Case Presentation: Pertussis: The Resurgence of an Old Disease. Case Presentation: Case Presentation: Case Presentation: Case Presentation:

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1 Pertussis: The Resurgence of an Old Disease Controlling an Outbreak in Your Community You have finally finished your training! As a new healthcare provider, you are working in a Family Medicine office. Michael Flanagan, M.D., FAAFP Associate Professor, Family and Community Medicine, Penn State College of Medicine About two weeks ago you developed rhinorrhea and congestion, an unavoidable risk of this rotation you think. However, you started to cough three days ago, and now it is keeping you up at night. Tonight, the cough is worse than ever. After a prolonged coughing episode, you actually vomit a small amount. Minutes later, after another severe coughing spasm, you gasp suddenly and note a whooping sound. At this point you suspect pertussis!

2 Questions/ #1 Pertussis/ history Isn t pertussis rare today, like measles? Doesn t whooping cough occur only in those that don t receive the appropriate vaccine series, as with tetanus? In the 20th century, pertussis was one of the most common childhood diseases. Prior to the 1940 s, pertussis was a major cause of childhood mortality. Pertussis/ history Pertussis/ history In the pre-vaccine era: there was an estimated yearly attack rate of 872 cases/ 100,000 population in the U.S. 1 During this time, more than 93% of reported cases were in children < 10 years old. The original DTP vaccine was introduced in the1940 s. By 1960 the attack rate fell to <10 cases/ 100, In the 1970 s, the rate was <1 case/ 100, Pertussis/ history BUT, pertussis is not a relic of the past. Worldwide in 2001: 285,000 deaths occurred due to pertussis. 1 A recent resurgence of cases has been reported in the U.S., as well as globally. Questions/ #2 How has the incidence of pertussis changed over the past 3 decades? How has the impact of pertussis changed over the past 75 years?

3 Discussion/ a re-emerging infection Pertussis is a re-emerging infectious disease. Before the introduction of the DTP vaccine, an average of 160, 000 reported cases of pertussis occurred in the U.S. each year. 2 This resulted in 5,000-10,000 deaths annually. 2,9 Discussion/ rates of pertussis Pertussis rates declined dramatically after immunizations began in the 1940 s, as shown in the graph below. An all time low in U.S. pertussis cases occurred in 1976, with 1,010 cases reported. The incidence of pertussis began to increase in the 1980 s. Pertussis/ resurgence Since 1980, about 4,400 cases have been reported per year. 3 Between : 7,000-8,000 cases of whooping cough occurred/ year. However, a marked resurgence of pertussis occurred in Pertussis/ incidence (Note cyclic spikes in # of cases every 3-4 years.) Cases Pertussis United States, Source: CDC, NIP. Clinical-education slide set: Pertussis (.ppt) Pertussis/ resurgence Incidence of pertussis as reported by the CDC: : 5, : 9, : 8, : 25, : 21,003 WA Pertussis Case Reports by State: 2004 OR ID NV UT CA AK AZ HI MT WY CO NM VT ME ND MN NH NY WI MA SD MI PA CT RI NJ NE IA OH IL IN DE WV MO VA MD KS KY NC OK TN AR SC MS AL GA TX LA N=25,827 FL Discussion/ the pertussis spike In 2004, reported pertussis cases spiked to a high of 25,827 cases. 4 This was more than 25 times greater than the all time low in Prevalence data suggests over 1 million cases/yr occur in the U.S cases cases cases >1000 cases Centers for Disease Control and Prevention. Provisional cases of selected notifiable diseases, United States, week ending January 1,

