Pertussis persists

The Centers for Disease Control and Prevention suggests that recurring pertussis outbreaks may be the “new normal.” Such outbreaks show that some of what we “know” about pertussis is still correct, but some things are evolving. So in this new year, what do we need to know about patient vulnerability post vaccine as well as the clinical course, diagnosis, and treatment of this stubborn persisting disease?

Vulnerability after acellular pertussis vaccine

The recent large 2014 California outbreak surpassed the record numbers for the previously highest incidence year, 2010 (MMWR 2014;63:1129-32). This is scary because more cases had been reported in California in 2010 than in any prior year since the 1940s. The overall 2014 California pertussis rate (26/100,000 population) was approximately 10 times the national average for the first 9 years of this century, Are there clues as to who is most vulnerable and why?

No age group was spared, but certain age groups did appear more vulnerable. Infants had a startling 174.6/100,000 incidence (six times the rate for the overall population). It is not surprising to any clinician that infants less than 1 year of age were hardest hit. Infants have the most evident symptoms with pertussis. Infants also have 5-7 months of their first year in which they are incompletely immunized. Therefore, many are not expected to be protected until about 7-9 months of age. This vulnerability could be partly remedied if all pregnant women got Tdap boosters as recommended during pregnancy.

Of note, 15-year-olds had an incidence similar to that of infants (137.8/100,000). Ethnically, non-Hispanic whites had the highest incidence among adolescents (166.2/100,000), compared with Hispanics (64.2/100,000), Asian/Pacific Islanders (43.9/100,000), and non-Hispanic blacks (23.7/100,000). Disturbingly, 87% of cases among 15-year-olds had received a prior Tdap booster dose (median time since booster Tdap = 3 years, range = 0-7 years). Previous data from the 2010 outbreak suggested that immunity to pertussis wanes 3-4 years after receipt of the last acellular pertussis (aP)–containing vaccine. This is likely part of the explanation in 2014 as well. However, waning immunity after the booster does not explain why non-Hispanic whites had two to six times the incidence of other ethnicities. Non-Hispanic whites are thought to be the demographic with the most vaccine refusal and vaccine delay in California, so this may partially explain excess cases. Racial differences in access to care or genetic differences in disease susceptibility also may play a role.

Why is this biphasic increase in incidence in California a microcosm of the new epidemiology of pertussis in the United States? A kinder, gentler DTaP vaccine replaced the whole-cell DTP in the late 1990s. This occurred in response to the public’s concern about potential central nervous system adverse effects associated with the whole-cell DTP vaccine. Immunogenicity studies seemed to show equivalent immune responses in infants and toddlers receiving DTaP, compared with those who received DTP. It has only been in the last 5 years that we now know that the new DTaP and Tdap are not working as well as we had hoped.

The two aspects to the lesser protection provided by aP vaccines are pertactin-deficient pertussis strains and quicker waning of aP vaccine–induced immunity. Antibody to pertactin appears to be important in protection against clinical pertussis. New circulating clinical strains of pertussis may not have pertactin (N. Engl. J. Med. 2013;368:583-4). The strains used in our current DTaP and Tdap were designed to protect against pertactin-containing strains and were tested for this. This means that a proportion of the antibodies induced by vaccine strains are not useful against pertactin-deficient strains. The aP vaccine still induces antibody to the pertussis toxin and other pertussis components in the vaccines, so they will likely still reduce the severity of disease. But the vaccines are not likely to prevent infections from pertactin-deficient strains. This is similar to the partial vaccine mismatch that we are seeing with the current seasonal H3N2 influenza vaccine strain.

The second aspect is that protection appears to wane approximately 3-5 years after the last dose of aP-containing vaccine. This contrasts sharply with expectations in the past of 7-10 years of protection from whole cell pertussis–containing vaccines. The less reactive aP vaccine produces fewer adverse effects by not producing as much inflammation as DPT. The problem is that part of the reason the DPT has such good protective responses is the amount of inflammation it produces. So with less aP vaccine–induced inflammation comes less robust antibody and T-cell responses.

