Clinical manifestations

Presentation and course

Pertussis, a highly communicable disease, is recognized by paroxysmal spasms of severe cough, without fever, followed by characteristic episodes of inspiratory whoop and posttussive vomiting. Encephalopathy is a rare complication of pertussis. As with other complications of pertussis, encephalopathy is more common in females, and a familial predisposition is observed. Most cases of pertussis encephalopathy are clinically apparent between the second and fourth weeks of paroxysmal cough. In an old review of 148 cases, 9% of cases of encephalopathy occurred during the first week of pertussis, 76% during weeks 2 to 4, and 16% during weeks 5 to 7 of the illness. There were two types of encephalopathy, one in which convulsions were the major manifestation in absence of other signs of cerebral dysfunction, and another variety with more insidious onset progressing to coma (44; 14). It was earlier alleged that vaccination, particularly whole-cell pertussis vaccines, cause vaccine encephalopathy in children with SCN1A mutations (05).

Pertussis encephalopathy is usually associated with fever; seizures; alteration of consciousness; and focal neurologic signs, most notably acute visual loss in the presence of normal optic discs. It has been suggested that pertussis encephalopathy is secondary to retinal changes induced by cough paroxysms. Computed tomography studies in pertussis encephalopathy are normal. Autoimmune encephalitis is an acute brain disorder; clinical manifestations range from psychiatric manifestations, movement disorders, cognitive decline, and autonomic dysfunction. It is still speculative to consider that tetanus, diphtheria, and pertussis vaccine may trigger the occurrence of autoimmune encephalitis (11; 40).

With reemergence of pertussis, new cases of pertussis encephalopathy in infants are reported. The more recent acellular vaccines have demonstrated efficacy against severe disease and a lower incidence of serious adverse events. However, they do have certain limitations, including their inability to prevent nasal colonization by the bacterium and the fact that their protective effects diminish relatively quickly over time (19). Anh Tuan and colleagues reported three such cases from Vietnam. Patients initially presented with whooping cough and then developed lethargy, encephalopathy, and seizures (01). In all three cases, Bordetella pertussis DNA was detected by polymerase chain reaction (PCR) in CSF. After treatment, two patients survived with normal neurologic examination on subsequent follow ups. One patient succumbed to her illness.

Neurologic complications are observed in neonatal pertussis. These include seizures, subarachnoid hemorrhage, and encephalopathy. Severe episodes of intractable hypoglycemia are reported by several authors. Feeding difficulties are common. Repeated vomiting may lead to derangement of the serum electrolytes and the acid-base balance, dehydration, and weight loss in some patients (09; 08; 38). An increased risk of epilepsy is noted in children with hospital-diagnosed pertussis infections compared with the general population. Investigators assessed 4700 patients with pertussis (from population-based medical registries covering all Danish hospitals), 90 of whom developed epilepsy during follow-up. The cumulative incidence of epilepsy at age 10 years was 1.7% for patients with pertussis and 0.9% for the matched comparison group (26). A study assessed the cognitive development of infants with laboratory-confirmed pertussis infection one year after pediatric intensive care unit discharge. Approximately 37% (41 out of 111) of patients had scores on the Mullen scales of early learning scores below the norm in at least one domain. Nine (10%) patients had a score that was below the population norms (03).

In typical cases, a diagnosis of whooping cough can be made on the basis of clinical presentation. A variety of viral and bacterial pathogens other than Bordetella pertussis can cause paroxysmal cough. Therefore, laboratory tests are used to confirm a diagnosis of Bordetella infection. Mild increases in the leukocyte count and marked lymphocytosis are classic markers of pertussis and have been shown to be useful in making an early diagnosis (Table 1).

Table 1. Diagnostic Criteria for Whooping Cough (12)

Prognosis and complications

The most frequent complication of pertussis is pneumonia, which occurs in 6% of cases. Other complications include sinusitis, otitis media, viral and bacterial superinfections, and nutritional deficiencies resulting from repeated vomiting. Lumbar disc herniation and rectal prolapses can occur because of increased intra-abdominal pressure as a consequence of frequent vomiting and coughing. Increased venous pressure at times produces subconjunctival hemorrhages.

Some children with pertussis develop encephalopathy, and approximately one third of them dies. Neurologic sequelae, such as learning disabilities, were seen in one third of the survivors; the remainder of survivors were normal (23; 39). A single case of central hypoventilation secondary to pertussis encephalopathy occurring during childhood has been described. The patient was successfully managed by negative pressure ventilation. In adult age, the patient was found asymptomatic (13).