4 Questions/ #3 Your cough continues, averaging about 15 episodes/ day. You begin to experience up to 5-10 seconds of apnea after these sudden bursts of coughing (i.e. paroxysms). How has the medical community interfaced with the increasing incidence of pertussis? Suspecting pertussis, you seek evaluation and treatment with your family physician. Pertussis/ medical community Pertussis is a familiar textbook infectious disease, like diptheria, tetanus, and measles. However, for many physicians it is not a familiar clinical disease. Pertussis/ medical community Most pertussis remains unrecognized, untreated, and unreported. The true incidence of pertussis may far exceed the number of reported cases. Most pertussis infections resemble viral upper respiratory infections. Pertussis/ prevalence Pertussis/ prevalence In the pre-vaccine era, pertussis epidemics peaked in 3-4 year cycles. In the vaccine era, the overall incidence of reported disease is much lower, BUT this cyclic occurrence pattern still persists. É there are between ~800,000 and 3.3 million cases per year in the United States. Used with permission: Sanofi-Pasteur Pharmaceuticals 10

5 Pertussis/ prevalence Cyclical epidemics and prevalence data suggests: While the incidence of reported pertussis disease is down overall since vaccine use began, The circulation of B. pertussis in the population as a whole is persistent. 1 Pertussis/ prevalence Immunity to pertussis disease after BOTH vaccination and natural infection wanes (i.e years). Adolescents and adults form a natural reservoir for the disease. Evidence suggests pertussis is endemic in these age groups. 1 Pertussis/ prevalence Pertussis illness does NOT always occur with pertussis infection (i.e. carrier state exists). 1 Frequent exposure to pertussis bacteria, maintains antibody levels at protective levels, preventing disease. Questions/ #4 What are the possible explanations for the recent increase in the incidence of pertussis? Illness occurs when antibody levels drop below a critical threshold, followed by pertussis exposure. Pertussis/ resurgence There are five possible causes for the reemergence of pertussis: 1 1). Genetic adaptations in B. pertussis (vaccines then become less effective). 2). Waning of vaccine induced immunity. Pertussis/ resurgence 3). Reduced potency of pertussis vaccines Different efficacies existed in different whole-cell DTP brands (1980 s): some weakly immunogenic. Slightly lower efficacy (though safer side effect profile) of acellular DTaP vs. most DTP (1990 s).

6 Pertussis/ resurgence 4). Improved laboratory tests (i.e. PCR) for diagnosing pertussis. 5). Increasing awareness of pertussis among medical practitioners. Questions/ #5 What causes pertussis? How does the classic whooping cough sound and appear? What are the characteristics of the etiologic organism? Pertussis/ the disease Whooping cough is a highly contagious respiratory infection caused by the bacteria Bordetella pertussis. Secondary household attack rate = 80%. However, about 5-10 % of whooping cough cases may be caused by the related organism, Bordetella parapertussis. PCR can test for both concurrently. Pertussis/ the disease B. pertussis can only be isolated from humans. It spreads by aerosolized respiratory droplets or direct contact with secretions. Pertussis/ the disease Classic symptoms include rapid bursts of sudden coughing, followed by post-tussive emesis and apneic episodes. An inspiratory gasp following the coughing spell, produces the pathonomonic whoop. Pertussis/ history Pertussis is an old disease, but not an ancient one: outbreaks were first described in the 16th century. In comparison, leprosy was described during biblical times. B. pertussis was first isolated in 1906.

7 Discussion/ Bordetella pertussis, the bacteria B. pertussis is a small, aerobic gram negative pleiomorphic rod. It is difficult to grow in culture, unless conditions are ideal (i.e. fastidious). Questions/ #6 Describe the pathogenesis of whooping cough as caused by B. pertussis. What pathogenic products does B. pertussis contain that allow it to cause disease? Source: Original illustration of microscopic view of B. pertussis Pertussis/ pathogenesis B. pertussis bacilli attach to cilia on human respiratory epithelial cells. Toxins are released to paralyze cilia and induce inflammation. This process interferes with the host s ability to clear respiratory secretions. Pertussis/ pathogenesis B. Pertussis produces several antigenic and biologically active products that aid pathogenesis. (See illustration on next slide). These include: filamentous hemagglutinin (FHA) pertactin(prn) fimbrial agglutinogens (FIM) tracheal cytotoxin adenylate cyclase pertussis toxin (PT). Pertussis/ pathogenesis Pertussis/ pathogenesis Illustration of B. pertussis pathogenic factors These antigenic factors and toxins: Allow B. pertussis to invade host tissues. Produce the clinical features of the disease. Induce the host immune response (i.e. lymphocytosis). Facilitate evasion of the host s defenses by interfering with immunologic chemotaxis. Used with permission: Sanofi-Pasteur Pharmaceuticals

