Report of the Task Force on Pertussis and Pertussis Immunization—1988

(1)

Report of the Task Force on Pertussis and Pertussis

Immunization-i

988 James

D. Cherry,

MD,

MSc

UCLA

Medical

Center

UCLA

School

of Medicine

Los Angeles

Philip

A. Brunell,

MD

Cedars-Sinai

Medical

Center

UCLA

School

of Medicine

Los Angeles

Gerald

S. Golden,

MD

University

of Tennessee

College

of Medicine

David

T. Karzon,

MD

Vanderbilt

University

School

of Medicine

Nashville,

Tennessee

This One

(2)

Pertussis (whooping cough) is an endemic and epidemic disease due to Bordetella pertussis. The disease has been and still is a major cause of mor-bidity and mortality in young children through-out the world. The World Health Organization es-timates that 600,000 deaths due to pertussis occur yearly; virtually all of these deaths occurred in unimmunized infants.’ In the United States, per-tussis has been successfully controlled by the rou-tine mass immunization of infants and children. In the prevaccine era, there were 115,000 to

270,000

cases of pertussis and 5,000 to 10,000

deaths due to the disease each year.2 During the last 10 years, there have been 1,200 to 4,000 cases and five to ten deaths per year.36

Unfortunately, the control of pertussis by im-munization has not enjoyed sustained interna-tional success because of controversy relating to vaccine reactions and effectiveness. Since 1982 this controversy has been a problem in the United States. Most pediatricians as well as a large num-ber of parents are aware of the present pertussis vaccine controversy; however, few understand the facts. This controversy involving the media, political and legal sectors, and the scientific com-munity is a major threat to our present immu-nization program and the future control of per-tussis in the United States7” (“20/20,” ABC News, Feb 5, 1985; “DPT: Vaccine Roulette,” Na-tional Broadcasting Co, Date, 1982; Democrat and Chronicle, Rochester, NY, March 8-12, 1987, p 1;

The Fresno Bee, Dec 2-3, 1984, p 1; Dec 5, 1987, p B14). Because of this, a task force on pertussis and pertussis vaccine was created by the Execu-tive Board of the American Academy of Pediatrics to review the problem. In this report an objective, broad up-to-date review of pertussis and pertussis immunization is presented.

Although pertussis-like illness can be caused by several types of adenoviruses, Bordetella parapertussis and Bordetella bronchiseptica, the overwhelming majority of cases and all major epi-demics are due to infection with B pert ussis.

Therefore, in this article only disease due to B

per-tussis is considered.

CHARACTERISTICS OF THE ORGANISM

Classification and Morphology12

The genus Bordetella contains four species: per-tussis, which is the agent responsible for human

pertussis; parapertussis, which causes a mild per-tussis-like disease in humans; bronchiseptica,

which is primarily an animal pathogen but may infect humans; and avium, which causes respi-ratory disease in The four species are dif-ferentiated from each other by their phenotypic characteristics. Recent DNA homology studies have shown that B pertussis, B parapertussis, and

B bronchiseptica are genetically similar and, therefore, might more appropriately be desig-nated biotypes of the same

B pertussis is a Gram-negative coccobacillus that measures 0.2 to 0.8 pm in size. The colony, when grown aerobically on Bordet-Gengou me-dium at 35.5#{176}C,is punctiform, convex, glistening, and translucent. A hazy zone of hemolysis sur-rounds the colony. In 1931, Leslie and Gardner’s noted four phases (phases I, II, III, IV) when B

pertussis was cultured on artificial medium. Change from phase I to phase IV is associated with loss of virulence in laboratory animals.’6

Growth in Vitro and in V1vo12

B pertussis was first cultured by Bordet and Gengou’7 in 1906. They used a medium consisting of potato starch infusion, glycerol, and defibri-nated blood. Bordet-Gengou medium is still fre-quently used for the isolation ofB pertussis today. All members of the genus Bordetella have an ab-solute requirement for niacin or nicotinamide. Unsaturated fatty acids are toxic to the organism and, therefore, media usually contain substances that adsorb fatty acids such as starch, charcoal, ion exchange resins, or albumin. Rigorous clean-ing of glassware to remove contaminating fatty acids also improves growth of B pertussis.

In vivo B pertussis has a marked tropism for ciliated cells of the respiratory epithelium. Bac-teria attach and multiply at the tips of, between, and at the base ofcilia and this leads to ciliostasis, cell death, and shedding of the epithelial cells. The bacteria are not invasive and do not infect submucosal cells or other sites in the body.

Antigenic and Biologically Active Factors

B pertussis contains many antigenic and bio-logically active factors (Table 1). The effects of these factors have been demonstrated in animal systems following infection or the injection of killed organisms. Although it is clear that infec-tion with B pertussis or the injection of killed B

(6)

Agglutinogens

Factor Location and Structure Biologic Functions

Adenylate cyclase

TABLE 1. Biologically Active and Antigenic Components of Bordetella pertussis

Filamentous hemagglutinin (FHA)

Lymphocytosis-promoting factor (LPF) (lymphocytosis-promoting toxin, lymphocytosis promoting factor-hemagglutinin,

leukocytosis-promoting factor, histamine-sensitizing factor, islet-activating protein,

pertussigen, and pertussis toxin)

Heat-labile toxin, also called dermonecrotic toxin, lethal toxin, or lienotoxin

Endotoxin, also called lipopolysaccharide Tracheal cytotoxin

Hemolysin

Outer membrane proteins

Protein surface antigens; multiple serotypes, some located on fimbriae (pili).

A cell-surface protein that is a hemagglutinin; it is liberated into fluid of statically grown broth cultures.

An envelope protein which is a hemagglutinin. It is liberated into the fluid of static or submerged cultures.

Extracytoplasmic enzyme that is liberated into culture

supernatants

Heat-labile protein toxin found in cytoplasmic fraction of cell lysates

Envelope toxin

Small glycopeptide found in

culture supernatants

Unknown

Outer membrane of organism

Provide serologic markers for study of epidemiologic

characteristics of pertussis, used as a measure of pertussis

immunity, may play role in attachment of bacteria to ciliated cells, antibody to agglutinogens may contribute to protection against infection Important mediator of attachment

of bacteria to ciliated epithelial cells, antibody to FHA may protect against infection of ciliated cells

Is a toxin with many biologic functions in animal model systems such as: histamine sensitization, lymphocytosis promotion, enhancement of insulin secretion, and adjuvant and mitogenic activity; antibody to LPF is protective in intracerebral mouse protection test

Interferes with host defense mechanisms by impairing phagocyte functions

Causes skin necrosis in mice, rabbits, and guinea pigs and is lethal in mice after IV

administration

Activities similar to endotoxins of other Gram-negative bacteria Causes ciliostasis and

cytopathology of hamster

tracheal epithelial cells in organ culture

Hemolysin-deficient mutant had reduced virulence in mice Have adjuvant activity for

Haemophilus influenzae type B

polysaccharide

immunologic effects in humans, studies have been performed.

