PERTUSSIS AND LEGIONELLOSIS

Transcription

1 by George A. Wistreich Ph.D., F(AAM) RC Educational Consulting Services, Inc Van Buren Blvd, Suite B, Riverside, CA (800) 441-LUNG / (877) 367-NURS

2 BEHAVIORAL OBJECTIVES UPON COMPLETION OF THE READING MATERIAL, THE PRACTITIONER WILL BE ABLE TO: 1. Describe the general properties of the two genera Bordetella and Legionella. 2. Summarize the epidemiological factors associated with pertussis (whooping cough), Legionnaires disease and Pontiac fever syndrome. 3. Briefly discuss the virulence factors associated with Bordetella pertussis and Legionella pneumoniae. 4. List the diseases caused by members of the genera Bordetella and Legionella. 5. Briefly describe the means of transmission involved with pertussis and Legionnaires disease. 6. Describe the pathogenesis of pertussis and Legionnaires disease. 7. Describe the clinical features of pertussis, Legionnaires disease, and related disease syndromes. 8. Outline the general laboratory approach used to identify Bordetella pertussis and Legionella pneumoniae. 9. Briefly describe the approaches followed in the treatment of pertussis and Legionellacaused diseases. 10. Discuss the possibility of immunity to reinfection resulting upon recovery from pertussis and Legionnaires disease. 11. Briefly describe the approaches to the prevention and control of pertussis and Legionnaires disease. 12. Describe the general properties of pertussis vaccines and their application. 13. Briefly discuss the nature of, and the problems associated with pertussis vaccines. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 2

3 COPYRIGHT 2003 By RC Educational Consulting Services, Inc. TX Authored by: George A. Wistreich, Ph.D., F(AAM) 2003 Revised by: George A. Wistreich, Ph.D., F(AAM) 2007 Revised by: George A. Wistreich, Ph.D., F(AAM) 2008 ALL RIGHTS RESERVED This course is for reference and education only. Every effort is made to ensure that the clinical principles, procedures and practices are based on current knowledge and state of the art information from acknowledged authorities, texts, and journals. This information is not intended as a substitution for a diagnosis or treatment given in consultation with a qualified health care professional. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 3

4 TABLE OF CONTENTS PREFACE...7 INTRODUCTION...7 THE GENUS, BORDETELLA...8 PERTUSSIS (WHOOPING COUGH)...8 HISTORICAL ASPECTS OF THE DISEASE...8 EPIDEMIOLOGY...9 TRANSMISSION...9 PROPERTIES OF BORDETELLA PERTUSSIS...10 MICROSCOPIC FEATURES...10 CULTURAL CHARACTERISTICS...10 VIRULENCE FACTORS...11 THE DISEASE...11 PATHOGENESIS...12 CLINICAL MANIFESTATIONS...12 THE STAGES...13 LABORATORY DIAGNOSIS...13 SPECIMENS...13 TREATMENT...14 SIDE EFFECTS...15 PREVENTION AND CONTROL...15 This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 4

5 VACCINES...16 CURRENT VACCINES...16 BOOSTER VACCINES FOR ADOLESCENTS AND ADULTS...17 VACCINE SHEDULE...17 A CATCH-UP SCHEDULE FOR CHILDREN...17 SIDE EFFECTS...18 THE QUESTION OF IMMUNITY...18 LEGIONELLOSIS AND THE LEGIONELLA...18 HISTORICAL ASPECTS...19 LEGIONNAIRES DISEASE...19 EPIDEMIOLOGY...19 HABITAT...19 ENVIRONMENTAL RESISTANCE...20 TRAVEL-ASSOCIATED LEGIONNAIRES DISEASE...20 COMMUNITY OUTBREAKS AND PREVENTION...20 NOSOCOMIAL OUTBREAKS AND PREVENTION...21 PROPERTIES OF THE GENUS LEGIONELLA...21 MICROSCOPIC FEATURES...21 CULTURAL CHARACTERISTICS...21 VIRULENCE FACTORS...22 LEGIONELLA PNEUMOPHILA...22 THE DISEASE...22 This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 5

6 RISK FACTORS...22 PATHOGENESIS...22 TRANSMISSION...23 CLINICAL MANIFESTATIONS...23 PONTIAC FEVER...23 LEGIONNAIRES DISEASE...23 LABORATORY DIAGNOSIS...24 SPECIMENS...24 DIFFICULTIES OF DIAGNOSIS...24 TREATMENT...25 PREVENTION AND CONTROL...25 THE QUESTION OF VACCINES...26 CONCLUDING STATEMENTS...26 GLOSSARY...27 PRONUNCIATION GUIDE...27 TERMINOLOGY...28 SUGGESTED READING AND REFERENCES...30 This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 6

