Branhamella catarrhalis and croup: Toxicity in the upper respiratory tract

Case Report Am J Gtolaryngol 12:113-116.1991

Branhameh Toxicity

catarrhah and Croup:

in the Upper Respiratory

Tract

JAMES PATRICK DUDLEY, MD

Branhamella catarrhalis has gained increasing recognition as a pathogen in the respiratory tract. During the past 18 years, since its transfer from the genus Neisseria, it has been associated with infection in cavities of the respiratory tract (sinuses and middle ear). It has been recognized as playing a role in laryngitis. Its isolation in large numbers from the surface and core of acutely and chronically infected tonsils indicates a possible role in these infections. Croup (two patients reported here) can now be added to this list. The toxic potential of B catarrhalis, its movement from commensal to pathogen for the upper respiratory tract, and the pathogenic mechanisms by which this has occurred are reviewed. AM J OTOLARYNGOL 12:113-116. Copyright 0 1991 by W.B. Saunders Company Key words: Branhamella catarrhalis, croup, respiratory infection.

subglottic edema and erythema, toms of croup.

Branhamella catarrhalis, formerly known as Neisseria catarrhalis, has long been identified as part of the normal flora of the upper respiratory tract. The phrase “normal flora” usually implies that these microorganisms are not responsible for infection in healthy hosts. Therefore, despite its recognition as a pathogen in acute middle ear infection in 1927l and 1967,' the perception of B catarrhalis as a pathogen for other parts of the upper respiratory tract has been slow to evolve. However, over the last decade, this microorganism has been linked to acute otitis media,3-6 sinusitis,7*8 laryngitis,g tracheitis,“,” prolonged cough in children,” acute tonsillitis,13 and chronic tonsillitis.14 Its role as a pathogen has been complicated by an unfortunate development. At least 80% or more of isolates produce beta-lactamase. B catarrhalis can apparently induce yet another acute infection on respiratory membrane: the organism was isolated in pure culture from a 9year-old boy and a lo-week-old male infant with

resulting

in syp-

CASE REPORTS Case NO. 7. A g-year-old boy developed a mild upper respiratory tract infection (minimal nasal stuffiness and slight rhinorrhea) 3 days prior to fracturing his wrist. He was intubated with a 5.5-mm endotracheal tube without complications and underwent an uneventful fracture reduction lasting 45 minutes. Over the next 2 days, he developed increasing inspiratory stridor with beginning retractions. Several treatments with racemic epinephrine resulted in the disappearance of respiratory distress. However, stridor persisted, as did a croupy cough. Examination with the Berci-Ward telescope (Karl Storz, Inc, Culver City, CA) revealed a very erythematous, edematous subglottic mucosa. The remainder of the upper respiratory tract examination was normal. Auscultation of his chest revealed normal breath sounds, and a chest roentgenogram was normal. A culture was obtained by having the patient cough vigorously on a swab held in the hypopharynx. B catarrhalis, beta-lactamase positive, grew in pure culture from this swab. Because he was still in the hospital, the patient received ceftazadime, 50 mg/kg, every 6 hours. In 36 hours, the stridor and croupy cough had subsided, and the subglottic mucosa was no longer edematous or erythematous when visualized with the telescope. The patient was discharged on cefaclor, 250 mg four times daily for I week. The subglottic area appeared normal on follow-up, and a repeat culture of the same area failed to demonstrate any B catarrhalis.

Received August 9, 1990, from the Department of Surgery, Division of Head and Neck Surgery, UCLA Medical Center, Los Angeles, CA. Accepted for publication January 9, 1991. Presented at the Southern California American College of Surgeons, Palm Springs, CA, January 28, 1989. Address correspondance and reprint requests to James Patrick Dudley, MD, Department of Surgery, UCLA Medical Center, Division of Head and Neck Surgery, Los Angeles, CA 90024. Copyright 0 1991 by W.B. Saunders Company

&Se NO. 2. A lo-week-old male infant developed rhinorrhea and irritability. Three days later, stridor was heard. He gradually became tachypneic as stridor grew louder and retractions developed. Because he failed to respond to racemic epinephrine, he was intubated.

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Bronchoscopy through the endotracheal tube revealed an erythematous and edematous subglottis. A culture taken through the endotracheal tube from the subglottis revealed many B cafarrhalis organisms and few alphahemolytic streptococci. Ceftazidime, 40 mg/kg, was given intravenously every 8 hours, and the patient was extubated on the sixth day of antibiotic therapy.