Agglutinogens

few adequate

Agglutinogens are protein surface antigens of

Bordetella sp.’2”8-2’ They stimulate the produc-tion of antibodies that cause agglutination of

Bor-detella sp organisms. All smooth Bordetella sp

strains have a common heat-stable 0 antigen and one or more heat-labile K antigens (agglutino-gens).22 Of the 14 antigenic types of agglutino-gens, type 7 is common to all Bordetella sp and type 1 is carried by all B pertussis strains. Strains of B pertussis may also possess agglutinogens 2 to 6 in various combinations; agglutinogens 2 and 4 and agglutinogens 3 and 6 tend to occur to-gether.20

The demonstration of serum agglutinins has been useful in the epidemiologic study of pertus-sis; their importance in protection from disease has been a major point of discussion for about 30 years. In the extensive Medical Research Council vaccine trials in England in the 1950s, it was noted that the presence of agglutinins related to vaccine efficacy.2325 More than 40 years ago, it was noted that some children were immune to per-tussis even though they lacked demonstrable ag-glutinins.26 However, in the same study, all chil-dren with high agglutinin titers were protected.

In the early 1960s, pertussis vaccine efficacy in the United Kingdom had decreased. Preston27’28 postulated that this decline in vaccine efficacy was due to the fact that the vaccines of the time did not contain agglutinogen 3 and the most

(7)

1.3. Efficacy increased following the addition of serotype 3 containing strains to the vaccines which supported the hypothesis.2931 However, the increased efficacy cannot be wholly attributed to the vaccines which now contained a full corn-plement of agglutinogens because the protective unitage of the vaccines was also increased at the same time.2#{176}

Recent data indicate that agglutinogens 2 and 6 are located on the fimbriae (pili) of the bacter-ium.32’33 Immunization of mice with purified fim-briae (serotype 2 agglutinogens) protected them from lethal respiratory infections with two differ-ent B pertussis strains.34

Filamentous

Hemagglutinin

(FHA)

FHA is a surface protein of B pertussis 12

It had been hypothesized that FHA was derived from fimbriae,35 but this has not been supported by more recent study.36 FHA is liberated into the medium of broth cultures, and it causes the ag-glutination of erythrocytes of many animals such

as sheep, chickens, and geese.37 FHA may be an important factor in the attachment of bacteria to ciliated epithelial cells.3843 Antibody to FHA may be important in immunity to pertussis. FHA does not protect the mouse against intracerebral challenge, but it does protect against lethal res-piratory infection.44 Recent data suggest that both FHA and agglutinogens together are impor-tant in the adhesion of B pertussis to cell surfaces39 ; the greatest inhibition of adhesion of the organism was produced with addition of im-munoglobulin containing both anti-FHA and spe-cific agglutinins.

Tuomanen4’ noted that when Streptococcus pneumoniae, Haemophilus influenzae, and Staph-ylococcus aureus were pretreated with FHA they

acquired the ability to adhere to cilia in vitro and in vivo. She suggested that the ability of these bacteria to attach to respiratory cilia by the piracy of FHA adhesin might contribute to superinfec-tion in clinical pertussis.

Lymphocytosis-Promoting

Factor

(LPF)

Evolving studies during the last 50 years have indicated that there is a major component of B

pertussis that has many biologic activities.’2’21’37’ This component has been designated by many different names, many of which refer to spe-cific unique activities. These names and abbre-viations are as follows: lymphocytosis-promoting

factor (LPF), lymphocytosis-promoting toxin (LPT), lymphocytosis-promoting factor-hemag-glutinin (LPF-HA), leukocytosis-promoting factor

(LPF), histamine-sensitizing factor (HSF),

islet-activating protein (lAP), heat-labile adjuvant (HLAd), pertussigen, and pertussis toxin (PT). In this paper we will refer to this factor as LPF. The term “pertussis toxin” is confusing because it was first used to indicate dermonecrotic toxin and

be-cause B pertussis contains several other impor-tant toxins.

LPF is an envelope protein antigen which is a hemagglutinin. Recently, the complete nucleotide

sequence of the LPF gene was determined.54 LPF has two components, an enzymatically active A

subunit and a B oligomer which binds the toxin to eukaryotic cell surfaces.5557 LPF is liberated into the fluid of static or submerged B pertussis

cultures. LPF has many biologic effects in animals when infection is induced and also when the an-imals are injected with killed organism prepara-tions. These biologic activities will be reviewed.

Histamine Sensitization. Parfentjev and Goodline58 in 1948 reported that mice vaccinated intraperitoneally with pertussis vaccine subse-quently became hypersensitive to injected hista-mine. Specifically, they found that 2 mg of his-tamine was approximately as lethal to sensitized (previously vaccinated) mice as 50 mg was to un-vaccinated mice. Death in sensitized mice oc-curred within 30 minutes of histamine injection. During the last 40 years, histamine sensitization has been studied by many investigators,52’5965 but only five studies involving humans have been reported.667#{176} In the mouse, histamine sensitivity following intraperitoneal pertussis vaccination increases throughout four to five days, plateaus, and then diminishes throughout 3 to 4 weeks.52 Following intravenous vaccination, sensitization occurs within 90 minutes and peaks at one day. Pittman63 noted that histamine sensitization also

occurs after respiratory infection in mice. Natural sensitivity to histamine varies mark-edly among animals. Mice are resistant to his-tamine toxicity, whereas rabbits and guinea pigs are highly susceptible. Interestingly, pertussis immunization does not increase the susceptibility of rabbits and guinea pigs to lethal histamine tox-icity; in fact, following immunization these ani-mals appear to become more resistant to hista-mine.62’65

In 1960, Sanyal69 reported that, following per-tussis, children had increased sensitivity to

his-tamine. However, his study contained no control data (ie, histamine sensitivity in children without pertussis). In a small controlled study, Pieroni

(8)

chil-dren but no such response in diphtheria-tetanus vaccine (DT) recipients. However, in this study the observations were not made in a blinded fash-ion and the controls were older than the DTP recipients. In vaccinated allergic children, Mathov67 could not demonstrate a significant in-crease of skin sensitivity to histamine compared with skin sensitivity in unvaccinated allergic children. In a recent study, Gifford and col-leagues66 compared skin test sensitivity to his-tamine in DT- and DTP-immunized children. There was no significant difference in wheal size between the two groups.

Lymphocytosis Promotion. About 90 years ago,

it was first noted that a marked leukocytosis and lymphocytosis occurred in the blood of children with pertussis,7’ and this observation has been a consistent marker ofthe disease ever since. In ex-perimental studies in mice, it was found that sim-ilar leukocytosis occurs following injection with either living B pertussis organisms, killed B

per-tussis cells, or B pertussis culture superna-tants.7274 This factor (LPF) ofB pertussis causes lymphocytosis in many diverse species such as lampreys, swine, guinea pigs, rabbits, monkeys, calves, sheep, and mice.49

In the mouse, following intravenous injection of purified LPF, the leukocytosis peaks at about four days and decreases to normal values after 2 to 3 weeks.75 There is an increase in both neutrophils and lymphocytes, but the lymphocytic response is greater. The leukocytosis is not due to increased cell production but due to the release of cells into the blood from extravascular sites and the failure of the recirculating lymphocytes to emigrate nor-mally from the blood.76 Both B and T cells are increased in the circulation.75

Surprisingly, there are few data regarding lym-phocytosis in children following immunization. In two studies, Sauer77 noted leukocytosis in chil-dren on the day when they had received the last injection of a pertussis vaccination series. Specif-ically, in one of his studies, 93 children were im-munized weekly for 8 weeks and in another study the children received a double dose of vaccine weekly for 4 weeks. These children received in 4 to 8 weeks a vaccine dose of about two and one-half times that which children presently receive in the initial three doses of vaccine during a 4-month period.