Nevertheless, the current acellular pertussis vaccines remain the most effective available tools to reduce pertussis disease (Cochrane Database Syst. Rev. 2014;9:CD001478]). But until we have new versions of pertussis vaccines that address these two issues, we clinicians need to remain vigilant for signs and symptoms of pertussis.

Clinical course

Remember that a whoop is rarely seen in young children and often also not seen when older patients present. The many outbreaks over the last 10 years have confirmed that paroxysmal cough with/without apnea in an infant/toddler should raise our index of suspicion. Likewise, older children, adolescents, and adults with persistent cough beyond 2 weeks are potential pertussis cases. Once the diagnosis is made, treatment is not expected to have a major impact on the clinical course, in part because the diagnosis is usually delayed (more than 10 days into symptoms). This delay allows more injury to the respiratory mucosa and cilia so that healing can require 6-12 weeks after bacterial replication ceases. This prolonged healing process is what is mostly responsible for the syndrome known as the “100-day cough.” So the clinical course of pertussis has not changed in the last 10 years. However, there have been changes in the commonly used diagnostic approach.

Pertussis diagnosis and contagion

During the last 5 years, polymerase chain reaction (PCR) testing has become the preferred technology to detect pertussis. This is due to the sensitivity and quick turnaround time of the assay. The gold standard for pertussis diagnosis remains culture, but it is expensive, cumbersome, and slow (up to a week to provide results). An ongoing debate arose about how long PCR testing remains positive after the onset of symptoms or treatment. This was not the problem when culture was the diagnostic tool of choice. Data from the 1970s and 1980s indicated that cultures were rarely positive after the third week of symptoms even without treatment. Furthermore, macrolides eliminated both contagion and positive culture results of infected patients after 5 days of treatment.

So now that we use PCR most often for diagnosis, what is the outer limit of positivity? A recent prospective cohort study from Salt Lake City suggests that PCR may detect pertussis DNA way beyond 3 weeks after symptom onset (J. Ped. Infect. Dis. 2014;3:347-9). Among patients hospitalized with laboratory-confirmed Bordetella pertussis infection, half had persistently positive pertussis PCR testing more than 50 days after symptom onset, despite antibiotic treatment and clinical improvement. The median (range) for the last day for a positive test after symptom onset was 58 days (4-172 days).

This raises the question as to whether there are viable pertussis organisms in the respiratory tract beyond the traditional 3 weeks defined by culture data. It is likely that DNA persists in the thick mucus of the respiratory tract way beyond viability of the last pertussis organisms. Put another way, PCR likely detects bacterial corpses or components way beyond the time that the patient is contagious. Unfortunately, current PCR data do not tell us how long patients remain contagious with the current strains of pertussis as infecting agents. Some institutions appear to be extending the isolation time for patients treated for pertussis beyond the traditional 5 days post initiation of effective treatment. Until more data are available, we are somewhat in the dark. But I would take comfort in the fact that it is unlikely the “new” data will be much different from those derived from the traditional studies that use culture to define infectivity. The American Academy of Pediatrics Committee on Infectious Diseases Red Book appears to agree.

For hospitalized pertussis patients, the AAP Committee on Infectious Diseases Red Book recommends standard and droplet precautions for 5 days after starting effective therapy, or 3 weeks after cough onset if appropriate antimicrobial therapy has not been given.

In addition, the CDC states: “PCR has optimal sensitivity during the first 3 weeks of cough when bacterial DNA is still present in the nasopharynx. After the fourth week of cough, the amount of bacterial DNA rapidly diminishes, which increases the risk of obtaining falsely negative results.” Later in the same document, the CDC says: “PCR testing following antibiotic therapy also can result in falsely negative findings. The exact duration of positivity following antibiotic use is not well understood, but PCR testing after 5 days of antibiotic use is unlikely to be of benefit and is generally not recommended.”

