Archives of Disease in Childhood, 1971, 46, 55.

Fatal Pseudomonas aeruginosa Bronchopneumoniain a Children's Hospital

A. J. BARSONFrom the Department of Pathology, Hospital for Sick Children, Toronto, Canada

Barson, A. J. (1971). Archives of Disease in Childhood, 46, 55. Fatal Pseudo-monas aeruginosa bronchopneumonia in a children's hospital. Forty fatalcases of pseudomonas bronchopneumonia were found in a retrospective review of 600consecutive necropsies in a children's hospital. This type of infection has been muchmore common in recent years and was shown to have a predilection for the prematureinfant dying in the neonatal period, who had been mechanically ventilated.

Over the past 25 years there has been a progressiveincrease in the proportion of terminal broncho-pneumonic infections attributable to Gram-negativebacteria. This trend was reviewed recently byPierce et al. (1966). The most common Gram-negative bacteria to be incriminated has beenPseudomonas aeruginosa. Kneeland and Price (1960)reported that this organism was cultured fromnearly a quarter of all their patients dying withpneumonia. Their series was concerned with adultpatients but there is evidence of a similar trend inchildren (Asay and Koch, 1960; Cooper, 1967).Pseudomonas infections are an increasing problemin neonatal units, particularly in the prematureinfant (Laursen, 1962; Barrie, 1965; Bassett,Thompson, and Page, 1965; Arniel et al., 1966;Fierer, Taylor, and Gezon, 1967; Jellard andChurcher, 1967; Monnet, Chassignol, and Vaillaud,1967; Knights, France, and Harding, 1968). Inmany of these cases, pseudomonas has been traced toincubators or resuscitation equipment.

Since Fraenkel's description of pseudomonasinflammation in 1917, it has been known that thehistopathology produced by this organism is sodistinctive as to be diagnostic. It is possible to usethis in conjunction with the bacteriology to assessthe incidence of pseudomonas infection in necropsymaterial. The present study is a retrospectivereview of pseudomonas bronchopneumonia occur-ring in 600 consecutive necropsies in a large child-ren's hospital, particular attention being paid to thetype ofpatient affected and the relation to mechanicalventilation.

Received 30 June 1970.

Materials and MethodsThe material for this study was based on 600

consecutive necropsies performed in The Hospital forSick Children, Toronto, during 1967 and 1968. All ofthese had had the lungs and air passages examinedroutinely, both by gross inspection and histopathologi-cally. Two groups of patients, which partly overlapped,were differentiated from these.

First, an assessment was made of those children whohad bronchopneumonia to a degree sufficient to con-tribute significantly to their death. The histologicalsections from the lungs of these cases were reviewed inorder to differentiate from the rest those with patho-logical lesions typical of a pseudomonas infection.Those cases were then correlated with the bacteriology ofantemortem blood cultures or postmortem cultures oflung tissue where these were available. Only thosepatients were accepted as instances of pseudomonasbronchopneumonia where a typical lung pathology wassupported by bacteriological culture. In fact, thecorrelation was very high. Occasionally a positiveculture was not supported by the histopathology,presumably because a septicaemia had not established apneumonia in the tissue sampled by the pathologist orbecause of postmortem contamination of lung tissue.However, the converse did not occur. When thehistopathology was typical of pseudomonas broncho-pneumonia the diagnosis was always corroborated by thebacteriology when this had been undertaken.The second group of patients to be differentiated from

the series were those who were recorded at necropsy ashaving laryngeal or tracheal ulceration characteristic ofthat resulting from intubation. Insufflation of the cuffof a laryngeal tube is often associated with discretesymmetrical ulcers of the mucosa immediately beloweach vocal cord. Similarly prolonged tracheal intuba-tion often results in ulceration of the anterior wall ofthe trachea overlying the forward projection of the tip

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A. J. Barson

FIG. 1.-Pseudomonas bronchopnewnonia in an infant dying at 3 weeks of age. Note the dark areas of necrosis whichstain deep blue with haematoxylin. (Haematoxylin and eosin. x 60.)

of a curved tracheotomy or endotracheal tube. Anendotracheal cuff may produce a sharply delineatedcircumferential ulceration of the trachea. The natureand position of the ulcers are so characteristic as to bereliable pathological evidence that the patient wasintubated during life, and, by inference, ventilated byexternal means. This group of patients was correlatedwith those having terminal bronchopneumonia.

