Diphtheria

Diphtheria is an upper respiratory tract illness characterized by sore throat, low fever, and an adherent membrane (called a pseudomembrane) on the tonsils, pharynx, and/or nasal cavity.  Diphtheria toxin produced by C. diphtheriae, can cause myocarditis, polyneuritis, and other systemic toxic effects. A milder form of diphtheria can be restricted to the skin.

 

Nature of Diphtheria:

 

Diphtheria is a disease of the throat, nose, or trachea, caused by a germ called the Klebs-Löffler bacillus. The bacilli produce a white or yellow membrane which is usually plainly visible when it is on the tonsils and surrounding parts, but it may be so thin that it can scarcely be noticeable. If it is in the nose or trachea, its location prevents it from being seen. Other bacteria often grow with the diphtheria bacilli and produce swellings and abscesses. The disease will usually develop within a few hours or days after infection with the germs.

 

 

Recognition of Diphtheria

There are two methods of recognizing diphtheria: 1, by looking into the throat for a membrane; and 2, by taking a culture from the throat or nose.

When a doctor is called to see a sick child, the invariable rule ought to be that he look into the child’s throat. Doctors sometimes yield to the desires of the child or of its parents and do not examine the throat, and thus they often fail to recognize diphtheria in its early stages while it may readily be cured. The presence of spots or a membrane on the tonsils or other situation in the back part of the throat is strongly suggestive of diphtheria, but it is not always a proof of the disease, for they may be due to other causes, such as simple tonsillitis, or septic sore throat, or Vincent’s angina.

Cultures.—The only sure indication of diphtheria is to find diphtheria bacilli in a culture from the throat or nose.

 

Carriers.Diphtheria germs may grow in the throat without producing sickness. They usually disappear from the throat in about two weeks after a person recovers from diphtheria. If they persist for three weeks or more, the person is classed as a carrier.

Carriers harbor the bacilli in situations to which the blood-serum is unable to penetrate. The bacilli have been found among the epithelial cells of the tonsils. They may also grow in the crypts of the tonsils and in folds of the mucous membrane of the nose. An abnormal condition of the nose or throat can be seen in nearly every diphtheria carrier, and the germs persist because of the abnormality.

 

 

A diphtheria carrier can give the disease to another person. Most cases of diphtheria are caught from unrecognized and unsuspected carriers.

Virulence Test.—Diphtheria bacilli vary in their virulence and in their ability to produce toxin. If a variety has only a slight virulence, it cannot produce the disease in another person, and the carrier is harmless.

A virulence test is performed in the following manner: A culture is taken from a carrier, and the diphtheria germs are isolated from it in a pure culture. A small quantity of the germs are taken and killed and are then injected into the skin of a normal guinea-pig. If the bacilli are virulent, they will produce a red, sore spot in three or four days. The test is like the Schick test on human beings. Laboratories of departments of health are now prepared to make virulence tests on cultures from carriers.

 

Treatment of Carriers.—A healthy nose or throat will seldom harbor diphtheria bacilli. The procedures which are of value in ridding a carrier of the bacilli are those which would tend to restore the throat to a normal state if no diphtheria germs were present. Most carriers have enlarged tonsils. The removal of the tonsils and adenoids from the throats of those who have them is almost certain to rid a carrier of the germs. Nearly every diphtheria carrier is immune. If he were not immune he would have the disease in an active form. The administration of antitoxin, therefore, has no effect on the bacilli in their throats.

 

Routine Diphtheria tests were stopped because the majority of people were positive for Diphtheria in the throat and the skin.

Diphtheria infections are further complicated by the toxigenicity factor. If one is infected with a toxigenic strain of C. diphtheriae, two factors must be present to cause the production of the Diphtheria toxin:

  • 1. Low extracellular concentrations of inorganic iron. In the presence of iron, a repressor molecule, coded for by the diphtheria toxin repressor (DtxR) gene, is activated by iron and prevents transcription of the tox gene. When concentrations of iron drop, the repressor molecule is inactivated and transcription of the tox gene proceeds, resulting in production of diphtheria toxin.[11]
  • 2. Presence in the bacterial chromosome of a lysogenic prophage which contains the tox gene. The bacterium originally receives the tox gene from a specific Beta-phage.[11]

Diphtheria Toxin is a bacterial exotoxin which consists of an active (A) domain, and a binding (B) domain. The toxin acts by binding to the HB-EGF receptor on cells and enters by receptor-mediated endocytosis. The acidic environment of the endosome causes the toxin to undergo a conformational change which causes part of the A domain to enter the endosomal membrane. The A domain is then cleaved from the B domain and passes through the membrane into the cell cytoplasm. The A domain then catalyzes the transfer of ADP-ribose from NAD to Elongation Factor II (EF2), a key protein in protein synthesis during translation. With the addition of ADP-ribose to EF2, EF2 is deactivated. Once a significant amount of EF2 proteins have been deactivated, the cell death occurs.[11]

 

Diagnosis and Treatment

Clinically, the disease is described as: “An upper-respiratory tract illness characterized by sore throat, low-grade fever, and an adherent membrane of the tonsils, pharynx, and/or nose” [3]

If diphtheria is suspected, then a sample of the bacteria is isolated from the patient and cultured, and toxigenicity testing is performed. If the bacteria is C. diphtheriae, the substrain is further identified – intermedius, mitis, and gravis. To test for toxigenicity, the Elek test is performed. The CDC can also perform a PCR test, but it is not typically used when forming a diagnosis. Another test is serologic testing, which determines the level of antibodies to the diphtheria toxin. [3]

Diphtheria is treated with diphtheria antitoxin, and a 14-day course of antibiotics, preferably Erythromycin or Penicillin.

 

Is it Diphtheria or something else?  

The Acute Infectious Diseases Of Childhood. Diphtheria

This is a disease of the throat. It is caused by the germ that causes diphtheria, that is, by the Bacillus diphtherae. There is no doubt about this. In fact so certain are medical men that this germ causes the trouble that when they fail to find the germ in the excretions (“Bacteriological examination is necessary for diagnosis since some cases cannot be told on inspection alone from acute tonsilitis, and other cases have no membrane at all”Emerson, Essentials of Medicine), they name the disease something else. The disease may present a perfect clinical picture of diphtheria and no germ be present. This is pseudo-diphtheria and receives another name. One may only have ordinary tonsilitis, “sore throat,” and, if the germ is found, it becomes diphtheria. It was adding thousands of cases of this latter type to the diphtheria figures that enabled them to show a 100% increase in the diphtheria case rate and a corresponding nearly 50% decrease in the death rate, without any lessening of the actual number of deaths, but often with an increase in deaths, when diphtheria antitoxin came into use. The supposed diphtheria germ is often found in the mouth and throat of healthy people who do not have, have not had, and do not subsequently develop diphtheria.

The Encyclopedia Britannica tells us: “If, in diphtheria, the bacillus is not found, the illness is renamed something else.” Sir Wm. Oster, M. D., says in his The Principles arid Practice of Medicine, Page 151, under diphtheria: “The presence of the Klebs-Loeffler baccillus is regarded by bacteriologists as the sole criterion of true diphtheria and as this organism may be associated with all grades of throat affections, from a simple catarrh to a sloughing, gangrenous process, it is evident that in many instances there will be a striking discrepancy between the clinical and the bacterial diagnosis.”

The germ is found in simple catarrhal conditions and also in the mouth and throats of healthy infants and children; and is often absent from the throats of those presenting clinical pictures of diphtheria…

In his Mother’s Hygienic Handbook, 1874, Dr. Trall asserted “the pathological identity of croup and diphtheria.”

Membranous croup” is the worst form of diphtheria. These cases seldom appear to be very ill. For two or three days there is a rough, croupy cough which becomes a little more croupy each afternoon and evening, but wearing off somewhat in the forepart of the night and in the morning. The child’s breathing is not affected, he has an appetite and there is usually little uneasiness on the part of parents. Then, suddenly, the child almost suffocates. He tosses about on the bed, sits up and struggles in various ways in an effort to breathe. He becomes blue. In severe cases the child suffocates unless relieved by incubation or tracheotomy. In the milder cases the paroxysms are soon over, but they some times recur later…

CROUP:

Formerly croup was divided into membraneous and nonmembraneous or simple croup. Membraneous croup is now regarded as diphtheria. Dr. Trall thought the two croups differed only in degree and said “in the former case the exudation which forms on the mucous lining of the wind pipe (trachea) concretes into a membraneous covering, and in the latter case, the excreted matter is expectorated without consolidation.”

The differences in the behavior of the two exudates show a big difference in their characters, and points to differences in their causes. Simple croup is of a catarrhal nature and results from carbohydrate plethora; membraneous croup is of a serous nature and is the result of protein poisoning. Protein poisoning is more virulent than starch poisoning.

Croup is breathing difficulty accompanied by a “barking” cough. Croup, which is swelling around the vocal cords, is common in infants and children and can have a variety of causes.

…Before the era of immunizations and antibiotics, croup was a dreaded and deadly disease, usually caused by the diphtheria bacteria. Today, most cases of croup are mild. Nevertheless, it can still be dangerous.

Croup tends to appear in children between 3 months and 5 years old, but it can happen at any age. Some children are prone to croup and may get it several times.

In severe cases of croup, there may also be a bacterial super-infection of the upper airway. This condition is called bacterial tracheitis and requires hospitalization and intravenous antibiotics. If the epiglottis becomes infected, the entire windpipe can swell shut, a potentially fatal condition called epiglottitis.