7 PREFACE There are several barriers to overcome in the long-term mission of controlling or eliminating several infectious diseases. This course is concerned with two of such diseases, namely pertussis and legionellosis. It is not uncommon to ask the question, why is there still a concern about pertussis (whooping cough) in this day and age, since the general perception persists that this is a pediatric illness, well controlled with the present immunization program in the United States? The control of pertussis has become much more complicated in recent years, especially in light of the large number of reports showing an increase in the proportion of pertussis cases in age groups older than 10 years. Although pertussis rates are highest during infancy, it is important to recognize the fact that this disease can affect persons of any age. This disease can occur as a mild or moderate cough illness in persons who are partially immune. Full appreciation of the Legionnaires disease role other than an exotic disease has only come in the past several years. Outbreaks of Legionnaires disease in hotels, cruise ships, and office buildings have contributed to its recognition as a more wide spread illness by the news media. Legionella pneumophila, the cause agent of legionellosis is considered to be among the top three or four microbial causes of community-acquired pneumonia. This course presents the features of pertussis and legionellosis, and their respective bacterial causes. INTRODUCTION This course primarily concentrates on two significantly important infectious diseases, namely pertussis (whooping cough) and legionellosis. Despite the effectiveness of vaccination, pertussis continues to occur in the United States among all age groups. Unfortunately, the burden of the disease remains highest in infants, who also have the highest rates for complications and death. Abbreviations Used AAP: American Academy of Pediatrics ACIP: Advisory Committee on Immunization Practices ap: acellular pertussis BAL: bronchial alveolar lavage C: Celsius CDC: Centers for disease Control and Prevention DFA: direct fluorescent antibody DNA: deoxyribonucleic acid DTP: diphtheria and tetanus toxoids DtaP: diphtheria, tetanus toxoids and acellular pertussis (the combined vaccine) FDA: Food and Drug Administration This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 7

8 g: gram kg: kilogram LD: Legionnaires disease mg: milligram mm 3 : millimeter PCR: polymerase chain reaction PD: Pontiac fever S: sulfamethoxazole T: trimethoprim U.S.: United States WHO: World Health Organization THE GENUS, BORDETELLA The bordetellae are tiny Gram-negative rods (coccobacilli), occurring singly or in pairs. Cells frequently exhibit a bipolar (stain more pronounced at opposite ends of cells) appearance. Members of the genus are strict aerobes, nonspore-forming, and grow best at 35 o C. Only two pathogenic species are recognized, namely Bordetella pertussis, the cause of pertussis (whooping cough), and B. bronchiseptica, a well-known pathogen of lower animals such as dogs, rabbits, and swine. B. bronchiseptica may localize at a body site in infected animals. There are case reports citing its detection in wounds, sputum, and various body fluids. PERTUSSIS (WHOOPING COUGH) Among the diseases for which universal childhood vaccination is recommended, only pertussis (whooping cough) has increased in incidence in the United States since the early 1980s. From various studies it is quite apparent that the demographics of this disease has changed, especially in the case of adolescents and adults. Both such individuals might be a reservoir for Bordetell pertussis in communities, since immunity from childhood vaccination decreases beginning 5 to 15 years after the last immunization with a dose of the pertussis vaccine. Despite an increasing recognition of pertussis as a disease affecting older children and adults, the disease often is overlooked in the differential diagnosis of a cough illness. Clinicians might not consider pertussis as a cause of illness. Adults with pertussis can exhibit mild signs and symptoms and might not seek medical care. Pertussis can be highly infectious during the 3 weeks following the onset of the disease. Moreover, infection can spread to exposed infants, who have the highest rates for complications and death. Historical Aspects of the Disease Pertussis was a major cause of morbidity and mortality among infants and children in the United States during the pre-vaccine era, which was before the mid-l940s. Following the introduction and widespread use of a whole bacterial cell (Bordetella pertussis) vaccine combined with diphtheria and tetanus toxoids among infants and children in the late 1940s, the incidence of reported pertussis cases was reduced to an all-time historic low of 1,010 cases in Unfortunately, since the early 1980s, cases of the disease have increased cyclically with peaks This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 8

9 appearing every 3 to 4 years. Epidemiology Surveillance information concerning the number of pertussis cases and the effectiveness of vaccination against pertussis use the following definitions: 1. Clinical case of pertussis: an acute cough illness lasting 14 days or longer occurring in an individual with at least one pertussis-associated sign such as a sudden (paroxysmal) cough, post-cough vomiting; or an inspiratory whoop (the characteristic convulsive, inspiratory harsh loud sound following the paroxysmal cough, or 14 days or longer of coughing in an individual living in an outbreak setting). Transmission Figure 1: A child experiencing a paroxysmal cough. Courtesy of World Health Organization 2. Confirmed case of pertussis: a cough illness of any duration in an individual from whom Bordetella pertussis was isolated, or a condition that meets the clinical case definition and is confirmed by the laboratory diagnostic test known as the polymerase chain reaction (PCR), or by epidemiological connection (linkage) to a laboratoryconfirmed case. 3. Probable case of pertussis: a condition meeting the clinical case definition, but is not laboratory-confirmed, or epidemiological linked to a laboratory-confirmed case of the disease. Bordetella pertussis is transmitted from person-to-person by aerosolized droplets from a cough This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 9

