeter (81% in the early-therapy group vs. 71% in the deferred-therapy group), which suggests different levels of adherence to therapy.

Some additional limitations should be considered. A relatively high proportion (approximately 45%) of patients in each study-specified stratum of CD4+ counts either did not initiate antiretroviral therapy or did not have a decline in the CD4+ count. These patients are not included in the comparative analysis, and we have no way of knowing whether antiretroviral therapy would have been beneficial in this group. Broader use of antiretroviral agents may increase the incidence of viral resistance. However, since data regarding resistance are unavailable at this time, we do not know how an earlier starting strategy would influence future treatment options. Data on certain toxic effects of antiretroviral therapy (most notably, metabolic and morphologic side effects) are not provided, and potential long-term toxicity cannot be addressed. The causes of death are available for only 16% of the patients who died; it will be important to obtain more complete follow-up on these patients to better understand the deleterious effects of poorly controlled HIV infection on end-organ dysfunction. It also must be determined whether some of the deaths might have been related to underlying differences (including lifestyle choices) between the two nonrandomized study groups.

Finally, the specific therapies that patients underwent reflected an earlier era in HIV therapy (the median year for starting treatment in these patients was 2000), so a high proportion of patients began regimens containing an unboosted protease inhibitor, a strategy that is no longer recommended, in part because of reduced efficacy in patients with more advanced HIV infection. Conversely, one could argue that the results of the NA-ACCORD study are all the more remarkable, given the numerous improvements in treatment since that time.

Even with the above limitations, the NA-ACCORD study adds to a growing body of data supporting earlier treatment for HIV infection. The Strategies for Management of Antiretroviral Therapy (SMART) trial (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov] ) showed that continuous antiretroviral therapy was safer than intermittent antiretroviral therapy; this was true even among patients who had a CD4+ count of more than 350 cells per cubic millimeter but who were not receiving antiretroviral therapy at baseline. Therefore, in some ways, the SMART trial mimicked a study of early versus deferred therapy.¹² Another critical observation of the SMART trial was that non-AIDS complications occurred more commonly in patients in the intermittent-therapy group, which suggests that whatever the side effects of antiretroviral therapy, they were not as deleterious as untreated HIV infection.¹³

Potential additional benefits of earlier therapy for HIV may include a lower rate of drug-specific toxic effects, a greater likelihood of achieving a normal CD4+ count, a reduction in immune activation and inflammation, and a decreased risk of HIV transmission. Analyses of cost-effectiveness have shown that antiretroviral therapy also compares favorably with other widely adopted medical interventions.⁴ Increasing the CD4+ threshold to start therapy at a range of 350 to 500 cells per cubic millimeter would add only a few years of additional therapy onto projected decades of treatment and hence generate a relatively small added lifetime cost. The impending availability of a greater number of generic antiretroviral drugs, including lamivudine in 2010, could further reduce the cost of treatment.

As we learned regarding the use of estrogen in postmenopausal women,¹⁴ we must be cautious in interpreting observational data despite efforts to control for confounding. The NA-ACCORD data do not provide definitive proof that we should be starting antiretroviral therapy in all patients with HIV infection. Such a conclusion would require data from a randomized, prospective clinical trial, and at least three such studies are either ongoing or planned. However, the supportive evidence for the benefits of earlier therapy continues to increase, making strategies to identify patients with HIV infection before the onset of substantial immunodeficiency all the more compelling.¹⁵

Five years ago, if an asymptomatic patient with HIV infection and a CD4+ count of more than 500 cells per cubic millimeter wished to start antiretroviral therapy, most experienced clinicians could have made an excellent case why treatment should be deferred. Today, if a similar patient were eager to start, we should be ready and willing to prescribe therapy — with ongoing careful monitoring of toxic effects that could arise during decades of treatment.

Dr. Sax reports receiving research support from GlaxoSmithKline, Merck, and Tibotec and consulting fees from Abbott, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck, Pfizer, and Tibotec. No other potential conflict of interest relevant to this article was reported.
Source Information

From the Division of Infectious Diseases and the Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School — both in Boston.

This article (10.1056/NEJMe0902713) was published at NEJM.org on April 1, 2009.