 

Tonsillitis is diptheria

Tonsil and throat infections may be caused by either a virus or bacteria, and can be spread from one person to the other through coughing, sneezing and nasal fluids. In preschool children and infants, the common cold virus or flu virus often causes chronic tonsillitis. In adults and adolescents, it is more likely to be caused by bacteria—the streptococcus, staphylocci, pneumococci, or hemophilus bacteria. In rare cases, the bacteria responsible for scarlet fever, diphtheria and mononucleosis can cause tonsillitis.

 

 

Acute Infectious Laryngitis


Acute infectious laryngitis is a common illness in all age groups and again is caused by viruses, especially influenza A, rhinovirus, and adenovirus. Diphtheria is a rare cause.

The illness is generally quite mild with sore throat, hoarseness, cough, and possibly mild inspiratory stridor. Respiratory distress is rare with the exception of young infants. If diphtheria is the cause, respiratory distress with airway compromise is quite marked secondary to the pseudomembrane blocking the laryngeal inlet . Complete obstruction and respiratory arrest may occur. Fortunately, immunization for diphtheria in the United States has made this disease extremely rare.

At one time, the term croup was primarily associated with diphtheria, a life-threatening respiratory infection. Owing to widespread vaccinations, diphtheria has become rare in the United States, and croup currently refers to a mild viral infection of the larynx. Croup is also known as laryngotracheitis, a medical term that describes the inflammation of the trachea (windpipe) and larynx.

Vincent’s angina is a form of sore throat in which there is usually a membrane resembling that of diphtheria. It usually begins as a small, whitish ulcer upon the tonsils or other part of the throat. The ulcer often extends through the crypts of the tonsils and produces an extensive loss of tissue. The disease is to be suspected when a deep ulcer can be seen in the throat or when the throat remains sore and raw after what was called diphtheria. It is caused by a spirochete which occurs in two forms: (1) a large crescent-shaped organism which stains heavily and unevenly; (2) a long, slender spirillum which stains faintly. A diagnosis may be made by taking a specimen of membrane with a swab, making a smear upon a cover-glass, and examining it at once. Large numbers of both organisms will usually be present in a smear from a positive case. A health officer can make a smear from a suspected case and send it to a laboratory for examination.

Vincent’s angina is not common, but it sometimes occurs in epidemics, and a health officer must keep the disease in mind. A case must be controlled in the same manner as one of diphtheria. Its treatment consists of swabbing the ulcer daily with a 20 to 50 per cent. solution of silver nitrate, and of painting the throat frequently with weaker solutions. A cure is indicated by a healing of the ulcer and by the absence of the organisms from smears.

 

…a milder tonsil infection due to the presence of organisms called the streptococcus and staphylococcus. But the existence of such an infection shows that the little patient’s throat membranes afford good soil for germs, and so it should be guarded against diphtheria with unusual vigilance. Bad teeth, mouth sores, enlarged tonsils, catarrhal inflammations and other abnormalities in the respiratory tract also predispose to the disease. Susceptibility is increased, again, by measles and scarlet fever. In the majority of cases, the germs first find a lodgment in the tonsils.

 

 

Immunity to Diphtheria

 

Acquired immunity to diphtheria is due primarily to toxin-neutralizing antibody (antitoxin). Passive immunity in utero is acquired transplacentally and can last at most 1 or 2 years after birth

 

 

…the increasing percentage of diphtheria cases in adults suggests that many adults may not be protected against diphtheria

 

 

The vaccine does not prevent carriage. The purpose of the vaccine is to make you immune to the toxins the toxogenic strains release. It is the toxins that can make you sick, and the toxins the bacteria releases that make the tonsils or sinuses, etc, an unfriendly environment to other floral bacteria. This in turn, allows the Diphtheria bacteria to take over and become an acute infection. 

 

Antitoxin does not cure the disease and toxin-antitoxin does not prevent it. Both these foreign proteins are responsible for many deaths in both the well and the sick, and for much other injury short of death.

Although comparatively few who come in contact with this disease develop it, it is considered highly contagious and, due to the contagion-superstition, these cases are quarantined. The writer has never handled but one case and saw this but once. After the quarantine was slapped on the case I handled it over the phone. The child made rapid recovery with no complications or sequelae. otein decomposition and by maintaining good health. Diphtheria is a phase of albumenuria.

 

The use of Diphtheria toxoid in children began in the 1930’s and 1940’s but uptake remained low. However,

..in the 1930s, a gradual rise in diphtheria incidence to 200 cases per 100,000 in the prewar period occurred in Germany and several other central European countries with partially implemented vaccination programs. The onset of World War II in 1939 and the occupation by German troops of many Western European countries led to the last diphtheria pandemic in western industrialized countries.

 

 The Diphtheria Shift

 

United States

Diphtheria cases remain isolated, with the last outbreaks reported between 1972-1982. Diphtheria incidence continued to decline steadily throughout the vaccine era in the United States and Western Europe (after the immediate postwar period). Cases of clinical diphtheria became extremely uncommon after the 1970s. Residual indigenous cases have been concentrated among incompletely vaccinated or unvaccinated persons of low socioeconomic status…

A feature of these epidemics concerns the age group; most cases have occurred in adolescents and adults, rather than in children.

Age

When diphtheria was endemic, it primarily affected children younger than 15 years; recently, the epidemiology has shifted to adults who lack natural exposure to toxigenic C diphtheriae in the vaccine era and those who have low rates of receiving booster injections. In the 27 sporadic cases of respiratory tract diphtheria reported in the United States in the 1980s, 70% occurred in persons older than 25 years.

Data from Europe are particularly noteworthy because the childhood immunization rate exceeds 95% in some countries (eg, Sweden), but approximately 20% of persons younger than 20 years and as many as 75% of persons older than 60 years lack the protective antibody….

 

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Epidemiology

 

Infection can occur in immunized, partially immunized, and unimmunized persons. However, disease is usually less severe in those who are partially or fully immunized. Diphtheria is endemic in many parts of the world, including countries of the Caribbean and Latin America. The incidence of respiratory diphtheria is greatest in the fall and winter, but summer epidemics may occur in warm moist climates in which skin infections are prevalent. During the 1990s, large epidemics of diphtheria, primarily in adolescents and adults, occurred throughout Asia, the Middle East, Turkey, Albania, Russia, and the independent countries of the former Soviet Union

 

 

The Russian Experience:

What the Russians found was that with toxic diphtheria it wasn’t the antitoxin antibodies in the blood that was important, but how well the person could initiate the interferon response. If a person had difficulty producing interferon, they would get diphtheria and die regardless of their vaccination status or antibody status. If the person’s nutrition, immunity, and their innate immune system are working correctly, diphtheria isn’t a high risk.

 

Take a look at these studies. What sense does it make for an immunodeficeint child to have a vaccine for which they many not be able to make antibodies for?

 

  
A Russian study- child with an immunodeficiency: 


 
“Thymomegalia is registered in every third child in some regions [of Russia].” In this paper the authors confirm that after DPT-immunization of the children with thymomegalia the anti-diphtheria antibodies is not being produced at all or in an insufficient quantity.” (Source: The insufficiency of the anti-diphtheria antibodies production after immunization with DPT vaccine. Kuz’menko L. G., Arziamova V. V. Nedostatochnost’ produktsii protivodifteriinyh antitel u detei s timomegaliei pri immunizatsii vaktsinoi AKDS. Detskie infektsii (Children infections), 2004, 2(7), с. 24-26.)

  

Also- Clinical-immunological characteristics of the vaccinal process in children with 1st grade thymomegalia:


 
 
“It is known that DPT vaccination even in healthy children not only produces a specific immune response, but causes the allergic reorganization in the body, lowers the specific resistance…

  The children with modified reactivity from the high-risk groups react to DPT-vaccination by the long-term suppression of resistance, by developing postvaccinal complications, by defective immune response, by high morbidity

 

It was demonstrated the DPT-vaccinations (from the first to the third shot) in the most children with thymomegalia of the 1st grade by their first year of life caused the complicated course of the vaccinal process, namely allergic complications, acute respiratory diseases, the lack or inferior immune reaction to diphtheria or pertussis toxins and enlarging the thymus up to 2nd-3rd grade. The result of the three shots was the factual absence of immunity to whooping cough, low anti-diphtheria and high anti-tetanus… immunity.”  (Source: Clinical-immunological characteristics of the vaccinal process in children with 1st grade thymomegalia. Adishcheva N. I. Kliniko-immunologicheskie pokazateli vaktsinal’nogo protsessa AKDS u detei s uvelicheniem timusa I stepeni (Abstract of PhD thesis. Tomsk, 1996, pp. 2 and 24. )
 

 

What has some other medical research shown?

 

 
Incidence of infectious disease and the licensure of immunobiologics in the 
United States. 
( Am J Prev Med. 1997 Mar-Apr;13 (2):98-103.Campos-Outcalt D, Aickin M. Department of Family and Community Medicine, Maricopa Health System, Phoenix, 
Arizona, USA.) 
 
INTRODUCTION: Our objective was to investigate the relationship of vaccine or 
toxoid licensure with the incidence of the target disease in the United States. 
METHODS: We used a historical correlational study design with outcome measures of the national incidence and elimination rate of polio, pertussis, diphtheria, and  measles as well as the New York City incidence and elimination rate of mumps, rubella, and tetanus.

 

RESULTS: The licensure of pertussis, measles, polio, mumps, and rubella vaccine was followed by an increase in the elimination rate of disease. The elimination rates of diphtheria and tetanus apparently worsened following the licensure of the respective toxoids.

 

CONCLUSIONS: Historical data provide evidence of proof of efficacy of mass immunization for measles, polio, rubella, mumps, and pertussis, but not for diphtheria or tetanus. 

