University of Alberta, Edmonton, Alberta, Canada
Publication Date: January 31, 2017
Bordetella pertussis, the bacteria responsible for whooping cough, was the most common cause of childhood disease and mortality prior to introduction of its vaccine (World Health Organization, 2014). The infection focuses largely on youthful population, with 80% of cases occurring in children under the age of three, and under 3% of cases developing in people over the age of fifteen. Without the vaccine, over 50% of cases were estimated to become clinical and present the hallmark feature of extreme coughing with “whooping” gasps of breath between coughing attacks due to excess mucus production. During 1974, the Pertussis booster vaccine was conceived, and implemented in the World Health Organization’s (WHO) Expanded Programme on Immunization. Currently, it is administered with diphtheria and tetanus toxoids, and is called the Diptheria, Tetanus, and acellular Pertussis vaccine (DTaP). The WHO has estimated that without this vaccine, over 1.3 million pertussis-related deaths would have occurred in 2001 worldwide (Brenzel, Wolfson, Fox-rushby, Miller, & Halsey, 2015). In 2013, the WHO estimated 63 000 pertussis-related deaths in children under the age of five (World Health Organization, 2013), despite vaccine coverage rates reaching 86% in 2014 (WHO, 2009). Interestingly, the WHO has found that pertussis is shifting its attack age from children to adolescents and young adults and that pertussis is resurfacing in four developed countries, despite vaccination (WHO SAGE pertussis working group, 2014; Wright, 1998). Bordetella pertussis is neither a disease of the past nor docile, but with renewed interest from the scientific community, it may be placed on an endangered species list.
Stages of Infection and Complications
The infections has three stages: catarrhal, paroxysmal, and convalescent. The catarrhal resembles minor upper respiratory tract infection symptoms—infrequent cough, coryza, rhinorrhea, and mild fever. These symptoms usually develop 5-10 days after being exposed, but development may take up to three weeks of incubation (Tozzi, Celentano, Ciofi degli Atti, & Salmaso, 2005). The paroxysmal stage proceeds and is marked by paroxysms of coughing, vomiting after paroxysms, characteristic whooping, and cyanosis of the face. The whooping gasps and paroxysms may cause significant brain damage, break ribs of young children, or rupture vasculature. Vaccination may limit the severity of the “whooping” sound during inter-paroxysm breathing, and children under the age of 6 months do not always exhibit “whooping” (Hoppe, 2000; Wang et al., 2002). However, studies revealed roughly 77% of hospitalized victims will exhibit whooping while only 47% of non-hospitalized victims exhibit it (Stojanov, Liese, & Belohradsky, 2000). This is likely due to more severe cases being hospitalized. The paroxysmal coughing, exhibited in 55% of hospitalized victims and 22% of non-hospitalized victims may lead to complications such as brain damage resulting from lack of oxygen. For example, patients have developed clonic-tonic seizures resulting from hypoxia (Stojanov et al., 2000). B. pertussis itself may enter the lungs and cause bronchopneumonia (Paddock et al., 2008), which is deadly in children. It may cause leukocytosis, which then leads to pulmonary hypertension, exacerbating the hypoxic conditions through restricted blood flow (Paddock et al., 2008). The final stage, if the second is survived, is convalescence. By this point symptoms begin fading. The chronic cough persists, but eases over the span of weeks. Generally, symptoms have disappeared within 2-3 weeks, but may last months. The paroxysms may recur during this time, and subsequent respiratory infections are common. Treatment of paroxysms, inhibition of migration to lungs, and protection from secondary infections are all necessary to ease infection by B. pertussis as well as increase survival rate.