10 or sneeze, or by direct contact with respiratory tract secretions of infectious individuals. Pertussis is highly contagious. Secondary spread in families, schools, and health care facilities is common, although often not recognized, due to the mildness of the signs and symptoms in immunized individuals. Adult cases with signs and symptoms resembling the common cold represent a significant reservoir of B. pertussis, and have been a source of outbreaks in highly susceptible populations, such as newborns. B. pertussis enters the body by the mouth and nose and is discharged in buccal and nasal secretions, and sticky sputum that is coughed up by the infected individual. Pertussis should be suspected in persons of any age with acute cough illnesses. Nasopharyngeal specimens should be obtained from such persons for culture purposes. Recognizing pertussis outbreaks in educational institutions can be difficult for several reasons. These include: 1) individuals usually do not seek medical care early, 2) a diagnosis of pertussis might be delayed or not even considered, and 3) the sensitivity and specificity of appropriate diagnostic tests will be low in the event nasopharyngeal specimens are not taken and transported to the laboratory in time and under the best of conditions. Adolescents and adults with unrecognized or untreated pertussis contribute to the reservoir of B. pertussis in the community. Properties of Bordetella Pertussis Bordetella pertussis was first observed in the sputum of patients with whooping cough by Jules Jean Baptiste Bordet and Octave Gengou in Hence at times, the pathogen is referred to as the Bordet-Gengou bacillus. Microscopic Features. B. pertussis is typically a small Gram-negative, nonmotile, nonsporeforming coccobacillus that may exhibit bipolar staining. The pathogen often forms an enclosing polysaccharide capsule that contributes to its disease causing ability (virulence), and protects it s normal host defense processes. B. pertussis also possesses submicroscopic pure protein structures known as pili. These cellular parts, also known as fimbriae, aid in the attachment of the pathogen to susceptible ciliated bronchial epithelium. Cultural Characteristics. The culturing of B. pertussis can pose problems. Specimens for isolation, as a later section indicates, are best obtained using a wire calcium alginate or Dacron nasopharyngeal swab. Cotton swabs should not be used for specimen collection because cotton fibers contain fatty acids, which inhibit the growth of the pathogen. Freshly isolated from the body, B. pertussis grows on special media containing blood. The media routinely used are: 1) a glycerin-potato-blood preparation known as Bordet-Gengou agar; and 2) a charcoal, cephalexin, and sheep s blood combination called Regan-Lowe agar. After incubation of up to 10 days, colonies appear with pearl-like or drops of mercury characteristics. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 10

11 B. pertussis can be differentiated from other Bordetella species on the basis that biochemically the pathogen produces the enzymes catalase and oxidase. Virulence Factors. B. pertussis produces five products that contribute to the severity of the disease it causes. These are as follows: 1. Adenylate cyclase: an enzyme that inhibits phagocytosis of B. pertussis by the host. 2. Dermonecrotic toxin: a heat-labile toxin that causes vascular smooth muscle contraction, which results in necrotic lesion at locations of bacterial reproduction. 3. Filamentous hemagglutinin: a surface protein located on the organism s cell wall, and aids in its attachment onto respiratory surfaces. 4. Pertussis toxin: an exotoxin that increases histamine release and enhances other aspects of the host s inflammatory response (cholera and diphtheria exotoxins act in a similar manner). 5. Tracheal cytotoxin: a protein that immobilizes tracheal cilia, inhibits host DNA synthesis, causes tissue necrosis and the ultimate death of ciliated epithelial cells, and brings about airway obstruction as the pathogen establishes itself in the host (colonization). THE DISEASE The term pertussis refers to the intensive cough exhibited by patients (Figure 2). The whooping (hooping) stage is not found with all cases, but it has given the disease its original name. Bouts of coughing can last so long that patients deprived of oxygen, are caused to forcefully draw air back into their lungs with the characteristic whoop. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 11

12 Pathogenesis Figure 2: A child experiencing the painful whoop of a typical pertussis case. Courtesy of American Academy of Pediatrics When introduced into the respiratory tract, B. pertussis attaches to ciliated respiratory epithelial cells in the bronchi and trachea. Attachment is generally controlled by several factors including pili, filamentous hemagglutinin, and an outer membrane protein of the pathogen called pertactin. As B. pertussis reproduces, it produces the various virulence factors described earlier. Among the first effects caused by these factors is the immobilization of cilia. This action begins a sequence of reactions in which ciliated epithelial cells are progressively destroyed and forced out from the epithelial border. Subsequently, local tissue damage by the dermonecrotic toxin results in the clinical signs and symptoms of the first or catarrhal stage of pertussis. The clinical features of this as well as the other stages of the disease are described in the next section. Clinical Manifestations For purposes of detection and diagnosis, a distinction should be made among clinical, confirmed and probable cases of pertussis. A clinical case of the disease is defined as an acute cough illness lasting 14 or more days in an individual with at least one sign characteristic of pertussis such as a paroxysmal cough, post-tussive vomiting, or inspiratory whoop. A confirmed case of pertussis is defined as a cough illness of any duration with the isolation of Bordetella pertussis or a case that is consistent with the clinical case definition described earlier, and a laboratory confirmation by means of the polymerase chain reaction (PCR) or linked to an epidemiologically confirmed case of the disease. A probable case of the disease is one that meets the clinical case defintion, but is not laboratory confirmed or linked to an epidemiologically laboratory-confirmed case of the disease. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 12