 

 

Diphtheria: changing patterns in the developing world and the industrialized world.  

 

 

 

In the past, diphtheria was considered one of the most serious childhood diseases because it took a heavy toll in health and life among preschool-aged children. Prior to the widespread availability of diphtheria toxoid, nearly 70% of cases were in children younger than 15 years of age. In the industrialized countries, immunization against diphtheria became widespread in the 1940s and 1950s. This led to a marked decrease in the incidence of diphtheria. There was also a decrease in circulating toxigenic Corynebacterium diphtheriae organisms, resulting in less natural boosting of antibody levels. This had led to gaps in the immunity of the adult population. Since 1990, diphtheria has made a spectacular comeback in several European countries, with a high proportion of cases in adults

But recently, several developing countries where coverage has been high for 5-10 years have reported diphtheria outbreaks. These outbreaks have been characterized by high case fatality rates, a large proportion of patients with complications, and their occurrence in both young and older age groups…

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The Changing Epidemiology of Diphtheria in the Vaccine Era

(pdf: http://www.journals.uchicago.edu/cgi…e?JID981402PDF )

 

 

Patterns of Spread

 

The diphtheria epidemic in NIS provided important information. First, there was a high proportion of cases among adolescents and adults, especially in Belarus, Russia, Ukraine, and in Baltic States (Estonia, Latvia, and Lithuania), and a lower proportion of cases in these age groups in the southern republics of the Caucasus area and Central Asia. Second, the epidemic began as an urban epidemic, with a progressive transition to include rural areas over time. Third, the epidemic initially amplified in groups with high rates of close contacts (e.g., hospitals, military troops, indergartens, schools), and later, it made a transition to a more generalized epidemic involving socioeconomically disadvantaged groups (e.g., alcoholics).

 

Changes in Immunity Patterns by Age

 

Changes in the age-wise distribution of the immunity patterns usually have been explained by the argument that immunization led to a marked decrease in the incidence of the disease and to a subsequent reduction of the reservoir of toxigenic C. diphtheriaeorganisms. In the prevaccine era, exposure to toxigenic strains of diphtheria organisms was common, and this provided natural boosts to the development and maintenance of immunity against diphtheria. Children were susceptible, and most adults remained immune to the disease. However, after  immunization of children became widespread, diphtheria became rare, so exposure to these bacteria (and the concomitant natural boost of immunity) become uncommon. If adults do not have natural exposure to diphtheria-causing organisms or receive booster doses of diphtheria toxoid, their immunity induced by childhood immunization wanes, and they become susceptible to the disease [6, 14, 15].

 

*Blogger Note: Exposure to Diphtheria organisms is still common as Diphtheria bacteria are all around you, all the time. But you won’t find what you don’t test for.

 


A large body of evidence has documented changes in the immunity levels of various age groups in the pre- and postvaccine eras. In the prevaccine era, when the circulation of C.diphtheriae organisms was common and the prevalence of diphtheria cases was high, natural immunity was acquired by overt or subclinical infection. Most newborn infants passively acquired antibodies from their mothers via the placenta. In 1914 in Vienna [16] and in 1923 in New York City [17], »80% of newborns showed evidence of diphtheria immunity (figure 1). During the first several months of life, this passive immunity waned and was gradually replaced by active immunity, which was acquired through increasing exposure to natural infection.

 

 

By 15 years of age, 80% of the children had acquired natural immunity against diphtheria. The rate of acquisition of natural immunity, however, differs from country to country, probably due to differences in the intensity of early contact with diphtheria organisms, overcrowding, sanitation, and hygiene [15].

 

 …  In the early 1980s, the lowest levels of diphtheria antibodies in various areas of the Soviet Union were found in persons 20–40 years old [40–42], and at present, this least protected group has shifted to persons 30–40 years old. In other countries, low-level protection was found in persons 40–50 years old in Australia [43], England [44], Germany [45], and Poland [32, 33] and in persons 150 years old in Denmark [46], Finland [29], Sweden [47], and the United States [26].

 

Changes in the Age Distribution of Diphtheria Cases

 

When diphtheria was a common disease, it most frequently affected children: At least 40% of diphtheria cases were among children !5 years of age, and some 70% of the cases were among children 15 years of age. This classic pattern of diphtheria cases was seen in many countries, including the United States in 1908–1934 [48], Germany in 1929–1931 [49], and England and Wales in 1936–1937 [50]. Shifts in the age distribution of diphtheria cases has usually been explained by the impact of immunization. However, historical data show that a shift of the disease to older ages began before mass immunization was introduced.

 

All these observations suggest that changes in the age distribution of diphtheria cases resulted from factors other than vaccination. Socioeconomic factors, such as a general increase in the standard of living, smaller families, and less overcrowding, created an environment in which children were not subjected to the same intensity of infection in their preschool years as they had been previously. On the other hand, increasing enrollment in schools, summer camps, and meetings of children, adolescents, and adults from different neighborhoods and social backgrounds probably  contributed to wider circulation of C.diphtheriae within these age groups. Likewise, migration and displacement of many people during World War II probably enhanced the circulation of diphtheria organisms and contributed to the shift toward more adult cases [15].

 

 

Host susceptibility is the key to Diphtheria. Even fully immunized persons can have asymptomatic infections of C. diphtheria and can transmit diphtheria. The vaccine won’t make a bit of difference when it is solely the host factors that will determine the nature of the disease and its outcome.  Are you told that those who have adequate iron won’t get Diphtheria because the toxin can’t be produced in the presence of iron? The iron issue has more to do with the link to poverty than any other factor. You can have Diphtheria more than once if the conditions are right.

 

 
IMMUNIZATION

Clinical diphtheria does not necessarily confer natural immunity.

  

1990 Case Definition

Clinical case definition

An upper respiratory tract illness characterized by sore throat, low-grade fever, and an adherent membrane of the tonsil(s), pharynx, and/or nose without other apparent cause (as reported by a health professional)

Laboratory criteria for diagnosis

·         Isolation of Corynebacterium diphtheriae from a clinical specimen

Case classification

Probable: meets the clinical case definition, is not laboratory confirmed, and is not epidemiologically linked to a laboratory-confirmed case

Confirmed: meets the clinical case definition and is either laboratory confirmed or epidemiologically linked to a laboratory-confirmed case

Comment

Cutaneous diphtheria should not be reported.

1995 Case Definition

The 1995 case definition appearing on this page was re-published in the 1997 MMWR Recommendations and Reports titled Case Definitions for Infectious Conditions Under Public Health Surveillance [MMWR 1997;46(RR10)] (available at http://www.cdc.gov/mmwr/preview/mmwrhtml/00047449.htm). Thus, the 1995 and 1997 versions of the case definition are identical.

Clinical description

An upper respiratory tract illness characterized by sore throat, low-grade fever, and an adherent membrane of the tonsil(s), pharynx, and/or nose

Laboratory criteria for diagnosis

  • Isolation of Corynebacterium diphtheriae from a clinical specimen, or
  • Histopathologic diagnosis of diphtheria

Case classification

Probable: a clinically compatible case that is not laboratory confirmed and is not epidemiologically linked to a laboratory-confirmed case

Confirmed: a clinically compatible case that is either laboratory confirmed or epidemiologically linked to a laboratory-confirmed case

Comment

Cutaneous diphtheria should not be reported. Respiratory disease caused by nontoxigenic C. diphtheriae should be reported as diphtheria. All diphtheria isolates, regardless of association with disease, should be sent to the Diphtheria Laboratory, National Center for Infectious Diseases, CDC.

 

What Do They Know and When Did They Know It?

Global Epidemiology of Infectious Diseases

 

To date, diphtheria has not been a major problem in most developing countries. Immunization for infants and children was introduced with the Expanded Programme on Immunization in the late 1970s. Coverage of infants in developing countries with three doses of  DPT vaccine rose gradually from less than 10 per cent in 1974 to 81 per cent in 1995 (Expanded Programme on Immunization 1996). In these countries, the process of maintaining immunity still operates through natural mechanisms, including frequent skin infections caused by C. diphtheriae.

Socioeconomic changes, especially rapid urbanization with migration from rural areas, and sociocultural changes, including improved hygiene and different lifestyles, are changing the epidemiological patterns of diphtheria, so that in some developing countries epidemics are occurring, with more serious faucial and laryngeal forms. Algeria, China, Ecuador, Jordan,

Lesotho, and Yemen have reported diphtheria outbreaks which occurred following a 5 to 10 year period of high immunization coverage. These outbreaks have been characterized by high case fatality rates (CFRs), a large proportion of patients with complications, and occurrence in both young and older age groups (Galazka & Robertson 1995).

 

Completeness of routine reporting:

 

The true numbers of diphtheria cases and deaths are unknown. In developed countries, where diphtheria occurs in the form of single imported cases or, as recently in the Russian Federation and Ukraine, in defi nite outbreaks, the reporting may be assumed to be good. In developing countries, however, where the disease is usually endemic, reporting systems are

weak and the impact of immunization on disease incidence is monitored primarily through national incidence fi gures. Such statistics are often inaccurate because they are based on incomplete data gathered by the routine surveillance systems, which are usually hospital-based.

 

Completeness of reporting depends mainly on two elements. First, the public must have access to health services and use them. Second, the health services must report cases accurately and regularly to the appropriate public health authorities. A study in 13 developing countries that compared survey data with reported data found that only 2 to 5 per cent of tetanus cases and 1 to 26 per cent of poliomyelitis cases were detected and reported through routine surveillance systems (Expanded Programme on Immunization 1982). Overall reporting efficiency for the vaccine preventable diseases is estimated to be less than 10 per cent, although this estimate does not specifi cally address diphtheria case reporting (Expanded Programme on Immunization 1994b). Further efforts are needed to establish highly efficient surveillance systems capable of detecting most cases of targeted diseases.