References

1. Friedland GH. Early treatment for HIV: the time has come. N Engl J Med 1990;322:1000-1002. [ISI][Medline]
2. Ho DD. Time to hit HIV, early and hard. N Engl J Med 1995;333:450-451. [Free Full Text]
3. Henry K. The case for more cautious, patient-focused antiretroviral therapy. Ann Intern Med 2000;132:306-311. [Free Full Text]
4. Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis 2006;194:11-19. [CrossRef][ISI][Medline]
5. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med 2003;349:1993-2003. [Erratum, N Engl J Med 2004;350:955.] [Free Full Text]
6. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Washington, DC: Department of Health and Human Services, November 3, 2008:1-139. (Available at http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.)
7. Hammer SM, Eron JJ Jr, Reiss P, et al. Antiretroviral treatment of adult HIV infection: 2008 recommendations of the International AIDS Society-USA panel. JAMA 2008;300:555-570. [Free Full Text]
8. Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med 2009;360:1815-1826. [Free Full Text]
9. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS 2008;22:841-848. [CrossRef][ISI][Medline]
10. Egger M, May M, Chêne G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002;360:119-129. [Erratum, Lancet 2002;360:1178.] [CrossRef][ISI][Medline]
11. Cole SR, Li R, Anastos K, et al. Accounting for leadtime in cohort studies: evaluating when to initiate HIV therapies. Stat Med 2004;23:3351-3363. [CrossRef][ISI][Medline]
12. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis 2008;197:1133-1144. [CrossRef][ISI][Medline]
13. Currier JS, Baden LR. Getting smarter — the toxicity of undertreated HIV infection. N Engl J Med 2006;355:2359-2361. [Free Full Text]
14. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333. [Free Full Text]
15. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep 2006;55:1-17. [Medline]

SHEA 2009: Inappropriate Catheterization Is Common

From Medscape Medical News
SHEA 2009: Inappropriate Catheterization Is Common

Kristina Rebelo

March 24, 2009 (San Diego, California) — Inappropriate urinary catheterization in hospitalized patients is common but should not be used as a remedy for incontinence because it is significantly associated with urinary complaints and increased hospital length of stay, according to a poster presented here at the Society for Healthcare Epidemiology of America (SHEA) 19th Annual Scientific Meeting.

The research said inappropriate use has been identified as 1 of the risk factors for catheter-associated urinary tract infections, primarily the result of indwelling urinary catheters. To date, data on risk factors associated with this inappropriate use have been scarce.

“This study reinforces just how prevalent these devices are in modern hospitals and how frequently their use is unnecessary,” said SHEA president Mark E. Rupp, MD, medical director, healthcare epidemiology/infection control professor, Section of Infectious Diseases, University of Nebraska Medical Center, in Omaha. He is the senior author of the study.

Convenience a Factor

Dr. Rupp told Medscape Infectious Diseases that “the number 1 reason for this is that people become complacent about them and they forget that they’re in. Nurses may leave them in because they’re convenient — nobody likes to change diapers or change bedding. If a patient has incontinence, this is 1 way to prevent them from soiling the bedding, but it puts the patient at risk of developing a urinary tract infection or something more severe, with the infection developing into bacteremia due to catheter-related infection.”

Using electronic-data-capture methods, the University of Nebraska Medical Center researchers conducted a prospective study analyzing the medical records of 391 adult patients admitted to their medical center. Between October and December 2007, a total of 444 urinary-catheter-days were recorded among 123 patients with urinary-catheter use in a medical/surgical-care unit.

Their results indicated that 31.5% of patients had a urinary-catheter device at some point during their hospital stay. The most common indication for Foley-catheter use in this patient group was surgery or postoperative management (75%). Patient age was the only risk factor that was significantly associated with urinary-catheter use (P < .05).

No significant association was found between urinary-catheter use and outcome measures, such as mortality, intensive-care-unit admission, and readmission or culture-order rates. The study did find, however, that urinary-catheter use was significantly associated with urinary complaints, such as urinary frequency, hematuria, fever, and urinary tract infections (P < .05).

Dr. Rupp said that their study wasn’t designed to closely examine outcome measures.

“Presumably, this could contribute to morbidity and mortality, but this was a very small study focused on establishing the extent of inappropriate catheter use and not the complications of that misuse — we looked at 123 patients, but to establish morbidity and mortality, we would need to have looked at literally thousands of episodes,” said Dr. Rupp.

Study results indicated that 38.2% of patients with a urinary catheter had at least 1 day of inappropriate catheter use, and 32.9% of all catheter-days were regarded as unnecessary. Inappropriate catheter use was significantly associated with length of hospital stay and duration of catheterization (P < .05).

Other Methods Available

Dr. Rupp explained there are other ways incontinent patients can be cared for during hospitalization that do not involve the use of a catheter: “Diapers can be used, the patient can perhaps be more frequently reminded to use the restroom, or the urinal [or bedside commode] can be brought to them.”

“There’s even information to indicate that intermittent catheterization is less likely to cause infections than an indwelling catheter,” Dr. Rupp added. “In other words, put someone on a schedule where you insert the tubing several times a day rather than permanently. For men, there’s such a thing as a condom catheter. It fits over the penis using adhesive and collects the urine as it drains, rather than having a tube that goes into the bladder.”

When asked if nurses would be able to make time for patient bladder surveillance, Dr. Rupp said that “they should have time, and if they don’t, that’s an indication that we need to increase our staffing ratios so we have enough people on the wards to care for our patients; we’re working toward trying to establish that.”

