Clinical Infectious Diseases Advance Access published August 6, 2014 1
An Expanded Role for Therapeutic Lumbar Punctures in Newly
Peter G. Pappas
us
Professor of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, 1900 University Blvd, 229 THT, Birmingham, AL 35294‐0006
934‐5155, [email protected]
Ac
ce
pt ed
M
an
Corresponding author: Peter G. Pappas, MD, FACP, Tele: 205‐934‐9951, Fax: 205‐
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e‐mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
cr ipt
Diagnosed AIDS‐Associated Cryptococcal Meningitis?
2
For decades, clinicians have debated the role of repeat lumbar punctures in the management of increased intracranial pressure (ICP) among patients with cryptococcal meningitis. Following
cr ipt
the initial diagnosis of cryptococcal meningitis, most experts agree that repeat lumbar
punctures (LPs) are appropriate for the following reasons: first, in the management of
increased ICP through the removal of cerebrospinal fluid (CSF); second, to follow the mycologic
us
or relapsing disease and the development of immune reactivation in inflammatory syndrome (IRIS). Among these indications, management of increased ICP is the most common reason for
an
performing repeat LPs among patients with newly diagnosed cryptococcal meningitis.
M
These so‐called “therapeutic LPs” have been endorsed by several groups including the Infectious Diseases Society of America (IDSA), the South African AIDS Council, and the World
pt ed
Health Organization (WHO), and are performed in lieu of more invasive procedures such as the placement of a lumbar drain or temporary ventriculostomy (1‐3). Indeed, the IDSA guidelines for the management of cryptococcal meningitis go so far as to recommend daily LPs in situations that dictate a more aggressive approach to control persistently elevated ICP (in
ce
excess of 250 mm of CSF) in an effort to improve overall survival, to prevent neurologic consequences, such as sudden blindness, deafness, and/or other cranial nerve abnormalities,
Ac
and to improve symptom control (1). There are no randomized control trials which explore the optimal frequency of therapeutic LP, the amount of CSF to be removed at each interval, or important parameters that inform the clinician if and when to place a permanent ventricular
shunt. There are even fewer data exploring such temporary interventions as lumbar drains and
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
and inflammatory response to antifungal therapy; and third, to look for evidence for persistent
3
external ventriculostomy drains. Thus, our current recommendations are based on large datasets, smaller observational studies, and anecdotal experience.
cr ipt
It is undeniable that outcomes are worse among HIV‐infected patients with newly diagnosed
cryptococcosis in the developing world in comparison to those in the industrialized world (4‐7).
us
with limited access to care, limited resources including access to antifungal and antiretroviral therapy, and logistical challenges (5‐8). Much effort has expended towards significantly
an
improving access to antifungal therapy for those patients in greatest need (9,10); less attention has been given to the importance of therapeutic LPs in the management of cryptococcal
M
meningitis. Why is this important? Because many investigators have demonstrated that poorer outcomes in these patients are not only due to limited access to rapidly fungicidal drugs such as
pt ed
amphotericin B and flucytosine, but also to inadequate management of increased ICP (11). The relative influence of these two factors towards the poor outcomes among these patients are difficult to determine, but most agree that they are inextricably linked.
ce
In this issue of Clinical Infectious Diseases, Rolfes and colleagues provide more observational data supporting the use of therapeutic LPs among patients with newly diagnosed AIDS‐
Ac
associated cryptococcal meningitis (12). Most of these patients were enrolled into the recently published Cryptococcal Optimal ART Timing (COAT) trial which demonstrated a survival advantage to patients with deferred (5 weeks) versus early (1‐2 weeks) antiretroviral therapy
among patients with newly diagnosed cryptococcal meningitis (13). In the current study,
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
Factors contributing to these poorer outcomes are complicated, but are certainly associated
4
investigators were encouraged to perform therapeutic LPs among patients with high initial opening pressures and/or among those who were experiencing symptoms consistent with
cr ipt
increased ICP. The primary endpoint was mortality at 11 days, thus all of the data relate to
acute mortality. When these data were adjusted for patient weight, CSF fungal burden, and
Glascow coma score, the authors observed significantly improved short term survival among
us
surprising is that these observations occurred independent of initial opening pressure. These data are both interesting and important because they argue for a much more careful look at the
an
indications for performing therapeutic LPs in the acute management of cryptococcal meningitis. There are several plausible explanations for the observations in this paper, but the most likely is
M
that patients with initial normal ICP may developed increased ICP over the ensuing days, with or without symptoms, and that the reduction in ICP was beneficial. This ‘pre‐emptive’
pt ed
approach to therapeutic LPs seems to have had a significant influence on mortality.