ObservationsPseudomonas aeruginosa bronchopneumonia is

characterized by well-demarcated areas of necroticconsolidation within the lung parenchyma. Underlow power magnification these areas of necrosis stainan intense blue with haematoxylin (Fig. 1). Unlikeother types of bronchopneumonia, it is essentially avasculitis, large numbers of bacilli accumulating inthe walls of arterioles and venules. So thickly arethe vessel walls colonized that they display adistinctive blue haze with a haematoxylin stain orpink with a Gram stain (Fig. 2). The rod-likeform of the bacteria is usually readily apparent with

higher magnification. This vasculitis itself differsfrom that seen in other infections in that there isoften a completelackof an intraluminal inflammatoryresponse. Peripheral to the vessel there is usually asurprisingly mild inflammatory cell infiltration inwhich lymphocytes and mononuclear cells pre-dominate together with an extensive necrosis. Ata later stage, the vessel wall is disrupted (Fig. 3),and haemorrhage into adjacent alveoli is a commonlyassociated feature.On the basis of this histopathology, substantiated

by bacteriological culture, 40 cases of Pseudomonasaeruginosa bronchopneumonia were found in 600consecutive necropsies in 1967 and eight months of1968. A comparison with the incidence ofstaphylococcal bronchopneumonia in necropsiesperformed in the same hospital shows how this hasdeclined in importance since the 1950's. Theincidence of terminal pseudomonas lung infectionsince the beginning of 1967 was comparable to thatformerly seen with staphylococcus (Table I).

TABLE IIncidence of Staphylococcal and Pseudomonas Bronchopneumonia in Necropsies at the Hospital for Sick

Children from 1955 to 1968

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Pseudomonas aeruginosa Bronchopneumonia

FIG. 2.-An arteriole cut longitudinally to show the dense bacterial colonization of the wall. There is no intralwninalpathology but peripherally there are a few mononuclear inflammatory cells. (Gram. x 120.)

Altogether 176 (29%) of the necropsies had acomplicating terminal pneumonia, and pseudo-monas infection accounted for just over a fifth ofthem. The relation of these cases to intubation andlaryngeal or tracheal ulceration is shown in Table II.

Nearly one-third of all the necropsies (193) hadairway mucosal ulceration evident at necropsy. Ofthese, nearly half (93) had a bronchopneumonia.The clinical histories of all the children with

pneumonia were reviewed to assess the relation of

FIG. 3.-A pulmonary arteriole ruptured by pseudomonas inflammation, with haemorrhage into the adjacent alveolae.The lumen contains thrombus. The elastic fibres in the wall of the vessel on the right are splayed and fragmented.

(Elastic van Gieson. x 90.)

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TABLE IIAnalysis of 600 Consecutive Necropsies in 1967-8According to Presence and Type of Bronchopneumoniaand Occurrence of Laryngeal or Tracheal Ulceration

600 Necropsies (1967-68)

Bronchopneumonia 176 (29%) Laryngeal or trachealulceration-193 (32%/)

Intubated 113 (64%) Bronchopneumonia 93 (48%)

Laryngeal or trachealulceration -93 (82%)

L- Pseudomonas aeruginosa bronchopneumonia--0 (23%)

Bronchopneumoniia of other aetiology-136 (77%)

Percentages in brackets are those within immediately precedingcategory.

intubation to ulceration. It was found that themajority of the cases with terminal broncho-pneumonia had been intubated during their lastillness (113 out of 176) and that 93 (82%O) of thesehad had airway ulceration observed after death.A comparison is made in Table III between the

incidence of intubation and of ulceration in childrenwith pseudomonas bronchopneumonia and withpneumonias due to other organisms. Applying thex2 test both intubation (001<P<0.025) andulceration (0-025<P<0-05) were significantlymore frequent with pseudomonas infections com-pared with other bacteria. Out of the 40 childrendying with pseudomonas bronchopneumonia, 32had been artificially ventilated before death. 3of those were intubated less than 24 hours beforedeath, which is probably too short a time for theventilator to be incriminated as a source of infection.For 29 children the infection could have been

