Fatal Bordetella Pertussis Infection
Sherif R. Zaki
Centers for Disease Control and Prevention
The patient was an ex-premie four-month old female who had been hospitalized for 3 months and
intubated for 1 month, underwent ligation of patent ductus arteriosis, but eventually discharged home in
good health and put on an apnea monitor.
She presented to a children's hospital ER on April 28, 1997 afebrile with a 3 day history of upper
respiratory tract infection. BP was 110/86, heart rate 160, and respiratory rate in the 50s. Lung
auscultation revealed good air exchange. WBC was 17,900 with 17% segs, 15% bands, 57% lymphocytes.
Hemoglobin, hematocrit, and platelet count were within normal limits. RSV titer was negative. Chest
X-ray revealed bilateral central infiltrates. She was admitted with a diagnosis of bronchiolitis and
possible pneumonia. Oxygen and erythromycin therapy were started. Follow-up chest X-ray demonstrated
worsening perihilar central densities and episodes of intermittent stridor were also noted.
On the 3rd day of hospitalization, WBC was 40,000 and she developed bradycardia and
projectile vomiting. Ultrasound findings suggested pyloric stenosis. On the fourth day of
hospitalization, WBC rose to 90,000. Pertussis cultures and Chlamydia titers were negative. Appropriate
empiric antibiotic therapy was initiated. Her respiratory status deteriorated and was noted to have
intercostal and subcostal retractions.
She was transferred to PICU, intubated, and follow-up chest X-ray showed increasing consolidation of
the right upper lobe. Gentamicin, Timentin, and Vancomycin were added to the antibiotic regimen. An
echocardiographic study on the 5th day of hospitalization revealed a dilated right ventricle
and atrium, dilated superior vena cava, depressed ventricular function, under filled left ventricular and
left atrium, tricuspid regurgitation, moderate pulmonary insufficiency and a patent foramen ovale. BP
dropped to 60/30 and intravenous fluid therapy was started. She had an episode of hypertension and
tachycardia of 190 with subsequent drop to 140. Her pupils became fixed and dilated. Aggressive
cardiopulmonary resuscitative efforts were unsuccessful and she was pronounced dead on 05/02/97. A
complete post-mortem examination was requested and permission was granted by the next of kin for an
Glass slide of Lung (hematoxylin and eosin)
Images H&Es of lung pathology, Special stains (Brown and Brenn, Giemsa, and Steiner), and IHC for
Fatal Bordetella Pertussis Infection
Sections of trachea showed damaged mucosa with extensive loss of cilia, denuded and attenuated
epithelium, and moderate-to-marked squamous metaplasia. Lung sections showed multifocal pulmonary
hemorrhages and necrotizing bronchiolitis characterized by partial-to-complete luminal occlusion of
bronchioles, terminal bronchioles, and respiratory bronchioles by varying amounts of necrotic debris,
infammatory cells, and denuded epithelium. Section provided showed focal bronchopneumonia, and
intra-alveolar collections of macrophages and coarse, amphophilic, fbrinous edema. Focal had
hyaline membranes in alveoli indicative of diffuse alveolar damage were also seen. Prominent edema and
lymphangiectasia was present in the adventitia of pulmonary arteries and arterioles and in the
interlobular septa and visceral pleura. Aggregates of granulocytes, lymphocytes, monocytes, and large
immature leukocytes were identifed in pulmonary arterioles, small arteries, and venules and in
dilated lymphatics in the interlobular septa and visceral pleura.
Clusters of innumerable intra- and extracellular coccobacilli were identifed in the bronchiolar
and alveolar infltrates by histochemical stains for bacteria. These minute bacteria were more
easily detected by Steiner and Giemsa stains than by Brown and Brenn or Brown-Hopps stains. Bordetellae
were easily identifed by IHC staining in the cilia of columnar epithelial cells in the trachea,
bronchi, or bronchioles. Abundant extracellular bordetellae and bacterial antigens were seen in the
alveoli. Bacteria were also identifed in the cytoplasm of alveolar macrophages and in columnar
epithelial cells lining the airways.