This study has its shortcomings. It is not a randomized trial. The sample size is relatively small. Moreover, there are a number of factors which influence the decision to perform LPs, including
ce
physician preference and patient acceptability, and these confounders are difficult to measure. Nonetheless, these data provide more insights into the value of therapeutic LPs in the acute
Ac
setting among patients with cryptococcal meningitis, and emphasize that the baseline opening pressure and/or the development of symptoms related to increased ICP may not be the only indications for this procedure. Indeed, ICP is such a dynamic process among these patients that a single measurement at the time of diagnosis is not always reflective of significant changes
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
patients who underwent at least one therapeutic LP following the initial diagnostic LP. What is
5
which occur in ICP over time. In essence these data cause us to ask the question: should all of these patients undergo a repeat LP early (eg, within the first 3 days) following the initial
cr ipt
diagnosis of cryptococcal meningitis?
There are several barriers to the standard use of therapeutic LPs in the developing world,
us
manometers and sterile LP needles. Some groups have recently called for governmental and WHO initiatives to provide more ready access to LP kits which include LP needles and
an
manometers. An alternative to traditional manometers are makeshift manometers utilizing disposal IV tubing attached to a metered stick (14). This alternative has not been validated on a
M
large scale, must be considered because of reduced cost.
pt ed
Education for healthcare providers is another potential barrier, but I have learned that most of the providers caring for these patients are keenly aware of the message contained within the treatment guidelines. Specifically, most can provide a fairly detailed understanding of the need for repeat LPs for therapeutic purposes. In my opinion, it is more an issue of making therapeutic
ce
LPs a priority in the management of these patients.
Ac
Imagine for a moment that you are a physician working in a medical facility in sub‐Saharan Africa (or any other part of the developing world), charged with the responsibility of caring for the 10‐15 patients you admitted within the last 24 hours. You also have 60‐80 patients to see in clinic today. Without additional support from other providers, the performance of a repeat
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
particularly in sub‐Saharan Africa. Not the least of these is limited access to proper
6
LP to improve symptoms possibly improve the outcome in a patient with cryptococcal meningitis becomes a low priority given the expense of the procedure, the time commitment,
cr ipt
and the competing demands of other patients with similarly critical issues.
The other important barrier is cultural. Indeed, patients in sub‐Saharan Africa are generally
us
cryptococcal meningitis based on a perception that LPs are unnecessary, dangerous, and may lead to death. Indeed, cryptococcal meningitis and death are closely linked in sub‐Saharan
an
Africa, and the causation is often mistakenly attributed to the LP. Convincing an individual with few symptoms to undergo repeat LPs in this setting is very challenging.
M
Despite these challenges, I believe that data from this study and previous observations provide
pt ed
sufficient evidence to warrant a prospective evaluation of the influence of routine therapeutic LPs on morbidity and mortality in the acute management of cryptococcal meningitis. The design of such a trial would be challenging, but it is worth the effort, in my opinion. In the meantime, health care providers must continue to push to obtain greater access to LP needles and
ce
manometers for these highly vulnerable patients. This important and simple intervention has tremendous potential impact on short‐term mortality and morbidity, but it must be studied and
Ac
validated before becoming a part of routine practice. If validated, then this approach will require the acceptance of busy clinicians, and will have to be presented to patients in manner that emphasizes both the importance and safety of the procedure.
