- Email: [email protected]
New insight on the pathogenesis and treatment of pneumococcal meningitis
IIDN1 Editor
Associate Editors
Charles W. Stratton, MD
Roger G. Finch,
Department of Pathology Vanderbilt UniversityMedicalCenter Nashville, Tennessee
Volume 9, Number 5, May 1990
FRCP, MRC Path NottinghamCity Hospital Nottingham, United Kingdom
Ruth M. Lawrence, MD
H. Bradford Hawley,
John T. Sinnott IV, MD
MD Wright State Schoolof Medicine Dayton, Ohio
VeteransAdministrationOutpatientClinic Sacramento, California Universityof South Florida Tampa, Florida
R i c h a r d F. J a c o b s , MD Arkansas Children's Hospital Little Rock, Arkansas
New Insight on the Pathogenesis and Treatment of Pneumococcal Meningitis Elaine Tuomanen, MD
2ontent~,
New Insight on the Pathogenesis and Treatment of Pneumococcal Meningitis Elaine Tuornanen
Laboratory of Microbiology, Rockefeller University, New York, NY
33
Haemophilus influenzae Type B
Conjugate Vaccines Janet R. Gilsdorf
35
CASE REPORT Richard F. Jacobs
37
COMMENTS ON CURRENT PUBLICATIONS
Elsevier 0278-2316/90/$0.00 + 2.20
38
It is particularly exciting when new understanding of the molecular pathogenesis of a disease rapidly catalyzes testing and establishment of improved therapies in medicine. This phenomenon is currently underway in the field of bacterial meningitis, in which efforts to optimize the therapy of meningitis in the laboratory have translated to remarkably successful clinical trials. The rapid pace of developments in this field in the past 2 years has spawned two major workshops on the pathophysiology of the infection and many updates summarizing the latest changes in therapeutic regimens that benefit outcome. This summary will focus on the subset of this data base pertinent to the most devastating meningitis, pneumococcal meningitis, recognizing that basic differences in pathophysiology and approaches to improved treatment exist between gram-positive and gram-negative infection. It is reasonable to expect that many of the principles
guiding new therapies for meningitis will also be appropriate for other systemic infections. However, it is important to emphasize that each organ system responds differently during activation of host defenses, and regimens effective in one site should not be extrapolated to other body sites unless rigorously tested. This is illustrated by the success of indomethacin in decreasing inflammation and improving outcome of meningitis but not of otitis media or pneumonia.
The Sequence of Events in Meningitis On a molecular level, the onset of meningitis is abrupt, arising when a threshold concentration of pneumococcal cell wall pieces (either free in solution or attached to bacteria) is surpassed. As bacteria multiply in the subarachnoid space in the absence of host defenses, a period of reversible central nervous system (CNS) injury occurs during which individual com0278-2316 IDINDN9(5) 33-40, 1990
34 Infectious Diseases Newsletter 9(5) May 1990 ponents of the cell wall bind to CNS endothelia and resident leukocytes, initiating activation of the cytokine cascade. Evidence suggests that the central cytokine in the CNS may be interleukin 1 (IL-1), which is detectable in both bacterial and viral meningitis. IL-1 in turn can stimulate production of tumor necrosis factor (TNF), the concentration of which is correlated to outcome of disease and the presence of which has been suggested in two studies to be a marker exclusive to bacterial meningitis. The clinical hallmarks of these events are those associated with increasing permeability of the blood-brain barrier: cerebrospinal fluid (CSF) leukocytosis and increased protein and lactic acid concentrations. At some point after defenses are recruited from serum into the CSF, irreversible CNS injury begins to occur, associated with persistently increased cytokine concentrations and ischemic injury to neurons as autoregulation of cerebral blood flow is lost and peripheral perfusion pressure decreases. Brain edema or increased intracranial pressure may also develop by independent routes because of the specific toxicities of two different components of the pneumococcal cell wall. At present, the line between reversible and irreversible injury cannot be distinguished clinically. All that is known is that irreversible damage is associated with IL-II3 concentrations >200 pg/mL of CSF and that such damage is dramatically reduced if the peripheral leukocyte is prevented from moving into the CSF by any number of means. The consequences of these pathophysiologic-derangements is most dramatically illustrated in the context of initiation of antibiotic therapy, which causes disintegration of the
bacteria and release of the inflammatory library of cell wall pieces, resuiting in a burst of CSF inflammation over such a short time as to overwhelm the adaptive capacity of the closed intracranial space. This determines a causal linkage of bacterial death to neuronal death. If this burst of inflammation is down-modulated, ultimate CNS injury is reduced. Thus, the target of all current adjuncts to the therapy of meningitis is the antibiotic-induced burst of inflammatory tissue damage. This phenomenon, first described in an animal model of pneumococcal meningitis, has subsequently been shown to occur in animals and children with pneumococcal, Haemophilus influenzae, and Escherichia coli meningitis. The principle of improved outcome associated with decreasing tissue injury occurring during bacterial death is valid for all sites of infection studied thus far, but the modulators appropriate for each infection are site-specific.