New Guidelines on Catheter Placement

Jennifer Meddings, MD, clinical lecturer at the University of Michigan Health System, in Ann Arbor, who presented 2 research posters at SHEA in the same clinical area, said that Dr. Rupp’s conclusions did not surprise her.

“I would have been surprised at a different conclusion. We’ve known about this inappropriate catheter use for decades,” said Dr. Meddings, who mentioned that new guidelines, by the Healthcare InfectionControl Practices Advisory Committee (HICPAC) of the US Centersfor Disease Control and Prevention, for catheter placement intended to provide evidence-based recommendations for preventing catheter-related infections are coming out in a few months.

“The new HICPAC [guidelines] will say that placing these catheters for convenience or incontinence is clearly inappropriate and will not be tolerated,” she said. “Oftentimes, nurses will place catheters on their own without a physician’s order; according to the studies, this happens in different settings in maybe 1 out of 3 cases [because] patients that may have difficulty getting out of bed or staff may not want to change the linens.”

Dr. Meddings said that researchers in the area of catheter-related infections are hoping that the new Medicare regulations, where hospitals will no longer receive high payments for costs associated with treating patients for certain hospital-acquired infections, will cut inappropriate catheter use.

“The number 1 risk factor is prolonged placement and the first way to prevent infection is that patients don’t get it if they don’t need it,” she said.

“We need to look at this from 2 perspectives: first, to minimize placement on the front end — who gets them in the first place; and second, to remove them once they’ve been in place,” Dr. Meddings concluded. “It’s a 2-pronged approach, when it goes in and when it comes out, and we need to look at both problems. Trying to solve 1 problem won’t do it; we need to address both problems in a healthcare setting.”

The study authors and Dr. Meddings have disclosed no relevant financial relationships.

Society for Healthcare Epidemiology of America (SHEA) 19th Annual Scientific Meeting: Poster 138. Presented March 20, 2009.

Increased Risk of Reinfarction With Clopidogrel and Proton-Pump Inhibitors

Increased Risk of Reinfarction With Clopidogrel and Proton-Pump Inhibitors

Michael O’Riordan

Heartwire 2009. © 2009 Medscape

(UPDATED January 30, 2009) January 29, 2009 (Toronto, Ontario) — The addition of a proton-pump inhibitor (PPI) to clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) in acute-MI patients significantly increases the risk of recurrent infarction, a new study has shown [1]. The findings support suspicions that the drug combination diminishes the beneficial effect of the antiplatelet therapy and increases the risk of future events, say researchers.

“Effectively, we’re taking a patient who should be getting a benefit from clopidogrel, they have the genetic makeup that allows them to get the benefit, but we’re turning them into the equivalent of someone who cannot activate clopidogrel by prescribing selected PPIs,” lead investigator Dr David Juurlink (Institute for Clinical Evaluative Science, Toronto, ON) told heartwire. “We’re doing this unintentionally, and we’re doing it on a massive scale, and we’re doing it, quite frankly, without any appreciation of what we’re doing.”

The study, published online January 28, 2009 in the Canadian Medical Association Journal, showed that while selected PPIs seem to “turn off” the body’s natural process of converting clopidogrel into its active form, pantoprazole (Protonix, Wyeth Pharmaceuticals), which does not interfere with clopidogrel’s conversion, was not associated with an increased risk of reinfarction.

FDA Now Has Eye on Possible Interaction

Earlier this week, the Food and Administration (FDA) announced that it was working with Bristol-Myers Squibb and Sanofi-Aventis, the makers of clopidogrel, to further study the effectiveness of the drug in patients taking other medications, particularly PPIs, and in those with genetic variants linked with clopidogrel resistance.

Clopidogrel is a prodrug converted in the liver to its active form by cytochrome P450 isoenzymes, with P450 2C19 playing a particularly important role. Speaking with heartwire, Juurlink said there is evidence suggesting that various PPIs can inhibit P450 2C19, which would alter the effectiveness of clopidogrel and potentially lead to an increased risk of adverse cardiovascular outcomes.

To assess the potential effects of the drug interaction, researchers identified more than 13 000 patients prescribed clopidogrel following an acute MI. Of these, 734 patients were readmitted with MI and 2057 served as event-free controls matched based on age, PCI, and risk score.

Among patients currently prescribed a PPI along with clopidogrel, the risk of reinfarction within 90 days was 27% greater than among those taking clopidogrel only. The risk is limited to those currently taking a PPI and did not extend to pantoprazole, a drug that does not interfere with the conversion of clopidogrel to its active form.

