Pertussis: Not Your Typical URI

It’s been a quiet night so far in the ED. You see two patients appear on your tracking board, a 33-year-old female and 4-year-old male. The mother and son are placed in the same room by your triage nurse, both with normal vital signs. The mom states she has been experiencing a cough for three weeks that is severe in nature, worsened by yawning, laughing, or exercise. However, everything started with congestion. She is concerned and came to see you because of the duration and severity of the cough. Her son has had similar symptoms, though his cough seems to come in a long series. He struggles for breath after this series of coughing, and he has vomited after coughing. Neither have any other medical problems, but mom is not a big believer in vaccinations. What could this be? Is this just another viral upper respiratory infection?

Bordetella pertussis is a highly infectious gram-negative bacterium which produces a toxin in the human respiratory tract [^1-3]. This infection is commonly known as “whooping cough,” due to the classic noise from the forced inspiratory effort made after coughing. This disease causes the greatest morbidity and mortality in the very young, specifically those younger than one year [^1-4]. The incidence of pertussis is cyclic, occurring with peaks every three to five years in the United States. A peak was observed in 2010, followed by 2014 [^4-9]. In California, a pertussis epidemic was declared in January 2014 due to an incidence five times greater than baseline levels. These increasing numbers of pertussis cases may include increased diagnosis, increased reporting, waning vaccine immunity, decreased vaccination, and true increase in pertussis loads [^5]. Patients often present with prolonged cough, but this is seen in a variety of diseases [^8,9]. What can you do to effectively evaluate and manage these patients?

A little background
Even though the vaccination for pertussis is widespread, the incidence has been increasing since the 1990s, with those under a year old having the greatest morbidity and mortality [^8,9]. Before the introduction of a vaccine for the disease in the 1940s, infants and young children were the primary population affected, with over 200,000 cases annually [^2,3,10,11]. This disease has decreased by more than 80% with the vaccine, and now more than half of patients with symptoms include adolescents and adults, who also serve as a reservoir for infection. Adults more commonly present in a more atypical or mild fashion, which results in under recognition of the disease [^10-15].

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Pertussis is spread through respiratory droplets aerosolized by coughing. The microbes survive only for several hours outside of respiratory secretions [^3,10-15]. Risks for developing the disease include extremes of age, incomplete vaccination status, obesity, and asthma [^2,3,16]. The incubation period is typically seven to 10 days (with range one to three weeks), with the classic presentation including paroxysms of coughing, inspiratory whoop, and post-tussive vomiting. This most commonly occurs in patients less than 10 years who are unvaccinated [^2,3,10-15]. Table 1 discusses the three phases of pertussis including the catarrhal, paroxysmal, and convalescent stages [^3,16-20].

Just like chest pain in the elderly patient, atypical can be typical…
Atypical presentations of pertussis are common in specific populations, especially vaccinated patients [^21]. Symptoms vary with age and length of time from vaccination, and unfortunately, these atypical presentations often result in under recognition of the disease [^3,21].

Infants
Patients less than four months of age may present with a short or even absent catarrhal stage with only mild cough [^13,14,23]. The paroxysmal stage may not have a paroxysmal cough, and the patient may experience gagging, gasping, vomiting, bradycardia, and cyanosis [^13,14,23].

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Several symptoms or signs are suggestive of the disease in infants, though none are diagnostic alone. One of the major issues is differentiating pertussis from your normal run-of-the-mill URI. Associations are shown in Table 2, where pertussis is compared to other viral URIs [^24].

Older Children, Adolescents, and Adults
If vaccinated, these patients may display few symptoms and a mild cough, often with no classic features such as the paroxysms, whoop, or vomiting [^25,26]. Wheezing may occur in 8% of these patients [^26]. Prior infection or vaccination attenuates the symptoms, but they do not provide lifelong immunity. Prolonged cough may be the only symptom, though coryza, sweating, sore throat, and increased sputum can occur [^27-29]. Interestingly, one study found that in patients with cough < 28 days, pertussis accounted for 3% of symptoms, with cough greater than two weeks drastically increasing the likelihood of pertussis [^27-29]. A JAMA review found that post-tussive emesis had a likelihood ratio (LR) of 1.8, inspiratory whoop 1.9 for diagnosis, while absence of paroxysmal cough demonstrated a LR of 0.52 and absence of post-tussive emesis 0.58 for disease exclusion [^28]. 