Adjuncts to Antibiotic Therapy That Target Various Steps along the Inflammatory Cascade The obvious first step in preventing the antibiotic-induced burst of inflammation is to use an antibiotic that kills but does not release surface components of the bacteria. Unfortunately, there does not exist such an antibiotic in common clinical use today that also penetrates the bloodbrain barrier. The best candidate was chloramphenicol, but it is bactericidal for common meningeal pathogens and causes release of exdotoxin and cell wall. Newer penem antibiotics, by virtue of their novel killing mechanism, may induce noninflammatory killing, although this remains to be definitively shown. Given then that
the cell wall pieces are going to be rapidly released during bacterial death, can the pieces be captured and rendered inert? Anti-cell wall antibodies decrease the inflammatory potential of pneumococcal cell walls (similarly, anti-lipid A antibodies neutralize endotoxin), but they must be administered intrathecally in order to achieve sufficient concentrations locally in the CSF. This drawback also applies to anti-cytokine antibodies, which block inflammation after cell wall activates the cytokine cascade in host tissues. Two other modes of adjunct therapy are now undergoing or being prepared for clinical assessment: interruption of the cytokine cascade by steroids or nonsteroidal agents, or inhibition of leukocyte movement across the blood-brain barrier by systemically administered anti-integrin antibodies. Both approaches achieve dramatic beneficial responses in the animal model, but only the steroids have undergone trials in humans to this point in time. Most recently, Grigis et al completed a trial including both children and adults that demonstrated that the incidence of overall neurologic sequelae was reduced significantly by the use of dexamethasone and for the first time, a striking beneficial effect on mortality was evident for pneumococcal meningitis (13% mortality in patients receiving dexamethasone with antibiotics vs. 41% for those receiving ampiciilin and chloramphenicol alone). Greater reduction in the incidence and severity of sequelae appears to occur if the steroid is administered together with, not after, initiation of antibiotic therapy. This is an unfortunately small window of opportunity that hopefully will widen as other agents are tested. For instance, postanti-
NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein, No suggested test or procedure should he carried out unless, m the reader's judgment, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verficatiou of diagnoses and drug dosages should be made. Discussions, views and recommendations as to medical procedures, choice of drugs and drug dosages are the responsibility of the authors. Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, New York 10010. Printed in USA at Hanover, PA 17331. Subscription price per year: institutions, $148.00; individuals, $86.00. For postage outside the U.S.. add $37.00 (Canada and Mexico require no additional postage). Second-class postage paid at New York, NY, and at additional totaling offices. Postmaster: Send address changes to Infectious Diseases Newsletter. Elsevier Science Publishing Co.~ Inc., 655 Avenue of the Americas, New York, New York 10010.
© 1990 Elsevier Science Publishing 0278-2316/90/$0.00 + 2.20
Co.,
Inc.
35 Infectious Diseases Newsletter 9(5) May 1990 biotic efficacy has been shown for therapy with the intravenous anti-leukocyte integrin antibody in the animal model. The therapies developed in experimental models have proved highly efficacious in humans, forming a strong experimental and clinical data base for considering recommendation of a new standard for therapy of bacterial meningitis in children and adults that includes anti-inflammatory agents. It remains to be determined which single agent or combination of agents will yield the most benefit. New trials in neonates will determine if this group will also derive benefit from adjunct therapy as predicted by experimental evidence. What is certain is that a new avenue finally exists to decrease
the up to 30% mortality in children and 50% mortality in neonates who contract bacterial meningitis.