Association Between Acid-Reducing Therapy and Recurrent MI
End point Odds ratio (95% CI)
Recurrent MI within 90 d
Current exposure to PPI (within 30 d) 1.27 (1.03–1.57)
Previous exposure to PPI (31–90 d) 0.86 (0.63–1.19)
Remote exposure to PPI (91–180 d) 0.81 (0.57–1.18)
End point based on PPI type
Pantoprazole 1.02 (0.70–1.47)
Other 1.40 (1.10–1.77)

Juurlink noted that recent guidelines issued by the American Heart Association, American College of Cardiology, and American College of Gastroenterology call for PPI therapy for a majority of patients taking aspirin after MI, including all patients 60 years and older.

“This is important, because patients taking clopidogrel are almost always taking aspirin,” he said. “As a result, we’re going to end up with millions of people who are taking the combination of clopidogrel and a proton pump inhibitor, and our results suggest that if this is not done with some caution, thousands, perhaps tens of thousands, of recurrent heart attacks could result.”

Still, the news is not all bad for patients who need to turn off gastric acid, as they can take an older drug, such as an H2 blocker like Zantac or Pepcid, or pantoprazole, he added.

Speaking with heartwire, Dr Dan Roden (Vanderbilt University School of Medicine, Nashville, TN), who was not part of the Canadian analysis, said that the interaction between clopidogrel and PPIs was addressed by several abstracts presented at the most recent AHA meeting.

“I think it’s evident there are people out there in which this is a big deal,” he said. “The basic science is there, and the fact that CYP 2C19 affects cardiovascular outcomes is also there, so it’s not rocket science to think there are patients being treated with clopidogrel with the expectation they’re going to be better, but they’re not because they’re also getting a drug that inhibits its bioactivation.”

Despite the results from this and other studies, Roden said a randomized trial would still be the best way to prove a clinically significant interaction and to estimate its severity, although he doubts one will be ever done.

“I believe the results, but this isn’t a very strong paper to prove it,” he added. “The problem here is whether the increased MI rates observed are a result of the drug interaction or because sicker patients tend to end up on proton-pump inhibitors. The finding that the most potent CYP 2C19 inhibitor has the greatest effect makes one think this is a real result.”

Last week it was announced that Cogentus Pharmaceuticals (Palo Alto, CA) halted its COGENT 1 trial, a 4000-patient study testing a single-pill combination of clopidogrel and omeprazole to reduce the incidence of GI side effects. The company has filed for bankruptcy.

1. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009; DOI: 10.1503/cmaj.082001. Available at: http://www.cmaj.ca.

Low Vitamin D Levels Linked to Colds

Low Vitamin D Levels Linked to Colds
Study Shows Vitamin D May Have a Role to Play in Preventing Colds and Flu
By Jennifer Warner
WebMD Health News
Reviewed by Louise Chang, MD

Feb. 23, 2009 — A walk in the sun may be better than popping a vitamin C tablet for boosting your chances of preventing the common cold or flu.

A new study adds to mounting evidence that vitamin C may have been stealing the spotlight all these years from the real cold fighter, vitamin D.

The study, the largest to date on the link between vitamin D and common respiratory infections, shows that people with the lowest vitamin D levels report having significantly more cases of cold and flu than those with higher levels. Vitamin D is produced by the body in response to sunlight and is also found in fortified foods such as milk.

Researchers say that although vitamin C has been used for the prevention of common colds and other respiratory infections for decades, there is little scientific evidence to support its effectiveness. However, several recent studies have suggested that vitamin D, better known for its role in building strong bones, may also play a critical role in immune system function.

“The findings of our study support an important role for vitamin D in prevention of common respiratory infections, such as colds and the flu,” says researcher Adit Ginde, MD, MPH, of the University of Colorado, Denver, Division of Emergency Medicine, in a news release. “Individuals with common lung diseases, such as asthma or emphysema, may be particularly susceptible to respiratory infections from vitamin D deficiency.”
Vitamin D vs. Colds

Although circumstantial evidence has implicated wintertime low levels of vitamin D to the seasonal increases in colds and flu, some smaller studies have also hinted at a link between low vitamin D level and a higher risk of respiratory infections.

In this study, published in the Archives of Internal Medicine, researchers analyzed information on vitamin D levels and respiratory infections from nearly 19,000 adults and adolescents who participated in the Third National Health and Nutrition Examination Survey (NHANES III) from October 1988 to October 1994.

The results showed those with the lowest vitamin D levels (less than 10 nanograms per milliliter of blood) were 36% more likely to report having a recent upper respiratory tract infection than those with higher levels (30 ng/mL or higher).

This association persisted during all four seasons and was even stronger among those with a history or asthma or chronic obstructive pulmonary disease ( COPD).

For example, people with asthma with the lowest vitamin D levels were five times more likely to have had a recent respiratory infection. Among those with COPD, recent respiratory infections were twice as common among those with lowest vitamin D levels.