Transmission and Infectivity
B. pertussis is well known to be transmitted by droplets and direct contact, but there seems to be no evidence for other mechanisms of transmission, even fomites (Brachman, 2009). The catarrhal stage is the most infectious, and infectiousness begins decreasing in the paroxysmal stage, finally becoming minimal in convalescence (Brachman, 2009). Antibiotics as well as vaccinations reduce infectivity (Préziosi & Halloran, 2003). Interestingly, a recent study placed two B. pertussis inoculated baboons in cages seven feet away from two caged B. pertussis naïve baboons, and found 100% infection rate amongst naïve baboons despite lack of direct contact (Warfel, Beren, & Merkel, 2012), providing strong evidence that B. pertussis is actually capable of airborne transmission. The baboon model created by this group proved an excellent model of Bordetella pertussis infection in humans, due to exhibition of all cardinal symptoms (Warfel, Beren, Kelly, Lee, & Merkel, 2012), further strengthening their results. As previous research has used varying models, there are significant gaps in knowledge. Use of a standardized model such as this would allow negation of model error propagation and contradictory results.
Virulence Factors and Pathogenesis
Bordetella pertussis is a non-motile strictly aerobic encapsulated gram-negative coccobacilli approximately 0.8 micrometers by 0.4 micrometers which does not form spores (Finger, Koenig, & Von, 1996). It survives optimally at 35-37˚C, allowing it to spread into the lungs. It is a human disease, with no known animal vector or reservoir, but is able to infect animals. The virulence factors are fairly well known, but less well localized genetically. The hexameric Pertussis Toxin itself is composed of S1, S3, S4, S5, and two S2 protein subunits. As with many exotoxins, it has an A domain (S1) for biological activity, and a B domain for complexing with cells (S2-S5). The toxin is transported to cells using a Type IV secretion apparatus, where it binds to binds to glycosylated molecules, triggering endocytosis (N. Carbonetti, 2010). The Pertussis Toxin exhibits its effect through both A and B units. The A unit may enter host cells to ADP-ribosylate the α-subunit of heterotrimeric Gi/o proteins, causing inhibition of the Gi/o signalling pathway, resulting in various downstream effects (N. Carbonetti, 2010; Pizza, Bartoloni, Prugnola, Silvestri, & Rappuoli, 1988). The B unit seems to activate Gi/o protein-independent signalling via binding to host receptors, but may be in high enough concentration to operate during an infection (N. Carbonetti, 2010). This toxin has been clearly implicated in the systemic symptoms of B. pertussis infection such as leukocytosis, hypoglycemia, and histamine sensitivity (Munoz, Arai, Bergman, & Sadowski, 1981). It also seems heavily implicated in the cause of mortality in neonatal mouse models (Goodwin & Weiss, 1990). Interestingly, treatment of mice with intranasal pertussis toxin caused ADP-ribosylation of G proteins largely in airway macrophages (N. H. Carbonetti, Artamonova, Van Rooijen, & Ayala, 2007). These macrophages rely upon the G protein signalling pathway to effectively operate (Lattin et al., 2007). As pertussis inhibits macrophages, it may allow longevity and increased severity of the infection. Administration of pertussis toxin 14 days prior to inoculation with B. pertussis enhances the infection (Nicholas H Carbonetti, Artamonova, Mays, & Worthington, 2003), likely through priming of the tract via inhibition of airway macrophages. The pertussis toxin also seems to inhibit the recruitment of neutrophils and opsonizing antibodies during early infection, as seen between comparison of pertussis toxin treated mice and wild-type mice (Andreasen & Carbonetti, 2008; Kirimanjeswara, Agosto, Kennett, Bjornstad, & Harvill, 2005). This was achieved by inhibition of upregulation of genes necessary for signalling (Andreasen & Carbonetti, 2008; Kirimanjeswara et al., 2005)—a process heavily reliant upon G-protein pathways.
Adenylate cyclase toxin (ACT) is secreted from the bacteria through a type I secretion apparatus to act on host cells. ACT seems to have hemolytic activity (Vojtová, Kofronová, Sebo, & Benada, 2006), as it enhances/causes apoptosis of macrophage and non-immune cells (Hewlett, Donato, & Gray, 2006; Johansson et al., 2006), and inhibits the activity of macrophages through catalysis of adenylate cyclase (Kamanova et al., 2008). ACT seems to prolong the ability of B. pertussis to survive in the upper respiratory tract, while pertussis toxin seems to soften the immune system for initial infection (N. Carbonetti, 2010). ACT may also increase fluid secretion and therefore paroxysm-causing mucous amounts due to increased levels of cyclic adenosine-monophosphate in mucosa causing osmotic drag (Chmel, Bendinelli, & Friedman, 1994).