Meningitis Study Group: Report of a workshop: Pathophysiology of bacterial meningitis--Implications for new management strategies. Pediatr Infect Dis J 6:1143-1171, 1987.
Bibliography
Meningitis Study Group: Report of a second workshop: Pathophysiology of bacterial meningitis. Pediatr Infect Dis J 8:899-933, 1989.
Giebink G, Batalden P, Le C, et al: A controlled trial comparing three treatments for otitis media with effusion. Pediatr Infect Dis J 9:33-40, 1990. Grigis N, Farid Z, Mikhail I, et al: Dexamethasone treatment for bacterial meningitis in children and adults. Pediatr Infec Dis J 8:848-851, 1989. Jacobs R: Gram-negative enteric meningitis in the neonate. Infect Dis Newsletter 8:60-62, 1989. Lebel M, Freij B, Syroglannopoulos G: Dexamethasone therapy for bacterial meningitis: Results of two double-blind, placebo-controlled trials. N Engl J Med 3:964-971, 1988.
Haemophilus influenzae Type B Conjugate Vaccines Janet R. Gilsdorf, MD Department of Pediatric Infectious Diseases, University of Michigan, C.S. Mort Children's Hospital, Ann Arbor, MI
Haemophilus influenzae type B is a major pathogen in children, causing serious infections such as meningitis, facial cellulitis, pneumonia, septic arthritis, and epiglottitis in approximately 20,000 children in the United States (U.S.) annually. In spite of the availability of good antibiotic therapy, the mortality rate of H. influenzae type B meningitis, the most lifethreatening of these infections, is 5% to 10%. In addition, significant neurologic sequelae occur in many children following H. influenzae meningitis. In order to prevent infection with H. influenzae type B, several vaccines have been licensed for use in children. The first series of these vaccines, which were introduced in 1985, contained only the purified capsular material, polyribosylribose phosphate or PRP. Extensive experience with
the plain PRP vaccines demonstrated their poor immunogenicity in young children <24 months of age. However, the majority of H. influenzae infections occur in younger children with the peak incidence at about 9 to 11 months of age. In attempting to develop vaccines that would be effective at younger ages, the newer H. influenzae type B vaccines have used the plain PRP polysaccharide conjugated to various proteins. The first H. influenzae type B protein conjugate vaccine became available in 1987 with the licensure PRP-D, which contained plain PRP conjugated to diphtheria toxoid, and has been marketed under the name PROHIBIT by Connaught Laboratories. More recently, PRP-CRM, which contains smaller PRP molecules or oligosaccharides, conjugated to a mutant diphtheria protein called CRM197 has been li© 1990 Elsevier Science Publishing Co., Inc. 0278-2316/90/$0.00 + 2.20
Tuomanen E, Hengstler B, Rich R, et al: Nonsteroidal antiinflammatory agents in the therapy for experimental pneumococcal meningitis. J Infec Dis 155:985990, 1987. Tuomanen E, Saukkonen K, Sande S, et al: Reduction of inflammation, tissue damage, and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes. J Exp Med 170:959-968, 1989.
