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Pertussis Not Only a Disease of Childhood

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jurnal pertusis
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  Deutsches Ärzteblatt International  Dtsch Arztebl Int 2008; 105(37):623–8   623 MEDICINE P ertussis, also known as whooping cough, is a clas-sical childhood disease. After a vaccine becameavailable, the number of notified cases fell dramatically(1), leading to the removal of pertussis from the list of notifiable diseases in West Germany in 1963. In manyindustrialized nations, however, the number of pertussisnotifications has increased substantially in recent years,especially among school-age children, adolescents, andadults – a trend that has also been observed in formerEast Germany (2). In the present study, we performed asystematic search of clinically relevant internationalliterature and reviewed national and internationalrecommendations for treatment and vaccination (box 1) . Epidemiology and disease burden Natural infection with the bacterium Bordetella pertus-sis confers only 3.5 to 12 years of protective immunityagainst reinfection (3, 4). Data on the duration of immu-nity are sparse, however, due to the practical difficultiesof distinguishing between first infection and reinfection,and because the symptoms of pertussis can vary widely.The protective effect induced by acellular vaccines isapproximately 85% after three doses and lasts for atleast five years (1, 3), after which a gradual decrease inimmunity is observed. As a result, the incidence of per-tussis can be expected to be high in school-age children,adolescents, and adults who do not receive booster vac-cinations, even in settings where high vaccine coveragein young children has been achieved.In many countries, the annual incidence of pertussisin adolescents and adults ranges from 0.18% to 0.51%,independently of vaccine coverage in childhood (5). InGermany, a study conducted in Rostock and Krefeldpointed to a frequency of 165 cases per 100 000 popula-tion per year (6). Whereas almost all birth cohorts since1964 have been vaccinated in Rostock, vaccine coveragein Krefeld was low from the 1970s until around 1995.Nevertheless, there was no statistical difference in theincidence of pertussis among adults in the two cities,demonstrating that vaccination during infancy has noinfluence on the incidence of disease during adulthood.Pertussis is endemic in Germany (2). Every three tofour years, a wave of infections occurs, which at its peak shows an incidence that is three to four times as high asduring the interepidemic periods. Due to differentsurveillance systems, the notification data in Europeshow stark variations, ranging from <1 (Portugal) to200 (Switzerland) registered cases per 100 000 inhabi-tants per year (7). In eastern Germany, the incidence of  REVIEW ARTICLE Pertussis: Not Only a Disease of Childhood Marion Riffelmann, Martina Littmann, Wiebke Hellenbrand, Christel Hülße, Carl Heinz Wirsing von König SUMMARY  Introduction:Pertussis is not just a childhood disease,but a respiratory infection that causes persistent cough in allage groups,from newborns to the elderly.Methods:The authors performed a selective literaturesearch and reviewed national and international recom-mendations for treatment and vaccination.Results:Pertussis is found principally in young unvaccinat-ed infants,but school-age children,adolescents,andadults are also affected. Up to 1% of infants contract per-tussis,and their respiratory symptoms are often accompa-nied by apnea. School-age children occasionally displaythe coughing spasms typical of the disease. Annually,0.2%to 0.5% of all adolescents and adults are infected and sufferfrom prolonged,frequently non-paroxysmal coughing.Severe and fatal cases of pertussis occur mainly in new-borns and infants,and 25% of affected adults experiencecomplications. Bordetella DNA may be detected by poly-merase chain reaction (PCR) for four weeks after symptomonset; except in infants,the sensitivity of this diagnostictechnique is low. Although the diagnosis can be confirmedby serological tests,the methods are not well standard-ized. Treatment with a macrolide prevents the spread ofinfection,but generally does not alleviate the symptoms.Combination vaccines are the most effective means ofprophylaxis.Discussion:Pertussis is usually not included in the differ-ential diagnosis of persistent respiratory symptoms. Theconsiderable burden of disease could be reduced in adultsand young infants by vaccinating adults with acellularcombination vaccines.Dtsch Arztebl 2008; 105(37):623–8DOI:10.3238/arztebl.2008.0623 Key words:pertussis,epidemiology,pediatric disease,treatment concept,vaccination recommendations Institut für Infektiologie Krefeld GmbH,Krefeld:Dr.med.Dipl.Biol.Riffelmann Landesamt für Gesundheit und Soziales MV,Rostock:Dr.med.Littmann,Prof.Dr.med.Hülße Robert-Koch-Institut,Berlin:Dr.med.Hellenbrand