Effects Upon Glucose Metabolism. In 1949, Par-fentjev and Schleyer75 reported that mice im-munized intraperitoneally with pertussis vaccine experienced a marked decrease of their blood glu-cose concentrations (55% of the normal value), and this hypoglycemia lasted at least 1 week. In addition, these investigators, as well as Stronk

and Pittman,65 found that pertussis-vaccinated mice did not experience the hyperglycemic effect that usually follows the administration of hista-mine. In both mice and rats, hyperinsulinemia occurs after the administration of pertussis vac-cine.79 In the studies of Gulbenkian and associ-ates,79 peak levels of insulin occurred three days after intraperitoneal injection in the rat and seven days after similar injection in the mouse. The elevated levels persisted 17 days in the mouse and more than 24 days in the rat. In normal rats, epinephrine causes a slight decrease in plasma insulin levels, but in pertussis-vaccinated rats, epinephrine causes a marked increase in plasma insulin levels.80

There are two mechanisms involved in the hy-perinsulinemia demonstrated in mice after ad-ministration of pertussis vaccine: an acute hy-perinsulinemia associated with hypoglycemia due to endotoxin and an apparent sustained hyper-insulinemia without hypoglycemia due, appar-ently, to LPF.8’ Importantly, the acute hyperin-sulinemia effect of endotoxin with associated hy-poglycemia in mice is the opposite of the response to endotoxin in humans. Furman et al82 have demonstrated that the chronic hyperinsulinemia induced by pertussis toxin is an artifact of ether anesthesia used to sample the blood and, in fact, those mice have normal insulin levels.

Oddy and Evans83 noted a terminal hypogly-cemia in rabbits administered a lethal dose of a crude B pertussis extract, and Pittman et alM noted prolonged hypoglycemia in mice with B per-tussis respiratory infections.

Fifty years ago, Regan and Tolstoouhov85 ob-served that children with pertussis tended to have serum glucose values in the lower limit ofthe nor-mal range (mean of 41 determinations of 63 mgI 100 mL with a range of35 to 80 mgIlOO mL). They noted that some ofthe low values could have been due to partial starvation due to vomiting. How-ever, they also observed the persistence oflow val-ues during convalescence when nutrition was not thought to be a problem. There were no blood glu-cose determinations in age-matched controls in this study, so its significance must be questioned. Sen et al7#{176}showed a blunted hyperglycemia re-sponse to epinephrine after DTP vaccination in children which appeared 24 hours after vaccina-tion and slowly resolved within 1 month. In a controlled trial, Badr-el-Din et al86 noted that children with pertussis and convalescing from pertussis had a decreased hyperglycemia response following epinephrine injection when compared with unvaccinated normal children or children with acute bronchitis.

(9)

vac-cine had a temporary beneficial hypoglycemic ef-fect in 18 of 20 patients with insulin-resistant di-abetes. The factor responsible for these effects upon glucose metabolism has been called islet-ac-tivating protein, and it has been isolated and pur-ified.88 This purified protein is similar to purified LPF.52 In a more recent study, islet-activating protein was administered intravenously to six healthy adult volunteers. An enhanced insulin se-cretory response was observed which persisted for 1 to 2 months without adverse effects.89 Finally, Hannik and Cohen9#{176}found that the plasma in-sulin level increased slightly but significantly in infants vaccinated with a pertussis vaccine with a bacterial concentration of 16 opacity units but no increase occurred in infants who received a vaccine containing only 10 opacity units. There was no observed effect on the blood glucose con-centration in these children. In organ culture with mouse, rat, and human islets, it was found that islet-activating protein induced a persisting aug-mentation of insulin secretion.9’

Adjuvancy. LPF has several adjuvant actions in immunologic systems in several animals and man.49.52’60’74’92’#{176}8 In many early studies, aciju-vant activity was observed following the inocu-lation ofwhole pertussis cells rather than purified LPF. Therefore, it is possible that the observed findings were due to substances other than LPF. For example, endotoxin is known to have adju-vant activity. However, an analysis ofrecent data indicates that the most important cause of adju-vancy is LPF.’#{176}8The following immunologic phe-nomena are the main adjuvant actions resulting from LPF: enhancement of serum antibody re-sponse to various antigens, increased delayed hy-persensitivity to various protein antigens, con-tribution to hyperacute experimental autoallergic encephalomyelitis, and increased anaphylactic sensitivity.

In early studies, it was found that pertussis vac-cine enhanced the immunizing ability of diphthe-na toxoid in guinea pigs.’#{176}9The same investi-gators in similar studies found that antitoxin re-sponses to both diphtheria and tetanus toxoids were enhanced in children as well as in guinea pigs.”#{176}” Similar findings for many antigens in many animal species have been demon-strated.74”2

Studies by Mota”3”4 and Mota and Peixoto”5 noted that pertussis vaccine had an adjuvant ef-fect on the production in mice and rats of homo-cytotropic antibodies that had similar character-istics to human IgE reaginic antibodies. This enhanced production of IgE antibodies to an un-related antigen is due to LPF.’#{176}#{176}”o3”#{176}5”#{176}6”6

Another adjuvant activity of pertussis vaccine

that can be attributed to LPF is its role in ana-phylaxis. Malkiel and Hargis”7 first demon-strated that B pertussis had an anaphylactic sen-sitizing effect in mice. In the mouse, it usually requires more than one immunizing dose of a sol-uble protein antigen to sensitize the animal to an-aphylactic shock. It was found that if the protein antigen was mixed with pertussis vaccine, sen-sitization with one injection was of such degree that homologous antigen challenge resulted in fatal shock. The mechanism of adjuvancy may be due to a combination of IgE reaginic antibody stimulation plus histamine sensitization and the release of endogenous vasoactive amines as a re-suit of the immediate antigen-antibody reac-tion.52

For more than 25 years, it has been known that pertussis vaccine is a reliable adjuvant for the pro-duction of experimental allergic encephali-tis.74’99”8 This experimental allergic encephal-omyelitis is mediated by sensitized lymphocytes rather than serum antibody mechanisms.52 Per-tussis vaccine has also been used as an adjuvant in the following experimental autoimmune dis-eases: thyroiditis, myocarditis, glomerulonephri-tis, uveoretinitis, and hemolytic anemia.49”9 Except for the adjuvant effect upon antibody re-sponses to specific vaccines, there is no evidence that any of the experimental adjuvant activities of pertussis vaccine, and specifically LPF, occur in vaccinated children.