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
reluctant to undergo initial LPs, much less repeat LPs, for diagnosis and management of
7
cr ipt
us
an
M
pt ed
ce
Ac
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
References 1. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:291‐322. 2. Govender N, Meintjes GA, Bicanic T, et al. Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV‐infected persons: 2013 update. SAJHIVMED 2013; 14:76‐86. 3. World Health Organization. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV‐infected adult, adolescents and children. Geneva: 2011. 4. Park BJ, Wannemuehler K, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/ AIDS. AIDS 2009;23(4):525‐30. 5. Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis 2008; 46:1694‐1701. 6. Kisenge PR, Hawkins AT, Maro VP, et al. Low CD4 count plus coma predicts cryptococcal meningitis in Tanzania. BMC Infect Dis 2007; 7:39. 7. Jarvis JN, Bicanic T, Loyse A, et al. Determinants of mortality in a combined cohort of 501 patients with HIV‐associated cryptococcal meningitis: implications for improving outcomes. Clin Infect Dis 2013; 1‐10. 8. Bicanic T, Brouwer AE, Meintjes G, et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS 2009; 23:701‐6. 9. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000; 30:47‐54. 10. Loyse A, Dromer F, Day J, Lortholary O, Harrison TS. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50‐year‐old antifungal. J Antimicrob Chemother 2013; 68:2435‐44. 11. Loyse A, Thangaraj H, Easterbrook P, et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource‐poor countries. Lancet Infect Dis 2013; 13:629‐37.
8
us
14. Meda J, Kalluvya S, Downs JA, et al. Cryptococcal meningitis management in Tanzania with strict schedule of serial lumbar punctures using intravenous tubing sets: an operational research study. J Acquir Immune Defic Syndr Hum Retrovirology 2014; published ahead of print.
an
M
Ac
ce
pt ed
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
cr ipt
12. Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis 2014. 13. Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, Nabeta HW, Schutz C, Williams DA, Rajasingham R, Rhein J, Thienemann F, Lo MW, Nielsen K, Bergemann TL, Kambugu A, Manabe YC, Janoff EN, Bohjanen PR, Meintjes G, COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis.N Engl J Med. 2014;370:2487‐98
An Expanded Role for Therapeutic Lumbar Punctures in Newly
Peter G. Pappas
us
Professor of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, 1900 University Blvd, 229 THT, Birmingham, AL 35294‐0006
934‐5155, [email protected]
Ac
ce
pt ed
M
an
Corresponding author: Peter G. Pappas, MD, FACP, Tele: 205‐934‐9951, Fax: 205‐
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e‐mail: [email protected].
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
cr ipt
Diagnosed AIDS‐Associated Cryptococcal Meningitis?
2
For decades, clinicians have debated the role of repeat lumbar punctures in the management of increased intracranial pressure (ICP) among patients with cryptococcal meningitis. Following
cr ipt
the initial diagnosis of cryptococcal meningitis, most experts agree that repeat lumbar
punctures (LPs) are appropriate for the following reasons: first, in the management of
increased ICP through the removal of cerebrospinal fluid (CSF); second, to follow the mycologic
us
or relapsing disease and the development of immune reactivation in inflammatory syndrome (IRIS). Among these indications, management of increased ICP is the most common reason for
an
performing repeat LPs among patients with newly diagnosed cryptococcal meningitis.
M
These so‐called “therapeutic LPs” have been endorsed by several groups including the Infectious Diseases Society of America (IDSA), the South African AIDS Council, and the World
pt ed
Health Organization (WHO), and are performed in lieu of more invasive procedures such as the placement of a lumbar drain or temporary ventriculostomy (1‐3). Indeed, the IDSA guidelines for the management of cryptococcal meningitis go so far as to recommend daily LPs in situations that dictate a more aggressive approach to control persistently elevated ICP (in
ce
excess of 250 mm of CSF) in an effort to improve overall survival, to prevent neurologic consequences, such as sudden blindness, deafness, and/or other cranial nerve abnormalities,
Ac
and to improve symptom control (1). There are no randomized control trials which explore the optimal frequency of therapeutic LP, the amount of CSF to be removed at each interval, or important parameters that inform the clinician if and when to place a permanent ventricular
shunt. There are even fewer data exploring such temporary interventions as lumbar drains and
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
and inflammatory response to antifungal therapy; and third, to look for evidence for persistent
3
external ventriculostomy drains. Thus, our current recommendations are based on large datasets, smaller observational studies, and anecdotal experience.