So what do we know? Not all PCR assays use the same primers, so some variance from the usual experience of up to 4 weeks of positive PCR results may be due to differences in the assays. But this raises concern that the PCR that you order may be positive at times when the patient is no longer contagious.

Pertussis treatment

If strains of pertussis have changed their pertactin antigen, are they changing their antibiotic susceptibility patterns? While there have been reports of macrolide resistance in a few pertussis strains, these still remain rare. The most recent comprehensive review of treatment efficacy was a Cochrane review performed in 2005 and published in 2007 (Cochrane Database Syst. Rev. 2007;3:CD004404). They evaluated 10 trials from 1969 to 2004 in which microbiologic eradication was defined by negative results from repeat pertussis culture. While meta-analysis of microbiologic eradication was not possible because of differences in antibiotic use, the investigators did conclude that antibiotic treatment “is effective in eliminating B. pertussis from patients with the disease to render them noninfectious, but does not alter the subsequent clinical course of the illness.”

Further, they state that “the best regimens for microbiologic clearance, with fewer side effects,” are 3 days of azithromycin (a single 10-mg/kg dose on 3 consecutive days) or 7 days of clarithromycin (7.5-mg/kg dose twice daily).

Another effective regimen is 14 days of erythromycin ethylsuccinate (60 mg/kg per day in 3 divided doses) .

CDC treatment recommendations include azithromycin or erythromycin, with trimethoprim-sulfamethoxazole as a possibility for macrolide-intolerant patients, although there are less data and success rates may not be as high.

Conclusion

So what do we know now about pertussis?

• Outbreaks are ongoing and likely will continue until newer more effective vaccines are produced, including those that circumvent the problem of pertactin-deficient strains.

• Pertussis is likely contagious up to 5 days on effective therapy, and for as long as 3 weeks if effective therapy has not been administered.

• PCR is a sensitive test that may remain positive for many weeks beyond contagion.

• Treatment with macrolides appears to be the most effective way to eradicate replicating pertussis pathogens.

• Treatment is not likely to have a major impact on the clinical course of disease because most of the damage to the respiratory tract is done prior to diagnosis and treatment. Treatment does reduce infectivity and subsequent cases.

• Current aP vaccines currently are our best preventative tools – including use in pregnant women to protect young infants.

As clinicians, our best course is to continue to immunize with the current vaccines, and remain vigilant for symptoms and signs of pertussis infection of patients so that early diagnosis and treatment can prevent further spread.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. Children’s Mercy Hospitals receives funds from GlaxoSmithKline for Dr. Harrison being principal investigator on a multicenter research study of a hexavalent pertussis-containing infant vaccine. E-mail Dr. Harrison at [email protected].

The Centers for Disease Control and Prevention suggests that recurring pertussis outbreaks may be the “new normal.” Such outbreaks show that some of what we “know” about pertussis is still correct, but some things are evolving. So in this new year, what do we need to know about patient vulnerability post vaccine as well as the clinical course, diagnosis, and treatment of this stubborn persisting disease?

Vulnerability after acellular pertussis vaccine

The recent large 2014 California outbreak surpassed the record numbers for the previously highest incidence year, 2010 (MMWR 2014;63:1129-32). This is scary because more cases had been reported in California in 2010 than in any prior year since the 1940s. The overall 2014 California pertussis rate (26/100,000 population) was approximately 10 times the national average for the first 9 years of this century, Are there clues as to who is most vulnerable and why?

No age group was spared, but certain age groups did appear more vulnerable. Infants had a startling 174.6/100,000 incidence (six times the rate for the overall population). It is not surprising to any clinician that infants less than 1 year of age were hardest hit. Infants have the most evident symptoms with pertussis. Infants also have 5-7 months of their first year in which they are incompletely immunized. Therefore, many are not expected to be protected until about 7-9 months of age. This vulnerability could be partly remedied if all pregnant women got Tdap boosters as recommended during pregnancy.