8 Pertussis/ pathogenesis Questions/ #7 These antigenic factors and toxins, ALSO: Allow the development of acellular pertussis vaccines against these antigenic components. (Example) DTaP and TdaP vaccines contain: Pertussis Toxoid antigen Filamentous hemaglutinin (FHA)antigen Pertactin antigen Fimbriae type 1 and 2 antigens (Some brands, but not all) What is the timeline for pertussis pathogenesis and onset of illness? Pertussis/ illness Questions/ #8 Pertussis Stages, Period of Communicability exposure period of communicability paroxysmal cough onset catarrhal stage 3 weeks of cough paroxysmal stage CDC. Epidemiology and Prevention of Vaccine-Preventable Diseases. PHF 2004 convalescent stage Incubation period: 7-10 days (can range from 4-21 days). Contagious period: with onset of congestion/ rhinorrhea, and extending to about 3 weeks after cough begins. Onset of illness: insidious, mimics typical viral URI, fever minimal. Used with permission: Sanofi- Pasteur Pharmaceuticals What are appropriate diagnostic tests for pertussis? How long after cough onset can pertussis be reliably isolated from the nasopharynx with available tests? Discussion/ diagnostic testing Discussion/ diagnostic testing Diagnostic testing for pertussis includes culture, polymerase chain reaction (PCR) and serology. None of these tests are perfect, and all present challenges. Clinical symptoms are nonspecific, so often it isn t obvious who should be tested. Ideally, culture and PCR should be obtained within three weeks of cough onset.

9 Discussion/ diagnostic testing Testing nasopharyngeal (NP) secretions is ideal. This can be obtained via an NP aspirate or NP swab. CDC recommends NP aspirate with suction device (same or higher recovery rates vs. NP swab). Discussion/ NP culture Advantages: Culture is the traditional standard for pertussis diagnosis. Specificity is 100% (by definition) 10 Sensitivity is % 10 Used for strain analysis and ABT susceptibility testing. Low cost. Discussion/ NP Culture Disadvantages- decreased sensitivity with: Antibiotic use Prior immunization Increased elapsed time b/w specimen collection and onset of cough. 10 Polymerase Chain Reaction (PCR) tests for specific pertussis nucleic acids. Potentially superior to other methods. Potentially rapid results: < 24 hours. Discussion/ PCR PCR presents minimal problems with specimen transport Discussion/ PCR Culture can lose sensitivity w/ transport. Sensitivity is 56-97% (much greater than culture, especially in 3 rd -4 th weeks of illness). Specificity approaches 100%. Discussion/ PCR PCR is rapidly evolving. However, the process needs to be standardized to ensure quality control. PCR can be significantly more costly than culture. CDC recommends culture whenever PCR is performed

10 Discussion/ serology Discussion/ serology Most labs performing serology lack a reliable standardized method. 6 Serology (i.e. pertussis antibody levels) detects the same antibodies as those induced by vaccination (IgG). Not affected by antibiotic therapy. Serology requires simultaneous testing of acute and convalescent titres to interpret accurately. 6 Currently, the CDC does not recognize serologic results for pertussis diagnosis. A standardized single serum sample is under development in the U.S. 3 Your family physician also suspects pertussis. Both culture and PCR are readily available at your medical center. NP swabs are obtained and sent for both culture and PCR. Questions/ #9 What is the proper technique to obtain an NP swab? How should an NP swab for culture be processed? How should an NP swab for PCR be processed? Discussion/ nasopharyngeal swab collection A Dacron NP swab should be used for both culture and PCR sampling. The swab is inserted through the nares into the posterior nasopharynx. Leave swab in place for 10 seconds. Discussion/ NP swab for culture If a swab for culture is obtained, immediately inoculate culture media (i.e. Reagan-Lowe). Alternatively, place in an appropriate transport media.