“We are planning clinical trials to test the effectiveness of vitamin D to boost immunity and fight respiratory infection, with a focus on individuals with asthma and COPD, as well as children and older adults — groups that are at higher risk for more severe illness,” Ginde says. “While it’s too early to make any definitive recommendations, many Americans also need more vitamin D for its bone and general health benefits.”

Drink Up, Boost Pancreatic Cancer Risk?

Drink Up, Boost Pancreatic Cancer Risk?
Two or More Alcoholic Drinks Daily May Raise Pancreatic Cancer Risk, Study Shows
By Kathleen Doheny
WebMD Health News
Reviewed by Louise Chang, MD

March 3, 2009 — Two alcoholic drinks a day could boost your risk of pancreatic cancer, according to a new study that reanalyzed the results of 14 previously published studies.

“We saw a 22% higher risk of pancreatic cancer in those who drank two or more alcoholic beverages a day compared to nondrinkers,” says study researcher Jeanine M. Genkinger, PhD, an assistant professor of oncology at the Lombardi Comprehensive Cancer Center at Georgetown University, Washington, D.C. That risk is termed ”modest” by Genkinger and her co-researchers.

Pancreatic cancer, often deadly because it is difficult to diagnose early, was found in nearly 38,000 people in the U.S. in 2008, according to the American Cancer Society. An estimated 6% of U.S. cancer deaths in 2008 were attributed to pancreatic cancer in both men and women.

Two recent high-profile patients include actor Patrick Swayze and Supreme Court Justice Ruth Bader Ginsburg.
Alcohol and Pancreatic Cancer: Study Details

Research about alcohol intake as a risk factor for pancreatic cancer has produced conflicting findings. Heavy alcohol intake has been linked to both chronic inflammation of the pancreas ( pancreatitis) and type 2 diabetes, both associated with an increased pancreatic cancer risk. But studies about alcohol intake haven’t been clear.

So, Genkinger and her colleagues pooled the results of the 14 previously published research studies on alcohol intake and pancreatic cancer that included nearly 863,000 men and women, with data available about their dietary habits before the cancer diagnosis.

In the study sample, 2,187 men and women were diagnosed with pancreatic cancer.

First, Genkinger’s team looked at men and women together, finding the 22% increase in risk for two or more drinks a day. One drink went by the standard definitions — 12 ounces of beer, 4 ounces of wine, or 1.5 ounces of 80-proof liquor.

“When we looked at men and women separately, the women who drank two or more a day had a 41% increased risk compared to nondrinkers,” Genkinger says. “That was statistically significant.”

Men who drank two or more drinks a day had a 12% increased risk compared to nondrinkers, which was not statistically significant. So they looked further.

When men drank more than three, the risk rose to nearly 60% compared to nondrinkers, when looking at a specific kind of pancreatic cancer, an adenocarcinoma. That was a significant association. The majority of pancreatic cancers are adenocarcinomas.

The effect was the same regardless of type of alcohol, she says. “It doesn’t appear to be associated with a specific beverage; it is associated with total alcohol intake.”

Why alcohol boosts risk isn’t known, but one of several theories is that a by-product of alcohol metabolism acts as a co-carcinogen.

The researchers also found that the link between alcohol and pancreatic cancer was stronger for those of normal weight than for obese or overweight participants. “Obesity is thought to be strongly associated with pancreatic cancer,” Genkinger says. So it could be that in the study, the strong obesity connection masked the connection with alcohol for the overweight participants, she says.

Smoking is also a risk factor for pancreatic cancer.

The study was supported by the National Cancer Institute and is published in the March issue of Cancer Epidemiology, Biomarkers and Prevention.
Second Opinion

Peter Shields, MD, deputy director of the Lombardi Comprehensive Cancer at Georgetown University but not a co-researcher of the study, reviewed the paper for WebMD and put the findings in perspective. Excess alcohol intake is already known to play a role in many cancers, he says, including esophageal, oral, liver, and breast cancers.

“Now there is some reasonable evidence it might also cause pancreatic cancer,” Shields says.

“No single study is ever definitive,” he adds. But, being an analysis of previously published studies, the new report, he says, is “better than a single study.”
The Best Alcohol Advice?

The wisest course? Drinking one drink a day may be good for warding off heart disease, as several studies show, Shields says, “but there are other ways to prevent heart disease.”

At the least, he says, people should be aware of the new findings.

Genkinger notes that based on their findings, the standing advice from the American Cancer Society and American Heart Association — limit consumption to no more than two drinks a day for men and one for women — makes sense.

Best Diet? The One You’ll Follow

Best Diet? The One You’ll Follow
Study Shows Weight Loss Is Similar in Four Types of Diets
By Kathleen Doheny
WebMD Health News
Reviewed by Elizabeth Klodas, MD, FACC

Feb. 25, 2009 — If you are trying to lose weight, just pick a diet, any heart-healthy diet, and stick to it.