13 The Stages Pertussis has an insidious onset with catarrhal signs and symptoms and include nasal congestion, runny nose, mild sore-throat, mild dry cough, and minimal or absence of a fever. These signs and symptoms can be indistinguishable from those found with minor respiratory tract infections. After an incubation period of 7 to 10 days, pertussis follows a prolonged course consisting of the following three overlapping stages: 1. Catarrhal stage: occurs from week 0 to 1; the onset is insidious; infants have a mild fever, a non-productive cough, and exhibit coryza; some may exhibit a temporary stopping of breathing and/or respiratory distress. Individuals experiencing this stage are the most infectious, and may continue to be so during the first three weeks after the onset of the next stage (paroxysmal stage). 2. Paroxysmal stage: occurs from week 2 to 6; episodes of paroxysmal coughing occur up to 50 times/day for 2 to 4 weeks; the characteristic whoop follows a series of coughs as air is drawn through a narrowed glottis; other signs and symptoms include vomiting following the whoop (post-tussive vomiting), production of large amounts of mucoid secretions, respiratory distress, and the laboratory finding of a significant increase in lymphocytes with counts up to 40,000/mm 3 ; pneumonia is a common occurrence with infants. 3. Convalescent stage: occurs from week 3 to 12; the frequency and severity of paroxysmal coughing and the other signs and symptoms gradually fade. A nonparoxysmal cough can continue for a period of 2 to 6 weeks or longer. Partially immune individuals and infants under 6 months of age may not exhibit all the typical signs and symptoms of pertussis. The most common complication of pertussis is a pneumonia resulting from a secondary infection caused by Streptococcus pneumoniae. Other complications include seizures, encephalopathy, hemorrhaging events caused by high blood pressure exerted during coughing episodes, and coma. Laboratory Diagnosis Specimens. Specimens for laboratory isolation and culture of Bordetella pertussis include nasopharyngeal swabs or nasopharyngeal aspirates. Such specimens should be obtained within two weeks of the cough onset. Laboratory confirmation of the clinical diagnosis of pertussis includes attempts to culture B. pertussis from a nasal pharyngeal aspiration or a swab obtained during the catarrhal stage. Bordet-Gengou or Regan-Low media are used for this purpose. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 13

14 The use of the direct fluorescent antibody (DFA) staining procedure is the most rapid diagnostic approach. However, while it is highly specific, it is estimated to be only 60 per cent sensitive. A positive result is diagnostic but not always confirmatory. Furthermore a negative result does not rule out a case of pertussis. The polymerase chain reaction assay technique in addition to bacterial culture also is currently an acceptable diagnostic test to confirm a clinically diagnosed case of pertussis. Treatment The choice of antimicrobal agents for purposes of treatment and/or prevention should take into account factors such as: 1) effectiveness, 2) safety, which includes the potential for adverse events and drug interactions, 3) tolerability, and 4) cost. The recommended treatment for pertussis involves a 14-day course of erythromycin. The administration of the antibiotic should be given according to the following schedule: 1. Children - 40 to 50 milligrams(mg)/kilogram(kg) of body weight/day (the antibiotic should be divided into four doses). 2. Adults - 2 grams (g)/day (the antibiotic should be divided into four doses). Two additional macrolides, clarithromycin and azithromycin also can be used for the treatment of pertussis in persons aged 1 month and older. Azithromycin is preferred for the treatment of infants aged 1 month or younger. Erythromycin and clarithromycin are not recommended for this age group. Trimethoprim(T)-sulfamethoxazole(S) can be used alternatively for the treatment of persons aged 2 months and older according to the following schedule: 1. Children - (T): 8 mg/kg/day; (S): 40 mg/kg/day (the drug combination should be divided into two doses); 2. Adults - (T): 320 mg/day; (S): 1600 mg/day (the drug combination should be divided into two doses); Infants aged less than 1 year should be treated within 6 weeks of cough onset. Persons aged 1 year or older should be treated within 3 weeks of cough onset. School-aged children and working adults should be excluded from school and the work place respectively, for the first 5 days of the cough onset. Antibiotic treatment of the disease and the judicious use of antimicrobial drugs for postexposure prevention will eradicate B. pertussis from the nasopharynx of both asymptomatic and symptomatic individuals. The administration of a macrolide antibiotic such as erythromycin, This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 14

15 early in the course of the pertussis can reduce the duration and severity of the signs and symptoms of the disease. In addition, this approach can lessen the period of communicability of the disease agent. Side Effects. Table 1 summarizes the general side effects reported to occur among some patients with the macrolides. Table 1. Side Effects Reported with the Macrolides Macrolide Azithromycin Clarithromycin Erythromycin Reported Side Effects abdominal discomfort or pain, diarrhea, nausea, vomiting, headache, and dizziness epigastric distress, abdominal cramps, nausea, vomiting, and diarrhea; hypersensitivity reactions such as skin rashes, drug-associated fever, hepatotoxicity,and anaphylaxis are rare epigastric distress, abdominal cramps, nausea, vomiting, and diarrhea; hypersensitivity reactions such as skin rashes, drug-associated fever, sensorineural hearing loss have occurred, but are rare Prevention and Control Outbreaks of pertussis in adults are largely controlled with the prompt treatment of patients and antimicrobial prophylaxis for their close contacts. The dosages specified for the 14-day course of antibiotic administration described in the Treatment section is the same one recommended for close contacts. Such treatment should be given to the following groups: 1. Individuals aged one year or older should receive treatment within 3 weeks of exposure. 2. Infants under one-year of age should receive treatment within 6 weeks of exposure. In addition, the combined vaccine containing the diphtheria, and tetanus toxoids, and acellular B. pertussis (DTaP) should also be given to individuals aged 6-weeks to under seven years of age. (It should be noted that the DTaP vaccine is as of yet not licensed for individuals 7 years or older. In addition to the above procedure children aged 6-weeks to those under seven year of age should be vaccinated with DTaP. Maintaining high vaccination coverage rates among pre-school children, adolescents, and adults and minimizing exposures of infants and persons at high risk for pertussis is the most effective way to prevent and control the disease. All cases of suspected pertussis cases should be reported to local and state health departments as This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 15