Institut für Hygiene und Labormedizin,HELIOS Klinikum Krefeld:Prof.Dr.med.Wirsing von König  624 Deutsches Ärzteblatt International  Dtsch Arztebl Int 2008; 105(37):623–8   MEDICINE registered pertussis cases in 2006 ranged from 12 inSaxony to 68 in Mecklenburg-West Pomerania per100000 population per year (2). Infants under sixmonths of age had the highest rate of hospitalization.Forty percent of cases registered with the Robert KochInstitute between the years 2002 and 2007 involvedchildren under the age of one (2), and 63 of the 88 deathsdue to pertussis between 1980 and 2006 occurred in thisgroup (www.gbe-bund.de). Among newborns and younginfants, pertussis is the most common infectious cause of death (8).Complications associated with pertussis occur inapproximately 25% of adults, and in approximately40% of those over the age of 60 (9). Between 1% and 4%of adult cases require hospitalization (9). Mortality is rare. Chain of infection Because maternal antibodies do not reliably confer im-munity to pertussis, newborns are susceptible to infectionimmediately after birth. The incubation period of per-tussis can last from 7 to 28 days, and communicability ishighest during the first two weeks of infection.In infants, the source of infection cannot be indentifiedin 30% to 69% of cases (10–13). In cases in which thesource of infection can be traced, half of the childrenhave been infected by their parents – usually by themother. Older siblings are another frequent source of infection even if they have been vaccinated, because oftentheir immunity has waned in the absence of a boostervaccination. In one study, grandparents were the sourceof infection in 8% of cases, and other adult householdmembers in 22% of cases (13). Although school-agechildren are infected primarily by their classmates,parents are also a source of infection. Adolescents areinfected, for the most part, by friends and classmates. Case definition and notification requirement Pursuant to the Infection Prevention Act (Infektions-schutzgesetz; IfSG), pertussis is currently not includedon the national list of notifiable diseases in Germany;there are, however, state-specific regulations in theeastern part of the country that do require notification.As specified in the pertussis case definition given in box 2 ,an infection can be confirmed directly by means of culture or through detection of bacterial nucleic acidswith polymerase chain reaction (PCR). Serological con-firmation of infection is currently defined as a singlehigh pertussis-specific IgAtiter or an increase in IgGantibody titers between two samples. In the revised casedefinition expected to become effective in early 2009, asingle high IgG antibody titer, rather a than single highIgAantibody titer, is required to confirm the diagnosis. Symptoms and complications The symptoms of pertussis can vary widely, dependingon age, individual immunity (first infection or reinfec-tion), and time elapsed since previous pertussis infectionor vaccination. Newborns and young infants Some newborns may not present with the coughingspasms typical of pertussis. Following an atypical onset,up to 90% of infants experience typical paroxysmalcoughing (1). Severe complications such as apnea, encephalopathy,and pneumonia are most common in this group. In a studyof admissions to pediatric departments for pertussiscomplications, 75% of infants under the age of sixmonths were diagnosed with pneumonia, 25% with apnearequiring respiratory support, 14% with seizures, and5% with encephalopathy (14). School-age children This group of children, the majority of whom have beenvaccinated, is more likely to display the typical symp-toms of pertussis, including coughing spasms followedby the signature inspiratory whoop and vomiting. Theprinciple complications in this group are pneumonia andotitis media. Adolescents and adults Approximately 10% to 20% of all adults with coughingthat persists for more than seven days have pertussis (5).Adolescents and adults may present only with prolongedcoughing (which in 70% to 90% of cases is paroxysmalin nature), but without other typical findings such aswhooping or vomiting. The average duration of coughingranges from 36 to 48 days.In a quarter (23% to 28%) of adult patients, pertussisleads to complications such as (5, 9)  weight loss  seizures  syncope  pneumonia (approx. 10%)  otitis media  incontinence  pneumothorax  rib fracture  hernia. BOX 1 Search Strategy  D   ata sour   ce   s:PubMed,Cochrane Database,Robert KochInstitute databases,vaccination and treatment recommen-dations in Germany and the USPublic   ation d   ate   s:1998-2008Se   ar   ch term   s: pertussis and disease, clinical, com-plication, hospitalisation, death, reinfection, epide-miology, newborn, infant, children, adolescents, adults, culture, PCR, serology, vaccination, acellular, cost Filter:The clinical relevance of the identified publicationswas evaluated based on their abstracts.Relevant reviewarticles are cited whenever possible.  