It doesn’t matter much if it’s high in protein or not, high in unsaturated fat or not. You can expect to lose about the same amount of weight on any weight loss plan, according to a new study which found that the best diet is the one you will follow.

“Find a diet type that is comfortable for you,” says study researcher Frank M. Sacks, MD, a professor of cardiovascular disease prevention at the Harvard School of Public Health. As long as the diet is heart-healthy, and calorie-controlled for your needs, he says, you will lose weight if you stick to it. It also helps to get support in the form of loved ones or an organized group, he found.

In his study, he didn’t find a significant difference in weight loss regardless of the diet type. In each of the four groups, participants averaged a 13-pound loss at the six-month mark.

The study is published this week in The New England Journal of Medicine.
Comparing Diets

For years, debate has raged about whether a diet that focuses on protein, carbs, or fat is best for weight loss. So Sacks and his colleagues randomly assigned 811 people to one of four diet plans commonly used to lose weight:

* A low-fat, average-protein diet
* A low-fat, high-protein diet
* A high-fat, average-protein diet
* A high-fat, high-protein diet

Protein in the diets ranged from 15% to 25% of calories, fat from 20% to 40% of calories, and carbs from 35% to 65% of calories. No specific popular diets were studied, Sacks tells WebMD, although the four resemble some popular weight loss strategies. Each of the four diets used in the new study had the same personalized calorie-reduction goals and all were low in saturated fat and cholesterol and high in dietary fiber so as to be heart-healthy.

Participants in this clinical trial, funded by the National Institutes of Health, were 30 to 70 years of age, and were either overweight or obese, with a body mass index (BMI) of 25 (the start of overweight) or higher. They recorded food intake in a diary or an online tool that kept them posted on how their intake compared with their goals. Group diet counseling sessions were scheduled at least twice a month for the study, which ran from late 2004 through the end of 2007, and one-on-one sessions were held every eight weeks.

Participants were each given a calorie goal ranging from 1,200 to 2,400 calories a day, and were asked to do moderate-intensity activity for 90 minutes a week, with brisk walking acceptable.

Participants lost similar amounts of weight — 13 pounds on average at six months — on each of the eating plans; they maintained a 9-pound loss, on average, at the two-year follow up mark, when 80% were still in the study.

All the diets also improved risk factors for cardiovascular disease, although there were some differences in specific results. For instance, the lowest-carb diet boosted HDL “good” cholesterol levels 9% while the higest-carb plan increased it by 6%.

Similar reports of hunger, fullness, and cravings were given by the dieters on all four eating plans.

While the 13-pound initial loss may not seem like much, Sacks says it represents 7% of the dieters’ starting weight; previous studies have shown a loss of 5%-10% will help reduce heart disease risk factors and other problems.
‘No Magic Diets’

“The message is people can lose a modest amount of weight and keep it off for an extended period of time,” says George A. Bray, MD, a professor of medicine at the Pennington Biomedical Research Center of the Louisiana State University System in Baton Rouge, and a study co-author.

“I think the important message for people is, there are no magic diets,” he says.

Next, the researchers hope to tease out whether the diet works better for obese dieters — about 75% of the participants — or for those who are overweight but not obese. That subgroup analysis is underway now, Bray tells WebMD. “My guess is, those who are overweight will do almost as well as the obese.”

The counseling sessions and meetings were a valuable part of the program, Sacks says, and those who attended lost a bit more. “They gave people a sense of support, gave participants a chance to ask questions, meet other people, and get tips.”

Sack’s advice? “Find a diet that’s heart-healthy. Follow it, and really be mindful of your intake. Get some support from other people in your life or from organized groups.”

Finally, give it time. The best way, Sacks add, is to focus on a mild reduction in intake over the long haul.
Second Opinions

The best-diet study findings don’t surprise Lona Sandon, RD, a spokeswoman for the American Dietetic Association and an assistant professor of clinical nutrition at the University of Texas Southwestern Medical Center, Dallas.

“As shown in this study, any diet will help you lose weight regardless of where the calories come from,” she tells WebMD.

Ultimately, she adds, “the diet that works for weight loss is the one that is right for you.” She urges dieters to approach weight loss on an individual level, taking into account their dietary needs and preferences.

Martijn Katan PhD, from the Institute of Health Sciences, VU University, Amsterdam takes a somewhat different view of the findings.

In an accompanying editorial, he notes that at the end of two years, average body mass index of participants was still in the obese range and their weight was going back up. Pointing to successful community programs in Europe, Katan argues that rather than an individual diet approach, perhaps what we really need is a change in paradigm, where groups and communities come together to encourage healthier food consumption and increased movement. “Obesity may be a problem that cannot be solved by individual persons but that requires community action,” he says.

Bipolar I Disorder

Bipolar I Disorder
What Is Bipolar I Disorder?