16 soon as possible. VACCINES Effective pertussis programs require the immunization of young infants beginning at 2 months of age, because the morbidity and mortality of the disease is greatest in infants, especially those younger than 6 months of age. Individuals who were immunized against as infants may still be susceptible to infection with Bordetella pertussis because immunity resulting from immunization wanes after five to ten years. Current Vaccines A whole-cell vaccine, which has been in use for many years, contains a suspension of inactivated B. pertussis, and is combined with diphtheria and tetanus toxoids in the preparation known as DPT. Since this vaccine has a history of a high incidence of associated local and systemic reactions, it has been the basis of controversial and even at times, emotional, issues in many countries. Various groups have argued that permanent neurologic sequelae are occasionally caused by the vaccine associated with it. Critical epidemiologic analyses of available data do not support such claims. In order to reduce the incidence of adverse reactions, acellular (cell-free) pertussis (ap) vaccines consisting of one or more purified components and/or products of Bordetella pertussis have been developed and combined with diphtheria and tetanus toxoids into DTaP vaccines (Table 2). (A toxoid is a toxin that has been processed to inactivate its toxicity, but still keep its capability to induce antibody (anti-toxin) formation.) Table 2. Diphtheria, Tetanus, Acellular Pertussis (DTaP) Combined Vaccines Vaccine Trade Name Manufacturer Date of US Licensure Dose in Approved for Series ACEL-IMMUNE Lederle Laboratories Certiva Baxter Hyland Immuno Vaccine DAPTACEL Aventis Pasteur, Ltd (Toronto, Canada) Infanrix Glaxo SmithKline Tripedia Aventis Pasteur Several acellular vaccines have been formulated from different B. pertussis components and have been clinically tested. All vaccines contain detoxified pertussis exotoxin (pertussis toxoid). In addition, most vaccines contain one or more of the following B. pertussis components, which are antigenic: 1) filamentous hemagglutinin, 2) peractin, and 3) pili (fimbrial) proteins. Five acellular vaccines are approved for the primary vaccination series for infants. Two of these preparations, ACEL-IMUNE and Certiva, were withdrawn from use in the United States, in Tripedia is currently licensed for the recommended five-dose DTaP vaccination series. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 16

17 DAPTACELL and Infanrix are licensed for the first four doses of the vaccination series (Table 1). DTaP vaccines might have a future role in the prevention and control of pertussis outbreaks in older age groups. Booster Vaccines for Adolescents and Adults Two booster vaccines for adolescents were approved by the Food and Drug Administration in The preparation known as BOOSTRIX (GlaxoSmithKline Biologicals, Rixenstart, Belgium) was licensed on May 3, 2005, for use with individuals aged years. Another vaccine ADACEL (Sanofi Pasteur, Toronto, Canada) was licensed on June 10, 2005, for use with persons aged years. Vaccine Schedule In addition to maintaining high vaccination rates among preschool-aged children, prevention efforts should be directed at: 1) treatment of pertussis cases to prevent further spread of the disease, 2) the use of antimicrobial prophylaxis in pertussis case contacts, and 3) minimizing infant exposures to children and with cough-associated illnesses. Pertussis vaccination is routinely recommended for children at 2, 4, and 6 months of age, followed by a fourth dose at 12 to 18 months of age and a fifth dose at 4 to 6 years of age. As of January 2000, the ACIP and the American Academy of Pediatrics (AAP) recommend exclusive use of acellular pertussis (DTaP) vaccines for all doses of the pertussis immunizations. The DPT vaccine is no longer an acceptable alternative preparation. This is largely because of its higher rates of local adverse reactions including pain and swelling at sites of vaccine administration, fever, and other systemic reactions. The ACIP also recommends that whenever feasible, the same brand of DTaP vaccine is used for all doses in a vaccination series. In the event the vaccine provider does not know, or does not have available the type of vaccine used previously, any of the licensed vaccine preparations can be used to complete the immunization schedule. A Catch-Up Schedule for Children. For the first time the CDC s Advisory Committee on Immunization Practices presented a catch-up immunization schedule for children and adolescents who start late or who are more than one month behind. This schedule, which was published in the January 31, 2003 issue of Morbidity and Mortality Weekly Report, lists the minimum ages and minimum intervals between doses for each of the routinely recommended childhood and adolescent vaccines. The schedule for DTaP for children aged 4-months to 6 years is shown in Table 3. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 17