Role of LPF in Immunity to Pertussis. Recent studies indicate that LPF is an important “pro-tective antigen” in experimental ani-mals.’2’52’74’91”2025 Immunization of mice with purified LPF will protect them from intra-cerebral challenge and also from aerosol-induced respiratory infection. Data from the recent effi-cacy trial in Sweden indicated that a LPF toxoid vaccine afforded an appreciable level of protection to vaccine recipients.’26 However, there was no relationship between specific serum anti-LPF ti-ters and protecton.’27

Lipopolysaccha

ride

Like other Gram-negative bacteria, B pertussis

contains endotoxin.49’52’60’74”2”28’3#{176} B pertussis

lipopolysaccharide is a heat-stable substance lo-cated in the cell envelope. The lipopolysaccharide

of B pertussis has been demonstrated to have

(10)

nonspe-ride. cific resistance in mice. Importantly, there are

two lipid fractions that have been identified, lipid A and lipid X.’3’ The lipid A, which possesses the toxic activity in other bacterial endotoxins, is in-active in B pertussis and the biologic activity is associated with the lipid X fraction. Specific stud-ies with B pertussis lipopolysaccharide in humans have not been reported. All whole-cell pertussis vaccines contain endotoxin.

Heat-Labile

Toxin

or Dermonecrotic

Toxin

Heat-labile toxin was the first demonstrated toxin of B pertussis. Bordet and Gengou74”32 in 1909 noted a dermonecrotic substance that they extracted from dried B pertussis organisms. Heat-labile toxin is a cytoplasmic protein that is labile. It can be destroyed by heat (56#{176}Cfor ten minutes) and inactivated by chemicals such as formalde-hyde. The toxin is dermonecrotic in guinea pigs, sheep, pigs, mice, chickens, and rabbits.52 In mice it retards the normal rate ofweight gain and large doses are lethal. In chicken embryos, it produces lesions in the epithelium of the lung; lesions in the brain and meninges of guinea pigs have been observed.74 Recently, Roop and associates’33 noted that nasal and lung lesions in neonatal pig-lets correlated directly with the level of dermo-necrotic toxin production of infecting strains of B

bronchiseptica.

Tracheal

Cytotoxin

Tracheal cytotoxin is a recently described toxin isolated from B pertussis culture supernatant by Goldman et al.’34 This toxin is derived from the peptidoglycan of the bacterial cell envelope.’35 In hamster tracheal organ cultures, this toxin causes ciliary stasis and a marked cytopathic effect is seen.

Adenylate

Cyclase

Adenylate cyclase is an extracytoplasmic en-zyme that B pertussis organisms liberate into the surrounding medium during growth.’2’52”36’4’ It can also be detected in intact organisms. It is rela-tively heat stable and activated by calmodulin. Adenylate cyclase may act as a virulence factor

in B pertussis infections by interfering with host

phagocytic cell functions. Specifically, it enters phagocytic cells, is activated by calmodulin, and catalyzes the formation of cyclic adenosine mon-ophosphate which has an adverse effect on phag-ocytic functjon.’36 This effect upon phagocytosis may allow the organism to survive at the site of infection. Some pertussis vaccines contain

signif-icant levels of adenylate cyclase enzymatic activ-ity, but its effect in vaccinees, if any, is

un-known.’42

Outer

Membrane

Proteins

The outer membrane proteins of B pertussis

may have adjuvant activity.’43 A purified outer membrane component containing mainly a 30,000-dalton protein strongly enhanced the im-munogenicity of H influenzae type b

polysaccha-Other

Activities

In addition to the effects relating to specific components of the B pertussis organism, there are other activities that have been observed in ex-perimental animals. The cause of these effects is unknown. In some instances, they may be due to a combination of the biologically active factors of

B pertussis.

Of particular interest has been the effect of per-tussis vaccine on the susceptibility of animals to other infections.74 In some model systems, in-creased susceptibility occurs, whereas in others an increased resistance is observed. For example, two groups of investigators found that pertussis immunization made mice more susceptible to fatal infection with Proteus vulgaris, Pasteurella

multocida, Pseudomonas fluorescens, and

Esche-richia coli’44”45 In contrast, B pertussis lipo-polysaccharide increased the resistance of mice to

Salmonella typhi.’46 In 1955, Parfentjev’47 re-ported that mice vaccinated with pertussis vac-cine had an increased susceptibility to influenza virus infection. In contrast, Bell and Munoz94 found that B pertussis extracts increased the re-sistance of mice to rabies virus infection. More recently, Winters and associates’48 found that pertussis vaccine rendered normally sensitive mice resistant to fatal adenoviral infections. B

pertussis endotoxin fragments have been found to

offer protection in mice against encephalomy-ocarditis virus, Semliki Forest virus, and influ-enza A and B virus infections.’28

Pertussis vaccine has also been found to in-crease resistance to Cryptococcus and Candida in-fections in animals.’49”5#{176}

Other activities of pertussis vaccines in animals include production of hypoproteinemia in mice, increased susceptibility to cold stress in mice, en-hancement or suppression of tumor growth in mice, the induction of interferon in rabbits, and the inhibition of macrophage response to brain injury in rats.74

(11)

about this hemolysin, but recently it was noted that a hemolysin-deficient mutant had moder-ately reduced virulence in the mouse.’4’

CLINICAL MANIFESTATIONS OF PERTUSSIS49”552

Historical Overview

Pertussis was not differentiated from other res-piratory entities with any certainty until 1578 when Guillaume de Baillou described the first ep-idemic.’53 His description is vivid.

The lung is so irritated by every attempt to expel that which is causing the trouble it neither admits the air nor again easily expels it. The patient is seen to swell up and as if strangled holds his breath tightly in the middle of his throat. . . .For they are without the

trou-blesome coughing for the space of four or five hours at a time, then this paroxysm of coughing returns, now so severe that blood is expelled with force through the nose and through the mouth. Most frequently an upset sthm-ach follows. . . . For we have seen so many coughing in

such a manner, in whom after a vain attempt semi-putrid matter in an incredible quantity was ejected.

The widespread use of pertussis immunization has markedly reduced the incidence of disease. This has obscured in contemporary US medicine

the dreaded nature of pertussis infection in its classical form. Many physicians and most parents have little or no personal experience with the dis-ease. In this climate, adverse events which are temporally associated with effective pertussis im-munization may be considered unacceptable con-sequences. The recommendation by physicians, scientists, and public health groups to continue universal immunization should be placed in per-spective by a review of the unmodified disease.

Typical Pertussis

Catarrhal

Stage

The incubation period is seven to ten days and usually not more than 14 days. The onset of illness is subtle, resembling a mild and nondistinctive upper respiratory tract infection with rhinorrhea, mild conjunctival injection, tearing, occasional sneezing, and a mild cough. There may be a slight

and transient fever, but most commonly fever is not recognized. The cold-like symptoms continue, with persistent and increasing dry hacking cough. By seven to ten days the illness enters the parox-ysmal stage.