Globally, pertussis is ranked among the 10 leading causes of childhood mortality and causes an
estimated 294,000 pediatric deaths each year, predominantly among young nonvaccinated children. Rates of
reported infant pertussis and mortality associated with Bordetella pertussis infection have increased in
the United States and in other industrialized nations during the past several decades, and 174 (86%) of
the 203 deaths due to pertussis that were reported to the Centers for Disease Control and Prevention
during the period 1990–2004 occurred in children aged < 4 months. The disproportionate severity of B.
pertussis infection in young children has been recognized for >100 years ; however, the most
catastrophic clinical complication of pertussis in infants, intractable pulmonary hypertension, was not
reported until 1993. Refractory pulmonary hypertension, leading to cardiac failure and shock, is now
recognized as a frequent problem in infants with fatal pertussis.
Early 20th century descriptions of the histopathologic characteristics of pertussis emphasized large
airway disease as the principal component of B. pertussis infection and documented masses of bordetellae
in the cilia of the tracheal and bronchial mucosa, with damage to this epithelium. Pathologists later
reported a sequence of events for fatal pertussis in which endobronchitis and endobronchiolitis evolved
to peribronchitis and peribronchioloitis and, eventually, to bronchopneumonia. Diffuse bronchopneumonia
has been documented in most of the limited contemporary histopathologic descriptions of fatal pertussis.
B. pertussis is distributed abundantly in alveolar macrophages that comprise the predominant
infammatory cell in the pulmonary infltrates. Animal models of pertussis and in vitro
studies using human monocytes have revealed that B. pertussis can enter, survive, and persist in
macrophages for as long as 40 days and that this process may contribute signifcantly to the total
bacterial load in the lungs. During one microbiologic study of pertussis-related deaths in the early
1930s, B. pertussis was routinely found by culture of lung specimens from patients who died within 30
days after illness onset. The clinical and pathogenic consequences of intracellular bordetellae in
patients with pertussis pneumonia are unknown; however, bacterial residence within macrophages may
hinder the ability of some antibiotics to effectively accumulate to bactericidal levels in this
intracellular compartment. The persistence of bacterial antigens in airway epithelium may also
contribute to the chronicity that characterizes the clinical syndrome of.
Although current numbers of pertussis cases and deaths due to pertussis are a small fraction of the
numbers observed during the prevaccine era, morbidity and mortality attributable to B. pertussis remain
underrecognized and underreported. IHC and other molecular assays that can be performed on
formalin-fixed tissues can be helpful to diagnose otherwise unexplained infant deaths or to confrm
presumptive cases of fatal pertussis, particularly when samples for culture or PCR are not available.
The paucity of contemporary pathologic descriptions of fatal pertussis refects the triumph of
effective vaccine strategies against this devastating childhood illness. Nonetheless, the recognized
incidence of B. pertussis infection among US infants increased by 49% during the 1990s, compared with
incidence during the 1980s. It is also likely that many infant deaths attributable to pertussis, even
among those children for whom autopsy data may be available, are missed, because many pathologists and
medical examiners are unfamiliar with the clinicopathologic features of fatal pertussis pneumonia.
Pertussis should be suspected in any infant death associated with marked leukocytosis, bronchopneumonia,
or refractory pulmonary hypertension, particularly in children more than 4 months old.
- World Health Organization. Pertussis: immunization surveillance, assessment and monitoring. Available at: http://www.who.int/immunization_monitoring/diseases/pertussis/en/index.html. Accessed 6 June 2008 .
- Vitek CR, Pascual FB, Baughman AL, Murphy TV. Increase in deaths from pertussis among young infants in the United States in the 1990s. Pediatr Infect Dis J 2003; 22:628–34.
- Crowcroft NS, Andrews N, Rooney C, Brisson M, Miller E. Deaths from pertussis are underestimated in England. Arch Dis Child 2002; 86:336–8.
- Williams GD, Matthews NT, Choong RKC, Ferson MJ. Infant pertussis deaths in New South Wales 1996–1997. Med J Aust 1998; 168:281–3.
- Floret D. Pediatric deaths due to community-acquired bacterial infection: survey of French pediatric intensive care units [in French]. Arch Pe´diatr 2001; 8(Suppl 4):705s–11s.
- Kretsinger K, Broder KR, Cortese MM, et al. Preventing tetanus, diphtheria, and pertussis among adults: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP) and recommendation of ACIP, supported by the Healthcare Infection Control Practices Advisory Committee (HICPAC), for use of Tdap among health-care personnel. MMWR Recomm Rep 2006; 55(RR-17):1–37.
- Dauer CC. Reported whooping cough morbidity and mortality in the United States. Pub Health Rep 1943; 58:661–77.
- Mattoo S, Cherry JD. Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies. Clin Microbiol Rev 2005; 18:326–82.