Among other virulence factors are the tracheal cytotoxin, which is released during the log-phase of growth (Goldman & Herwaldt, 1985) and is able to destroy a population of hamster ciliated cells in 60-96 hours (Finger et al., 1996). It is considered the cardinal cytotoxin. It works by destruction of the ciliary cells as well as restriction of their free-movement, causing aggregation of mucous which leads to the characteristic paroxysmal coughing and whooping of B. pertussis (Camille Locht, 1999; Luker, Collier, Kolodziej, Marshall, & Goldman, 1993). Dermonecrotic toxin also contributes to cytotoxicity, albeit not as potently at tracheal cytotoxin. Recently, it has been shown this also works through inhibition of signalling pathways, specifically through GTPase Rho inhibition (Fukui & Horiguchi, 2004). As a gram negative bacteria, it also has lipooligosaccharides (LOS) with weak pyrogenicity and capability to cause the Schwartzman reaction (Chmel et al., 1994). B. pertussis also has various agglutinogens. Agglutinogens 1 and 2 are fimbriae proteins, while 3 is cell-associated (Chmel et al., 1994; Finger et al., 1996; Pearce, Irons, Robinson, & Seabrook, 1992). These allow adhesion to eukaryotic cells, but not the cilia directly (Ashworth et al., 1988; Goldman & Herwaldt, 1985). The filamentous hemagglutinin expressed serves to enhance binding to host cells (37), and has been shown to be necessary for colonization in Bordetella bronchiseptica in the swine (Nicholson, Brockmeier, & Loving, 2009). It has at least three receptors, one for cilia, one for macrophages, and one binding heparin (C Locht, Bertin, Menozzi, & Renauld, 1993). Interestingly, in mouse models, it was not necessary in early colonization, but was in maintaining established colonization or expansion into the lungs (Kimura, MOUNTZOUROS, Relman, Falkow, & COWELL, 1990). Pertactin, an external membrane protein utilized in binding to ciliated cells is another toxin specific to B. pertussis. Using comparison of pertactin knock-out strains of Bordetella bronchiseptica in swine, it was found that infection severity was relatively similar, but that immune response was markedly higher without pertactin (Nicholson et al., 2009). This is supported by recent research proving pertactin works to reduce neutrophil-mediated clearance of Bordetella pertussis from mouse lungs (Inatsuka et al., 2010). However, pertactin-deficient strains of B. pertussis seem to be arising due to selective advantage in response to the aP vaccine (Hegerle, Dore, & Guiso, 2014; Martin et al., 2015; Safarchi et al., 2015).
Together, these toxins cause ciliostasis and destruction of ciliated cells with significant destruction of subcellular organelles, leading to extrusion of ciliated cells (Collier, Peterson, & Baseman, 1977). On top of cytopathology, B. pertussis confers enduring infection and opportunity for secondary infections through its inhibition of the immune system. This allows B. pertussis and other pathogens to descend into the lower respiratory tract with ease. Vaccination targeting early-colonizing virulence factors may prevent infection, which vaccination focusing on late-colonizers or cytotoxins may reduce severity.