The catarrhal stage is the most infectious pe-riod, with the risk of transmission decreasing through the paroxysmal and convalescent stages.

Paroxysmal

Stage

The coughing becomes increasingly forceful, dominating the clinical findings and appearing as

episodic paroxysms, often more frequent at night. At the height of the illness patients experience approximately ten to 20 or more paroxysms in 24 hours. The cough is in a staccato series with little or no effective inspiratory effort between coughs. At the termination of the paroxysm a long drawn inspiratory effort is usually accompanied by a whoop in children beyond the early infancy pe-nod. Most complications and deaths occur during the paroxysmal stage.

The following is a contemporary description of pertussis in the older child.49

The child possessed ofthe coughing fit is a pitiful sight, all the more so as the observer is helpless to alleviate or terminate the attack. Each attack consists of 10-30 forceful coughs per spasm, and into each cough the pa-tient appears to concentrate all his energy. He leans forward, or if standing, stands with legs spread, grasp-ing the nearest object and leaning forward, tongue pro-truding to the utmost, saliva and mucus streaming from nose and mouth, eye bulging with tears streaming, his entire body racked with the total exertion of each cough. The cough continues in a staccato series. The face becomes more and more cyanotic, the neck bulges with venous congestion and still the attack continues. Finally, when it seems certain that death is imminent, a final cough appears to clear offending secretions or mucus from the upper airway and the first opportunity to inspire is offered. With a massive effort inspiration ensues, air rushes into the lungs against a still nar-rowed glottis and the characteristic whoop is produced.

At the termination of a paroxysm the patient fre-quently will vomit.

A variety of stimuli may set off a paroxysm. Disturbances in the environment, feeding, suc-tion, or attempted examination of the pharynx may initiate a paroxysm. Each paroxysm may ap-pear to be life threatening and is likely to result in significant hypoxia, especially in young in-fants. In the older child, a sense of fear or im-pending doom may precede the onset of paroxysm, or the latter occurs without warning or evidence of local stimulation.

Convalescent

Stage

(12)

Morbidity and the Effect of Age

In small infants, pertussis is particularly severe and extracts a heavy toll in morbidity and mor-tality. This severe morbidity remains true in mod-em times. The illness also may be atypical in that the classical whoop is often absent in infants less than 6 months and especially in those less than 3 months of age.

A total of 5,865 cases were reported in the United States in the 2-year period 1984 and 1985. Detailed clinical data were available for 4,728 cases. Pertussis was laboratory confirmed in 70% of cases; 20% of these were confirmed by both cul-ture and direct fluorescent antibody testing of na-sopharyngeal secretions; 19% by culture only; and 61% by direct fluorescent antibody testing only. Of the reported cases, 48% were in infants and 37% were in babies less than 6 months of age. Whoop was present in approximately one half of these children. The percentage of patients with pertussis hospitalized and the percentage with complications by selected age groups are pre-sented in Table 2. Of those infants less than 6 months old, 74% were hospitalized, 20% had roentgenogram-confirmed pneumonia, 2.6% had seizures, 0.8% had encephalopathy, and 1.0% died. Surveillance of reported cases occurring in 1982 and 1983 revealed data similar to those pub-lished for 1984 to 1985. Historically, infants have always borne the brunt of pertussis mortality. In the period 1935 to 1939, 64.2% of deaths occurred in children less than 1 year of age.’54

In older children and adults, in addition to the typical syndrome, a milder atypical disease may occur, manifested by a persistent cough due to lin-gering tracheobronchitis.’55”59 The symptoms may persist for weeks and complications are not infrequent. Cases may be difficult to diagnose un-less there are epidemiologic features that suggest

B pertussis as the cause.

Complications of Pertussls49”5’52

Respiratory

Complications

B pertussis attaches to the superficial ciliated respiratory epithelium causing a marked endo-bronchial necrotizing inflammatory response. Stasis, inspissation of secretions, shedding of cells into the lumen, and paralysis of cilia lead to areas of patchy atelectasis and pneumonia. Lobar and sublobular atelectasis is frequent, and bronchiec-tasis may occur. Obstruction of large or small air-ways, in severely affected infants, may result in interstitial or subcutaneous emphysema or lead to pneumothorax. Secondary infection is usually associated with H influenzae, S pneumoniae,

Streptococcus pyogenes, or S aureus. When sec-ondary infection occurs, it is often accompanied by significant fever and tachypnea. Significant el-evation of temperature is not typical of uncom-plicated pertussis; its presence suggests infection with a second organism.

In long-term follow-up, pulmonary sequelae have been difficult to document, although atelec-tasis may persist for months to more than a year in some cases. Studies have been reported of def-icits in lung function and an excess occurrence of respiratory illnesses in children who had pertus-sis compared with controls with no history of

per-tU55i5.’60’16’ Other investigators found few

pul-monary residua that could be clearly attributed to pertussis.’62

Otitis media is also a frequent infectious com-plication of the acute disease, especially in in-fants.

CNS Complications

Severe CNS disturbances appear most fre-quently during the paroxysmal stage and occur most commonly in infants. Signs and symptoms vary; sometimes convulsions occur abruptly. In others, evidence of CNS involvement appears more insidiously but progresses to convulsions, semicoma, and coma. Reports regarding the fre-quency of CNS complications range from 1.7% to 7% or more of pertussis cases in large series of hospitalized ch.ildren.’63 These frequencies may be inflated because they are based on patients with complications requiring hospitalization. Nevertheless, it is clear that CNS involvement is relatively common, eg, four per 1,000 reported pa-tients with pertussis had encephalitis in 1982 to 1983 and in the period 1984 to 1985 the rate was five per i000.’

Acute neurologic manifestations may include persistent seizures, hemiplegia, paraplegia, ataxia, aphasia, blindness, deafness, and decere-brate rigidity. The CSF is typically normal or may have a mild pleocytosis (<100 cells) or a slight to moderate elevation of protein (<100 mgldL).

(13)

TABLE 2. Hospitalization Frequency and Complications of Patients With Pertussis by Selected Age Groups-United States, 1984 and 1985*

* From Centers for Disease Control.4 Presence of pneumonia was confirmed by roent-genographic findings.

t Includes patients of all ages and nine patients of unknown ages. Selected Ages No. ()

Hospitalized

<6 mo (n = 1,771) 1,302 (74.0)

6-11 mo (n 498) 294 (59.0) 1-4 yr (n = 1,000) 232 (23.0)

5-9 yr (n = 413) 33 (8.0)

10-14 yr (n 292) 16 (5.4) >14 yr (n 745) 43 (5.8) All agest (n = 4,728) 1,921 (41.0)

No.() No.(F) No.()

Pneumonia Seizures Encephalopathy

347 (20.0) 46(2.6) 14 (0.8) 92 (19.0) 15(3.0) 2(0.4) 96(9.6) 15(1.5) 3(0.3) 14 (3.5) 4 (1.0) 3 (0.7)

6 (2.1) 0 (0.0) 0 (0.0) 18 (2.4) 1 (0.1) 0 (0.0) 574 (12.0) 81(1.7) 22(0.5)

week in April 1970, it was found at 5-year follow-up that the children who had been hospitalized for pertussis were three times more likely than expected to be intellectually abnormal.’64 In an-other recent study of 360 patients with pertussis and matched controls, there was no difference found in anthropometric measurements, IQ, or reading 165 However, in this study,

there were few patients with infantile pertussis and none had a history of neurologic involvement during the acute phase of the illness.