TABLE IIIComparison of Pseudomonas Bronchopneumonia andPneumonias due to Other Organisms with regard toNumbers Intubated and Those Having Laryngeal or

Trachael Ulceration at Necropsy

Cases Intubated Ulcerated

Pseudomonas broncho-pneumonias 40 32 (80%) 27 (67 5%)

Other bronchopneumonias 136 81 (59 5%) 66 (48.5%)

Note: Significantly more infants with pseudomonas broncho-pneumonia were intubated (0-01 < P < 0 025) and more wereulcerated (0-025 < P < 0 05) compared with those dying fromother forms of bronchopneumonia.

acquired in this way but this is unproved bacterio-logically.

Fig. 4 illustrates the relation of pseudo-monas and other bronchopneumonias to the

All NecropsiesPseudomonos BronchopneumoniaOther Bronchopneumonias

v-O to I I to 4 4 to 52 52+

AGE IN WEEKS

FIG. 4.-A block graph showing the percentage incidence infour age categories of 600 consecutive necropsies comparedwith the children among these dying with pseudomonas andother forms of bronchopneumonia. Though there wereonly 40 cases of pseudomonas infection they had a relativepredilection for the neonatal period, whereas the othertermninal pneumonias (136 cases) were more similar in their

age distribution to the total necropsy population.

necropsy population as a whole. The highest deathrate in the hospital was among infants in the firstweek of life, with comparatively few deaths duringthe remaining 3 weeks of the neonatal period. Theincidence of pseudomonas bronchopneumonia wasdisproportionately high during this period.Pneumonias caused by bacteria other than pseudo-monas were relatively more common in childrenover 1 year of age.The influence of low birthweight (2,500 g or

below), on bronchopneumonic deaths in the neo-natal period is depicted in Table IV. Using thex2 test the number of low birthweight infants withpseudomonas bronchopneumonia is significantlyhigher than in the necropsy population as a whole(O * 01 <P <O0 025) whereas the number of lowbirthweight neonates dying with other forms ofpneumonia is not significantly higher (0 3< P<Pz0 4).The infection by pseudomonas was always a

complication of another disease. The primarydiagnoses in these cases are set out in Table V.The most common of these was respiratory distresssyndrome, followed by alimentary tract disorderseither obstructive or inflammatory in nature. The

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Pseudomonas aeruginosa Bronchopneumoniafour cases of congenital heart disease had all under-gone recent major surgery.

TABLE IVIncidence of Low Birthweight (2,500 g or less) AmongAll Neonatal Necropsies and Among Neonatal Deathswith Pseudomonas or Other Forms of Broncho-

pneumnia

Pseudomonas OtherAll Necropsies Broncho- Broncho-

pneumonia pneumonias

No. of neonatalnecropsies 293 26 46

Incidence oflowbirthweight 125 (42-7%) 16 (61-5%) 21 (45 -7%)

The incidence of low birthweight in those dying of pseudomonasbronchopneumonia is significant (0-01 < P < 0 025), but isnot significant among those dying with other types of broncho-pneumonia (0 3 < P < 0 4).

TABLE VPrimary Diagnosis in 40 Infants Dying with Pseudo-

monas Bronchopnewnonia

Primary Diagnosis No.

Respiratory distress syndrome 16Alimentary tract obstruction 5Congenital heart disease 4Leukaemia 3Gastroenteritis 2Intrauterine asphyxia 2Cystic fibrosis 2Burns 1Alymphoplasia 1Tracheo-oesophageal fistula 1Meningocele 1Adrenal hypoplasia 1Disphragmatic hemia 1

DiscussionThis retrospective study in a children's hospital

shows that terminal pseudomonas bronchopneu-monia has become common since 1966, assuming in

its incidence the place formerly held by staphylo-coccal infections. It is a peculiarity of pseudomonasaeruginosa, well illustrated by the present study, thatit has a predilection for the low birthweight neonatalpatient who has been treated by intubation andmechanical ventilation.