- Goulin GD, Kaya KM, Bradley JS. Severe pulmonary hypertension associated with shock and death in infants infected with Bordetella pertussis. Crit Care Med 1993; 21:1791–4.
- Donoso A, Leo´ n J, Ramı´rez M, Rojas G, Oberpaur B. Pertussis and fatal pulmonary hypertension: a discouraged entity. Scand J Infect Dis 2005; 37:145–8.
- Williams GD, Numa A, Sokol J, Tobias V, Duffy BJ. ECLS in pertussis: does it have a role? Intensive Care Med 1998; 24:1089–92.
- Halasa NB , Barr FE, Johnson JE, Edwards KM. Fatal pulmonary hypertension associated with pertussis in infants: does extracorporeal membrane oxygenation have a role? Pediatrics 2003; 112:1274–8.
- Lapin JH. Whooping cough. Springfeld, IL: Charles C. Thomas, 1943.
- Paddock CD, Sanden GN, Cherry JD et al. Pathology and Pathogenesis of Fatal Bordetella pertussis infection in infants. Clin Infect Dis 2008;47:328-38
- Tatti KM, Wu KH, Sanden GN, et al. Molecular diagnosis of Bordetella pertussis infection by evaluation of formalin-fxed tissue specimens. J Clin Microbiol 2006; 44:1074–6.
- Antila M, He Q, de Jong C, et al. Bordetella holmesii DNA is not detected in nasopharyngeal swabs from Finnish and Dutch patients with suspected pertussis. J Med Microbiol 2006; 55:1043–51.
- Lovell MA, Miller AM, Hendley JO. Pathological case of the month. Arch Pediatr Adolesc Med 1998; 152:925–6.
- Mallory FB, Hornor AA. Pertussis: the histological lesion in the respiratory tract. J Med Res 1912; 27:115–23.
- Smith LW. The pathologic anatomy of pertussis with especial reference to pneumonia caused by the pertussis bacillus. Arch Pathol Lab Med 1927; 4:732–42.
- Hackman R, Perrin DG, Karmali M, Cutz E. Fatal Bordetella pertussis infection: report of two cases with novel pathologic fndings. Pediatr Pathol Lab Med 1996; 16:643–53.
- Christie CDC, Baltimore RS. Pertussis in neonates. Am J Dis Child 1989; 143:1199–202.
- Cheers C, Gray DF. Macrophage behaviour during the complaisant phase of murine pertussis. Immunology 1969; 17:875–87.
- Saukkonen K, Cabellos C, Burroughs M, Prasad S, Tuomanen E. Integrin-mediated localization of Bordetella pertussis within macrophages: role in pulmonary colonization. J Exp Med 1991; 173:1143–9.
- Friedman RL, Nordensson K, Wilson L, Akporiaye ET, Yocum DE.
- Hellwig SMM, Hazenbos WLW, van de Winkel JGJ, Mooi FR. Evidence for an intracellular niche for Bordetella pertussis in broncho-alveolar lavage cells of mice. FEMS Immunol Med Microbiol 1999; 26:203–7.
- Bassinet L, Gueirard P, Maitre B, et al. Role of adhesions and toxins in invasion of human tracheal epithelial cells by Bordetella pertussis. Infect Immun 2000; 68:1934–41.
- Gueirard P, Bassinet L, Bonne I, Prevost MC, Guiso N. Ultrastructural analysis of the interactions between Bordetella pertussis, Bordetella parapertussis, and Bordetella bronchiseptica and human tracheal epithelial cells. Microb Pathog 2005; 38:41–6.
- Hopewell JW, Holt LB, Desombre TR. An electron-microscope study of intracerebral infection of mice with low-virulence Bordetella pertussis. J Med Microbiol 1972; 5:154–7.
- Gordon JE, Hood RI. Whooping cough and its epidemiological anomalies. Am J Med Sci 1951; 222:333–61.
- Crowcroft NS, Booy R, Harrison T, et al. Severe and unrecognised: pertussis in UK infants. Arch Dis Child 2003; 88:802–6.
- Shaikh R, Guris D, Strebel PM, Wharton M. Underreporting of pertussis deaths in the United States: need for improved surveillance. Pediatrics 1998; 101:323.
- Tanaka M, Vitek CR, Pascual FB, Bisgard KM, Tate JE, Murphy TV. Trends in pertussis among infants in the United States, 1980–1999. JAMA 2003; 290:2968–75.