 

 

 

Immunity to diphtheria and tetanus in inner-city women of childbearing age.

B A Koblin and T R Townsend. Am J Public Health. 1989 September; 79(9): 1297–1298.

 

Sera were collected between August 1984 and June 1986 from women …the last 20 years have found a higher percent of women susceptible compared to the present study. However, these studies have also reported an increase in the proportion susceptible with age. Millian, et al, found low levels of tetanus antitoxin (<0.01 unitlml) in 25 percent of women aged 20-29 years and 37 percent of women aged 30-39 years. Levels of diphtheria antitoxin <0.02 unit/ml were found in 15 percent of women aged 15-19 years, 19 percent of women 20-29 years, and 24 percent of women 30-39 years…

 

 In the present study, the percent of women susceptible to diphtheria was higher in all age groups compared to tetanus. One reason for this observation may be the use of tetanus toxoid alone as the practice for wound prophylaxis after trauma instead of the combined diphtheria-tetanus toxoids. Another reason is that diphtheria toxoid is less antigenic than tetanus toxoid and therefore the duration of seroprotection following immunization may be less than that observed for tetanus toxoid…

 

However, the protective level of antitoxin for diphtheria is less well defined than that for tetanus. Outbreaks do occur in communities in which immunization has been extensive and immunization with diphtheria toxoid may modify disease rather than prevent its occurrence.  Susceptibility to diphtheria in the older age groups can be a result of lack of exposure to diphtheria in the past, lack of completion of the primary series in childhood, or lack of boosters since childhood…

 

 

Diphtheria in the United States, 1971-81.

R T Chen, C V Broome, R A Weinstein, R Weaver, and T F Tsai.Am J Public Health. 1985 December; 75(12): 1393–1397.

 

 

General Trends.  Diphtheria case incidence remained relatively unchanged from the previous decade until 1975, when the rate began to plummet(Figure 1), reaching a low of two cases (0.01 case per million) in 1980. Mortality paralleled the decline in incidence, including no deaths in 1980. The death-to-case ratio remained close to the historically prevailing 10 per cent until 1976, demonstrating the continued high risk of death associated with diphtheria. It has since varied erratically because of the small number of cases annually….

 

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Carriers

 

The frequency of diphtheria carriage in the United States is not known accurately. Nontoxigenic isolates and carriers not associated with outbreaks were probably not detected by the surveillance system. The 471 noncutaneous carriers that were reported resembled the cases in age, sex, and racial distribution, but had better immunization status and a lower proportion of toxigenic strains isolated.

 

Discussion

 

Diphtheria incidence in the United States has fallen steadily since at least the 1920s (Figure 1). The reasons for the decline before the introduction of diphtheria toxoid immunization are

unclear, but may be related to factors such as diphtheria toxin-antitoxin use and general improvements in socioeconomic factors, nutrition, and housing

 

The incidence of noncutaneous diphtheria disease have reached the lowest recorded levels ever in the United States. While the degree of diphtheria underdiagnosis is unknown, the continued decline in incidence is further corroborated by the National Center for Health Statistics mortality data. The decline in diphtheria incidence in the United States during 1971-81 occurred despite serologic studies during the 1970s showing subprotective serum diphtheria antitoxin levels in approximately 25 per cent of the children’0″ and 75 per cent of the adults’2 tested in three US cities. Furthermore, the US Immunization Survey, based on interview question- naires, showed a gradual increase in the percentage of children less than 14 years old not immunized with at least three doses of diphtheria and tetanus toxoids and pertussis vaccine (DTP), from 17 per cent in 1971 to 26 per cent in 1981 ‘for Whites, and from 29 per cent to 47 per cent for non-Whites. Surveys of the actual immunization records of the children in the same age group, available since 1980, showed that 10 per cent of the Whites and 32 per cent of the non-Whites in 1981 were not fully immunized.

 

The experience with diphtheria immunization indicates that an immunization level of 70 per cent 80 per cent is needed to prevent epidemic spread. However, immunization with diphtheria toxoid is protective only against the phage-mediated toxin, and not against infection by the C. diphtheriae organism. Thus immunized persons have less severe disease when infected, but may remain important as asymptomatic carriers in the transmission of disease. Outbreaks in communities with up to 94 per cent immunization levels have been reported. Therefore, some authors have challenged whether “herd immunity” is applicable to diphtheria.

 

…Also, as diphtheria incidence decreases, the proportion of the population with natural immunity from prior exposure will also decrease.

 

 

Also see: Gross Estimation–Diphtheria Statistics Defy Reality

 

 

How Long Does Immunity to Diphtheria Last?

Eli Eichelberger.Am J Public Health Nations Health. 1948 September; 38(9): 1234–1238.

 

 

 

From these figures it becomes obvious that diphtheria can no longer be considered a disease of infancy and childhood alone. Such statistics bear out the conclusions of an editorial in the Journal of the American Medical Association  which concluded that diphtheria was increasing and that there was a tendency for the disease to become relatively more prevalent among the older age groups. It appears that our thinking regarding this disease will have to be revised, as well as our evaluation of the duration of diphtheria immunity. If a large per cent of adults are now susceptible, it must be assumed that they must never have been immunized, or if previously immunized,they must have lost their immunity. Consequently, one who thinks of diphtheria as a childhood disease may entirely miss the diagnosis in the adult unless facts regarding this disease are appreciated.

 

 

Exposure as a Factor in the Age Distribution of Measles, Diphtheria, and Poliomyelitis

W. Lloyd Aycock.Am J Public Health Nations Health. 1934 May; 24(5): 433–437.

 

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…actual infection in non-immunes produces diphtheria with approximately equal frequency at all ages. However, this does not mean that all infected non-immunes develop the disease, but only that risk of disease in infected non-immunes appears to be equal at all ages….

 

CONCLUSIONS

 

The variation in the occurrence of measles, diphtheria, and poliomyelitis in non-immune persons at different ages would appear to be due in part to a difference in the frequency with which persons of different ages are exposed to respective viruses, and in part to a difference in the frequency with which persons of different ages are infected under the same apparent degree of exposure. The differences in the risk of infection at different ages in measles, diphtheria, and poliomyelitis would appear to be due to quantitative or qualitative differences in personal, social or household habits of persons of different ages, which habits constitute sanitary habits in the present connection.

 

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MORTALITY FROM DIPHTHERIA DECREASING

Am J Public Health (N Y). 1926 June; 16(6): 621–622.

 

 

THE third annual summary of diphtheria mortality in the large cities of the United States deserves more than a passing mention. It has frequently been stated that while the use of diphtheria antitoxin has greatly lessened the mortality of the disease, the incidence of the disease has not shown any decided decrease. In addition to this every health officer knows that many cases of diphtheria are not treated promptly, and many times even where antitoxin is used, it comes too late to do much good. Every year sees the public becoming more and more educated, and there seems reason to believe that diphtheria antitoxin is being more and better employed. Until 1920 but little improvement could be demonstrated in- the mortality from diphtheria in the majority of cities. From 1910 to 1914 only 13 cities had rates which averaged under 10. In the periods from 1915 to 1919 and 1920 to 1924, only 18 cities had an average rate under 10, while in 1924, 37 cities, and in 1925, 49 cities, had rates under 10. Making the estimate according to the population of the 70 cities studied, 29,243,128 in 1923, and 31,049,595. in 1925, we find that the diphtheria death rate in the former year was 13.12 per 100,OQO against 9.74 for 1925. In spite of an increase of practically 2 million in population, the actual deaths for diphtheria decreased more than 800 for these cities. Perhaps even more encouraging than this figure is the fact that 10 cities, all of considerable size, showed death rates under 4 per 100,000, while 8 cities, including several of the largest in the United States, have shown a continuous decline in diphtheria death rate by 5-year periods from 1-890 to 1924.

 

CAN DIPHTHERIA BE ELIMINATED?

F. W. Sears.Am J Public Health (N Y). 1925 February; 15(2): 98–101.

 

The adult diphtheria previous to the beginning of our work was only a fraction of the total number of cases in the city, while during the past year the adult diphtheria cases have outnumbered both those of the school children and the preschool children. This is similar to what occurred following vaccination against smallpox. Previous to the days of vaccination smallpox was considered to be a children’s disease. Since general vaccination it has become an adult disease. May we not expect that the same thing will occur with general immunization of children against diphtheria ?

 

DIPHTHERIA MORBIDITY AND MORTALITY

Am J Public Health (N Y). 1924 May; 14(5): 427–429.

 

Laryngeal diphtheria is still a prime cause of death, and it seems that there are still a few physicians who consider membranous croup one disease and diphtheria another. It is especially difficult to obtain positive swabs from cases of laryngeal diphtheria, but it cannot be too strongly insisted upon that membranous croup is laryngeal diphtheria and should be treated as such. It seems necessary also to insist that in every case of sore throat or nasal discharge in which there is any suspicion or possibility of diphtheria swabs should be taken for laboratory examination.