censed and is marketed as HIBTITER by Praxis Biologics. A third conjugate vaccine, PRP-NOMP, called PEDVAX-HIB and made by Merck, Sharp, and Dohme, has most recently been licensed by the Food and Drug Administration. This vaccine contains plain PRP conjugated to an outer membrane protein of Neisseria meningitidis group B. All three of the conjugate vaccines have been licensed by the FDA for use in 18- to 71-month-old children, with permissive use at 15 months. A major concern in the development of new vaccine products is their safety. Experience with PRP-D has shown a few relatively minor reactions. The number and types of adverse reactions appear to be no different from those observed with the older, plain PRP vaccine, and include mild irritability and tenderness at the injection site in < 15% of recipients; and low-grade fever, mild erythema, and swelling at the injection site in <2% of recipients. Less information is available on reactions associated with PRP-CRM and PRP-NOMP, but they appear to be no different from those following PRP-D. Thus, H. in-
Associate Editors
Charles W. Stratton, MD
Roger G. Finch,
Department of Pathology Vanderbilt UniversityMedicalCenter Nashville, Tennessee
Volume 9, Number 5, May 1990
FRCP, MRC Path NottinghamCity Hospital Nottingham, United Kingdom
Ruth M. Lawrence, MD
H. Bradford Hawley,
John T. Sinnott IV, MD
MD Wright State Schoolof Medicine Dayton, Ohio
VeteransAdministrationOutpatientClinic Sacramento, California Universityof South Florida Tampa, Florida
R i c h a r d F. J a c o b s , MD Arkansas Children's Hospital Little Rock, Arkansas
New Insight on the Pathogenesis and Treatment of Pneumococcal Meningitis Elaine Tuomanen, MD
2ontent~,
New Insight on the Pathogenesis and Treatment of Pneumococcal Meningitis Elaine Tuornanen
Laboratory of Microbiology, Rockefeller University, New York, NY
33
Haemophilus influenzae Type B
Conjugate Vaccines Janet R. Gilsdorf
35
CASE REPORT Richard F. Jacobs
37
COMMENTS ON CURRENT PUBLICATIONS
Elsevier 0278-2316/90/$0.00 + 2.20
38
It is particularly exciting when new understanding of the molecular pathogenesis of a disease rapidly catalyzes testing and establishment of improved therapies in medicine. This phenomenon is currently underway in the field of bacterial meningitis, in which efforts to optimize the therapy of meningitis in the laboratory have translated to remarkably successful clinical trials. The rapid pace of developments in this field in the past 2 years has spawned two major workshops on the pathophysiology of the infection and many updates summarizing the latest changes in therapeutic regimens that benefit outcome. This summary will focus on the subset of this data base pertinent to the most devastating meningitis, pneumococcal meningitis, recognizing that basic differences in pathophysiology and approaches to improved treatment exist between gram-positive and gram-negative infection. It is reasonable to expect that many of the principles
guiding new therapies for meningitis will also be appropriate for other systemic infections. However, it is important to emphasize that each organ system responds differently during activation of host defenses, and regimens effective in one site should not be extrapolated to other body sites unless rigorously tested. This is illustrated by the success of indomethacin in decreasing inflammation and improving outcome of meningitis but not of otitis media or pneumonia.
The Sequence of Events in Meningitis On a molecular level, the onset of meningitis is abrupt, arising when a threshold concentration of pneumococcal cell wall pieces (either free in solution or attached to bacteria) is surpassed. As bacteria multiply in the subarachnoid space in the absence of host defenses, a period of reversible central nervous system (CNS) injury occurs during which individual com0278-2316 IDINDN9(5) 33-40, 1990
34 Infectious Diseases Newsletter 9(5) May 1990 ponents of the cell wall bind to CNS endothelia and resident leukocytes, initiating activation of the cytokine cascade. Evidence suggests that the central cytokine in the CNS may be interleukin 1 (IL-1), which is detectable in both bacterial and viral meningitis. IL-1 in turn can stimulate production of tumor necrosis factor (TNF), the concentration of which is correlated to outcome of disease and the presence of which has been suggested in two studies to be a marker exclusive to bacterial meningitis. The clinical hallmarks of these events are those associated with increasing permeability of the blood-brain barrier: cerebrospinal fluid (CSF) leukocytosis and increased protein and lactic acid concentrations. At some point after defenses are recruited from serum into the CSF, irreversible CNS injury begins to occur, associated with persistently increased cytokine concentrations and ischemic injury to neurons as autoregulation of cerebral blood flow is lost and peripheral perfusion pressure decreases. Brain edema or increased intracranial pressure may also develop by independent routes because of the specific toxicities of two different components of the pneumococcal cell wall. At present, the line between reversible and irreversible injury cannot be distinguished clinically. All that is known is that irreversible damage is associated with IL-II3 concentrations >200 pg/mL of CSF and that such damage is dramatically reduced if the peripheral leukocyte is prevented from moving into the CSF by any number of means. The consequences of these pathophysiologic-derangements is most dramatically illustrated in the context of initiation of antibiotic therapy, which causes disintegration of the
bacteria and release of the inflammatory library of cell wall pieces, resuiting in a burst of CSF inflammation over such a short time as to overwhelm the adaptive capacity of the closed intracranial space. This determines a causal linkage of bacterial death to neuronal death. If this burst of inflammation is down-modulated, ultimate CNS injury is reduced. Thus, the target of all current adjuncts to the therapy of meningitis is the antibiotic-induced burst of inflammatory tissue damage. This phenomenon, first described in an animal model of pneumococcal meningitis, has subsequently been shown to occur in animals and children with pneumococcal, Haemophilus influenzae, and Escherichia coli meningitis. The principle of improved outcome associated with decreasing tissue injury occurring during bacterial death is valid for all sites of infection studied thus far, but the modulators appropriate for each infection are site-specific.