cr ipt
It is undeniable that outcomes are worse among HIV‐infected patients with newly diagnosed
cryptococcosis in the developing world in comparison to those in the industrialized world (4‐7).
us
with limited access to care, limited resources including access to antifungal and antiretroviral therapy, and logistical challenges (5‐8). Much effort has expended towards significantly
an
improving access to antifungal therapy for those patients in greatest need (9,10); less attention has been given to the importance of therapeutic LPs in the management of cryptococcal
M
meningitis. Why is this important? Because many investigators have demonstrated that poorer outcomes in these patients are not only due to limited access to rapidly fungicidal drugs such as
pt ed
amphotericin B and flucytosine, but also to inadequate management of increased ICP (11). The relative influence of these two factors towards the poor outcomes among these patients are difficult to determine, but most agree that they are inextricably linked.
ce
In this issue of Clinical Infectious Diseases, Rolfes and colleagues provide more observational data supporting the use of therapeutic LPs among patients with newly diagnosed AIDS‐
Ac
associated cryptococcal meningitis (12). Most of these patients were enrolled into the recently published Cryptococcal Optimal ART Timing (COAT) trial which demonstrated a survival advantage to patients with deferred (5 weeks) versus early (1‐2 weeks) antiretroviral therapy
among patients with newly diagnosed cryptococcal meningitis (13). In the current study,
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
Factors contributing to these poorer outcomes are complicated, but are certainly associated
4
investigators were encouraged to perform therapeutic LPs among patients with high initial opening pressures and/or among those who were experiencing symptoms consistent with
cr ipt
increased ICP. The primary endpoint was mortality at 11 days, thus all of the data relate to
acute mortality. When these data were adjusted for patient weight, CSF fungal burden, and
Glascow coma score, the authors observed significantly improved short term survival among
us
surprising is that these observations occurred independent of initial opening pressure. These data are both interesting and important because they argue for a much more careful look at the
an
indications for performing therapeutic LPs in the acute management of cryptococcal meningitis. There are several plausible explanations for the observations in this paper, but the most likely is
M
that patients with initial normal ICP may developed increased ICP over the ensuing days, with or without symptoms, and that the reduction in ICP was beneficial. This ‘pre‐emptive’
pt ed
approach to therapeutic LPs seems to have had a significant influence on mortality.
This study has its shortcomings. It is not a randomized trial. The sample size is relatively small. Moreover, there are a number of factors which influence the decision to perform LPs, including
ce
physician preference and patient acceptability, and these confounders are difficult to measure. Nonetheless, these data provide more insights into the value of therapeutic LPs in the acute
Ac
setting among patients with cryptococcal meningitis, and emphasize that the baseline opening pressure and/or the development of symptoms related to increased ICP may not be the only indications for this procedure. Indeed, ICP is such a dynamic process among these patients that a single measurement at the time of diagnosis is not always reflective of significant changes
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
patients who underwent at least one therapeutic LP following the initial diagnostic LP. What is
5
which occur in ICP over time. In essence these data cause us to ask the question: should all of these patients undergo a repeat LP early (eg, within the first 3 days) following the initial
cr ipt
diagnosis of cryptococcal meningitis?
There are several barriers to the standard use of therapeutic LPs in the developing world,
us
manometers and sterile LP needles. Some groups have recently called for governmental and WHO initiatives to provide more ready access to LP kits which include LP needles and
an
manometers. An alternative to traditional manometers are makeshift manometers utilizing disposal IV tubing attached to a metered stick (14). This alternative has not been validated on a
M
large scale, must be considered because of reduced cost.
pt ed
Education for healthcare providers is another potential barrier, but I have learned that most of the providers caring for these patients are keenly aware of the message contained within the treatment guidelines. Specifically, most can provide a fairly detailed understanding of the need for repeat LPs for therapeutic purposes. In my opinion, it is more an issue of making therapeutic
ce
LPs a priority in the management of these patients.