Secondary

Pressure

Effects

Accompanying

Severe

Pertussis

The prolonged and violent expiratory efforts during pertussis paroxysms may have secondary consequences, including hemorrhagic events such as epistaxis, melena, petechiae, subdural hema-toma, and spinal epidural hematoma. Pressure may also cause umbilical or inguinal hernias, rec-tal prolapse, pneumothorax, and mediastinal or subcutaneous emphysema.

PATHOGENESIS OF

B

PER TUSS1S

I NFECTION

The clinical stages of infection as well as the complications of pertussis can be analyzed in terms of the interaction of B pertussis and the host, with particular reference to new information concerning the biologically active pertussis anti-gens.’2’20’47’53 An understanding of the mecha-nisms involved may lead to new immune

strate-gies to intercede in these pathophysiologic events. The transmission of infection from one person to another is presumed to be by airborne respi-ratory secretions from an ill patient to the res-piratory tract of the new host. It is also possible that respiratory secretions of the ill patient con-taminate the environment and that the new host infects his or her own respiratory tract indirectly by the hands. In the pathogenesis of pertussis the

following four steps are important: attachment, evasion of host defenses, local damage, and sys-temic disease. The antigenic and biologically ac-tive factors of B pertussis will be analyzed using the four steps in the infectious process.

Attachment

In the respiratory tract, B pertussis organisms attach to the cilia of the ciliated epithelial cells.42’53 Both FHA and LPF appear to be im-portant for attachment.42’43 The role of agglutin-ogens in attachment is unclear, but because fim-briae of other bacteria facilitate attachment, it is possible that some agglutinogens may be impor-tant.42’43’53”66

In studies with tissue cultures of nonciliated cells, it has been found that fimbriae do not me-diate attachment of B pertussis to the cells.43 Weiss and Hewlett53 pointed out that other fac-tors in addition to LPF and FHA are also neces-sary in the attachment process.

Evasion of Host Defenses53

Adenylate cyclase and LPF have profound ad-verse effects on host immune effector cell function and, therefore, contribute to the propagation of infection. In addition, tracheal cytotoxin disrupts normal clearance mechanisms which allows in-fection to persist.

Local Tissue Damage

(14)

Systemic Disease

Of the biologically active factors ofB pertussis,

only LPF and lipopolysaccharide produce sys-temic effects in experimental animals. Of these two antigens, LPF has been considered the lead-ing candidate for mediation of the systemic man-ifestations of disease.5#{176} However, the systemic ef-fects of human B pertussis infection are not well defined. For example, weight loss and hypogly-cemia which were commented on by Lapin’6 more than 40 years ago may well have been secondary to poor nutrition and not due to systemic toxicity. The finding of a decreased hyperglycemic re-sponse following epinephrine injection in children with pertussis indicates systemic activity of LPF.86 However, no systemic symptoms have been related to this observation. The leukocytosis that occurs in patients with pertussis is clearly a systemic manifestation of LPF.

The most important systemic manifestation of

B pertussis infection is encephalopathy. In 1956, Miller and colleagues’67 extensively reviewed the parainfectious encephalomyelitidies and at the time came to the conclusion that the neurologic complications of pertussis differed both clinically and pathologically from the neurologic compli-cations ofmeasles, varicella, rubella, and mumps. Although the literature prior to that time con-tamed many references suggesting pertussis en-cephalitis, the pathologic findings in most in-stances when other etiologies had been ruled out were not inflammatory in nature.

The usual findings on gross examination of the brain were edema and occasional hemorrhages. In some cases, no changes at all were noted. The meninges were usually edematous, and brain le-sions were most commonly found in the cerebral hemispheres and were vascular and degenerative. Perivascular hemorrhages and swelling of the capillary endothelium were frequently noted. Small subarachnoid hemorrhages were common, but massive hemorrhage was rare. Nerve cells showed an eosinophilic degeneration. This was most often seen in the pyramidal cells of the hi-pocampus and the Purkinje cells of the cerebel-lum. The small cerebral vessels frequently con-tained plugs of lymphocytes. The changes were consistent with those of anoxic brain damage. De-myelination is not a usual characteristic of per-tussis encephalopathy.’53”55”67”68

CSF pleocytosis is an inconsistent finding. In a study of 12 patients with pertussis and neurologic complications, Celermajer and Brown’69 noted five with pleocytosis.

In contrast with the more usual finding, occa-sional reports have suggested a

meningoence-phalitis-type picture. Specifically, Woolf and Caplin “‘#{176} noted severe diffuse lymphocytic

infil-tration in the perivascular cerebral tissue. A modern study’7’ reports a 4’/2-year-old child, later proven to have encephalopathy accom-panying pertussis infection, who was subjected to a right temporal lobe brain biopsy to evaluate the possibility of herpes simplex encephalitis. The bi-opsy was entirely normal as were two enhanced CT scans. The child was semicomatose and had multiple seizures, cortical blindness, and aphasia during the acute illness. He improved in the fifth week and was normal 1 year later. The authors believed that this case was consistent with a toxic encephalopathy and suggested that LPF was the possible toxic factor. However, it must be pointed out that the child did have meningitis (WBC count 204*1 in the CSF), and also echovirus type 24 was isolated from the stool, although no increase in viral antibody titer could be demonstrated;

At the present time, the cause of pertussis en-cephalopathy is not known. The most likely ex-planation for the majority of cases is anoxia as-sociated with coughing paroxysms. It is possible that cellular toxins such as LPF or adenylate cy-clase are responsible for some cases. The fact that Toyota and associates89 injected purified, nontox-oided, LPF (0.5 to 1.0 i.gIkg) intravenously into normal adult volunteers without adverse effects is evidence against this toxin being causative in manifestations of clinical pertussis and perhaps encephalopathy.

LABORATORY DIAGNOSIS OF PERTUSSIS

The diagnosis of pertussis is based upon a char-acteristic history and physical examination re-sults and is unmistakable in a typical case. How-ever, in young infants, atypical cases, and cases modified by vaccine, several laboratory tests are especially useful.’72”73 It is important to think of the possibility of pertussis early and institute fur-ther diagnostic procedures.’74”75

Lymphocytosis

(15)

Identification of B

pertussis

Isolation

of the Organism

Presently, the “gold standard” for the diagnosis of B pertussis infection is the culture of the or-ganism from nasopharyngeal swabs.’73 Unfor-tunately, the organism is fastidious and slow growing, and its culture is complicated by con-tamination and overgrowth by other nasopharyn-geal organisms. In outbreak situations, with op-timal specimen collection and laboratory tech-niques, 80% of suspected cases can be confirmed by culture. In the usual clinical situation, rates ofB pertussis isolated from suspected cases is con-siderably

Specimens for culture should be obtained from the nasopharynx rather than the throat,’79 and Dacron or calcium alginate swabs rather than cot-ton swabs should be used.’73”8#{176} Patient speci-mens should be directly plated onto selective media. Regan-Lowe charcoal agar, modified Stai-ner-Scholte agar, or fresh Bordet-Gengou medium are all effective for B pertussis culture. Isolation rates are highest during the initial 3 to 4 weeks of illness. Prior antibiotic treatment with eryth-romycin, tetracycline, or trimethoprim-sulfame-thoxazole will markedly reduce the isolation rate.