11 Because pertussis is highly suspected, your family physician recommends antibiotic treatment. You are told that you will be placed on a five day furlough from clinical duties. You may resume work after 5 full days of antibiotic therapy. Questions/ #10 Why is it appropriate to return to clinic after only 5 days of therapy? Will treatment end the paroxysms of coughing that you continue to experience? How long does the cough typically last? Discussion/ treatment Five days of an appropriate antibiotic eradicates B. pertussis from the nasopharyngeal airway, reducing the potential for spread. If treatment occurs after the cough begins, (paroxysmal phase), then the patient will continue to cough---typically for 4-7 weeks, and as long as 3 months. Discussion/ treatment While treatment eliminates contagiousness, the cough continues unabated. Questions/ #11 What is the incubation period of pertussis? What are the stages of pertussis? How long does each stage last?

12 Discussion/ incubation period The incubation period of pertussis is typically 7-10 days. It can range from 4-21 days. Rarely it may last as long as 42 days. Discussion/ stages of pertussis Stage Symptoms Duration Catarrhal Stage Paroxysmal Stage Convalescent Stage Congestion, coryza (i.e. runny nose) Spasms of severe coughing, posttussive emesis/ apnea, whoop Cough tapering, becoming less frequent/ severe 1-2 weeks 1-6 weeks 2-6 weeks (Total duration of cough may be up to 3 months) You are given a prescription for azithromycin (Zithromax) for 5 days. Because of mild wheezing and persistent paroxysms of cough, your physician also prescribes an albuterol MDI, and quaifenesin to reduce mucous production/ tenacity. Questions/ #12 What are the appropriate antibiotic regimens for treating pertussis? How does treatment/ dose vary by age? Do treatment and chemoprophylaxis protocols differ? Discussion/ antibiotic therapy The macrolides Azithromycin, Clarithromycin, and Erythromycin are the drugs of choice for pertussis. Trimethoprim-sulfamethoxazole is an alternative for patients allergic to macrolides. Discussion/ antibiotic therapy In vitro studies of the flouroquinolones suggest very good efficacy, but in vivo studies have not been done. Fluoroquinolones not recommended. Amoxicillin/ampicillin and cephalosporins ineffective in vivo. Not recommended.

13 Discussion/ antibiotic therapy Antibiotic prophylaxis for pertussis exposure, and treatment for suspected disease are the SAME. Duration of total treatment or prophylaxis depends on the antibiotic chosen. Five days of all approved antibiotic regimens eradicates the organism from the respiratory tract, preventing further transmission. Discussion/treatment & prophylaxis Age < 1 mo 1-6 mos Azithromycin (5 days) 10 mg/kg/d x 5 days 10 mg/kg/d x 5 days >6 mo 10 mg/kg x 1d, then 5 mg/kg x 4d Adults 500 mg x 1d then 250 mg daily x 4d Clarithromycin (7 days) Not recommended 15 mg/kg /d divided BID x 7 days (max 1g/d) 15 mg/kg divided BID x 7 d (max 1g/d) 500 mg BID x 7d TMP/SMX (14 days) < 2mos: Contraidicated 4 mg/kg/d (TMP) 2x/d x14d 4 mg/kg/d (TMP) 2x/d x14d DS: 1 tab BID x 14d Erythromycin (14 days) Avoid: risk of pyloric stenosis mg/kg/d (max 2 gm) divided QID x 14d mg/kg/d divided QID x14d 500 mg QID x 14d While on clinic furlough, you continue to experience significant coughing spasms, occasional whooping, and frequent posttussive apneic episodes. The cough is persistent and a right sided pleuritic chest pain develops. Questions/ #13 What are some of the complications that can occur with a pertussis infection? How might these complications differ according to age? You suspect a fractured rib, or pneumonia. Discussion/ complications Coughing spasms (paroxysms) associated with pertussis can be severe at times. Complications include: Sleep disruption, pneumonia, fractured ribs, apnea, otitis media, conjunctival/ scleral hemorrhages, pneumothorax, CNS hemorrhage, petechiae, subq emphysema, seizures, hernias, encephalopathy, and death. Discussion/ complications (infants) The most common complication in infants (0-12 months) is pneumonia. Hospitalization rate in infants < 6 months old is 63%. 7 Hospitalization rate for infants 6-11 months old is 28%. 7 Mortality rate for infants < 6mos old is 0.8%, and for infants 6-11 months is 0.1%. 7