Ac
Imagine for a moment that you are a physician working in a medical facility in sub‐Saharan Africa (or any other part of the developing world), charged with the responsibility of caring for the 10‐15 patients you admitted within the last 24 hours. You also have 60‐80 patients to see in clinic today. Without additional support from other providers, the performance of a repeat
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
particularly in sub‐Saharan Africa. Not the least of these is limited access to proper
6
LP to improve symptoms possibly improve the outcome in a patient with cryptococcal meningitis becomes a low priority given the expense of the procedure, the time commitment,
cr ipt
and the competing demands of other patients with similarly critical issues.
The other important barrier is cultural. Indeed, patients in sub‐Saharan Africa are generally
us
cryptococcal meningitis based on a perception that LPs are unnecessary, dangerous, and may lead to death. Indeed, cryptococcal meningitis and death are closely linked in sub‐Saharan
an
Africa, and the causation is often mistakenly attributed to the LP. Convincing an individual with few symptoms to undergo repeat LPs in this setting is very challenging.
M
Despite these challenges, I believe that data from this study and previous observations provide
pt ed
sufficient evidence to warrant a prospective evaluation of the influence of routine therapeutic LPs on morbidity and mortality in the acute management of cryptococcal meningitis. The design of such a trial would be challenging, but it is worth the effort, in my opinion. In the meantime, health care providers must continue to push to obtain greater access to LP needles and
ce
manometers for these highly vulnerable patients. This important and simple intervention has tremendous potential impact on short‐term mortality and morbidity, but it must be studied and
Ac
validated before becoming a part of routine practice. If validated, then this approach will require the acceptance of busy clinicians, and will have to be presented to patients in manner that emphasizes both the importance and safety of the procedure.
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
reluctant to undergo initial LPs, much less repeat LPs, for diagnosis and management of
7
cr ipt
us
an
M
pt ed
ce
Ac
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
References 1. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:291‐322. 2. Govender N, Meintjes GA, Bicanic T, et al. Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV‐infected persons: 2013 update. SAJHIVMED 2013; 14:76‐86. 3. World Health Organization. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV‐infected adult, adolescents and children. Geneva: 2011. 4. Park BJ, Wannemuehler K, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/ AIDS. AIDS 2009;23(4):525‐30. 5. Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis 2008; 46:1694‐1701. 6. Kisenge PR, Hawkins AT, Maro VP, et al. Low CD4 count plus coma predicts cryptococcal meningitis in Tanzania. BMC Infect Dis 2007; 7:39. 7. Jarvis JN, Bicanic T, Loyse A, et al. Determinants of mortality in a combined cohort of 501 patients with HIV‐associated cryptococcal meningitis: implications for improving outcomes. Clin Infect Dis 2013; 1‐10. 8. Bicanic T, Brouwer AE, Meintjes G, et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS 2009; 23:701‐6. 9. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000; 30:47‐54. 10. Loyse A, Dromer F, Day J, Lortholary O, Harrison TS. Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50‐year‐old antifungal. J Antimicrob Chemother 2013; 68:2435‐44. 11. Loyse A, Thangaraj H, Easterbrook P, et al. Cryptococcal meningitis: improving access to essential antifungal medicines in resource‐poor countries. Lancet Infect Dis 2013; 13:629‐37.
8
us
14. Meda J, Kalluvya S, Downs JA, et al. Cryptococcal meningitis management in Tanzania with strict schedule of serial lumbar punctures using intravenous tubing sets: an operational research study. J Acquir Immune Defic Syndr Hum Retrovirology 2014; published ahead of print.
an
M
Ac
ce
pt ed
Downloaded from http://cid.oxfordjournals.org/ at New Mexico State University Library on August 27, 2014
cr ipt
12. Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis 2014. 13. Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, Taseera K, Nabeta HW, Schutz C, Williams DA, Rajasingham R, Rhein J, Thienemann F, Lo MW, Nielsen K, Bergemann TL, Kambugu A, Manabe YC, Janoff EN, Bohjanen PR, Meintjes G, COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis.N Engl J Med. 2014;370:2487‐98
