Fatal Bordetella Pertussis Infection Sherif R. Zaki Centers for Disease Control and Prevention Atlanta, GA

Summary 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 unrestricted autopsy. Material provided Glass slide of Lung (hematoxylin and eosin) Images H&Es of lung pathology, Special stains (Brown and Brenn, Giemsa, and Steiner), and IHC for Bordatella pertussis) Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 IHC for etologic agent (?) Figure 6 IHC for etologic agent (?) Diagnosis Fatal Bordetella Pertussis Infection Pathologic Findings 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. Discussion 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. References 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. 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