Of note, 15-year-olds had an incidence similar to that of infants (137.8/100,000). Ethnically, non-Hispanic whites had the highest incidence among adolescents (166.2/100,000), compared with Hispanics (64.2/100,000), Asian/Pacific Islanders (43.9/100,000), and non-Hispanic blacks (23.7/100,000). Disturbingly, 87% of cases among 15-year-olds had received a prior Tdap booster dose (median time since booster Tdap = 3 years, range = 0-7 years). Previous data from the 2010 outbreak suggested that immunity to pertussis wanes 3-4 years after receipt of the last acellular pertussis (aP)–containing vaccine. This is likely part of the explanation in 2014 as well. However, waning immunity after the booster does not explain why non-Hispanic whites had two to six times the incidence of other ethnicities. Non-Hispanic whites are thought to be the demographic with the most vaccine refusal and vaccine delay in California, so this may partially explain excess cases. Racial differences in access to care or genetic differences in disease susceptibility also may play a role.

Why is this biphasic increase in incidence in California a microcosm of the new epidemiology of pertussis in the United States? A kinder, gentler DTaP vaccine replaced the whole-cell DTP in the late 1990s. This occurred in response to the public’s concern about potential central nervous system adverse effects associated with the whole-cell DTP vaccine. Immunogenicity studies seemed to show equivalent immune responses in infants and toddlers receiving DTaP, compared with those who received DTP. It has only been in the last 5 years that we now know that the new DTaP and Tdap are not working as well as we had hoped.

The two aspects to the lesser protection provided by aP vaccines are pertactin-deficient pertussis strains and quicker waning of aP vaccine–induced immunity. Antibody to pertactin appears to be important in protection against clinical pertussis. New circulating clinical strains of pertussis may not have pertactin (N. Engl. J. Med. 2013;368:583-4). The strains used in our current DTaP and Tdap were designed to protect against pertactin-containing strains and were tested for this. This means that a proportion of the antibodies induced by vaccine strains are not useful against pertactin-deficient strains. The aP vaccine still induces antibody to the pertussis toxin and other pertussis components in the vaccines, so they will likely still reduce the severity of disease. But the vaccines are not likely to prevent infections from pertactin-deficient strains. This is similar to the partial vaccine mismatch that we are seeing with the current seasonal H3N2 influenza vaccine strain.

The second aspect is that protection appears to wane approximately 3-5 years after the last dose of aP-containing vaccine. This contrasts sharply with expectations in the past of 7-10 years of protection from whole cell pertussis–containing vaccines. The less reactive aP vaccine produces fewer adverse effects by not producing as much inflammation as DPT. The problem is that part of the reason the DPT has such good protective responses is the amount of inflammation it produces. So with less aP vaccine–induced inflammation comes less robust antibody and T-cell responses.

Nevertheless, the current acellular pertussis vaccines remain the most effective available tools to reduce pertussis disease (Cochrane Database Syst. Rev. 2014;9:CD001478]). But until we have new versions of pertussis vaccines that address these two issues, we clinicians need to remain vigilant for signs and symptoms of pertussis.

Clinical course

Remember that a whoop is rarely seen in young children and often also not seen when older patients present. The many outbreaks over the last 10 years have confirmed that paroxysmal cough with/without apnea in an infant/toddler should raise our index of suspicion. Likewise, older children, adolescents, and adults with persistent cough beyond 2 weeks are potential pertussis cases. Once the diagnosis is made, treatment is not expected to have a major impact on the clinical course, in part because the diagnosis is usually delayed (more than 10 days into symptoms). This delay allows more injury to the respiratory mucosa and cilia so that healing can require 6-12 weeks after bacterial replication ceases. This prolonged healing process is what is mostly responsible for the syndrome known as the “100-day cough.” So the clinical course of pertussis has not changed in the last 10 years. However, there have been changes in the commonly used diagnostic approach.