Biological basis

Etiology and pathogenesis

Pertussis or whooping cough is caused by the organism Bordetella pertussis, a gram-negative coccobacillus, which is an obligate human pathogen. It is a strictly aerobic bacterium. Bordetella pertussis is encapsulated and does not produce spores. Bordetella pertussis is transmitted person to person by close contact with aerosolized droplets. The incubation period of pertussis averages 7 to 10 days (range: 5 to 21 days) and may be as long as 6 weeks. Bordetella pertussis has a strong affinity for the mucosal layers of the human respiratory system. Bordetella pertussis bacteria are not invasive, and they remain attached to the cilia of the respiratory epithelium. Bacteria damage the epithelium of the airway and the alveoli through the combined action of several virulence factors. These virulence factors include pertussis toxin, adenylate cyclase toxin, filamentous hemagglutinin, fimbriae, tracheal cytotoxin, pertactin, and dermonecrotic toxin. Bacteria attach to and multiply on the respiratory epithelium, starting in the nasopharynx and ending primarily in the bronchi and bronchioles (16; 21).

The exact etiology of the pertussis encephalopathy is debated. Suggested mechanisms include central nervous system hemorrhage, hypoxia, or vascular occlusions; loss of cerebral vascular autoregulation; secondary bacterial or viral infection; an unrecognized preexisting neurologic condition; or the effects of toxin(s) produced by Bordetella pertussis on the brain. Pertussis toxin has been postulated to act either directly on the central nervous system or indirectly by causing hypoglycemia or other metabolic disturbances (28; 34; 14). It was suggested that hypoxia might result in a breakdown of the blood-brain barrier, allowing the bacterial toxins to enter the central nervous system (23; 30). In some autopsied patients, the pathology was consistent with severe anoxic changes, possibly as a result of prolonged apnea during paroxysms of cough. Venous congestion, petechial hemorrhages, and thromboses were other changes that were observed (23).

In a murine model, respiratory infection with Bordetella pertussis resulted in persistent expression of mRNA transcripts for interleukin-1-beta and tissue necrosis factor-alpha and transient expression of interleukin-6 in the hippocampus and hypothalamus (20). These changes correlated with elevated levels of cytokine protein in the same brain areas. The results demonstrate that infection at a mucosal surface can result in the induction of proinflammatory cytokine production in the brain and suggest that these locally synthesized mediators may contribute to the pathogenesis of pertussis encephalopathy. The timing of the encephalopathy suggests that it results from increased lysis of bacteria and release of endotoxin (23).

Several investigations show that infants with vaccine encephalopathy have severe myoclonic epilepsy of infancy, which is a rare early childhood encephalopathy associated with unilateral and generalized convulsions that are often triggered by fever (18). SCN1A is the most important epilepsy gene, and mutations within the gene are seen in patients with severe myoclonic epilepsy of infancy (including generalized epilepsy with febrile seizure plus and Dravet syndrome). The generalized epilepsy with febrile seizures plus syndrome spectrum comprises a range of mild to severe phenotypes varying from classical febrile seizures to Dravet syndrome, which is a severe infantile-onset epilepsy syndrome with multiple seizure types, developmental slowing, and poor outcome (31). Genetic studies suggest that sodium channel mutations, rather than vaccines, are the cause of vaccine encephalopathy in most patients (33). Reyes and colleagues described five children who presented with presumed earlier diagnoses of alleged vaccine encephalopathy caused by pertussis vaccinations in infancy (29). All of the patients were diagnosed with Dravet syndrome years later with the help of genetic testing.

Berkovic and colleagues studied 14 patients with vaccine encephalopathy for whom the first seizure occurred within 72 hours of vaccination (04). Neuronal sodium channel alpha1 subunit (SCN1A) gene mutations were identified in 11 of 14, and a diagnosis of a specific epilepsy syndrome was made in all 14 individuals. Five mutations predicted truncation of the protein, and six were missense in conserved regions of the molecule (04). A report suggests that pertussis vaccination might trigger earlier onset of Dravet syndrome in children who, because of an SCN1A mutation, are destined to develop the disease (22). In a retrospective study of 70 patients with Dravet syndrome and SCN1A mutations, seizures following vaccinations were reported in 27% of patients (36). In 58% of these patients, vaccination-related seizures represented the first clinical manifestation of the syndrome. Most seizures occurred after diphtheria, pertussis, and tetanus (DPT) vaccinations and within 72 hours after vaccination. Two-thirds of events occurred in relation to fever.

A study investigated the genetic basis for seizures associated with the diphtheria, tetanus, and whole-cell pertussis vaccine in India, which is a major cause of vaccine hesitancy. Of the 54 children studied who had experienced these seizures, 33 showed pathogenic variants of 12 genes. The most commonly found variant was in the SCN1A gene. The study found significant predictors for a genetic diagnosis were five or more seizures, drug-resistant epilepsy, and neurodevelopmental impairment (25).