Bipolar I disorder (pronounced “bi-po-lar one” and also known as manic-depressive disorder) is a form of mental illness. A person affected by bipolar I disorder has had at least one manic episode in his or her life. A manic episode is a period of abnormally elevated mood, accompanied by abnormal behavior that disrupts life.

Most people with bipolar I disorder also suffer from episodes of depression. Often, there is a pattern of cycling between mania and depression. (This is where the term “manic depression” comes from.) In between episodes of mania and depression, many people with bipolar I disorder can live normal lives.
Who Is at Risk for Bipolar I Disorder?

Virtually anyone can develop bipolar I disorder. About 2.5% of the U.S. population suffers from bipolar disorder — almost 6 million people.

Most people are in their teens or early 20s when symptoms first start. Nearly everyone with bipolar I disorder develops it before age 50. People with an immediate family member with bipolar are at higher risk.
What Are the Symptoms of Bipolar I Disorder?

During a manic episode, elevated mood can manifest itself as either euphoria (feeling “high”) or as irritability.

Abnormal behavior during manic episodes includes:

* Flying suddenly from one idea to the next
* Rapid, “pressured” speech
* Increased energy, with hyperactivity and decreased need for sleep
* Inflated self-image
* Excessive spending
* Hypersexuality

People in manic episodes may spend money far beyond their means, have sex with people they wouldn’t otherwise, or pursue grandiose, unrealistic plans. In severe manic episodes, a person loses touch with reality. They may become delusional and behave bizarrely.

Untreated, an episode of mania can last anywhere from a few days to several years. Most commonly, symptoms continue for a few weeks to a few months. Depression may follow shortly after, or not appear for weeks or months.

Many people with bipolar I disorder experience long periods without symptoms in between episodes. A minority have rapid-cycling symptoms of mania and depression — even alternating between mania and depression in the same day.

Depressive episodes in bipolar disorder are similar to “regular” clinical depression, with depressed mood, loss of pleasure, low energy and activity, feelings of guilt or worthlessness, and thoughts of suicide. Depressive symptoms of bipolar disorder can last weeks or even years.
What Are the Treatments for Bipolar I Disorder?

Manic episodes in bipolar I disorder require treatment with medicines, such as mood stabilizers and antipyschotics.

Mood Stabilizers

Lithium: This simple metal in pill form is highly effective at controlling mania. Lithium has been used for more than a century to treat bipolar disorder. Lithium can take weeks to work fully, making it better for maintenance treatment than for sudden manic episodes. Blood levels of lithium must be monitored to avoid side effects.
What Are the Treatments for Bipolar I Disorder? continued…

Depakote (divalproex): This antiseizure medication also works to level out moods. It has a more rapid onset of action, often making it more effective for sudden mania than lithium. It can also be used for prevention. Only mood stabilizers that can be used with the loading dose method [when you start high and come down in dosage] allow the possibility of mood stabilization by four to five days.

Some other antiseizure medicines, such as Tegretol (carbamazepine), Lamictal, Gabitril, and Topamax are also effective mood stabilizers.

Antipsychotics

For severe manic episodes, antipsychotic medicines may be necessary. Zyprexa (Olanzapine) is often used, and many other drugs are available. Antipsychotic medicines are also used for preventive treatment.

Electroconvulsive Therapy (ECT)

Despite its scary reputation, ECT is an effective treatment for manic symptoms. Electroconvulsive therapy is seldom used to treat bipolar I disorder, but can be helpful if medicines fail or can’t be used.
Treatment for Depression in Bipolar I Disorder

Common antidepressants like Prozac, Zoloft, and Paxil can set off a manic episode in a person with bipolar disorder. For this reason, the first treatment for depression in bipolar disorder should be lithium, Depakote, or an antipsychotic. If these fail, after a few weeks an antidepressant can be safely started. Psychotherapy, such as cognitive-behavioral therapy, may also help.

People with severe or frequent symptoms of bipolar I disorder (mania or depression) should take medicines on a continuous basis for prevention.
Can Bipolar I Disorder Be Prevented?

The causes of bipolar disorder are not well understood. It’s not known if bipolar I disorder can be prevented entirely.

It is possible to prevent some episodes of mania or depression once bipolar disorder has developed. Regular therapy sessions with a psychologist or social worker can stabilize mood, leading to fewer hospitalizations and feeling better overall. Taking medicine on a regular basis also leads to fewer manic or depressive episodes.
How Is Bipolar I Disorder Different From Other Types of Bipolar Disorder?

People with bipolar I disorder experience true mania — the often severe abnormally elevated mood and behavior described above. These manic symptoms can lead to serious disruptions in life (for example, spending the family fortune, or having an unintended pregnancy).