Pertussis diagnosis and contagion

During the last 5 years, polymerase chain reaction (PCR) testing has become the preferred technology to detect pertussis. This is due to the sensitivity and quick turnaround time of the assay. The gold standard for pertussis diagnosis remains culture, but it is expensive, cumbersome, and slow (up to a week to provide results). An ongoing debate arose about how long PCR testing remains positive after the onset of symptoms or treatment. This was not the problem when culture was the diagnostic tool of choice. Data from the 1970s and 1980s indicated that cultures were rarely positive after the third week of symptoms even without treatment. Furthermore, macrolides eliminated both contagion and positive culture results of infected patients after 5 days of treatment.

So now that we use PCR most often for diagnosis, what is the outer limit of positivity? A recent prospective cohort study from Salt Lake City suggests that PCR may detect pertussis DNA way beyond 3 weeks after symptom onset (J. Ped. Infect. Dis. 2014;3:347-9). Among patients hospitalized with laboratory-confirmed Bordetella pertussis infection, half had persistently positive pertussis PCR testing more than 50 days after symptom onset, despite antibiotic treatment and clinical improvement. The median (range) for the last day for a positive test after symptom onset was 58 days (4-172 days).

This raises the question as to whether there are viable pertussis organisms in the respiratory tract beyond the traditional 3 weeks defined by culture data. It is likely that DNA persists in the thick mucus of the respiratory tract way beyond viability of the last pertussis organisms. Put another way, PCR likely detects bacterial corpses or components way beyond the time that the patient is contagious. Unfortunately, current PCR data do not tell us how long patients remain contagious with the current strains of pertussis as infecting agents. Some institutions appear to be extending the isolation time for patients treated for pertussis beyond the traditional 5 days post initiation of effective treatment. Until more data are available, we are somewhat in the dark. But I would take comfort in the fact that it is unlikely the “new” data will be much different from those derived from the traditional studies that use culture to define infectivity. The American Academy of Pediatrics Committee on Infectious Diseases Red Book appears to agree.

For hospitalized pertussis patients, the AAP Committee on Infectious Diseases Red Book recommends standard and droplet precautions for 5 days after starting effective therapy, or 3 weeks after cough onset if appropriate antimicrobial therapy has not been given.

In addition, the CDC states: “PCR has optimal sensitivity during the first 3 weeks of cough when bacterial DNA is still present in the nasopharynx. After the fourth week of cough, the amount of bacterial DNA rapidly diminishes, which increases the risk of obtaining falsely negative results.” Later in the same document, the CDC says: “PCR testing following antibiotic therapy also can result in falsely negative findings. The exact duration of positivity following antibiotic use is not well understood, but PCR testing after 5 days of antibiotic use is unlikely to be of benefit and is generally not recommended.”

So what do we know? Not all PCR assays use the same primers, so some variance from the usual experience of up to 4 weeks of positive PCR results may be due to differences in the assays. But this raises concern that the PCR that you order may be positive at times when the patient is no longer contagious.

Pertussis treatment

If strains of pertussis have changed their pertactin antigen, are they changing their antibiotic susceptibility patterns? While there have been reports of macrolide resistance in a few pertussis strains, these still remain rare. The most recent comprehensive review of treatment efficacy was a Cochrane review performed in 2005 and published in 2007 (Cochrane Database Syst. Rev. 2007;3:CD004404). They evaluated 10 trials from 1969 to 2004 in which microbiologic eradication was defined by negative results from repeat pertussis culture. While meta-analysis of microbiologic eradication was not possible because of differences in antibiotic use, the investigators did conclude that antibiotic treatment “is effective in eliminating B. pertussis from patients with the disease to render them noninfectious, but does not alter the subsequent clinical course of the illness.”

Further, they state that “the best regimens for microbiologic clearance, with fewer side effects,” are 3 days of azithromycin (a single 10-mg/kg dose on 3 consecutive days) or 7 days of clarithromycin (7.5-mg/kg dose twice daily).

Another effective regimen is 14 days of erythromycin ethylsuccinate (60 mg/kg per day in 3 divided doses) .