 

 

 

Reasons for the Failure of Our Methods to Control Diphtheria

J. W. Robinson.Am J Public Health (N Y). 1922 June; 12(6): 497–502.

 

quarantine is of no value in the control of diphtheria and only leads to a feeling of security that is false, for it is indeed a sad state of affairs that neither the morbidity nor mortality of diphtheria has declined to any great extent during the last ten years. Figures given by Weaver,” Carey,2 Hull,” and others, prove this…

 

First, transmission requires a close contact, such as actually coughing in the face while someone is inhaling, drinking out of a cup soon after a carrier has used it, or using some other equally good method to transmit the infection. Second, that the percentage of people of any age group who are susceptible, is much less than ‘tests by the Schick test would indicate. The number of secondary cases in families and’ institutions verifies this statement. There is usually more or less contact in either class of places before a diagnosis is made and precautions are taken. And in private homes, unless the case is removed to a hospital, it is exceptional that isolation of the case is carried out until negative cultures are obtained. And yet, what per cent of the other children contract clinical diphtheria? It is very much less than the percentage of susceptibles as determined by the Schick test would lead us to believe. ‘It is difficult to furnish exact figures, as isolation of some cases has been’ complete, and in others the contacts ‘have each’ received a prophylactic dose of antitoxin…

 

…occasionally one will carry bacilli for some time and then develop a clinical case, but such cases are uncommon. In this connection one must bear in mind that unless the symptoms are typical of diphtheria they may be due to other causes.  A point to which others have drawn attention is the occasional absence of a membrane, and other typical symptoms mentioned in text-books. Occasionally one sees a case of sore throat and fever from which a positive culture of diphtheria bacilli is obtained, and yet no benefit is derived from the use of antitoxin. These cases may well be some of those who are carriers that are always found if cultures are taken, and become sick with tonsilitis or other throat trouble.

 

…It seems from practical experience, as determined from statistics given by various writers and from analysis of conditions existing at present, and which probably will exist until a far future date, that the morbidity rate of diphtheria will remain practically the same.

 

 …Unless it is carefully explained to those immunized that the protection is of short duration, it may cause them to have a feeling of false security at a future date, and so throw them off their guard as to overlook a diagnosis with a possible fatality as the result. While the danger of anaphylaxis is so small as to be negligible, this does not hold true if it is necessary at a later date to use antitetanic or some other serum when the people may forget to tell the physician or he may not ask them of the use of the diphtheria antitoxin previously. The use of a prophylactic dose does not necessarily prevent them from becoming carriers, and it is always a disappointment to the people and disagreeable to the quarantine officers under those conditions to have to extend the quarantine period after the clinical case has cleared up or been removed to a hospital.

 

 

DIPHTHERIA CARRIERS AND THEIR RELATIONSHIP TO MEDICAL INSPECTION OF SCHOOLS

Henry Albert.Am J Public Health (N Y). 1912 October; 2(10): 794–798.

 

 

It is very certain that diphtheria has been kept alive for months in institutions and communities by such carriers. Indeed it is quite probable that carriers with either a normal throat or a slightly “sore” throat, are the source of more cases of diphtheria than persons affected by well marked cases of the disease.

 

…The proportion of children not affected by what is recognized as clinical diphtheria but wbo are diphtheria carriers varies naturally according to the extent of exposure. In 1894, Park* found virulent diphtheria bacilli in about one per cent of healthy tlhroats examined in New York City. In 1907, Fisher,t examining the throats of 4,081 healthy individuals living in the Connecticut Hospital for the Insane, where there were a number of cases of diphtheria, found that 2.08 per cent of them were diphtheria bacilli carriers. It has been shown by the examination of a large number of cases, that when clinical diphtheria is not present in a community about one per cent of the population are carriers of diphtheria bacilli, but that when diphtlheria is present in a conmmunity the percentage is very much higher-ranging from 5 to 10 percent. The percentage of carriers among healthy persons who have been quite directly exposed to infection, is often as high as 50.

 

 

 

Present Status of Diphtheria

William C. Woodward.Public Health Pap Rep. 1901; 27: 238–240.

 

Diphtheria infection apparently depends on the relation between the virulence of the infecting organisms and the susceptibility of the individual attacked. It involves, therefore, questions of quantity as well as quality of the infection, and of degree as well as character of

personal immunity and vital resistance. Unsanitary conditions tend to diminish the vital resistance of the animal organism and, therefore, make it more prone to succumb to attack. Personal uncleanliness on the part of the patient and of those in attendance on him favors

the spread of the disease by increasing the dissemination of infective particles through the atmosphere. Overcrowding tends to the same end by diminishing the absolute quantity of air in the infected room without a corresponding diminution in the amount of infection, thus increasing the density of the infection in the atmosphere, and increasing the likelihood of those exposed to such atmosphere receiving effectively toxic doses of infection. Unsanitary conditions, including personal uncleanliness and overcrowding, are, therefore, active agents in the spread of diphtheria infection.

 

The Official Definition of Diphtheria

Hibbert Winslow Hill. Public Health Pap Rep. 1899; 25: 243–248.

 

In no disease is this lack of definition more evident than in the case of diphtheria. Perhaps no disease has been more discussed, certainly no disease- is better known or understood, yet one hears again and again the question asked, where shall the line be drawn between diphtheria and not diphtheria? This question is asked publicly and privately, by the profession, by health officials and by the laity….

 

Given a combination of patient and bacillus, a long series of possibilities arise. Were all diphtheria bacilli equally virulent and all patients equally susceptible, such a combination of bacillus and patient would result in a definite set of pathological changes in almost all cases and leave little room for indecision in diagnosis. But because of the wide variations in the degree of virulence of the bacillus and in the degree of resistance of the patient, the pathological changes essential to the disease which are the resultant of these two forces (leaving out of the question for the present the effect of environment or of treatment) may be entirely absent, and when present vary in degree almost infinitely. Nevertheless, certain distinct classes may be recognized, and these classes give the key to the situation. The evidence accumulated in the last few years allows us to believe that we may classify the bacilli into two main groups, virulent and nonvirulent, and patients into two groups also, resistant and non-resistant. The virulence or non-virulence of a given diphtheria bacillus may be determined by animal inoculation. This admits of some discussion perhaps, but for our present purposes, we may accept the test as giving a basis for consideration. The resistance or non-resistance of the patient can be determined only, in any specific case, by the development or non-development of the disease, after infection with a virulent organism. This also is a determinable factor in some cases at least. Granting so much then, four classes of cases arise in which bacilli may be found.

 

Class 1. Non-virulent bacilli found in the throats of resistant subjects.

Class 2. Non-virulent bacilli found in the throats of non-resistant subjects.

Class 3. Virulent bacilli found in the throats of resistant subjects.

Class 4. Virulent bacilli found in the throats of non-resistant subjects.

 

Cases falling under classes 1 and 2 are probably rare and are not likely to be found except in epidemics or in other circumstances where wholesale bacteriological examinations are made, because ordinarily there would be nothing to call attention to the subject of such infection.

 

Class No. 3 in which virulent bacilli are found, producing, however, no lesions, on account of the resistance of the subject, are frequently met with.

 

Class No. 4 includes all the cases of clinical diphtheria-that is, where pathological conditions are present and are sufficiently marked to call -attention to the patient.

 

So far then, we have arrived logically at the conclusion that the problem presented is to decide whether “diphtheria” is patient + diphteria bacillus simply, or patient + diphtheria bacillus + typical lesions.

 

I think it will be admitted that the first combination, patient + diphtheria bacillus alone, does not predicate a disease at all-since the essential element of disease is pathological change-and if that combination is not a disease, it cannot be the disease of diphtheria. Nor

is it logical to assert that patient + diphtheria bacillus + typical lesions necessarly constitutes diphtheria although that formula will cover most cases. The typical lesion which attracts most attention and to which we may confine ourselves for the present purpose is an inflammation of the throat, or more definite still, the presence of a pseudo-membrane. If such inflammation, or pseudo-membrane never occurred except as a result of the presence of the diphtheria bacillus, then patient + diphtheria bacillus + inflammation or membrane would be decisive. To such a combination and to such only could the term “disease of diphtheria” be applied. But both inflammation and pseudo-membrane, indistinguishable in practice at times from those produced by the diphtheria bacillus, are of frequent occurrence-the bacilli nevertheless being absent.

 

Moreover upon such membranes, often due to streptococci, may be implanted diphtheria bacilli, both non-virulent and virulent forms. Thus the combination patient + diphtheria bacillus + pseudo-membrane may exist, where the pseudomembrane is due to a streptococcus solely. Such a case constitutes a disease certainly, but not necessarily the disease of diphtheria. Lest anyone should object that this is a purely hypothetical case, I may cite the not infrequent finding of diphtheria bacilli in the throats of scarlet fever patients suffering from a streptococcus pseudo-membrane, the diphtheria bacilli producing no appreciable effect whatever. It would be no more logical to say that such a patient was suffering from diphtheria because the combination of patient + diphtheria bacillus + pathological changes (due to the streptococcus) was present than to say that patient + diphtheria bacillus + pathological changes (due to the typhoid organism) constituted diphtheria. It seems plain then that the only possible combination which we can logically recognize as the disease of diphtheria is not patient + diphtheria bacillus + typical lesions, but patient + diphtheria bacillus + lesions, due to the diphtheria bacillus. Given this combination, the additional presence of an active streptococcus in the throat does not invalidate the diagnosis of diphtheria any more than would the additional presence of an active typhoid organism in the intestine.

 

It is evident that the reasoning here used will apply equally well to any other parasitic disease. My only reason for presenting so obvious a conclusion depends on the confusion which sometimes exists amongst the public, and even the profession, especially when the question of

reporting a doubtful case comes up. Thus, a positive culture is obtained from a healthy throat, or from a throat showing the mildest of lesions, or from a streptococcus throat in scarlet fever or other acute specific in which the previous diagnosis was established and the diphtheria bacillus discovered later shows no clinical indications of activity. Thereupon, the attending physician, and the legal medical officer of the district may be in doubt as to the proper classification of the patient.