18 Table 3. DTaP Catch-Up Schedule for Children Aged Four-Months to Six Years Minimum Interval Between Doses Dose 1 Dose 1 to Dose 2 to Dose 3 to Dose 4 to Dose 2 Dose 3 Dose 4 Dose 5 a Minimum age 4 weeks 4 weeks 6 months 6 months 6 weeks a The fifth dose is unnecessary if the 4 th dose was given after the 4 th birthday. Side-Effects Local and febrile reactions to whole cell vaccines are commonly reported among half of DPT recipients. These effects usually develop within the first 24 hours and fortunately, are of brief duration. The occurrence of such reactions following administration of DTaP vaccines is significantly lower. However, the rates of local reactions increase with each subsequent dose of DTaP vaccine. Severe reactions to acellular vaccines are rare. Booster doses may cause extensive local swelling. This type of response is generally associated with vaccines having a high diphtheria toxoid content. THE QUESTION OF IMMUNITY Humans do not have a natural immunity to pertussis. However, an attack and recovery, results in a long-lasting immunity. At one time, vaccination was assumed to provide a permanent state of immunity to the disease. Unfortunately, such is not the case as evidenced by recent outbreaks of pertussis involving previously immunized older persons. Vaccine-induced protection wanes with time. LEGIONELLOSIS AND THE LEGIONELLA Legionellosis classically takes 1 of 2 clinical forms, Legionnaires disease (LD), a severe multisystem disease involving pneumonia, and Pontiac fever (PF), a self-limited flu-like illness. Legionnaires disease has had and continues to have a false reputation of being an exotic infection. In reality, LD is a common form of severe pneumonia. It is estimated that from 8,000 to 18,000 cases of community-acquired legionellosis occur each year in the United States. Legionella pneumophila is considered to be a high-risk pathogen in community-acquired pneumonia, accounting for a substantial number of cases among immunocompetent individuals. Outside of research settings, confirmed diagnoses are infrequent. Such failures to diagnose Legionnaires disease in routine practice is mainly the consequence of three factors: 1) the inability to clinically and radiologically distinguish LD from other causes of pneumonia; 2) a lack of awareness of the disease coupled with the failure on the part of the clinician to order diagnostic tests for Legionella; and 3) the limited sensitivity of available laboratory tests to This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 18

19 detect clinically important legionellae. It should be noted that earlier recognition of Legionella pneumonias by means of urine antigen testing and new models of patient management have contributed to reductions in case fatality rates. HISTORICAL ASPECTS I n July and August of 1976, the world s attention was riveted to what might be considered a modern detective story. During the celebration of the Bicentennial of the 1776 Declaration of Independence, great interest was focused on the Bellevue-Stratford Hotel in downtown Philadelphia, which was the location of the 58 th annual convention of the American Legion s Pennsylvania branch. In most respects the gathering was a typical legionnaires convention, with some 4,400 delegates, members of their families, and other conventioneers on hand for a variety of activities that are customary for such events. Between July 22 nd and August 3 rd, 182 conventioneers were struck by a puzzling illness characterized by fever, coughing, and pneumonia, and unfortunately, 29 deaths related to the illness subsequently occurred. Since most of the convention attendees had returned to their homes before becoming ill it was not until August 2 nd that reports to the Pennsylvania Department of Health provided the basis for the claim that an epidemic had developed among those at the convention. News of a devastating respiratory disease epidemic among American legionnaires made major headlines for the news media. This date marked the beginning of one of the largest and most complex investigations of an epidemic ever undertaken. It was not until 6 months later that the cause of the illness, Legionella pneumophila, was identified and named after the American Legion. The cases of pneumonia subsequently caused by a number of Legionella species have retained the name Legionnaires Disease In addition to pneumonia, the most common manifestation, legionellae are associated with other clinical syndromes. These include: myocarditis, pericarditis, prosthetic valve endocarditis, and renal and tissue abscesses. EPIDEMIOLOGY Habitat. Legionellae are found worldwide in many natural habitats, particularly where standing bodies of fresh water are found, such as lakes, ponds, thermally polluted water-sand streams. Left to their natural state, legionellae would be an extremely rare cause of human disease, as natural freshwater environments have not been implicated as reservoirs of legionellosis outbreaks. The fact that Legionella longbeachae has been isolated from soil, poses the possibility that soil is the natural habitat for Legionella species. Legionellosis is a disease that has emerged in the last half of the 20 th century because of human-caused alterations of the environment. Legionellae survive in aquatic and moist soil environments as intracellular parasites of freeliving protozoa. These bacteria have been shown to multiply in a variety of protozoa that function as reservoirs for their survival in water environments. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 19

20 Legionellae are tolerant to chlorine and thus survive water-treatment processes and pass into human-made distribution systems. Such systems provide habitats and favorable growth conditions such as physical shelter, nutrients within biofilms, and most important, warm temperatures. Systems of this nature include: drinking fountains, evaporative condensers of airconditioning systems, hot-tubs, mist-generators, showerheads, water-cooling towers, and whirlpools. These devices often create aerosols that can disperse Legionella species into the air where they can be easily inhaled. Environmental Resistance. The legionellae are capable of tolerating both low and high temperatures easily. They can remain viable in groundwater at 4 o C. for significantly long periods, and can grow at temperatures as high as 50 o C. However, these bacteria are killed in water heated to 80 o C. and maintained for 30 minutes. Chlorination of 2 parts per million is effective in destroying legionellae. In addition, sunlight, and some common disinfectants are also effective in destroying these bacteria. Travel-Associated Legionnaires Disease. Travel-associated outbreaks of LD are difficult to detect for several reasons including: 1) attack rates are low, meaning that no clinician is likely to see more than one case; 2) the incubation period is long, which allows infected persons to leave the area in which they acquired the infection; and 3) surveillance is poor, which poses difficulties in connecting cases epidemiologically. For surveillance to be effective for travel-associated illness it needs to be timely, and should contain an epidemologic component that connects exposure to hotels, cruise ships, or other travel-associated locations, and a laboratory component so that isolated microorganisms can be identified and matched to one another. Whirlpool spas have been identified as sources for both Pontiac fever and Legionnaires disease, and have been associated with outbreaks in hotels and on cruise ships. Because spas are common features of hotels and cruise ships, they may have a significant role in travel-associated legionellosis. Publicly used whirlpool spas generally have a much heavier use than those located in homes and other private locations. The heavier use (bather load) can easily compromise the disinfectant concentration and facilitate the transmission of legionellae and other pathogens. Appropriate disinfectant concentrations and filter disinfection practices can minimize the potential for legionellae growth and transmission. Hotels and cruise ships must assume the responsibility for properly maintaining their facilities and for maintaining appropriate water conditions in whirlpool spas and related locations. Community Outbreaks and Prevention. The incidence of community-acquired legionellosis caused by Legionella species and serogroups is difficult to determine and remains largely unknown. This situation occurs primarily because current diagnostic tests are available for a limited number of legionellae. A least forty-eight Legionella species with 64 serogroups have only been classified as of late Nevertheless, in most studies L. pneumophila, serogroup 1 is usually the predominantly isolated species in both community and hospital-acquired outbreaks of Legionnaires disease. Other most commonly isolated species include L. anisa, L. bozemannii, L. dumoffii, L. feeli, L. longbeachae, L. micdadei, and L. wadsworthii. Because of the international nature of Legionella, it should be noted that certain species of Legionella are This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 20