In a similar review of adult necropsies usinghistopathological criteria for diagnosis, Pierce et al.(1966) accounted for the rise in pseudomonasinfections after 1963 on the basis of the increase inbroad spectrum chemotherapy and contaminationof nebulization reservoirs. Tracheotomy was not

of itself a predisposing factor, although shock andanaemia were.

At the Hospital for Sick Children, the rise inincidence of pseudomonas bronchopneumonia hasfollowed by some years the routine use of broadspectrum antibiotics, and the phenomenon cannotbe wholly explained on this basis. It is the opinionof the author that an important factor has been theincreasing use of humidified ventilatory apparatusfor debilitated infants, especially in the treatment ofrespiratory distress syndrome.Though the observations in the study support

such a contention, it is retrospective and no consistentbacteriological studies exist to confirm this.However recent outbreaks at other centres ofpseudomonas infection have been traced to incuba-tors (Barrie, 1965; Monnet et al., 1967) andresuscitation equipment (Bassett et al., 1965;Fierer et al., 1967; Phillips, 1967). Moisture is anessential factor in the epidemiology of pseudomonasinfections, airborne outbreaks being uncommon.

The organism has a low pathogenicity for healthypeople, and a carrier state as high as 12% has beenreported (British Medical Journal, 1967). It hasbeen shown in both children and adults undergoingmajor surgery with endotracheal intubation that theupper respiratory tract may become rapidly colonizedby Gram-negative organisms from the patient him-self rather than from the hospital environment(Redman and Lockey, 1967).

Eleven of the patients in the present study hadundergone surgery before infection, 5 of whom hadhad alimentary tract obstruction. An associationwith surgery for gastrointestinal defects has beennoted before (Asay and Koch, 1960; Cooper, 1967)and could be explained by a carrier state (Jellardand Churcher, 1967).

Nevertheless, it is likely that a high proportion ofthe cases was the result of cross-infection rather thanself-colonization. Humidifying equipment is themost common reservoir of pseudomonas infection inthe neonatal unit, and the difficulties in keeping thissterile cannot be stressed too much (Laursen, 1962).

Related to this problem is the fact that 82% of thechildren in this series with terminal bronchopneu-monia who had been intubated had developedmucosal ulceration of the larynx or trachea. Suchulceration produced by an indwelling tube can

easily become infected (Teplitz et al., 1964) bydirect inoculation with droplet borne pseudomonas.Inhalation of material from the infected ulcer maythen result in a fatal pneumonia.The proneness of the neonate to pseudomonas

infection in the present study is in agreement withthat found by Asay and Koch (1960) at another

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60 A. J. Barsoncentre. This is probably a reflection of a loweredimmunological capacity in early postnatal life.Similarly, when this capacity is decreased bydisease, such as leukaemia, or immunosuppressivedrugs such as the corticosteroids, there is also apredisposition to pseudomonas infection (BritishMedical Journal, 1967). Among the neonatalinfants in the present series, the low birthweightinfant was particularly at risk. This is in part aconsequence of its immunological immaturity, andin part a consequence of treatment by artificialventilation and humidification with broad spectrumantibiotic cover. Surgery and steroid therapy wereadditional factors in some cases.

It is likely that the active treatment of prematureinfants and the use of ventilatory apparatus willincrease in the future. Unless the most stringentbacteriological supervision is employed, the incid-ence of pseudomonas infection in the children'shospital is unlikely to diminish. Radiography mayalso provide a valuable aid to diagnosis (Joffe, 1969).

Pathologically pseudomonas infection is distinctin that bacillary invasion appears to originatewithin capillaries and subsequently invade largerblood vessels from the outer layers towards thelumen (Teplitz, 1965). Disruption of arteriolarwalls (Fig. 3) with haemorrhage is a commonfeature, and it is interesting that two elastases havebeen recently isolated from cultures of the organism(Suss et al., 1969). This vasculitis is sufficientlycharacteristic histologically for it to be worth notingat necropsy, even in the absence of bacteriologicalconfirmation. It is important to use this peculiarityto assess the future trends in the incidence ofpseudomonas infection.

I wish to thank Dr. M. J. Lynch and Dr. A. J. Wortfor their advice. The work was supported by grantsfrom the Wellcome Trust and the National Fund forResearch into Crippling Diseases.