 

To the physician, the recognition of the pathological changes and the determination of their cause is the important matter. To the medical officer, the diagnosis, so far as the patient’s welfare is concerned, is of less importance than the protection of the public health. To the one, the presence, or absence of the diphtheria bacillus is regarded chiefly as an aid to diagnosis; to the other, the presence or absence of the bacillus is the essential point at issue. The physician wishes to fortify his patient against the disease of diphtheria, the medical officer desires to protect the public from the bacillus of diphtheria. If a hypothetical case be considered in which the disease of diphtheria was produced by inoculation with the toxin of diphtheria only, the bacilli of diphtheria being absent, the physician would still have the interest of his patient to consider, while the medical officer might go his way free of responsibility. In the far more frequent cases where the bacillus is present, but the toxin absent or ineffective, it is the physician who is relieved of responsibility, whereas the medical officer’s duty to the public remains to be performed. To apply the foregoing considerations to actual practice, it must be remembered that it is impossible at the present time to observe such rules of procedure as will meet every possible condition here outlined.

 

For instance, it is usually impracticable, from the executive standpoint, to determine in every case the virulence or non-virulence of the bacilli found by the bacteriologist,-certainly it is impossible to determine it in time to be of service in diagnosis. It is necessary then to assume that all the diphtheria bacilli detected are virulent and experiment confirms the natural expectation that such an assumption is correct in the great majority of cases. Again, in any specific case when the diphtheria bacillus is present accompanied by lesions similar to those usually produced by this bacillus, it is often impossible at present to determine immediately and absolutely that those lesions are due to the diphtheria bacillus rather than to other organisms which may be also present. Here again it is usual to assume that the diphtheria bacillus is the cause of the lesions it accompanies,-and this assumption also is usually true. The evident necessity for making these assumptions in practice, perfectly right and proper as such assumptions are in the majority of cases, is just exactly the necessity which gives rise, in the minority of cases, to misunderstanding and confusion…

 

Report of the Committee on the Cause and Prevention of Diphtheria

J. J. Kinyoun. Public Health Pap Rep. 1896; 22: 56–67.

 

 

The so-called membranous croup is yet, we regret to state, a most serious disturbing factor in our fight against diphtheria. It is with surprise and regret that we see how firmly entrenched in the minds of the medical profession is the idea that croup is a non-infectious disease. It has been demonstrated over and over again, so plainly that he who runs may read that nearly nine tenths of these cases are laryngeal diphtheria. Yet despite all this, death certificates are constantly sent in to the board of health as “croup.” These are the landmarks, or rather, tombstones, marking the foci of epidemics of diphtheria. It is noted with satisfaction, however, that many of our state, provincial, and municipal boards of health are beginning to be emancipated from such ideas, and now regard the terms ” membranous croup ” or ” croup ” and ” diphtheria ” as synonyms, and treat them accordingly.

… It is noted especially that the death-rate from “croup ” in the cities of the United States which have not adopted microscopic examinations, is very high in proportion to the number of deaths from diphtheria, and also in proportion to the population; while on the other hand, the number of cases of death from croup in those places in which the diagnosis is made by the culture test, has fallen, and the number of cases of diphtheria has increased somewhat.

 

 

Since the adoption of this method for diagnostic purposes, there has been an increase in the number of cases of diphtheria, due in part to the croup cases, already referred to, being properly diagnosed, and the additional cases of laboratory diphtheria. It has been asserted that on account of including these latter cases the death-rate from diphtheria has not been diminished, and the statements made to the contrary are misleading. It must not be lost sight of that the microscopic examinations have been the cause of eliminating a considerable number of cases formerly classed as diphtheria….

 

It is to be regretted that the statistics from which these data are compiled are not more complete. Many states have a very imperfect system of their vital statistics, and while it is possihIe to obtain data from the majority concerning the death-rate from diphtheria and croup, it is difficult to obtain those dealing with their morbidity.

 

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As you can see, it has been freely admitted in the medical literature that the vaccine had nothing to do with the decline of Diphtheria or mortality rate. The records show that few children had the vaccine when the decline had already begun! Susceptibility is the key, not whether or not you have had the vaccine, and remains that way to this day.

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Chicken Pox and Shingles

Chicken Pox and Shingles

 

     In the pre-vaccine era, nearly all cases in the U.S. occurred in 3-6 year olds, and they developed permanent immunity. Before adults reached twenty years of age, 90% were immune. Infants were also protected by maternal antibodies. Today, adolescents (9-11 years old) are acquiring chicken pox which was highly unusual in the pre-vaccination era.  The rate of Shingles and Chicken Pox in adulthood is also increasing, and eventually the burden may shift and rise to infants.

 

 

 

    

     The Varicella vaccine is estimated to be 70% effective for up to 10 years, or as little as 5 years, after vaccination. 5% of vaccine recipients would go on to get a mild case of chicken pox within a year after the inoculation. The Varicella vaccine was first recommended as one dose given at one year of age.  Now, due to the lack of efficacy, and rapidly waning immunity, a second dose was recommended for 4-6 year olds.

 

 

 

 

     A 2007 study in the New England Journal of Medicine found that a single shot does not produce a sufficient immune response in approximately 20% of people who receive it. Therefore, it is hoped that a two-shot regimen will create a larger population of fully immunized people and should reduce breakthrough disease. Health officials admit they don’t now how long a second dose will provide immunity.

   

     As the Varicella vaccine became recommended and mandated for school attendance, natural circulation and ‘boosting’ of the virus became less. This not only put those who have acquired natural immunity at risk, but the vaccine recipients as well. Why? The vaccine does not allow the wild-type virus to circulate and boost protection for everyone, especially the older populations. This is why Japan never mandated the Varicella vaccine but left it as a ‘choice’ vaccine. Natural boosts, or exposures, from children also help keep Shingles from occurring. The effectiveness of the chicken pox vaccine is dependent upon natural boosting. As the chicken pox declines, so will the effectiveness of the vaccine.  Dr. James Cherry had this to say:

 

          “Our immunity is stimulated by being exposed to the Chicken Pox. When that stimulation goes away, our protection is going to decrease. So we’ll see more cases of Shingles. My guess is that we’re going to be giving doses of the [varicella] vaccine to 30 and 40 year olds to prevent Shingles. The better we do, [eradicating chickenpox], the more we’re going to see Shingles.”

 

 

     The adult Shingles rate increased by 90% from 1998-2003. A Shingles vaccine, Zostavax, was made, and its only purpose is to try and prevent Shingles cases in older susceptible adults.  The efficacy is only 41% for those aged 70-79 years, and an 18% efficacy for 80 years and older. The duration of protection is not yet known. Gary S. Goldman’s research shows that Shingles results in 3 times as many deaths and 5 times the number of hospitalizations.

 

     In the pre-vaccine era, serious problems or complications were rare. Parents and doctors knew exposing their children in early childhood reduced complication rates.  The highest complication rates or death have always been in very young infants, teens, adults, and those with compromised immune systems.  The United States is the only country that routinely vaccinates against Chicken Pox. It should also be noted that in 1981, chicken pox was removed as a nationally notifiable disease. Yet, the Varicella vaccine was licensed and recommended in 1995 with only 14 states reporting cases to the CDC. In 1998/99, only Varicella deaths were to be reported. In 2002, CSTE recommended Varicella once again be added as a nationally notifiable disease by the year 2003, with all states included by 2005.

 

 

     How many times have you heard that the Varicella vaccine would give a ‘milder’ infection? That the ‘milder’ infection is a good thing? Is a milder infection really a good thing? What about ‘recurrent’ cases or ‘breakthrough cases?  A milder infection can simply suppress the virus and eventually lead to a more serious infection or a chronic illness later on when reintroduced.

 

        Immunity acquired through natural infection still forms much of the population’s immune defense. The level of a population’s immunity to a disease depends upon both the proportion artificially immunized and the frequency of contact with the infectious organism (wild or attenuated). When exposure to the antigen becomes uncommon, there is no stimulus to maintain antibody levels, and susceptibility increases. If the organism causing a disease is then reintroduced while immunity is low it is likely to spread quickly and cause severe illness. A constant endemic level of a disease may cause less overall morbidity, mortality and disruption than periodic epidemics. Islands and other isolated areas demonstrate this principle. Their populations may not be exposed to a certain infectious disease for decades. If the organism is then reintroduced, the low immunity levels among these people permit the infection to spread rapidly throughout the entire population. Severe illness and a high case fatality rate usually result.”

 

   If natural infections are not allowed to boost the antibody titers from time to time, children could very well end up susceptible adults, and at a time when Chicken Pox can be more serious, and heightened secondary infections can result.

 

 

      Some children with histories of having acquired natural Varicella went on to experience Shingles, and the rate is approaching those of adults. Based on a study in the New England Journal of Medicine, 9.5% of children have breakthrough disease. Children 8-12 years who were vaccinated 5 years previously had a higher incidence of moderate to severe disease.  A study by Seward et al., indicated that 13% of Varicella cases diagnosed by pediatricians are recurrent.

 

 

 

 

     In the pre-vaccine era, when a child came down with an active chickenpox case, they were kept home for up to 2 weeks until the pox scabbed over. Any child who was known to have been exposed to a known case of Chicken Pox was also watched closely for the beginning of symptoms, and kept away from other susceptible people if needed.  If you have read the package insert for the Varicella vaccine, it warns that newly vaccinated persons could transmit the virus for up to 6 weeks, and to avoid associations with susceptible high risk persons. How many people do you know keep their newly vaccinated child out of daycare or school for 6 weeks? The issue of virus transmission after the vaccine is not generally discussed.