Epidemiology

Pertussis (whooping cough) is an important cause of infant death worldwide and continues to be a major public health problem, even in countries with high vaccination coverage. In 2019, the World Health Organization estimated 132,754 cases of pertussis globally, 95% of which were in developing countries. Approximately 89,000 children died from pertussis in 2019. Approximately 85% of all infants globally received three doses of pertussis vaccine. The advent of vaccination against pertussis prevented a large number of pertussis-associated deaths in developed countries. A significant increase in reported cases has occurred among adolescents, who become susceptible to pertussis approximately 10 years after childhood vaccination (42; 43). An upward trend was observed in the incidence of pertussis in countries that have switched to acellular vaccines. Acellular vaccines are less immunogenic, which leads to the early decline of vaccine-induced immunity (19).

Prevention

The mainstay for control of pertussis is vaccination. Vaccination is recommended routinely for infants and young children. Acellular vaccines are composed of one or more purified proteins from Bordetella pertussis. The acellular vaccine combined with diphtheria and tetanus is routinely provided to infants at 2, 4, and 6 months with boosters at 18 months and 4 to 6 years. Vaccinating mothers during the third trimester of pregnancy (at 27 to 36 weeks’ gestation) is now considered the most effective strategy to protect infants against pertussis because infants born to vaccinated mothers have a lower risk for pertussis in the first two months of life (41).

Differential diagnosis

Pertussis needs to be included in the differential diagnosis of chronic cough in persons of all ages, particularly among children. The differential diagnosis of chronic cough in adults include bronchial asthma, gastroesophageal reflux disease, postinfective bronchospasm, lung tuberculosis, chlamydia and mycoplasma infections, and lung malignancy.

Diagnostic workup

Diagnostic tests for pertussis include nasal swab culture, serology, direct immunofluorescent assay, and polymerase chain reaction on nasopharyngeal samples. Demonstration of the organism in nasopharyngeal specimens is possible during the first few weeks of illness. Polymerase chain reaction has sensitivity rates that are 2-fold to 3-fold higher than those of culture. With the advent of polymerase chain reaction methods, the value of culture for the diagnosis of pertussis has declined (35).

Later in the course of the disease, isolation of the organism or amplification of genomic material becomes difficult, and the diagnosis should then be made using serology. Paired serum specimens (the acute and the convalescent phases) can be obtained for the demonstration of significant antibody titer changes against specific pertussis antigens using enzyme-linked immunosorbent assay technology (35).

Management

The Centers for Disease Control and Prevention recommend macrolides erythromycin, clarithromycin, and azithromycin as choice treatments for pertussis infection. Antibiotics should be started no later than 21 days after the onset of cough. Antibiotics (erythromycin 40 to 50 mg/kg per day for 14 days) will eliminate viable Bordetella pertussis organisms from the respiratory tract within two days (02; 17; 12). Currently, shorter courses (3 to 5 days) of azithromycin or clarithromycin or erythromycin for a week is considered sufficient. A longer 14-day antibiotic treatment is now not required (12). Azithromycin and clarithromycin are easier to use as they need to be given fewer times a day and have shorter regimens. Erythromycin and azithromycin are associated with an enhanced risk of infantile hypertrophic pyloric stenosis that needs to be carefully monitored. Oral trimethoprim-sulfamethoxazole can be used as an alternative treatment for patients who do not tolerate erythromycin (02; 35; 07). Antibiotics in patients with encephalopathy may be administered through a nasogastric tube. Infants with encephalopathy should be carefully observed for apnea, cyanosis, or hypoxia. General supportive measures (eg, oxygenation, breathing treatments, and mechanical ventilation) should be administered as needed (17). It has been suggested that children receiving pertussis vaccination should not receive prophylactic antipyretics, as antipyretics do not decrease chance of febrile convulsions. In fact, prophylactic antipyretic use potentially decreases the immune response to these vaccines (24).

Outcomes

Pertussis related prognosis can be influenced by several factors. In a retrospective study involving 213 children with pertussis-like coughing, factors associated with a poor prognosis were the presence of Bordetella pertussis, a white blood cell count exceeding 20 × 10^9/L, and a lymphocyte ratio above 60%. Thus, these could serve as vital risk factors in assessing the likely outcomes for patients (06).

Between 1999 to 2004, a study examining U.S. infant mortality rates linked to pertussis found 91 deaths, all aged 7 months or younger. The average yearly infant mortality rate due to pertussis was 3.8 per 1 million live births, and 13.1 for infants aged less than two months. Factors significantly associated with pertussis deaths included low birth weight, female gender, low Apgar score, and maternal education of less than 12 years. Pertussis-related mortality rate was 2.6 times higher among Hispanic infants aged less than two months. To prevent pertussis transmission, adults and adolescents in close contact with infants should receive booster vaccinations, especially in higher-risk settings (15).

A Chinese study assessed medical records of 144 hospitalized children with severe pertussis, aiming to identify mortality risk factors. Patients' median age was two months, with the majority being less than 6 months of age. The mortality rate was 34.2%, with 76.9% of deaths occurring in patients under 6 weeks. Independent risk factors identified for death were a white blood cell count greater than 70.0 × 10^9/L and pulmonary hypertension (32).