REFERENCES

Arniel, C., Fleurquin, N., Larroche, J. C., and Minkowski, A. (1966).A propos de 18 observations d'infections A "Pseudomonas" dunouveau-ne. Considerations epidemiologiques. ArchivesFrancaises de Pidiatrie, 23, 413.

Asay, L. D., and Koch, R. (1960). Pseudomonas infections ininfants and children. New England Journal of Medicine, 262,1062.

Barrie, D. (1965). Incubator-borne Pseudomonas pyocyaneainfection in a newborn nursery. Archives of Disease in Child-hood, 40, 555.

Bassett, D. C. J., Thompson, S. A. S., and Page, B. (1965).Neonatal infections with Pseudomonas aeruginosa, associated withcontaminated resuscitation equipment. Lancet, 1, 781.

British Medical Journal (1967). Pseudomonas infection in hospital.(Leading article). 4, 309.

Cooper, R. G. (1967). Systemic Pseudomonas infection in child-hood. MedicalJournal of Australia, 1, 527.

Fierer, J., Taylor, P. M., and Gezon, H. M. (1967). Pseudomonasaeruginosa epidemic traced to delivery-room resuscitators.New EnglandJournal of Medicine, 276, 991.

Fraenkel, E. (1917). Weitere Untersuchungen ilber die Menschen-pathogenitat des Bacillus pyocyaneus. Zeitschrift fur Hygieneund Infektionskrankheiten, 84, 369.

Jellard, C. H., and Churcher, G. M. (1967). An outbreak ofPseudomonas aeruginosa (pyocyanea) infection in a prematurebaby unit, with observations on the intestinal carriage ofPseudomonas aeruginosa in the newbom. Journal of Hygiene,65, 219.

Joffe, N. (1969). Roentgenologic aspects of primary Pseudomonasaeruginosa pneumonia in mechanically ventilated patients.American Journal of Roentgenology, 107, 305.

Kneeland, Y., Jr., and Price, K. M. (1960). Antibiotics and terminalpneumonia: a post-mortem microbiological study. AmericanJournal of Medicine, 29, 967.

Knights, H. T., France, D. R., and Harding, S. (1968). Pseudo-monas aeruginosa cross infection in a neonatal unit. NewZealand Medical Journal, 67, 617.

Laursen, H. (1962). Incidence of Pseudomonas aeruginosa andother gram-negative rods in newborn infants. Acta Obstetriciaet Gynecologica Scandinavica, 41, 254.

Monnet, P., Chassignol, S., and Vaillaud, J. C. (1967). Infectionsa 'Pseudomonas aeruginosa' dans un centre de pr6maturesdurant les annees 1960 a 1963. Archives Frangaises de Pidiatrie,24, 543.

Phillips, I. (1967). Pseudomonas aeruginosa respiratory tractinfections in patients receiving mechanical ventilation. Journalof Hygiene, 65, 229.

Pierce, A. K., Edmonson, E. B., McGee, G., Ketchersid, J.,Loudon, R. G., and Sanford, J. P. (1966). An analysis offactors predisposing to gram-negative bacillary necrotizingpneumonia. American Review of Respiratory Disease, 94, 309.

Redman, L. R., and Lockey, E. (1967). Colonisation of the upperrespiratory tract with gram-negative bacilli after operation,endotracheal intubation and prophylactic antibiotic therapy.Anaesthesia, 22, 220.

Suss, R. H., Fenton, J. W., II, Muraschi, T. F., and Miller, K. D.(1969). Two distinct elastases from different strains of Pseudo-monas aeruginosa. Biochimica et Biophysica Acta, 191, 179.

Teplitz, C. (1965). Pathogenesis of Pseudomonas vasculitis andseptic lesions. Archives of Pathology, 80, 297.

-, Epstein, B. S., Rose, L. R., and Moncrief, J. A. (1964).Necrotizing tracheitis induced by tracheostomy tube: patho-genesis. Archives of Pathology, 77, 6.

Correspondence should be addressed to Dr. A. J.Barson, Department of Pathology, University ofManchester, Manchester, M13 9PL.

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