Since B catarrhalis was removed from the genus Neisseria because of a lack of DNA homology with other members of the genus,15 it seems to have emerged as a respiratory pathogen. In some instances, it has been easy to show a connection between disease and the presence of this microorganism. When found in acutely inflamed middle ears in pure culture or as a predominant organism, its association with disease has been difficult to dispute. For instance, in 1967, Coffey et al demonstrated it in pure culture in acute otitis media and they noted the presence of the microorganism in the cytoplasm of neutrophils, indicating phagocytosis.’ In two recent reports of otitis media, its recovery rate from the middle ear was 19%’ and 17%.6 B catarrhalis now ranks third among the microbial agents responsible for acute otitis media. It has also been found in 8%5 and 8.9%l” of middle ear effusions. In studies of acute maxillary sinusitis, it has been isolated in 8.5% of 105 sinus aspirates in adults’ and in 21% of 47 sinus aspirates in children.7 There appears to be little dispute about the role of B catarrhalis in acute otitis media and sinusitis. Otolaryngologists should be aware, however, that it also plays a role in other upper respiratory tract infections. Brorson and Malmvall have implicated B catarrhalis as a cause of cough in children. They cultured the nasopharynx of 180 children with a cough lasting more than 10 days. They found the organism present in 66% of children with cough, as opposed to 28% of controls.12 Another factor implicating B catarrhalis as a cause of cough in these children was the isolation rate of pneumococci and hemophilus in the nasopharynges of these children. The isolation rate of these two groups of organisms was identical in controls and in children with cough. This finding suggests that B catarrhalis can act alone in producing these symptoms. B catarrhalis is able to induce laryngeal and tracheal infection as well, Schalen et al cultured the nasopharynx of 40 adults with a diagnosis of acute laryngitis. They found B catarrhalis in the nasopharynx of 21 of these patients,’ a 55% recovery rate. The microorganism was found in the nasopharynx of only 9% of the control group, a recovery rate of 24%. B catarrhalis may play a role in bacterial tracheitis; it has been isolated from

CATARAHALIS

AND CROUP

the tracheal secretions of children with this infection in Africa” and in the United StateslO B catarrhalis has been associated with chronic tonsillitis.14 Brook and Yocum14 cultured the core of 22 surgically excised tonsils and found B catarrhalis in 15. The only other organism cultured as frequently was alpha-hemolytic Streptococcus (16 isolates]. Although anaerobes were the principal microorganisms recovered in this study, the high recovery rate of B catarrhalis implies that it may play a role in the persistence of symptoms of chronic tonsillitis. In a study of acute tonsillitis by Brook and Hirokawa, B catarrhalis was isolated from 35 of 45 surface cultures of patients with beta-hemolytic streptococcal disease,13 wheras Streptococcus pneumoniae and Haemophilus influenzae were cultured in only seven and 10 cultures, respectively. Again there seems to be a concurrence of B catarrhalis and symptomatic disease; in these cases, acute tonsillitis. There is, however, other evidence that implicates this organism as an upper respiratory pathogen. A serologic search for antibodies to B catarrhalis has shown that such antibodies are generated after infection. Investigators have found elevated levels of immunoglobulin A antibodies in one half of the children who had acute otitis media when B catarrhalis was the only middle ear isolate.17 An earlier study showed similar findings in acute maxillary sinusitis.” In this study, 25 of 97 patients developed complement fixing antibodies to B catarrhalis in episodes of acute maxillary sinusitis. The association of improved clinical condition with the disappearance of microorganisms can be offered as additional evidence that B catarrhalis has the potential to be a pathogenic organism on respiratory surfaces. Ninane et al have shown that the organism disappeared from sputum in nine of 10 patients with B catarrhalis-induced tracheitis followed after treatment. IQThey were also able to demonstrate the presence of the organism in leukocytes. Phagocytosis is generally taken as evidence that the microorganism has been identified by the phagocyte as a pathogen. A recent study using restriction endonuclease analysis of chromosomal DNA appears to provide incontrovertible evidence that B catarrhalis is capable of producing respiratory disease.” B catarrhalis was isolated from eight hospitalized patients, four with pneumonia and four with bronchitis, and was the only or predominating organism in each case. B catarrhalis from these eight symptomatic patients had the same DNA makeup whereas B catarrhalis from asymptomatic hospitalized patients and staff did not share this DNA homology. It is difficult to understand how a commensal