In bipolar II disorder, the symptoms of elevated mood never reach full-on mania. They often pass for extreme cheerfulness, even making someone a lot of fun to be around — the “life of the party.” This less-severe mania is called hypomania. Not so bad, you might think– except bipolar II also features episodes of significant depression.

Bipolar II Disorder

Bipolar II Disorder
What Is Bipolar II?

Bipolar II disorder (pronounced “bipolar two”) is a form of mental illness. Bipolar II is similar to bipolar I disorder, with moods cycling between high and low over time.

However, in bipolar II disorder, the “up” moods never reach full-on mania. The less-intense elevated moods in bipolar II disorder are called hypomanic episodes, or hypomania.

A person affected by bipolar II disorder has had at least one hypomanic episode in life. Most people with bipolar II disorder also suffer from episodes of depression. (This is where the term “manic depression” comes from.)

In between episodes of hypomania and depression, many people with bipolar II disorder live normal lives.
Who Is At Risk for Bipolar II Disorder?

Virtually anyone can develop bipolar II disorder. About 2.5% of the U.S. population suffers from some form of bipolar disorder — almost 6 million people.

Most people are in their teens or early 20s when symptoms first start. Nearly everyone with bipolar II disorder develops it before age 50. People with an immediate family member with bipolar are at higher risk.
What Are the Symptoms of Bipolar II Disorder?

During a hypomanic episode, elevated mood can manifest itself as either euphoria (feeling “high”) or as irritability.

Symptoms during hypomanic episodes include:

* Flying suddenly from one idea to the next
* Rapid, “pressured” speech
* Increased energy, with hyperactivity and decreased need for sleep

People experiencing hypomanic episodes are often quite pleasant to be around. They can often seem like the “life of the party” — making jokes, taking an intense interest in other people and activities, and infecting others with their positive mood.

What’s so bad about that, you might ask? Hypomania can also lead to erratic and unhealthy behavior. People in hypomanic episodes might spend money they don’t have, seek out sex with people they normally wouldn’t, and engage in other impulsive or risky behaviors.

Also, the vast majority of people with bipolar II disorder experience significant depressive episodes. These can occur soon after hypomania subsides, or much later. Some people cycle back and forth between hypomania and depression, while others have long periods of normal mood in between episodes.

Untreated, an episode of hypomania can last anywhere from a few days to several years. Most commonly, symptoms continue for a few weeks to a few months.

Depressive episodes in bipolar II disorder are similar to “regular” clinical depression, with depressed mood, loss of pleasure, low energy and activity, feelings of guilt or worthlessness, and thoughts of suicide. Depressive symptoms of bipolar disorder can last weeks, months, or rarely years.
What Are the Treatments for Bipolar II Disorder?

Hypomania often masquerades as happiness and relentless optimism. When hypomania is not causing unhealthy behavior, it generally goes untreated. This is in contrast to true mania, which nearly always requires treatment with medications.
What Are the Treatments for Bipolar II Disorder? continued…

People with bipolar II disorder can benefit from preventive medications that level out moods over the long term. These prevent the negative consequences of hypomania, and also help to prevent episodes of depression.

Mood stabilizers

Lithium: This simple metal in pill form is highly effective at controlling mood swings in bipolar disorder. Lithium has been used for more than a century to treat bipolar disorder. Lithium can take weeks to work fully, making it better for long-term treatment than for sudden hypomanic episodes. Blood levels of lithium must be monitored to avoid side effects.

Depakote (divalproex): This antiseizure medication also works to level out moods. It has a more rapid onset of action than lithium, and it can also be used for prevention.

Some other antiseizure medicines, such as Tegretol (carbamazepine), are also effective mood stabilizers.
Treatment for Depression in Bipolar II Disorder

When taken for depression by someone with bipolar II disorder, common antidepressants like Prozac, Zoloft, and Paxil can set off a full-on manic episode. For this reason, the first treatment for depression should be lithium, Depakote, or an antipsychotic. If these fail after a few weeks, an antidepressant can be safely started. Psychotherapy, such as cognitive-behavioral therapy, can also help.
Can Bipolar II Disorder Be Prevented?

The causes of bipolar disorder are not well understood. It’s not known if bipolar II disorder can be prevented entirely.

It is possible to prevent some episodes of hypomania or depression, once bipolar disorder has developed. Regular therapy sessions with a psychologist or social worker can stabilize mood, leading to fewer hospitalizations and feeling better overall. Taking medicine on a regular basis also leads to fewer hypomanic or depressive episodes.
How Is Bipolar II Disorder Different From Other Types of Bipolar Disorder?

People with bipolar I disorder experience true mania — a severe, abnormally elevated mood with erratic behavior. Manic symptoms lead to serious disruptions in life, causing legal or major personal problems.

In bipolar II disorder, the symptoms of elevate mood never reach full-on mania. Bipolar II can be thought of as a milder form of bipolar disorder.