Adjuncts to Antibiotic Therapy That Target Various Steps along the Inflammatory Cascade The obvious first step in preventing the antibiotic-induced burst of inflammation is to use an antibiotic that kills but does not release surface components of the bacteria. Unfortunately, there does not exist such an antibiotic in common clinical use today that also penetrates the bloodbrain barrier. The best candidate was chloramphenicol, but it is bactericidal for common meningeal pathogens and causes release of exdotoxin and cell wall. Newer penem antibiotics, by virtue of their novel killing mechanism, may induce noninflammatory killing, although this remains to be definitively shown. Given then that
the cell wall pieces are going to be rapidly released during bacterial death, can the pieces be captured and rendered inert? Anti-cell wall antibodies decrease the inflammatory potential of pneumococcal cell walls (similarly, anti-lipid A antibodies neutralize endotoxin), but they must be administered intrathecally in order to achieve sufficient concentrations locally in the CSF. This drawback also applies to anti-cytokine antibodies, which block inflammation after cell wall activates the cytokine cascade in host tissues. Two other modes of adjunct therapy are now undergoing or being prepared for clinical assessment: interruption of the cytokine cascade by steroids or nonsteroidal agents, or inhibition of leukocyte movement across the blood-brain barrier by systemically administered anti-integrin antibodies. Both approaches achieve dramatic beneficial responses in the animal model, but only the steroids have undergone trials in humans to this point in time. Most recently, Grigis et al completed a trial including both children and adults that demonstrated that the incidence of overall neurologic sequelae was reduced significantly by the use of dexamethasone and for the first time, a striking beneficial effect on mortality was evident for pneumococcal meningitis (13% mortality in patients receiving dexamethasone with antibiotics vs. 41% for those receiving ampiciilin and chloramphenicol alone). Greater reduction in the incidence and severity of sequelae appears to occur if the steroid is administered together with, not after, initiation of antibiotic therapy. This is an unfortunately small window of opportunity that hopefully will widen as other agents are tested. For instance, postanti-
NOTE: No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein, No suggested test or procedure should he carried out unless, m the reader's judgment, its risk is justified. Because of rapid advances in the medical sciences, we recommend that the independent verficatiou of diagnoses and drug dosages should be made. Discussions, views and recommendations as to medical procedures, choice of drugs and drug dosages are the responsibility of the authors. Infectious Diseases Newsletter (ISSN 0278-2316) is issued monthly in one indexed volume per year by Elsevier Science Publishing Co., Inc., 655 Avenue of the Americas, New York, New York 10010. Printed in USA at Hanover, PA 17331. Subscription price per year: institutions, $148.00; individuals, $86.00. For postage outside the U.S.. add $37.00 (Canada and Mexico require no additional postage). Second-class postage paid at New York, NY, and at additional totaling offices. Postmaster: Send address changes to Infectious Diseases Newsletter. Elsevier Science Publishing Co.~ Inc., 655 Avenue of the Americas, New York, New York 10010.
© 1990 Elsevier Science Publishing 0278-2316/90/$0.00 + 2.20
Co.,
Inc.
35 Infectious Diseases Newsletter 9(5) May 1990 biotic efficacy has been shown for therapy with the intravenous anti-leukocyte integrin antibody in the animal model. The therapies developed in experimental models have proved highly efficacious in humans, forming a strong experimental and clinical data base for considering recommendation of a new standard for therapy of bacterial meningitis in children and adults that includes anti-inflammatory agents. It remains to be determined which single agent or combination of agents will yield the most benefit. New trials in neonates will determine if this group will also derive benefit from adjunct therapy as predicted by experimental evidence. What is certain is that a new avenue finally exists to decrease
the up to 30% mortality in children and 50% mortality in neonates who contract bacterial meningitis.