What are complications of pertussis, and are any of them deadly?
There are two predominant forms of complications: those related to the infection and those due to mechanical problems from the severe cough [^{2,3,9,10,17,19].} All complications are more common in the pediatric and infant populations. Infectious complications include pneumonia and otitis media. Pneumonia is actually one of the most common complications. Pneumonia is associated with leukocytosis, pulmonary hypertension, and mortality in infants. Mechanical complications again are more common in infants. Apnea occurs almost exclusively in those < 6 months and is associated with coughing [^17,19]. Seizures occur in 1-2%, and encephalopathy can occur in 1%. In adults, mechanical sequelae include subconjunctival hemorrhage, worsening or development of hernia, rib fractures, lumbar strain, incontinence, or even worse issues such as cerebral hemorrhage, seizure, or stroke [^30]. Most deaths occur in patients younger than six months, with a case fatality rate of 1%. The association of SIDS and pertussis is controversial [^19,31]. However, older patients greater than 65 years have a higher need for hospitalization [^16].

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What are other conditions associated with these symptoms? 
In infants and children, foreign body/aspiration, asthma, allergic or infectious sinusitis, cardiac abnormalities, reflux, and pneumonia can present similarly. In adults, the differential of these symptoms is large as well. Remember, cough less than three weeks is defined as acute, three to eight weeks subacute, and eight weeks chronic [^32,33]. Many patients may present only with a prolonged cough. Cough accounts for approximately 30 million visits per year in the U.S. The most common causes for chronic cough include postnasal drip, asthma, and reflux. Other causes include ACE inhibitors, bronchiectasis, neoplasm, foreign body, eosinophilic bronchitis, or other infection. A chest X-ray should be completed in patients with chronic cough to evaluate for infection, mass, or obstruction. The history is often the most important aspect in differentiating what the most likely etiology is. If pertussis is doubtful, empiric treatment with an antihistamine-decongestant and primary care follow up is recommended [^32,33].

Evaluation
Early diagnosis and treatment is important to decrease the spread of the disease, and antibiotics in the early stages may shorten the symptom duration. Pertussis is a clinical diagnosis in the ED, though the U.S. Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) define a clinical case of pertussis through several means, shown in Table 3 [^9,35,36]. A clinical case is defined by cough greater than two weeks without another apparent cause and paroxysms of cough, inspiratory whoop, or post-tussive emesis. A confirmed case includes laboratory testing. If there is a known outbreak or close contact with a confirmed source, a cough for greater than two weeks is the only criteria needed for diagnosis. In outbreaks, this definition has a sensitivity and specificity of 84% and 63%, respectively [^9,35,36].

Laboratory confirmation is helpful for diagnosis in patients without exposure history, or with public health concerns. Labs including bacterial culture, PCR, and serology all differ based on age, time from symptoms, vaccination status, and exposure history. The organism is more difficult to identify during the paroxysmal stage or after antibiotics. Culture and PCR are part of the criteria per the CDC for confirmation, and direct fluorescent antibody testing can yield false positives and false negatives [^2,36]. Table 4 demonstrates test attributes.

The following is a suggested evaluation pathway for pertussis per the CDC [^{11,14,36,40]:}
For cough less than three weeks, PCR and culture of nasopharyngeal tissue is recommended in those less than four months, and in those over four months, PCR alone is recommended. For cough greater than three weeks, PCR and culture again are recommended. For those over four months, serology is recommended if there is more than one year since the last pertussis vaccine. PCR is accurate up to four weeks after onset of cough, but after this week, the false negative rate increases, and PCR is also not sensitive in patients who have received a vaccine. Obtaining specimens from the posterior nasopharynx is a must. This is uncomfortable for patients, and they should be told that the test will be uncomfortable. The patient will often cough or sneeze during the collection [^2,3,36,37].

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We know about testing and classification, but how do you diagnose it in the ED?
Most diagnoses will occur in non-outbreak settings. Pertussis should be a clinical diagnosis, especially with cough greater than two weeks with another feature suggestive of pertussis (paroxysms of cough, inspiratory whoop, post-tussive vomiting, and apnea). Per the CDC, no laboratory testing is needed with clinical findings in Table 3 above [^3,36]. In patients less than a year old, cough of any duration with a characteristic finding is diagnostic. One study found that one of the characteristic findings had a sensitivity and specificity of 95% and 15%, respectively. Three symptoms displayed sensitivity and specificity of 10% and 91%, respectively [⁴¹].

Pertussis should be considered in several other circumstances: cough that is not improving (or with paroxysms), rhinorrhea with clear discharge, or leukocytosis with lymphocytosis (WBC > 20,000 cells/microL with > 50% lymphocytes) [^17,24,31]. A low threshold for diagnosis and treatment is recommended. Any suspicion of the disease, specifically in those younger than four months, requires treatment, and labs should not delay antibiotics.