Deutsches Ärzteblatt International  Dtsch Arztebl Int 2008; 105(37):623–8   625 MEDICINE Complications occur in more than 40% of casesamong individuals over the age of 60 (9). Differential diagnosis In addition to B. pertussis and B. parapertussis, a numberof pathogens can cause pertussis-like symptoms (15),including adenoviruses, respiratory syncytial viruses(RSV), human parainfluenza viruses, influenza viruses,Mycoplasma pneumonia, and rhinoviruses. Infectionswith more than one pathogen are not uncommon, anddual infections with RSVand B. pertussis are frequentamong infants. Laboratory diagnosis Laboratory diagnosis of pertussis is challenging. Thebacteria can be identified directly by culture or bydetection of bacterial nucleic acids through PCR (16).Nasopharyngeal secretions or deep nasopharyngealswabs are appropriate specimens. In young unvaccinatedinfants, culture and PCR have a sensitivity of approxi-mately 70% (16). The only appropriate method for diag-nosing pertussis in school-age children, adolescents,and adults is PCR, which has a sensitivity of 10% to30%. However, because the sensitivity of PCR decreaseswith the duration of coughing, it is unlikely to be usefulafter four weeks. In Germany, culture and PCR are reim-bursed by the statutory health insurance (SHI) funds.Diagnosing pertussis using commercial serologicalassays (ELISA) is also problematic, because IgG andIgAantibodies against pertussis toxin (PT) are detectablein most school-age children, adolescents, and adults. Asa result, serological diagnosis must be based on a signif-icant increase in antibody titer or on a single high anti-body titer above an age-adjusted cutoff. An immuneresponse to vaccination cannot be distinguished from aninfection; it is also impossible to assess immunity to per-tussis using serological methods. Commercially availableassays use different antigens and interpretations. Forpractical purposes, the following approach is recom-mended:  IgG anti-PT  100 ELISAunits/mL(EU/mL) (rela-tive to a US FDAreference preparation) is indicativeof recent infection.  IgG anti-PT< 40 EU/mLis not indicative of recentinfection.  IgG anti-PT= 40 EU/mLbut < 100 EU/mLrequirestesting another sample or detecting antibodiesagainst other antigens to confirm the specificity of the assay (15, 17).  Treatment ACochrane analysis of 11 randomized controlled studieson antibiotic treatment of pertussis showed that althoughantibiotics were effective in eliminating B. pertussiswithin seven days (three to five days for azithromycin),the antibiotics did not alter the clinical course of theillness.Macrolides have been the mainstay of pertussis treat-ment for decades. Most recent studies have thus comparedthe different macrolides to one another. Although trimeth-oprim/sulfamethoxazole (TMP-SMZ) has been cited asan alternative for patients who cannot tolerate macrolides,its use has been evaluated only in one comparative studywith tetracycline (18).Randomized studies have demonstrated that therewas no difference in outcome between 7-day and 14-daycourses of treatment with erythromycin and treatmentwith the macrolides azithromycin or clarithromycin(18). Treatment with erythromycin is thus recommendedfor seven days, with azithromycin for three to five days,and with clarithromycin for seven days. Only a few controlled studies on symptomatic inter-ventions using salbutamol, diphenhydramine, or dexa-methasone have been conducted to date, and the availableevidence is insufficient to draw any conclusions abouttheir effects (19).  Box 3 gives a summary of recommendations onantibiotic treatment (20, 21). BOX 2 Robert Koch Institute CaseDefinition Clini   c   al pre   sentation:indicative of pertussis if at least oneof the following symptoms is present:  Paroxysmal coughing  Inspiratory stridor (i.e.whooping)  Post-tussive vomiting   Apnea,especially in infantsLab   orator   y confir   mation:positive result for at least oneof the following methods:  Isolation of pathogen from nasopharyngeal swabs orsecretions  Detection of bacterial nucleic acid (e.g.PCR fromnasopharyngeal swabs or secretions)  Detection of IgA antibodies  Detection of IgG/IgA antibodies (4-fold titer increase in two samples,e.g.ELISA)To be r   ep   or   ted to the appropri   ate state au   thorities:Clini   c   ally confir   med c   a   ses:Clinical presentation indicative of pertussis (except forapnea) if persists for more than 14 daysClini   c   ally/epidemiologic   all   y c   onfirmed c   ase   s:Clinical presentation indicative of pertussis with no labora-tory confirmation,but evidence of epidemiological linkage(incubation time approx.7 to 20 days) withlaboratory con-firmation of infectionClini   c   al and lab   orator   y confirmation:Clinical presentation indicative of pertussis and laboratoryconfirmation Source:www.rki.de/cln_91/nn_494670/DE/content/Infekt/EpidBull/ Merkblaetter/Ratgeber_Mbl_Pertussis.html  626 Deutsches Ärzteblatt