Antibiotic treatment of B. pertussis is common, and erythromycin seems the drug of choice for treatment although it commonly causes adverse gastrointestinal effects such as diarrhea, cramps, or vomiting (Kerr & Matthews, 2000; Langley, Halperin, Boucher, & Smith, 2004). It is usually given in a roughly 14 day regime with sub-optimal compliance due to the side-effects. However, a recent randomized multicenter study found a 5-7 day treatment regime of azithromycin to be as potent as erythromycin, and is more tolerable to the bodies of children aged from six months to sixteen years old, producing significantly fewer adverse gastrointestinal effects (Langley et al., 2004). This reduce in adverse effects resulted in higher patient compliance with azithromycin treatment regimes. A seven day clarithromycin regime produced a non-significant change from erythromycin, but also had significantly fewer side-effects than erythromycin during a randomized single-blind study (Lebel & Mehra, 2001). Treatment early in infection with high levels of immunoglobins raised from the acellular pertussis vaccine lowered duration and number of whoops during paroxysms (Granstrom, Ann Margreth, Olinder-Nielsen Per, Anders, & Kaj, 1991). However, another group fund no improvement, possibly due to poor testing conditions (Bettiol et al., 2010).
A recent collaboration studied the effects of multiple drugs upon the whooping cough symptom itself. However, Dexamethason, Diphenhydramine, pertussis immunoglobulin, and salbutamol showed no significant or large reduction in whooping frequency (Bettiol et al., 2010). The authors claim this may be due to insufficient sample size and lack of testing quality. This may also be temporally dependent, and significant results may be achieved if treatment occurs during catarrhal stage—although necessity of treatment would be difficult to identify, as it appears to be a minor infection.
At the moment, pertussis management in inpatients heavily relies on supportive therapy—the practice of reinforcing the well-being of an individual physiologically and psychologically is the crux of treatment for inpatients. Heart rate, blood pressure, hydration, and indications of symptoms are constantly monitored. Food may be given intravenously if unable to be ingested orally. Mechanical ventilation and oxygen supplementation are common practice.
I propose treatment of coughing symptoms using nerve paralysis. Injection or spray of soluble sodium channel blockers such as lidocaine onto the back of the throat, lower pharynx, and trachea may essentially stop the coughing reflex from initiating. Targeting would need to be directed towards the upper ciliated vagal and glossopharyngeal innervation areas of the pharynx well as the vagal innervation of the larynx (Polverino et al., 2012). This could be achieved through restraint of the head and body, while restricting movement of the mouth into an open position. A hard and hollow tube could be inserted into the mouth, exposing the pharynx and restricting obstructive movement. This would allow the pharynx to be sprayed/injected with paralytic. Direct injection/spray of paralytic onto the larynx from the exterior may be achieved in severe cases, but may be applied after arrest from initial pharyngeal injection after visualization of larynx via laryngoscope. Arrest of the coughing mechanism would further inhibit removal of B. pertussis, and may allow it to spread to the lungs and aggregate in the upper respiratory tract. For this reason, manual removal of mucous build-up must be performed after arrest of the coughing reflex. This may be maintained through the paroxysmal stage, and would likely prevent brain damage induced by hypoxia, or other side-effects.
B. pertussis has two vaccines: an acellular pertussis (aP) vaccine and whole-cell attenuated pertussis (wP) vaccine. Both vaccines produce minor adverse side-effects at the same frequency. Acellular vaccines rely upon purified and nullified toxins and antigens. Pertussis toxin, pertactin, filamentous hemagglutinin, and fimbrial antigens are commonly used. These will require boosters to maintain immunity, as only humoral immunity is activated, but adult cases of pertussis are fairly low. The wP vaccine relies upon introduction of an attenuated version of the viable microbe, allowing it to begin infection and be reacted to at a smaller scale than the proper infection. This causes a much stronger immune response than the aP vaccine and much long lasting immunity due to activation of humoral and cell-mediated immunity. A recent wP vaccine (BPZE1) has been developed which has the ability to develop long-term immunity in mice after a single intranasal dose (Feunou, Kammoun, Debrie, Mielcarek, & Locht, 2010), does not cause fatal dissemination upon introduction to mouse models (C. M. Skerry et al., 2009), and mice given immunity were able to successfully clear virulent B. pertussis while control mice developed chronic infection (Ciaran M. Skerry & Mahon, 2011)—a promising feat. This may be a response to the resurgence of pertussis seen in countries using the aP vaccine (WHO SAGE pertussis working group, 2014; Wright, 1998).
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