CDC treatment recommendations include azithromycin or erythromycin, with trimethoprim-sulfamethoxazole as a possibility for macrolide-intolerant patients, although there are less data and success rates may not be as high.

Conclusion

So what do we know now about pertussis?

• Outbreaks are ongoing and likely will continue until newer more effective vaccines are produced, including those that circumvent the problem of pertactin-deficient strains.

• Pertussis is likely contagious up to 5 days on effective therapy, and for as long as 3 weeks if effective therapy has not been administered.

• PCR is a sensitive test that may remain positive for many weeks beyond contagion.

• Treatment with macrolides appears to be the most effective way to eradicate replicating pertussis pathogens.

• Treatment is not likely to have a major impact on the clinical course of disease because most of the damage to the respiratory tract is done prior to diagnosis and treatment. Treatment does reduce infectivity and subsequent cases.

• Current aP vaccines currently are our best preventative tools – including use in pregnant women to protect young infants.

As clinicians, our best course is to continue to immunize with the current vaccines, and remain vigilant for symptoms and signs of pertussis infection of patients so that early diagnosis and treatment can prevent further spread.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. Children’s Mercy Hospitals receives funds from GlaxoSmithKline for Dr. Harrison being principal investigator on a multicenter research study of a hexavalent pertussis-containing infant vaccine. E-mail Dr. Harrison at [email protected].

The Centers for Disease Control and Prevention suggests that recurring pertussis outbreaks may be the “new normal.” Such outbreaks show that some of what we “know” about pertussis is still correct, but some things are evolving. So in this new year, what do we need to know about patient vulnerability post vaccine as well as the clinical course, diagnosis, and treatment of this stubborn persisting disease?

Vulnerability after acellular pertussis vaccine

The recent large 2014 California outbreak surpassed the record numbers for the previously highest incidence year, 2010 (MMWR 2014;63:1129-32). This is scary because more cases had been reported in California in 2010 than in any prior year since the 1940s. The overall 2014 California pertussis rate (26/100,000 population) was approximately 10 times the national average for the first 9 years of this century, Are there clues as to who is most vulnerable and why?

No age group was spared, but certain age groups did appear more vulnerable. Infants had a startling 174.6/100,000 incidence (six times the rate for the overall population). It is not surprising to any clinician that infants less than 1 year of age were hardest hit. Infants have the most evident symptoms with pertussis. Infants also have 5-7 months of their first year in which they are incompletely immunized. Therefore, many are not expected to be protected until about 7-9 months of age. This vulnerability could be partly remedied if all pregnant women got Tdap boosters as recommended during pregnancy.

Of note, 15-year-olds had an incidence similar to that of infants (137.8/100,000). Ethnically, non-Hispanic whites had the highest incidence among adolescents (166.2/100,000), compared with Hispanics (64.2/100,000), Asian/Pacific Islanders (43.9/100,000), and non-Hispanic blacks (23.7/100,000). Disturbingly, 87% of cases among 15-year-olds had received a prior Tdap booster dose (median time since booster Tdap = 3 years, range = 0-7 years). Previous data from the 2010 outbreak suggested that immunity to pertussis wanes 3-4 years after receipt of the last acellular pertussis (aP)–containing vaccine. This is likely part of the explanation in 2014 as well. However, waning immunity after the booster does not explain why non-Hispanic whites had two to six times the incidence of other ethnicities. Non-Hispanic whites are thought to be the demographic with the most vaccine refusal and vaccine delay in California, so this may partially explain excess cases. Racial differences in access to care or genetic differences in disease susceptibility also may play a role.

Why is this biphasic increase in incidence in California a microcosm of the new epidemiology of pertussis in the United States? A kinder, gentler DTaP vaccine replaced the whole-cell DTP in the late 1990s. This occurred in response to the public’s concern about potential central nervous system adverse effects associated with the whole-cell DTP vaccine. Immunogenicity studies seemed to show equivalent immune responses in infants and toddlers receiving DTaP, compared with those who received DTP. It has only been in the last 5 years that we now know that the new DTaP and Tdap are not working as well as we had hoped.