21 much more common in some countries than in others. For instance, in Australia, L. longbeachae is 10 times more common than L. pneumophila. Nosocomial Outbreaks and Prevention. Large buildings, such as health-care facilities, provide a more hospitable environment than small buildings, including residential homes, because, 1) the more extensive piping network of a large building provides a greater surface area with lower temperatures, 2) temperature stratification within larger water tanks is more variable, and 3) biofilm accumulation is greater. In health-care facilities aerosol-generating systems such as cooling towers, respiratory therapy equipment, and whirlpool baths have been linked to the transmission of legionellae. Aspiration has been under recognized as a mode of legionellae transmission. Nasogastric tubes have been implicated in several studies of nosocomial legionellosis. Microaspiration of contaminated water was the presumed mode of transmission. Properties of the Genus Legionella The genus Legionella was established in 1979 after the earlier mentioned large outbreak of pneumonia among members of the American Legion that occurred in Legionellae are found worldwide in many natural habitats, particularly where standing bodies of fresh water are found. These bacteria are capable of surviving up to one year in water. The legionellae are parasites of various protozoa. The number of species and serogroups of legionellae continues to increase. As of 2003 there are 48 species comprising 70 distinct serogroups in the genus. Less than half of the species have been linked to disease in humans. Legionella pneumophila, the major pathogen of the genus, has 15 serogroups. L. pneumophila, serogroup 1 is considered the most pathogenic member of the genus. L. micdadei (the Pittsburgh pneumonia agent), L. bozemannii, and L. longbeachae also are known pathogens. Some legionellae cannot be grown on routine Legionella media and have been designated as Legionella-like amoebal pathogens. Microscopic properties. The legionellae are Gram-negative, motile small rods with polar or lateral flagella. These bacteria do not form spores or capsules. Cultural Characteristics. Biochemical data for the legionellae other than L. pneumophila are limited. In general, the legionellae are positive for catalase activity and gelatin liquefaction, and negative for all carbohydrate fermentations, and nitrate and urease activity. Most species produce beta-lactamase, and enzyme that destroys penicillin activity Most legionellae are identified by growth on buffered charcoal yeast extract media, typical colonial appearance, and a requirement for the amino acid L-cysteine. Growth is best under normal incubation conditions using a temperature ranging from 35 o to 37 o. Colonies generally appear within 5 days, and are grayish white to blue-green in color. Colonies often exhibit a This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 21

22 yellowish or greenish fluorescent pigment. Virulence Factors. Pathogens that are able to survive in the environment for extended periods tend to be relatively virulent. L. pneumophila can infect and reproduce within various protozoa found in soil and natural water environments. Such associations may increase the disease causing ability (virulence) of legionellae. L. pneumophila appears to cause more severe disease than most common bacterial pathogens associated with community-acquired pneumonia. The various strains of this bacterium differ in virulence. In addition, multiple strains may colonize water-distribution system, but only a few strains will cause disease in patients exposed to contaminated water. Legionella Pneumophila L. pneumophila causes approximately 90 percent of all reported cases of legionellosis in the United States. This figure may be somewhat inflated at the present time since most diagnostic tests are specific for L. pneumophila. Seventy-nine percent of all culture-confirmed or urine antigen-confirmed cases are caused by L. pneumophila, serogroup 1. (Laboratory diagnostic tests are discussed in a later section.) The Disease Various studies have estimated that between 8,000 and 18,000 persons are hospitalized with legionellosis annually in the United States. The disease is a major concern of public health professions and individuals involved with maintaining building water systems. Legionellosis is generally considered a preventable illness because controlling or eliminating the causative agent in certain reservoirs will prevent cases of the disease. Risk Factors. A number of risk factors are recognized for legionellosis. These include increasing age, chronic lung disease, cigarette smoking, hematologic malignancies, diabetes, and immunosupression (especially that caused by cortico-steroid therapy). Surgery is a major predisposing factor in cases of nosocomial infections. The incidence of Legionnaires disease in AIDS patients is low, however, the signs and symptoms of the disease are more severe. Both community-acquired and nosocomial cases of legionellosis are also seen in children. Most of such patients are immunosuppressed. Moreover, a number of immunocompetent children have acquired LD post-operatively, or neonatally. Neonate cases have been linked to nosocomial ventilator-associated pneumonias. Pathogenesis. Two major areas of study have contributed to the understanding of the pathogenesis of L. pneumophila, namely the uncovering of the life cycle of legionellae and the identification of virulence factors by molecular biological techniques. The primary feature of the pathogenesis of legionellae is their ability to multiply intracellularly. The life cycle of theses bacteria has been defined in both protozoa and mammalian cells. There This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 22