Fluorescent

Antibody

Tests

Direct fluorescent antibody identification of B

pertussis in nasopharyngeal specimens is a useful technique when performed with good reagents by experienced personnel.’73 Both false-positive and false-negative results occur.’8’ Direct fluorescent antibody testing may be particularly useful in sit-uations late in disease or during antimicrobial therapy when viable organisms are no longer present.

Other

Direct

Tests

A rapid method for the identification of B

per-tussis infection that is easier to perform than di-rect fluorescent antibody testing and has high sensitivity and specificity would be useful. Such a test could lead to an accurate diagnosis in atyp-ical cases; this would decrease other diagnostic tests and inappropriate therapy.’75 Outbreaks of disease could be better monitored and prophylac-tic antibiotic use in disease control would be fa-cilitated.’73 Two direct techniques are presently being investigated. McLafferty et al’82 have de-veloped a DNA probe that hybridizes with a re-peating sequence that is present in the B pertussis

genome. Because similar type gene probes are now available for the identification of other

mi-croorganisms, it is likely that this procedure for

B pertussis will become clinically feasible in the next few years.

Another approach for the identification of B

pertussis in nasopharyngeal secretions is the iden-tification of specific products of the organism. Be-cause extracellular adenylate cyclase is uniquely associated with B pertussis infection, the identi-fication of this enzyme could be a specific marker of infection. Confer and Eaton’83 tested this method in vitro and noted that as few as 100 B pertussis organisms could be detected.

Antibody Assay

As an alternative to culture, the diagnosis of B

pertussis infection can be made by the demon-stration of a specific immunologic response. Clas-sically, a number of different serologic procedures have been used to study antibody responses such as agglutination, indirect hemagglutination, bac-tericidal reaction, immunodiffusion, immunofluo-rescence, and complement Recently, the enzyme-linked immunosorbent assay (ELISA) has been widely used. This allows the measure of antibody to specific purified antigens such as LPF and FHA and also allows the determination of the immune response by antibody class (1gM, IgG, and IgA). LPF antitoxin serum levels can also be de-termined by a neutralization test in tissue

cul-184,185

Because all standard serologic tests depend upon the demonstration of an antibody titer in-crease, they are generally not useful for the early diagnosis of an illness. Recently, single serum se-rologic tests have been used for the diagnosis of pertussis. These tests depend upon the presence of high titers to specific antigens or the presence of specific serum IgA or 1gM antibody or secretory IgA antibody in respiratory secretions. Unfortu-nately, none ofthe new serologic techniques pres-ently being investigated have been sufficiently standardized to ensure a high degree of sensitivity and specificity in the clinical setting.

Agglutination

186

(16)

ELISA

During the last 6 years, there have been flu-merous reports describing the use of ELISA tech-niques for the serologic diagnosis of pertussis. These reports have been summarized by Onorato and Wassilak.’73 At the present time, there is no specific routinely available ELISA technique in the United States.

In 20 different studies in which ELISA tech-niques were used for the diagnosis of pertussis, the sensitivity varied from 25% to 100% and the specificity from 15% to 100%.’ The median sen-sitivity was 80%, and the specificity was 65%.

Because acute-phase sera in pertussis are frequently not obtained early in the illness, anti-body titer increases are usually not demon-strated by the ELISA technique. Because of this, investigators have attempted to use single serum specimens for the diagnosis of pertussis. Individual antibody titers to different pertussis antigens (LPF, FHA, whole cells) in different immunoglobulin fractions (IgA, 1gM, IgG) have been compared with values determined for sera from persons presumably not infected with per-tussis. It is clear from the findings in several stud-ies that single high IgA and 1gM titers indicate acute infections in many culture-negative situa-tions.’72”87’9#{176} Hopefully, further study with standardized control sera will allow the eventual routine use of ELISA diagnostic antibody tests.

The demonstration of specific nasopharyngeal IgA B pertussis antibodies may also prove to be useful for the diagnosis of pertussis in culture-negative cases.’9’

MEDICAL MANAGEMENT

Antimicrobial Agents

Of the many antimicrobial agents studied, erythromycin is the most effective and least toxic. It can eradicate the organism after one to two days when administered in the catarrhal or even pa-roxysmal stage. However, relapses in shedding may occur in 10% of cases unless treatment is con-tinued for 14 days.’92

Erythromycin administration to a susceptible child during the incubation period or catarrhal stage may prevent or modify clinical disease.’92 Clinical observations have generally indicated that treatment initiated after paroxysmal cough has begun does not affect the duration or severity of clinical illness. Recently, however, Bergquist et al’93 noted in an open randomized study that patients in the treatment group had significantly fewer whoops than did the control group, even

though most of the patients had reached the pa-roxysmal stage of illness.

Erythromycin, 40 to 50 mg/kId in four doses (adults, 1 g/d), is recommended for a total of 14 days for either treatment or prophylaxis. The ef-ficacy of erythromycin in preventing or modifying disease in exposed susceptibles and in control of epidemics has not been documented in formal trials, although the information to date would suggest its use. Minimally, it should reduce the pool of organisms in the environment by decreas-ing the infectivity of the patient.

Trimethoprim-sulfamethoxazole has been sug-gested as an alternative to erythromycin. How-ever, documentation of efficacy is inade-quate.’94”95

DTP Prophyiaxis for Contacts

In addition to erythromycin prophylaxis, close contacts younger than 7 years of age should re-ceive a dose of DTP if they have not completed the four-dose primary series or if they have not received a dose within the prior 3 years.’94”96

General Medical Management

Isolation

B pertussis is readily contagious and hospital mini-outbreaks have been documented.’97”98 Early recognition of cases, especially atypical symptoms and signs in infants and adults, is im-portant. Strict respiratory isolation should be maintained for five days after initiation of eryth-romycin therapy. If appropriate antimicrobial therapy is contraindicated, the patient should be isolated until 3 weeks after the onset of parox-ysms.

General

Support

Young infants should be hospitalized until it is clear that paroxysms, apnea, cyanosis, and feed-ing problems can be safely managed at home. In-tensive care facilities and expert nursing may be critical and life saving. Two management modal-ities, corticosteroids and salbutamol (albuteral), the latter a 32-adrenergic stimulant, have shown promise in reducing paroxysms but require fur-ther critical testing before they can be recom-mended.’99 Recently, in a blinded placebo-con-trolled study, Mertsola et a120#{176}could demonstrate no decrease in paroxysmal cough in children given salbutamol.