The two aspects to the lesser protection provided by aP vaccines are pertactin-deficient pertussis strains and quicker waning of aP vaccine–induced immunity. Antibody to pertactin appears to be important in protection against clinical pertussis. New circulating clinical strains of pertussis may not have pertactin (N. Engl. J. Med. 2013;368:583-4). The strains used in our current DTaP and Tdap were designed to protect against pertactin-containing strains and were tested for this. This means that a proportion of the antibodies induced by vaccine strains are not useful against pertactin-deficient strains. The aP vaccine still induces antibody to the pertussis toxin and other pertussis components in the vaccines, so they will likely still reduce the severity of disease. But the vaccines are not likely to prevent infections from pertactin-deficient strains. This is similar to the partial vaccine mismatch that we are seeing with the current seasonal H3N2 influenza vaccine strain.

The second aspect is that protection appears to wane approximately 3-5 years after the last dose of aP-containing vaccine. This contrasts sharply with expectations in the past of 7-10 years of protection from whole cell pertussis–containing vaccines. The less reactive aP vaccine produces fewer adverse effects by not producing as much inflammation as DPT. The problem is that part of the reason the DPT has such good protective responses is the amount of inflammation it produces. So with less aP vaccine–induced inflammation comes less robust antibody and T-cell responses.

Nevertheless, the current acellular pertussis vaccines remain the most effective available tools to reduce pertussis disease (Cochrane Database Syst. Rev. 2014;9:CD001478]). But until we have new versions of pertussis vaccines that address these two issues, we clinicians need to remain vigilant for signs and symptoms of pertussis.

Clinical course

Remember that a whoop is rarely seen in young children and often also not seen when older patients present. The many outbreaks over the last 10 years have confirmed that paroxysmal cough with/without apnea in an infant/toddler should raise our index of suspicion. Likewise, older children, adolescents, and adults with persistent cough beyond 2 weeks are potential pertussis cases. Once the diagnosis is made, treatment is not expected to have a major impact on the clinical course, in part because the diagnosis is usually delayed (more than 10 days into symptoms). This delay allows more injury to the respiratory mucosa and cilia so that healing can require 6-12 weeks after bacterial replication ceases. This prolonged healing process is what is mostly responsible for the syndrome known as the “100-day cough.” So the clinical course of pertussis has not changed in the last 10 years. However, there have been changes in the commonly used diagnostic approach.

Pertussis diagnosis and contagion

During the last 5 years, polymerase chain reaction (PCR) testing has become the preferred technology to detect pertussis. This is due to the sensitivity and quick turnaround time of the assay. The gold standard for pertussis diagnosis remains culture, but it is expensive, cumbersome, and slow (up to a week to provide results). An ongoing debate arose about how long PCR testing remains positive after the onset of symptoms or treatment. This was not the problem when culture was the diagnostic tool of choice. Data from the 1970s and 1980s indicated that cultures were rarely positive after the third week of symptoms even without treatment. Furthermore, macrolides eliminated both contagion and positive culture results of infected patients after 5 days of treatment.

So now that we use PCR most often for diagnosis, what is the outer limit of positivity? A recent prospective cohort study from Salt Lake City suggests that PCR may detect pertussis DNA way beyond 3 weeks after symptom onset (J. Ped. Infect. Dis. 2014;3:347-9). Among patients hospitalized with laboratory-confirmed Bordetella pertussis infection, half had persistently positive pertussis PCR testing more than 50 days after symptom onset, despite antibiotic treatment and clinical improvement. The median (range) for the last day for a positive test after symptom onset was 58 days (4-172 days).