 

 

     The rate of Chicken Pox may indeed be lower in children today since the introduction of the vaccine, but at what cost and to whom? We have shifted a once normal and self-limiting childhood disease into an adult disease, and possibly down the road, an infant disease, when it can be much more serious. When you consider what is yet not ‘known’, the outcome is anyone’s guess.

 

 

 

 

 

Measles

Measles

     In the pre-vaccination era, Measles was a common childhood illness usually acquired before the age of 10 years old, and thus attained permanent immunity.  At least 95% of American children had Measles by the time they were 15 years old. Measles was rare in infants under the age of one as they were protected by their Mother’s natural immunity from childhood and through breastfeeding.

     As the Measles vaccination program increased, the epidemiology of Measles shifted. Measles cases began occurring in late adolescents, young adults, and babies under one year of age. This is not a new trend.  During the Measles outbreaks in 1976-1977, 60% of those cases occurred in children over age 10 and 26% occurred in children over age 15. This trend has continued to spite high vaccine coverage rates in developed and developing countries. It has also led to longer intervals between epidemic years; known as the “honeymoon effect’. In the 1984 Measles outbreak, 58% of school-age children who had been vaccinated caught Measles.

     A.W. Hedrich researched and published a study in 1933 on the patterns of Measles in Baltimore, Maryland from 1900-1931.  He surmised that the majority of children under 15 years of age who would catch Measles would not go above 53%, and would not drop below 32% during those 32 years.  At least 47% of children in Baltimore would not have Measles each time an outbreak ended. (2)  Hedrich’s research showed that the number of people in a community had nothing to do with the decline in virulence of the virus when an outbreak comes to an end. Measles is endemic and occurs whenever nature says it’s time. Epidemics have continued to occur even with high vaccine rate coverage, and occur in both vaccinated and unvaccinated.

     Where infants are concerned, vaccinated Mothers today do not have the full natural immunity to protect their infants.  In 1992 alone, 22.2% of measles cases were in infants less than 12 months of age. This was an increase from 19.2% in 1991 and 17.0% in 1990. In 1990, 27.9% of reported cases occurred in children 1-4 years of age, and 30.1% in 1991. In Texas alone, 75% of the cases were in children younger than 5 years old, and 35% in children less than 12 months old. In Kentucky, the opposite happened. Measles made up 49% of the cases in children 5-19 years old.

   According to the CDC’s Pink Book Measles Chapter, it is admitted that infants are now more at risk from Measles during outbreaks than in the pre-vaccination era.

     In addition, measles susceptibility of infants younger than 1 year of age may have increased. During the 1989–1991 measles resurgence, incidence rates for infants were more than twice as high as those in any other age group. The mothers of many infants who developed measles were young, and their measles immunity was most often due to vaccination rather than infection with wild virus. As a result, a smaller amount of antibody was transferred across the placenta to the fetus, compared with antibody transfer from mothers who had higher antibody titers resulting from wild-virus infection. The lower quantity of antibody resulted in immunity that waned more rapidly, making infants susceptible at a younger age than in the past.”

 

 

     According to a 1999 issue in Pediatrics:   “Infants whose mothers were born after 1963 are more susceptible to measles than are infants of older mothers. An increasing proportion of infants born in the United States may be susceptible to measles.” Mothers who had infants born after 1963, had a measles attack rate of 33%, compared with 12% for infants of older mothers.  The difference in infant’s immunity levels between the vaccinated Mothers and the unvaccinated Mothers can also be seen in the 1995 Pediatrics Journal.

      Even the World Health Organization has admitted that the vaccinated have a 14 times greater chance of contracting the disease than the unvaccinated.  ( National Health Federation Bulletin, (Nov. ‘69).

     Another issue worth mentioning is that without the circulating wild virus producing a boosting effect for older adults, and infants not as protected by maternal antibodies, the disease becomes more dangerous. A disease that a 5 year old could once recover from in 1-2 weeks has the potential to kill an infant, adolescent or adult. Measles used to have a natural virulence of every 3-4 years. The vaccine has caused longer intervals between exposures.

     

     “But the last generation to have routinely suffered through most of these diseases is crossing through mid-life and the first generation to have avoided them is hovering around 40.”

     Before vaccination became commonplace, adults often came in contact with youngsters suffering from mumps, measles and the other childhood diseases. That remained the case in the early days of vaccine administration when these diseases still commonly circulated.”

     “If people had protection – natural or vaccine-acquired – those exposures were actually helpful. They acted as a sort of natural booster shot, reminding the immune system to be on guard for this threat.  Some experts now wonder whether these unrecorded natural boosts may have led the medical community to overestimate the durability of immunity generated by childhood vaccinations. These days, few people are getting natural boosting to these diseases.”

     The Measles vaccine has made the disease rarer in childhood, but more dangerous when it does occur, due to the age shift. There can also be a higher case fatality rate in infant and adult infections.  When considering the risks or benefits of the vaccine, consider this:  Once a population is exposed to measles in childhood, few infants or adults will contract it as they will have acquired immunity for life.  The vaccine simply can not do that. All it has done is decrease the virulence, the circulation cycle of the disease, and pushed the disease incidence to older persons and infants when the disease can be more harmful and deadly.

   According to the American Journal of Epidemiology, it was projected, based on a computer model:

        “However, despite short-term success in eliminating the disease, long-range projections demonstrate that the proportion of susceptibies in the year 2050 may be greater than in the prevaccine era. Present vaccine technology and public health policy must be altered to deal with this eventually.” So the end result will be the same number (or more) of susceptibles, but “distributed evenly throughout all age groups”. Since adults and infants have higher risk of Measles complications and fatality, the Measles eradication plan has resulted in higher risk to the overall population. Obviously the public health policy solution is more and more vaccination, more boosters for children and adolescents, and adults as well. A very short-sighted, questionable and expensive campaign to eliminate a self-limiting childhood disease.”

     It should also be noted that in the pre-vaccine era, 10% of the population was always susceptible to Measles. After the Childhood Immunization Initiative from 1977-1979, it was admitted that at least 5 % would not develop Measles antibodies, and Measles would continue to occur despite high vaccination rates and it has. Those susceptible are those who have primary and secondary vaccine failure, adults who escaped natural Measles because of decreasing transmission in the late 1960’s, lack of virulence to boost natural immunity, infants under one year of age to decreased maternal antibodies, and waning immunity in the vaccinated. Therefore in the future, we may very well see a higher risk than 10% susceptible to Measles and spread out to all age groups in the overall population.

Rubella and CRS

Rubella and Congenital Rubella Syndrome

 

     Rubella had a natural virulence cycle of every 6-9 years and was once a disease of school-aged child that was typically caught between the ages of 5-9 year old. 80% thus developed natural antibodies to Rubella and protected them into adulthood, while 15% remained susceptible to the disease. The goal of the Rubella vaccine program was to prevent fetal infection, or CRS, in women in the childbearing years who had not acquired natural immunity in childhood.  Unfortunately, the original goal has not been obtained. The exact opposite is occurring as young adult women in their childbearing years now have the highest rate of Rubella incidence. Is this a new phenomenon occurring in today’s generation? No. To spite the large Rubella vaccine program, since 1969 there has been a shift in incidence and a shift in age susceptibility.

 
 
 
 
 
 
 

 

              

“During the 1990s, the characteristics (ie, age distribution, sex, and race/ethnicity) of rubella cases changed significantly. In 1990, incidence was higher among children younger than 15 years than among persons aged 15 to 44 years… since the mid 1990s, incidence has increased among persons aged 15 to 44 years and decreased among children younger than 15 years. In 1990, children younger than 15 years accounted for 69% of cases. Since 1996, the highest percentage of cases occurred among persons aged 20 to 29 years, with a high in 1999 of 49%.  

  

     According to a 1980 Pediatrics study, the susceptibility rate of 6th graders was 15% in those vaccinated. (2) The susceptibility rate has remained the same rate as in the pre-vaccine era, even after the late 1970’s initiative to re-immunize all females during the child bearing years.

 

 

      

     Has the Rubella vaccine reduced Congenital Rubella Syndrome? You be the judge. Rubella was not a nationally notifiable disease until 1966. Rubella vaccine was licensed and recommended in 1969 for girls and boys in infancy and/or the preschool years, and then eventually recommended for adolescents. Since 1969, Rubella cases have declined, yet CRS cases increased after the introduction of the vaccine. In 1966, the pre-vaccine era, there were 11 cases of CRS. In 1969, after the introduction of the vaccine, there were 31 CRS cases. By 1970, there was an increase of 77 cases and in 1971, 68 cases. During the 1980’s, CRS cases declined once again but still remained higher than the pre-vaccination era. In 1992, there were 11 cases of CRS which is the same exact number of cases in 1966 before the Rubella vaccine was routinely used.  In 2000, there were 9 cases of CRS and in 2006, one case.

 

     As you can see, the Rubella vaccine has had little impact on reducing the number of CRS cases over the last 40 years since its introduction, yet it increased CRS cases in some years. There are even incidences were women had high levels of antibodies to Rubella before pregnancy, yet the babies had CRS. There are also some women who will never seroconvert (show positive antibodies) no matter how many times they are vaccinated.

      

     What has vaccination really accomplish if immunity wanes from infancy, if vaccinated young women are made more susceptible when they need immunity the most, and the increase in congenital rubella syndrome? Yet, natural immunity in early childhood can protect for a lifetime. Think about this statement made in 1964, before there was a Rubella vaccine implemented, by Dr. Hugh Paul in The Control Of Diseases:

     “The disease (rubella) cannot be prevented, and in view of its very mild character, and the possibility that it may have catastrophic effects if contracted by an expectant mother, it is questionable if it should be prevented in childhood and adolescence even if this were possible.  It has been suggested that female children should be deliberately exposed to infection in order to achieve a life-long immunity from the disease and possibly from malformation in the offspring in later life.  This idea is not an unreasonable one… Rubella does not kill, and even complications are uncommon.” 