(17)

with-out value in prevention or treatment.20’ On the basis of studies in animals, it may be appropriate to reconsider this treatment using defined glob-ulin prepared from serum with high titers of ap-propriate immunogens for prophylaxis in high-risk settings, eg, infants younger than 6 months who are incompletely immunized or older suscep-tible children.202

EPIDEMIOLOGY OF PERTUSSIS

Ecology of B

pertussis

Knowledge of the ecology of B pertussis is im-portant in understanding the epidemiology of dis-ease and in anticipating the effects of immuni-zation intervention strategies. Man is the only known reservoir. Pertussis occurs in all parts of the world and remains an important cause of mor-bidity and mortality in regions with inadequate immunization. There is no evidence for decreased virulence of the organism where disease remains abundant in developing countries.203

Transmission is believed to occur by droplet, and secondary attack rates in unimmunized pop-ulations are high, ranging from 25% to 50% in schools to 70% to 100% in susceptible household contacts.’53”96’204’205 In most instances, trans-mission can be attributed to direct contact with infected persons or with individuals with cough or bronchitis, the latter presumably representing a highly modified disease.’53 The weight of evi-dence suggests that the completely silent carrier state is infrequent, transient in duration, and probably of little importance in maintenance of pertussis organisms in the community. Such car-riers have been found, however, in close contacts of persons with pertussis.

A detailed study of an outbreak of 115 individ-uals with laboratory-confirmed pertussis in At-lanta identified 14 asymptomatic household car-riers, four adults and ten children.206 Nine of the latter had received three or more doses of DTP, the tenth was a 1-month-old infant. Clinical dis-ease developed in none of the laboratory-defined silent carriers; however, all received erythromy-cm prophylaxis after they were identified. Con-tact with such carriers could explain the occur-rence of cases of pertussis without symptomatic contacts. In contrast with the findings of transient asymptomatic carriers among exposed members of households, extensive surveys of individuals in nonepidemic settings have failed to recover the organism.207

Immunity after clinical disease is believed to be relatively complete and permanent. Second clin-ical attacks were documented in the

prevaccina-tion era but apparently were uncommon.204 An epidemic reported in an unimmunized island pop-ulation, free from pertussis for 29 years, weighs against the need for continued antigenic stimu-lation through reinfection for long-term protec-tion. In this epidemic, no one older than 29 years of age acquired the disease, and no one younger escaped.208 Immunity induced by whole-cell per-tussis vaccines appears to be good but is less com-plete and less durable than following natural in-fection.209 This is also suggested by a study in monkeys which showed that active infection pre-vented recolonization of the respiratory tract, but immunization with killed whole-cell vaccine did not prevent recolonization on challenge.2’#{176} Main-tenance of immunity in a vaccinated population may depend to some extent upon continued cir-culation of B pertussis in the form of mild, often unrecognized disease, although asymptomatic in-fection appears to be rare.’53’21’

Morbidity and Mortality

Prior to widespread immunization, few children escaped pertussis. A history of recognizable din-ical pertussis was obtained in 73.5% of children by age 17 years.202 It was estimated that 95% of all individuals had classical or atypical pertussis sometime during life.204

Pertussis mortality declined between 1900 and 1940, and the decline significantly accelerated be-ginning in the 1940s, at the time of increasing use ofvaccine.213’214 In the immediate prevaccine era, there were approximately 157 cases of pertussis per 100,000 population reported in the United States, with 1.5 deaths per 1,000 infants less than 1 year ofage211’214 (Fig 1). The number of reported cases represents only a small proportion of actual cases.

Following the introduction and widespread use of pertussis vaccine, the attack rate in the United States declined steadily to less than one case per 100,000 in 1973 (Fig 1). From 1973 to 1985, the rate has varied from 0.5 to 1.5 per 100,000 pop-ulation.4

(18)

1000.000

100.000

10.000

Ui 1.000

0.100

0.010

PERTUSSIS VACCINE

-Minimum potency

established

N.Deaths

‘25 ‘35 ‘ ‘4 ‘55 ‘65 ‘75 85

YEAR

Fig I . Reported cases of pertussis and deaths

attrib-uted to pertussis per 100,000 population by year in United States, 1922 to 1981. (From Centers for Disease Control: Annual Summary 1981: Reported morbidity and mortality in the United States. MMWR 1982; 30:54.)

Pacific states.204 Dallas reports a summer increase215 and in Japan seasonal peaks occur in July or August.216

Host Factors, Age, and Sex

Presently, the highest incidence of pertussis in the United States occurs in infancy and the illness is most devastating in this period. Despite the relatively high resistance of the adult population, this protection is believed to be poorly transmitted to the newborn.204

Accompanying the marked decline in cases in recent years, there has been a relative increase in the percentage of cases of pertussis in infants less than 1 year of age and older than 15 years, accompanied by a relative decline in the age group 1 to 9 years.4’21’ The greater decline of disease in young children is probably indicative of vaccine-induced protection in this group rather than an absolute shift to infants and older age groups. In a study in Dallas, the age incidence of pertussis in the period 1965 to 1971 was compared with

1971 to 1977.215 The later period had a higher

ratio of infants younger than 12 weeks of age and the contact source shifted from siblings to adults in the household.

The attack rate in girls exceeds that in boys and is associated with increased severity and a higher fatality rate. This has been consistent in the pre-and postvaccine eras, in all geographic areas and in all age groups except those younger than 1 year.21’ The female preponderance increases with age, with an excess of girls of 5% younger than 5 years of age, 20% at the eighth year of life, and 50% by the tenth year in the prevaccine era.204 This sex ratio is anomalous in that other

com-municable diseases of childhood tend to show an excess of boys.204

Environmental Factors and Socioeconomic Status

In weighing the relative role of pertussis vac-cine in the control of pertussis, a variety of en-vironmental factors have also been considered in the analysis of secular trends.213 The general standards of health and hygiene of infants and children, as well as the technical advances in med-ical care (eg, nutrition, antibiotics, intensive care), have undoubtedly favorably altered the out-come of the B pertussis-host interaction.217 Epi-demiologic conditions that favor delay in trans-mission to infants or reduction of the infectious dose of the organism may alter the expression of disease. A low level offamily education, a greater number of small children in the household, and crowding were shown to be correlated with in-creased mortality.204 The exact operational mech-anisms have been difficult to interpret.

In the United States, the attack rate is approx-imately equal in whites and non-whites. However, the fatality rate in blacks in the prevaccine era was three to five times and American Indians six times that of whites. Chinese and Japanese fa-tality rates were similar to those of whites.’54’204 The simplest explanation of these data probably resides in socioeconomic factors rather than con-stitutional differences in resistance.

VACCINE

History

Because pertussis was a devastating disease with high mortality, the idea of vaccine devel-opment was immediately considered following the isolation of B pertussis in 1906.’ In 1925, Madsen218 reported the results of his vaccination trials in the Faroe Islands during the 1923 to 1924 period. His original vaccine was prepared by the Danish Serotherapeutic Institute in Copenhagen. It consisted of freshly isolated strains of B

Report of the Task Force on Pertussis and Pertussis Immunization—1988