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organism can become a pathogen. There are as yet no clues to the mechanism of microbial toxicity, but protease production, preexistent or coexistent viral infection, and beta-lactamase come to mind. Although Neisseria sp produces IgA proteases and these proteases are capable of inducing toxic changes on mucous membranes, such proteases are not produced by B catarrhaliszl Although viral infections are presumed to predispose bacterial infection, large numbers of acute middle ear infections occur without an initial viral infection.‘* B catarrhalis is able to produce a variety of beta-lactamases23 (in fact, as many as five different kinds), but beta-lactamase does not appear to be a pathogenic factor. Sweeney et al have found the same amount of beta-lactamase production in B catarrhalis that induced pneumonia and B catarrhalis that were colonizers in asymptomatic individuals.24 A shifting ecologic balance on mucous membrane surfaces appears to offer a theory that may explain this toxicity. Long et al have demonstrated that the greater the titer of H influenzae or B catarrhalis isolated from the nasopharynx, the greater the correlation of the respective microorganism in the middle ear during an acute episode of otitis media.25 It might appear that large numbers of organisms on this mucosal “microbial bank,” as termed by Long et al,25 can overwhelm local defense mechanisms and induce acute infection. There are eight proteins in the outer membrane of B catarrhalis,26 and antibodies to some of these surface antigens have been identified.27 It is conceivable that these surface proteins may become toxic when the total volume of antigen load becomes greater than a particular area of mucous membrane can tolerate. To summarize, there are two possible explanations for the toxicity of B catarrhalis. In one hypothesis, the pathogenic microorganism is somehow different from its nonpathogenic fellow genus member. Differences in the DNA makeup of B catarrhalis*’ appear in some instances to impart toxicity to some members of this genus. According to the other scenario, the overgrowth of a colonizing microorganism may place too great an antigen load on local defense mechanisms. Treatment of infections caused by B catarrhalis can present an antibiotic dilemma because of the high incidence of beta-lactamase production among these organisms. In 1980, only 27% of isolates produced beta-lactamase.28 During the past year at UCLA Medical Center, 87% of isolates were beta-lactamase producers. For outpatient use, most oral cephalosporins, such as cefaclor, can be considered effective against B catarrhalis.2g However, beta-lactamase production does seem to have some bearing on the minimal

inhibitory concentration (MIC) of a cephalosporin. Higher MICs are seen in beta-lactamase producers. For instance, the cephalosporin MIC of beta-lactamase-producing B catarrhalis may be double that of the isolate that does not produce beta-lactamase. Interestingly, in a study by Van Hare et al, cefaclor failed to sterilize middle ears after 3 to 5 days of treatment of acute otitis media.6 The same study showed that trimethoprim sulfamethoxazole or amoxicillinclavulanic acid are probably the best choices for B catarrhalis infection in the middle ear. They found that these two antibiotics completely sterilized the middle ears of patients with acute otitis media 3 to 5 days after treatment was begun. Erythromycin, tetracycline, and chloramphenicol are all effective against B catarrhalis in vitro,” but tetracycline is not prescribed for children under 12 years of age. Chloramphenicol is generally not used in an outpatient setting, except in rare instances for control of H influenzae infections. Its potential toxicity remains its main liability, despite its superb absorption from the gastrointestinal tract. CONCLUSION

Infections involving B catarrhaiis are encountered with increasing frequency. This emerging pathogen is still treatable with a variety of antibiotics. It would appear that amoxicillin-clavulanic acid and trimethoprim sulfamethoxazole offer the best treatment prospects, based on the results of studies by Van Hare et al.” However, tetracycline (in adults) and cefactor also offer possibilities. References 1. Hart VK: Bacteriology of acute ears. Laryngoscope 1927; 37:56-61 2. Coffey JD. Martin AD, Booth HN: Neisseria catarrhalis in exudative otitis media. Arch Otolaryngol 1967; 86:69-72 3. Howie VM, Ploussard JH, Lester RL: Otitis media. A clinical and bacterial correlation. Pediatrics 1970; 45:29-35 4. Kamme C: Evaluation of the in vitro sensitivity of Neisseria catarrhalis to antibiotics with respect to acute otitis media. Stand J Infect Dis 1970; 2:117-120 5. Kovatch AL, Wald ER, Michaels RH: P-Lactamaseproducing Branhamella catarrhalis causing otitis media in children. J Pediatr 1983; 102:261-264 6. Van Hare GF, Shurin PA, Marchant CD, et al: Acute otitis media caused by Branhamella catarrhalis: Biology and therapy. Rev Infect Dis 1987; 9:16-27 7. Wald ER, Milmoe GJ, Bowen A, et al: Acute maxillary sinusitis in children. N Engl J Med 1981; 304:749-754 8. Hamory BH, Sande MA, Sydnor A, et al: Etiology and antimicrobial therapy of acute maxillary sinusitis. J Infect Dis 1979: 139:197-202 9. Schalen L, Christensen P, Kamme C, et al: High isolation rate of Branhamella catarrhalis from the nasopharynx in adults with acute laryngitis. Stand J Infect Dis 1980; 12:277280