14 After starting treatment, you begin to investigate the number of patients that you may have inadvertently exposed. Identifying the start of first symptoms (congestion and cough) is determined by correlating events in your day planner with symptom onset. You decide that symptoms first began 11 days prior to cough onset. Questions/ #14 Consider the number of contacts you may have exposed in the past 11 days. What constitutes an adequate exposure to pertussis, allowing the infection to spread? Discussion/ exposure Patients with pertussis are most infectious during the first three weeks of symptoms. An adequate exposure to pertussis, allowing for transmission, involves direct face to face contact with a symptomatic patient, OR Sharing a confined space for a prolonged period with a symptomatic patient. Discussion/ exposure All close contacts of patients with untreated pertussis should be prophylaxed with an appropriate antibiotic. You are able to compose the following list of probable exposures: Clinic patients: 104 pts, 27 family members, 12 staff Hospital rounds: 21 pts, 8 family members, 14 nurses, 7 support staff, (xray, etc), 6 MD s, 3 residents, 4 med students Grand rounds: 6 residents, 2 physicians Church: 5 (with close proximity) Free Clinic (volunteer): 2 MD s, 2 med students, 1 resident, 12 patients Dental appointment: 1 dentist, 2 staff Neighbors: 1 Roommates: 2 Friends: 9 TOTAL: 251

15 While on your 5 day furlough, you volunteer to help call the 251 contacts that you may have exposed during your infectious period. All of the potentially exposed patients have had their charts pulled. You begin to call each patient individually and attempt to reach non-patient contacts, as well. You carefully document your conversations, recommendations, and prophylactic treatment. After 60 minutes, you have contacted and treated only 7 patients. It becomes obvious that a better system is needed if you expect to contact everyone promptly. Questions/ #15 When faced with a local epidemic of pertussis, how might you employ public health measures to effectively minimize the spread of disease? What measures might you take to increase your own efficiency? How might you minimize the morbidity, and even mortality, of a local pertussis outbreak? Discussion/ public health measures Triaging known exposures so that highest risk individuals are contacted first may help to reduce morbidity and mortality. Infants less than 6 months of age are at highest risk if they develop pertussis. Contact these individuals first. Discussion/ public health measures Other healthcare workers are at high risk to spread the infection. Contact these exposures early. Patients with asthma, COPD, or other chronic diseases are at higher risk for complications. Contact them early also. Discussion/ contacting patients Developing a flow sheet to facilitate information collection, recording of data and documentation of treatment is crucial to efficiently deal with multiple pertussis exposures. See next slide for an example of a contact flow sheet:

16 Pertussis Exposure Flow Sheet Questions/ #16 DATE: NAME: DOB: PENN STATE FAMILY MEDICINE PROGRESS NOTE PERTUSSIS EXPOSURE NOTE: Inform patient of exposure Is patient symptomatic? (runny nose, fever, cough) No Yes Describe Time of Onset: Recommend Medical Eval / Tx Was anyone else with patient in the exam room at the time of visit? No Yes Who Refer to their PCP for preventative treatment Our patient--pull chart and treat Document in their chart Does patient have antibiotic allergies? No Yes (list): Treat: Zithromax Z-pack as dir X 5 days D#1 R#0 Biaxin XL 500 mg_ Two po QD X 14 days D#28 Septra DS- One tab po BID X 14 days D#28 Erythromycin 500mg po Q6 hours X 14 days D#56 Doxycycline 100mg po BID X 14 days D#28 Levaquin 500 mg po daily X 7 days D#14 R#0 Other: Pharmacy called: Caution patient to be checked if symptoms develop Any questions answered Caller Signature MD/ CRNP: What outside resources might you employ to help prevent a widespread epidemic? Would you be surprised if the information you obtain from different sources doesn t always agree? Inform patient of treatment options Discussion/ resources Clear and concise clinical information and recommendations on treatment of pertussis or other infectious diseases, might be obtained from the following sources: -Infectious Diseases (ID) consultants from a regional teaching hospital -Local ID consultants Questions/ #17 What vaccines are available to prevent pertussis? -State Department of Health -Infection Control Nurse affiliated with local hospital -Appropriate internet sites (e.g. CDC website: Discussion/ childhood vaccines for pertussis Routine childhood DTaP (diptheria-tetanus toxoid acellular pertussis) immunizes against Bordetella pertussis. Efficacy for this childhood pertussis vaccine is about 64% (mild disease) and 95% (severe disease). 8, 11 Discussion/ childhood vaccines for pertussis The DTaP series of shots are typically 2, 4, 6 and 18 months, with a booster (i.e. DTaP #5) at 4-6 years of age.

17 Question/ #18 How long do the primary DTaP series and the 4-6 year old booster provide protection against pertussis? What new boosters are available to protect adolescents and adults? Discussion/ immunization Childhood immunizations for pertussis typically wane after 5-10 years. Consequently, adolescents and adults are a major reservoir for pertussis, and the source of many pediatric infections. Two TdaP (tetanus toxoid-reduced diptheria toxoid-acellular pertussis vaccine adsorbed) vaccines are available to boost pertussis immunity in adolescents and adults. Discussion/ pertussis boosters Boostrix (GSK Biologicals) is approved for year olds. Adacel (Sanofi-Aventis) is a second TdaP approved for the year old age group. Discussion/ pertussis boosters Both TdaP s are recommended for adolescents and adults whose last Td was > 5 years ago. The minimal interval since the last Td is two years, but shorter intervals can be used to control pertussis outbreaks. You/ staff contact all 251 exposed individuals Test and treat when symptomatic Treat all others prophylactically Follow-up completed within a 7- day window. No contacts develop pertussis Over100 unrelated cases diagnosed in the community from other exposures. You are able to return to work after 5 full days of antibiotic. Though you are no longer infectious, you continue to experience paroxysms of cough, which slowly improve over the weeks ahead.

18 Case presentation: Unfortunately your cough will last a full 103 days before it finally resolves. It becomes clear why the Chinese word for pertussis is one-hundred day cough! During that time, you can only wonder how you had become the index case in a community wide outbreak. Conclusion: Contracting pertussis has been an enlightening experience! Your hard work as impromptu public health agents has been effective in helping to prevent a widespread epidemic. In Appreciation for Their Contributions to this Project: Garrick Baskerville, Medical Student, Penn State M. S. Hershey College of Medicine Michelle Sudol, Medical Student, Philadelphia College of Osteopathic Medicine Penn State Family Medicine: Juan Qiu, M.D. Kathy Shultz, R.N. Shannon Smeltzer, L.P.N. Pam Leah, L.P.N.