Now that you know how to diagnose pertussis, how do you treat it?
Most patients will clear the infection without antibiotics within six weeks [^42]. Antibiotics given during the catarrhal phase can decrease the duration and severity of the cough, but unfortunately many are not diagnosed in this period. Patients treated later in the disease course can reduce the spread of infection, but effect on symptoms is minimal [^{9,35-38,43,44} ].

Supportive care is the mainstay of management in adolescents and adults. However, in pediatric patients treatment can be more complicated, specifically in those less than six months. Ultimately, patients with clinical suspicion or positive studies for pertussis require treatment. If symptoms have been present less than three weeks with confirmed pertussis, antibiotics are needed [^43,44]. In those less than one year, the recommendation is  six weeks from time of cough onset. If patients have had symptoms longer than this period, antibiotics may still be needed for patients who are in contact with high risk people [^43,44].

The macrolide class of antibiotics is effective in treatment, specifically azithromycin and clarithromycin. Dosing is demonstrated in Table 5 [^43,44]. The alternative is TMP-SMX, though the efficacy is decreased. Doxycycline, beta-lactams, and fluoroquinolones should not be given. Many patients will desire treatment for the cough, which is the main symptom that causes morbidity. Destruction of the respiratory ciliated cells by pertussis toxin results in secretions that trigger the cough reflex. Resolution of the cough requires replacement of these respiratory cells, which can take weeks. Patients with obstructive symptoms such as wheezing may benefit from beta agonist inhaler/nebulizer. However, a systematic review finds insufficient evidence for antihistamine, beta agonists, and pertussis immunoglobulin [^45]. Corticosteroids also do not show benefit [^45].

Can everyone be treated in the outpatient setting?
Most patients can be treated as outpatients, except for several populations. Pertussis in younger patients is severe. For pediatric patients with respiratory distress, pneumonia (radiographic findings, SIRS criteria), inability to feed, seizures, cyanosis, apnea, and less than four months old, admission is recommended. If admitted, droplet precautions are needed, but not contact [^3,10,19,44]. On the other hand, patients who can tolerate coughing without hypoxia or bradycardia, are able to eat, have reliable caretakers, and can obtain close follow-up may be appropriate for discharge home [^3,10,19,44]. Adults with toxic appearance, multiple comorbidities (specifically lung disease), or who meet sepsis criteria may need admission.

What’s the vaccine?
Vaccines for pertussis were developed in the early 1940s, which contained dead whole cell pertussis organisms. Acellular pertussis vaccines have been used since 1991, containing acellular purified components [^2,3,46]. This vaccine contains far less side effects, though it may create less immunity. Vaccination during childhood is very effective in prevention, with efficacy approaching over 80% [^46,47]. Routine vaccination in childhood utilizes the DTaP vaccine (acellular pertussis with tetanus and diphtheria toxoids). We will not discuss vaccination recommendations, but providers should understand that immunity can wane into adolescence. A booster with Tdap is recommended past age 11 years. Patients older than 65 should receive another booster [^48].

What about postexposure prophylaxis? Is it required?
Importantly, postexposure prophylaxis with antibiotics is warranted for close contacts, defined by: face to face exposure within three feet, close contact with secretions (respiratory, nasal, oral), living in the same household, sharing same confined close space for > 1 hour [^43,49]. Also, high risk patients should be given prophylaxis including infants younger than one year, pregnant women, immunodeficiency, underlying medical condition with severe lung disease, or those with contacts with infants [^43,49]. Prophylaxis medications include the same regimen for full treatment. Contacts who are not vaccinated or under immunized require pertussis immunization. If vaccines are current, no further vaccine is needed [^43,46-49].

All cases should be reported to public health for tracking.

Back to our case…
Other conditions don’t seem as likely to you. You clinically diagnose pertussis, call the public health department, and give both azithromycin. You ask about household contacts, and the mother states they live alone. A discussion on the recommendation for vaccination is conducted, but mom states she would like to think about it. You document the conversation in the chart. Both patients seem appropriate for discharge, as the young boy has been eating and drinking appropriately. You discharge both home.

Take Home Points

• Pertussis is a gram-negative bacterium spread by respiratory droplets.
• Vaccines have drastically reduced the incidence of this disease.
• Pertussis is a clinical diagnosis. PCR, culture, and serology can assist diagnosis, but any clinical suspicion warrants treatment and postexposure prophylaxis.
• Infants less than four months, those with severe symptoms (seizure, pneumonia, apnea), and those over 65 years will likely need admission.
• Cases of pertussis should be reported to public health.

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