This raises the question as to whether there are viable pertussis organisms in the respiratory tract beyond the traditional 3 weeks defined by culture data. It is likely that DNA persists in the thick mucus of the respiratory tract way beyond viability of the last pertussis organisms. Put another way, PCR likely detects bacterial corpses or components way beyond the time that the patient is contagious. Unfortunately, current PCR data do not tell us how long patients remain contagious with the current strains of pertussis as infecting agents. Some institutions appear to be extending the isolation time for patients treated for pertussis beyond the traditional 5 days post initiation of effective treatment. Until more data are available, we are somewhat in the dark. But I would take comfort in the fact that it is unlikely the “new” data will be much different from those derived from the traditional studies that use culture to define infectivity. The American Academy of Pediatrics Committee on Infectious Diseases Red Book appears to agree.

For hospitalized pertussis patients, the AAP Committee on Infectious Diseases Red Book recommends standard and droplet precautions for 5 days after starting effective therapy, or 3 weeks after cough onset if appropriate antimicrobial therapy has not been given.

In addition, the CDC states: “PCR has optimal sensitivity during the first 3 weeks of cough when bacterial DNA is still present in the nasopharynx. After the fourth week of cough, the amount of bacterial DNA rapidly diminishes, which increases the risk of obtaining falsely negative results.” Later in the same document, the CDC says: “PCR testing following antibiotic therapy also can result in falsely negative findings. The exact duration of positivity following antibiotic use is not well understood, but PCR testing after 5 days of antibiotic use is unlikely to be of benefit and is generally not recommended.”

So what do we know? Not all PCR assays use the same primers, so some variance from the usual experience of up to 4 weeks of positive PCR results may be due to differences in the assays. But this raises concern that the PCR that you order may be positive at times when the patient is no longer contagious.

Pertussis treatment

If strains of pertussis have changed their pertactin antigen, are they changing their antibiotic susceptibility patterns? While there have been reports of macrolide resistance in a few pertussis strains, these still remain rare. The most recent comprehensive review of treatment efficacy was a Cochrane review performed in 2005 and published in 2007 (Cochrane Database Syst. Rev. 2007;3:CD004404). They evaluated 10 trials from 1969 to 2004 in which microbiologic eradication was defined by negative results from repeat pertussis culture. While meta-analysis of microbiologic eradication was not possible because of differences in antibiotic use, the investigators did conclude that antibiotic treatment “is effective in eliminating B. pertussis from patients with the disease to render them noninfectious, but does not alter the subsequent clinical course of the illness.”

Further, they state that “the best regimens for microbiologic clearance, with fewer side effects,” are 3 days of azithromycin (a single 10-mg/kg dose on 3 consecutive days) or 7 days of clarithromycin (7.5-mg/kg dose twice daily).

Another effective regimen is 14 days of erythromycin ethylsuccinate (60 mg/kg per day in 3 divided doses) .

CDC treatment recommendations include azithromycin or erythromycin, with trimethoprim-sulfamethoxazole as a possibility for macrolide-intolerant patients, although there are less data and success rates may not be as high.

Conclusion

So what do we know now about pertussis?

• Outbreaks are ongoing and likely will continue until newer more effective vaccines are produced, including those that circumvent the problem of pertactin-deficient strains.

• Pertussis is likely contagious up to 5 days on effective therapy, and for as long as 3 weeks if effective therapy has not been administered.

• PCR is a sensitive test that may remain positive for many weeks beyond contagion.

• Treatment with macrolides appears to be the most effective way to eradicate replicating pertussis pathogens.

• Treatment is not likely to have a major impact on the clinical course of disease because most of the damage to the respiratory tract is done prior to diagnosis and treatment. Treatment does reduce infectivity and subsequent cases.

• Current aP vaccines currently are our best preventative tools – including use in pregnant women to protect young infants.

As clinicians, our best course is to continue to immunize with the current vaccines, and remain vigilant for symptoms and signs of pertussis infection of patients so that early diagnosis and treatment can prevent further spread.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. Children’s Mercy Hospitals receives funds from GlaxoSmithKline for Dr. Harrison being principal investigator on a multicenter research study of a hexavalent pertussis-containing infant vaccine. E-mail Dr. Harrison at [email protected].