Meningitis Study Group: Report of a workshop: Pathophysiology of bacterial meningitis--Implications for new management strategies. Pediatr Infect Dis J 6:1143-1171, 1987.
Bibliography
Meningitis Study Group: Report of a second workshop: Pathophysiology of bacterial meningitis. Pediatr Infect Dis J 8:899-933, 1989.
Giebink G, Batalden P, Le C, et al: A controlled trial comparing three treatments for otitis media with effusion. Pediatr Infect Dis J 9:33-40, 1990. Grigis N, Farid Z, Mikhail I, et al: Dexamethasone treatment for bacterial meningitis in children and adults. Pediatr Infec Dis J 8:848-851, 1989. Jacobs R: Gram-negative enteric meningitis in the neonate. Infect Dis Newsletter 8:60-62, 1989. Lebel M, Freij B, Syroglannopoulos G: Dexamethasone therapy for bacterial meningitis: Results of two double-blind, placebo-controlled trials. N Engl J Med 3:964-971, 1988.
Haemophilus influenzae Type B Conjugate Vaccines Janet R. Gilsdorf, MD Department of Pediatric Infectious Diseases, University of Michigan, C.S. Mort Children's Hospital, Ann Arbor, MI
Haemophilus influenzae type B is a major pathogen in children, causing serious infections such as meningitis, facial cellulitis, pneumonia, septic arthritis, and epiglottitis in approximately 20,000 children in the United States (U.S.) annually. In spite of the availability of good antibiotic therapy, the mortality rate of H. influenzae type B meningitis, the most lifethreatening of these infections, is 5% to 10%. In addition, significant neurologic sequelae occur in many children following H. influenzae meningitis. In order to prevent infection with H. influenzae type B, several vaccines have been licensed for use in children. The first series of these vaccines, which were introduced in 1985, contained only the purified capsular material, polyribosylribose phosphate or PRP. Extensive experience with
the plain PRP vaccines demonstrated their poor immunogenicity in young children <24 months of age. However, the majority of H. influenzae infections occur in younger children with the peak incidence at about 9 to 11 months of age. In attempting to develop vaccines that would be effective at younger ages, the newer H. influenzae type B vaccines have used the plain PRP polysaccharide conjugated to various proteins. The first H. influenzae type B protein conjugate vaccine became available in 1987 with the licensure PRP-D, which contained plain PRP conjugated to diphtheria toxoid, and has been marketed under the name PROHIBIT by Connaught Laboratories. More recently, PRP-CRM, which contains smaller PRP molecules or oligosaccharides, conjugated to a mutant diphtheria protein called CRM197 has been li© 1990 Elsevier Science Publishing Co., Inc. 0278-2316/90/$0.00 + 2.20
Tuomanen E, Hengstler B, Rich R, et al: Nonsteroidal antiinflammatory agents in the therapy for experimental pneumococcal meningitis. J Infec Dis 155:985990, 1987. Tuomanen E, Saukkonen K, Sande S, et al: Reduction of inflammation, tissue damage, and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes. J Exp Med 170:959-968, 1989.
censed and is marketed as HIBTITER by Praxis Biologics. A third conjugate vaccine, PRP-NOMP, called PEDVAX-HIB and made by Merck, Sharp, and Dohme, has most recently been licensed by the Food and Drug Administration. This vaccine contains plain PRP conjugated to an outer membrane protein of Neisseria meningitidis group B. All three of the conjugate vaccines have been licensed by the FDA for use in 18- to 71-month-old children, with permissive use at 15 months. A major concern in the development of new vaccine products is their safety. Experience with PRP-D has shown a few relatively minor reactions. The number and types of adverse reactions appear to be no different from those observed with the older, plain PRP vaccine, and include mild irritability and tenderness at the injection site in < 15% of recipients; and low-grade fever, mild erythema, and swelling at the injection site in <2% of recipients. Less information is available on reactions associated with PRP-CRM and PRP-NOMP, but they appear to be no different from those following PRP-D. Thus, H. in-