23 are striking similarities in the processes by which legionellae infect protozoa and mammalian phagocytic cells. Microscopically, the processes are virtually identical, although differences in the mechanisms of entering and exiting host cells do exist. L. pneumophila can enter host cells by the conventional form of phagocytoisis involving host macrophages. Once inside the host cell, the pathogen occupies a unique phagosome known as an endosome. This endosome does not follow the usual endosome cellular pathway in that it protects L. pneumophila from intracellular digestion and destruction by the cell s enzymes. In macrophages and alveolar epithelial cells, the pathogen reproduces, brings about apoptosis (cellular disintegration and death), and exits the host cell during the early stages of infection. The reproduction of L. pneumophila and associated destruction of host cells induces the development of an inflammatory infiltrate in human host alveoli consisting of neutrophils, macrophages, and fibrin deposits. A loss of gas exchange in the alveoli causes the clinical syndrome of pneumonia. Transmission. Aerosols created by the various human-made habitats described earlier are the most common route of airborne transmission. The legionellae cause respiratory disease in humans when a susceptible host inhales aerosolized water containing the pathogens, or aspirates water containing the pathogens. Some outbreaks of legionellosis have been associated with construction, and were originally believed to be the result of exposure to contaminated soil. It is now known that L. pneumophila does not survive in dry environments, and these outbreaks were more likely to have been associated with plumbing systems during construction. Clinical Manifestations Pontiac Fever Patients with Pontiac fever (PF), unlike those with Legionnaires disease (LD), have normal results of chest radiography, without evidence of pneumonia. The incubation period after exposure is short and usually is 1 to 2 days. Clinical manifestations are mild. The most frequently signs and symptoms experienced by patients include: fever (often with chills), fatigue, malaise, muscle pain, nonproductive cough, and chest pain. Persons with Pontiac fever generally experience an acute, febrile, nonpneumonic illness, and a rapid recovery. PF differs from LD in being self-limited, and full recovery usually occurring within one week and without sequelae. Legionnaires Disease After the initial exposure to L. pneumophila, Legionnaires disease manifests itself within a 2 to 10 day incubation period. Pneumonia is the predominant clinical syndrome. The disease presents a broad range of illness, ranging from a mild cough and low-grade fever to stupor, respiratory failure, and multi-organ failure. Early in the illness, patients exhibit the typical signs and symptoms such as fever, headache, muscle pain, non-productive cough, and a loss of This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 23

24 appetite. The temperature often exceeds 40 o C. The cough is only slightly productive. Chest pain, occasionally accompanied by an inflammation of the pleura, can be prominent, and, when coupled with hemoptysis, may suggest pulmonary emboli. Gastrointestinal signs and symptoms are quite evident, especially diarrhea, which occurs in 20 to 40 percent of cases. The stool is watery rather than bloody. Some patients may be asymptomatic. It is not possible to clinically distinguish patients with Legionnaires disease from patients with other types of pneumonia. Although no chest X-ray pattern can separate this infection from other types of pneumonia, alveolar infiltrates are more common with LD. The key to diagnosis involves the use of appropriate microbiologic procedures when a patient is in a high-risk category. Low serum sodium concentration occurs more frequently in Legionnaires disease than in other types of pneumonia. Fatalities occur in older and/or debilitated patients. Laboratory Diagnosis Specimens. The legionellae generally can be isolated from a number of specimens including blood, stool, lung tissue, lung biopsy preparations, and respiratory secretions such as sputum, bronchial alveolar lavage (BAL), and bronchial aspirates. Respiratory secretions are considered to be the specimen of choice. When culturing sputum, it is best to pretreat the specimen by either acidification or heat. Legionella species have also been isolated from various extrapulmonary sites such as bone marrow, prosthetic heart valves, and sternal wounds. Difficulties of Diagnosis. The ability to diagnose Legionella infections is limited by the nonspecific nature of clinical features and the shortcomings of currently available diagnostic tests. Table 4 lists and provides a comparison of the diagnostic tests used for Legionella infections. Although diagnostic methods have improved during the years since L. pneumophila was first described, existing tests either lack a high degree of sensitivity and specificity for detecting all clinically important legionellae, or are unable to provide results within a clinically useful time frame. However, in most situations, the use of both the urinary antigen test, and the sputum culture is the best diagnostic combination. The urinary antigen detection is easy to perform, rapid in that results can be obtained within 15 minutes, and has been a useful tool for the investigation of L D outbreaks. DNA detection techniques such as the polyermase chain reaction (PCR) assay have shown promise for the rapid diagnosis of Legionella infection. The PCR assay enables the specific increase (amplification) of minute amounts of Legionella DNA, provides results within a short time frame, and has the potential to detect infections caused by any Legionella species or subgroup. Unfortunately, at the time of writing, standardized assay were not available commercially. Legionella PCR assays are only available in a limited number of laboratories. This material is copyrighted by RC Educational Consulting Services, Inc. Unauthorized duplication is prohibited by law. 24