 

      

 

 

 

 

 

 

 

Mumps

      The Mumps vaccine was developed for the protection of adult males who may not have acquired mumps in childhood and gained natural immunity. In the pre-vaccine era, and for more than 10 years after the recommended Mumps vaccine, children typically caught Mumps between 5-9 years of age. The shift in incidence from childhood to adolescents was seen in 1985 to 1988. Then in 1992, there was another shift as Mumps was increasing and occurring in adolescents and young adults (10-19 years old) and exceeded all other age groups. The exact opposite of what the vaccine was intended for has been occurring; despite large vaccine coverage rates in childhood.  It should also be noted that the seasonal pattern of Mumps from 1988-1993 was consistent with the pre-vaccine era.

 

     During the 2005-2006 outbreaks, 51% had received 2 doses of Mumps vaccine, yet the incident rate was highest in those aged 18-24 years. Even after the ACIP made new recommendations in the 1980’s, adolescents and adults in 1982, 1986, and 1987 had the highest infection rates. During the 1989-1991 outbreaks amongst children in primary and secondary school, the majority were vaccinated. From 1988-1993, 75% of Mumps cases were seen in adolescents over 15 years of age and young adults. This trend has continued.

      “The shift in higher risk for mumps to these other age groups (i.e., from younger children of school ages to older children, adolescents, and young adults) — which occurred after the routine use of mumps vaccine was initiated — has persisted despite minimal fluctuations in disease incidence that occurred in recent years among the various age groups.” ( The resurgence of Mumps in Young Adults and Adolescents. John D. Shanley, M.D. Shanley_07 [1] pdf, pg. 1-4.)

 

     Young adults in high school and colleges were the primary target of the 2006 Mumps outbreak, even though most (84%) had received 2 doses of MMR. The ACIP then recommended yet another Mumps ‘booster’ vaccine, and for CSTE to update its case definition.  2010 was the goal set for elimination of Mumps in the United States. That year appears to be no longer attainable.

          “Despite a high coverage rate with two doses of Mumps-containing vaccine, a large Mumps outbreak occurred, characterized by 2-dose vaccine failure, particularly among Midwestern college adults who probably received the second dose as school children.  A more effective Mumps vaccine or changes in vaccine policy may be needed…” 

      The Mumps vaccine program has essentially put all adult males at a greater risk, since it can be cause more complications in adulthood.  If the vaccine had only been offered to susceptible males and females after puberty, who had not acquired a natural case in childhood, we might very well see a different picture than we see today.  

Pertussis (Whooping Cough)

     In the pre-vaccine era, 93% of Pertussis cases occurred in children between 1-5 years old. Since the 1980’s, the high incidence rate shifted to children over 5 years of age and older. In 2005, booster vaccines were recommended for adolescents and adults between the ages of 11-64 years old.

 

      From 1985-1987, 25% of reported cases were in children 10 years of age and over. From 1995-1998, that number increased to 42%. The largest majority of cases have been in the vaccinated populations. During the 1980’s, 1990’s and 2000’s, the number of adolescents and adults acquiring Pertussis has increased to spite high vaccination rates. (1) (2) (3) (4) (5)

              “Although pertussis incidence remains highest among young infants, rates are also on the rise in adolescents and adults and there may be significant under-reporting in these age groups, especially those with mild or atypical infection. Compared with surveillance data from 1994 to 1996, the pertussis incidence rate among adolescents and adults increased 62% and 60%, respectively, from 1997 to 2000.”

 

     There has also been an increase in babies under 1 year acquiring Pertussis. The number of cases in babies under 3 months of age from 1990-1997 did not lower. From 1999-2000, 48% of cases were in this age group. In 2001, 62% were under 3 months old. (6)

 

     According to a 2000 CDC MMWR report: “Despite record high vaccination coverage levels with 3 doses of DTaP among U.S. children aged 19–35 months, pertussis continues to cause fatal illness among vulnerable infants. During 1980–1998, the average annual incidence of reported pertussis cases and deaths among U.S. infants increased 50%. The increased morbidity and mortality occurred primarily among infants aged <4 months, who were too young to have received the recommended three DTaP vaccinations at ages 2, 4, and 6 months.” (7)

 

 

     Pertussis has always been endemic despite a vaccine.  It has a natural circulation every 2-5 years. This has not changed since the introduction of the vaccine, and thus indicates that the vaccine may prevent some disease, but has had little impact on transmission amongst the population. The efficacy of the DTaP is roughly 85% effective but waning immunity occurs after 2-5 years. In a case controlled study, it was found that infants of adolescent Mothers, aged 15-19 years, were 6 times more likely to acquire Pertussis compared to infants of older Mothers aged 20-29 years. Death from Pertussis is rare today. The majority of deaths, 90%, are in babies under 6 months of age. DTaP is also a reactive vaccine which means it does not prevent carriage or transmission of the disease. Therefore, vaccinated adolescents, adults and children can serve as reservoirs and transmitters to unprotected infants. (8) (9)

 

 

     Some epidemiologists believe B. Pertussis has mutated by changing its DNA and genetic coding.  Scientists in the Netherlands observed changes in the structure of the circulating wild-type bacteria when compared with those who were vaccinated. The differences were the outer membrane protein pertactin and the pertussis toxin itself. Similar genetic changes have been observed in Poland, Finland and the U.S. Any changes would thus render mutated bacteria immune to vaccination. As far as changing its character, many new cases lack the common ‘whoop’, yet 30% of cases were infected. Some cases were misdiagnosed as atypical asthma.(10) (11)

 

 

     In 2005, Tdap vaccines were recommended for adolescents over age 9 and adults under age 65 due to waning immunity from the DTaP vaccine given in infancy or childhood. There are no pertussis vaccines approved for children 7–9 years of age or for persons older than 64 years. The efficacy is similar and ‘inferred’ to that of DTaP. It is unknown if immunizing adolescents and adults will actually reduce the risk of transmission to infants. Nor is it known how long this vaccine may provide some people with protection. (12)

 

     

In the early 1900’s, it was questioned whether the control of Whooping Cough was even practicable. It has and remains to this day a more severe disease in infancy than in any other age group. A vaccine has not changed that fact. Generations passed have always known that the proper care in treatment of whooping cough would not lead to fatality, and most fatalities were the result of other complications mainly in the immune suppressed. (15)

 

 

Footnotes: 

 

       1.        Medscape Today. Epidemiology and Transmission of Disease. http://www.medscape.com/viewarticle/549508_2

 

2.        CDC MMWR, September 05, 1997 / 46(35);822-826. Pertussis Outbreak Vermont, 1996.  http://www.cdc.gov/mmwr/preview/mmwrhtml/00049244.htm

 

3.        The New England Journal of Medicine. Vol. 331:16-21. July 7, 1994. The 1993 Epidemic of Pertussis in Cincinnati — Resurgence of Disease in a Highly Immunized Population of Children.  http://content.nejm.org/cgi/content/full/331/1/16

 

4.        CDC MMWR, March 27, 1987 / 36(11);168-71. Epidemiologic Notes and Reports Pertussis Surveillance — United States, 1984 and 1985. http://www.cdc.gov/mmwR/preview/mmwrhtml/00000893.htm

 

5.        See #1

 

6.        CDR Weekly 21, June 2001. Enhanced surveillance of laboratory confirmed cases of Bordetella pertussis, England and Wales: 1999 to January-March quarter 2001. www.hpa.org.uk/cdr/archives/2001/cdr2501.pdf

 

7.        CDC, MMWR. July 19, 2002 / 51(28);616-618 Pertussis Deaths — United States, 2000. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5128a2.htm

 

8.        Medscape Today. Epidemiology and Transmission of Disease. http://www.medscape.com/viewarticle/549508_2

 

9.        Clinical Infectious Diseases.Epidemiological, Clinical, and Laboratory Aspects of Pertussis in Adults. 01 JUNE 1999 Supplement, Volume 28, Number S2.  James D. Cherry. http://www.journals.uchicago.edu/toc/cid/28/s2

 

8.        Medscape Today. Epidemiology and Transmission of Disease. http://www.medscape.com/viewarticle/549508_2

 

9.        Clinical Infectious Diseases.Epidemiological, Clinical, and Laboratory Aspects of Pertussis in Adults. 01 JUNE 1999 Supplement, Volume 28, Number S2.  James D. Cherry. http://www.journals.uchicago.edu/toc/cid/28/s2

 

10.     See #9.

 

11.     Emerging Infectious Diseases. Changes in Predominance and Diversity of Genomic Subtypes of Bordetella pertussis Isolated in the United States, 1935 to 1999.Terri Hawes Hardwick, et al. http://www.cdc.gov/ncidod/EID/vol8no1/01-0021.htm

 

12.     Adacel Tdap Package Insert. www.fda.gov/cber/label/adacelLB.pdf

 

13.     IS THE CONTROL OF MEASLES AND WHOOPING-COUGH PRACTICABLE? Am J Public Health (N Y). 1916 March; 6(3): 265–268. FRANCiS GEORGE CURTIS, M. D., Chairman, Board of Health, Newton, Mass. Read at a General Session of the American Public Health Association, Rochester, N. Y., September 10, 1915.

 

14.   Whooping Cough. Am J Public Health Nations Health. 1936 May; 26(5): 523–524.

 

15.     A STATISTICAL STUDY OF WHOOPING COUGH. FREDERICK S. CRUM, PH. D., Am J Public Health (N Y). 1915 October; 5(10): 994–1017.