International  Dtsch Arztebl Int 2008; 105(37):623–8   MEDICINE Newborns and young infants As a rule, newborns and young infants should still bea treated with erythromycin. For this group,erythromycin is available as a syrup and as an intravenoussolution, and clarithromycin as a syrup. Azithromycin hasbeen approved for children older than six months. USCenters for Disease Control (CDC) guidelines (20) andthe 2006 Report of the Committee on Infectious Diseases(21) recommend azithromycin as the antibiotic of choicein newborns, because erythromycin treatment is associatedwith an increased risk of pyloric stenosis (20). However,pyloric stenosis has also been reported in association withthe use of azithromycin (22). Young and school-age children Clarithromycin and azithromycin are as effective aserythromycin, but are better tolerated. Although thereare data on the in vitro susceptibility of B. pertussis toroxithromycin, no clinical studies have been conductedto date (18). Adolescents and adults Macrolides are also the standard form of treatment inthis group. Adverse events are less common under treat-ment with azithromycin or clarithromycin compared toerythromycin (18). To lessen the period of communica-bility, experts recommend initiating antibiotic treatmentwithin four weeks of cough onset (20, 21).  Antibiotic prophylaxis Because only two controlled studies have investigatedantibiotic prophylaxis in pertussis contacts to date, thereis insufficient evidence to determine the effectiveness of this approach (18). Based on its potential benefits,however, experts recommend antibiotic prophylaxis inhouseholds with young unvaccinated infants. Recom-mendations for the duration and dose of prophylaxis aresimilar to those for treatment (20, 21). Costs of disease Studies in the US and Germany have estimated directcosts per adult case to be  € 104 (DE) or between $141to $326 (US), and indirect costs to be  € 434 (DE) or be-tween $447 and $1232 (US) (6, 23).  Vaccination strategies The currently approved acellular pertussis vaccines havedemonstrated their efficacy in a range of randomizedcontrolled studies in infants (1) and in a smaller,randomized controlled study in adolescents and adults(24). Because pertussis vaccines are not available as asingle vaccine, the German Standing Vaccination Com-mittee (Ständige Impfkommission, STIKO) alwaysrecommends combination vaccine products (25).Formulations with reduced concentrations of the pertussisantigenic components are available for immunizationagainst tetanus, diphtheria, and pertussis (Tdap) andagainst tetanus, diphtheria, pertussis, and polio (Tdap-IPV); both are approved for adolescents and adults, aswell as for children above the age of three (Tdap) or four(Tdap-IPV). The current STIKO recommendations aresummarized in the table .Primary immunization requires a series of four injec-tions using combination vaccines with the full concen-tration of pertussis antigens. The first three injectionsshould be administered at the end of the second, third,and fourth months after birth. In Germany, approximately95% of children have completed this series by the age of two (data from 2003 to 2006) (e1).Primary immunization needs to be initiated as earlyas possible to limit the period during which infants arevulnerable to infection. Even a single dose of vaccinecan provide measurable protection against a severecourse of disease (1). Primary immunization is completedby administering a fourth dose of the vaccine between12 and 15 months after birth. In Germany, 85% of chil-dren aged two and 90% of children aged three to six havecompleted the four-dose series. Among older children,this percentage is lower, at 69.5% (26).Booster vaccination is given to preschool-age childrenusing a vaccine formulation with reduced concentrationsof pertussis antigenic components (Tdap). STIKO hasrecommended this dose since January 2006 (25). In adolescents (9 to 17 years), the reduced-antigen-content combination vaccine is also used for boostervaccination. The vaccination coverage in this age groupis between 30% and 50%.Routine booster vaccination for adults is currentlyunder discussion in Germany; it has recently beenrecommended in Saxony, France, Austria, the UnitedStates, Canada, and Australia. The aim of boostervaccination in this group is to reduce disease burdeninvaccinated individuals, to decrease the number of  BOX 3 Suggestions for Treatment and Antimicrobial Prophylaxis of Pertussis (20,21) Newb   orn   s  Erythromycin 40 mg/kg BW per day in 3 to 4 doses for7 (14) days  6 months and older:azithromycin 10 mg/kg BW oncedaily for 5 daysChildren   Azithromycin 10 mg/kg BW once daily for 3 days  or:azithromycin 10 mg/kg BW once daily for 1 day and5 mg/kg BW for an additional 4 days  or:clarithromycin 15 mg/kg BW in 2 doses for 7 days Adole   scent   s   Azithromycin 500 mg once daily for 3 days  or:clarithromycin 2 × 500 mg daily for 7 days
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