10. Ernest TN, Philip M: Bacterial tracheitis caused by Bmnhamella catarrhalis. Pediatr Infect Dis 1987; 6:574

116 11. Bogaerts J, Lepage P, VandeWeghe JP, et al: Severe respiratory infection with Bmnhamella cotarrhalis in African child. Em J Pediatr 1985; 143:303-304 12. Brorson J, Malmvall B: Branhamella catarrhalis and other bacteria in the nasopharynx of children with longstanding cough. Stand J Infect Dis 1981; 13:111-113 13. Brook I, Hirokawa R: Treatment of patients with a history of recurrent tonsillitis due to group A beta-hemolytic streptococci. Clin Pediatr 1985: 24:331-336 14. Brook I, Yocum P: Bacteriology of chronic tonsillitis in young adults. Arch Otolaryngol 1984; 110:803-805 15. Catlin BW: Transfer to the organism named Neisseria catarrhalis to Branhamella gen. nov. Int J Sys Bact 1970; 20:155-159 16. Giebink GS, Juhn SK, Weber ML, et al: The bacteriology and cytology of chronic otitis media with effusion. Pediatr InfectDis 1982; 1:98-103 17. Leinonen M. Luotonen 1. Herva E, et al: Preliminarv serologic evidence for a pathogenic role of.BranhameJla cat&halis. J Infect Dis 1981; 144:570-574 18. Brorson J, Axelsson A, Holm S: Studies on Branhamella catarrhalis (Neisseria catarrhalis) with special reference to maxillary sinusitis. Stand J Infect Dis 1976; 8:151-155 19. Ninane G, Joly J, Kraytman M: Bronchopulmonary infection due to Bmnhamella catarrhalis: 11 cases assessed by transtracheal puncture. Br Med J 1978; 1:276-278 20. Patterson TF, Patterson JE, Masecar BL, et al: A nosocomial outbreak of Bmnhamella catarrhalis confirmed by re-

B CATARRHALE AND CROUP striction endonuclease analysis. J Infect Dis 1988; 157:9961001 21. Mulks MH, Plaut AG: IgA protease production as a characteristic distinguishing pathogenic from harmless Neisseriaceae.N EnglJ Med 1978; 299:973-976 22. Klein BS, Dollete FR, Yolken RI-I: The role of respiratory syncytial virus and other viral pathogens in acute otitis media. J Pediatr 1982; 101:16-20 23. Stobberingh EE, Davies BI, van Boven CPA: Branhamella catarrhalis: Antibiotic sensitivities and Blactamases. J Antimicrob Chemother 1984; 13:55-64 24. Sweeney KG, Verghese A, Needham CA: In vitro susceptibilities of isolates from patients with Branhamella catarrhalis pneumonia compared with those of colonizing strains. Antimicrob Agents Chemother 1985; 27:499-502 25. Long SS, Henretig FM, Teter MJ, et al: Nasopharyngeal flora and acute otitis media. Infect Immunol 1983; 41:987-991 26. Bartos LC, Murphy TF: Comparison of the outer membrane proteins of 50 strains of Branhamella catarrhalis. J Infect Dis 1988; 158:761-765 27. Finch R: Treatment of respiratory tract infections with cephalosporin antibiotics. Drugs 1987; 34:180-204 (suppl 21 28. Karma P, Virtanen T, Pukander J, et al: Branhamella catarrhalis in acute otitis media. Acta Otolaryngol 1985; 99:285-290 29. Doern GV: Bmnhamella catarrhalis-An emerging human pathogen. Diagn Microbial Infect Dis 1986; 4:191-201