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Microbial dynamics of purulent nasopharyngitis in children
International Journal of Pediatric Otorhinolaryngology (2003) 67, 1047 /1053
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REVIEW ARTICLE
Microbial dynamics of purulent nasopharyngitis in children Itzhak Brook* Department of Pediatrics, Georgetown University School of Medicine, 4431 Albemarle St. NW, Washington, DC 20016, USA Received 20 March 2003; received in revised form 11 June 2003; accepted 17 June 2003
KEYWORDS Nasopharyngitis; Anaerobic bacteria; Interference; Haemophilus influenzae ; Streptococcus pneumoniae ; Streptococcus pyogenes
Summary This review presents the microbiological dynamic and therapeutic options in the management of purulent nasopharyngitis (NPT). The nasopharynx (NP) of healthy children is generally colonized by relatively non-pathogenic aerobic and anaerobic organisms, some of, which possess the ability to interfere with the growth of potential pathogens. Conversely, carriage of potential respiratory aerobic pathogen such as Streptococcus pneumoniae , Haemophilus influenzae and Moraxella catarrhalis , as well as some anaerobic bacteria (Peptostreptococcus , Fusobacterium and Prevotella spp.) increases during purulent NPT. The development of purulent NPT in children is associated with the pre-existing colonization by potential pathogens and the absence of interfering organisms in the NP. Controversy exists regarding the management of NPT as no conclusive evidence exists to date that the administration of antimicrobials will shorten the illness. Published by Elsevier Ireland Ltd.
1. Introduction Purulent nasopharyngitis (NPT) is common in children, especially in the fall, winter, and early spring. This infection is often part of an inflammatory response of the upper respiratory tract that also involves the tonsils, adenoids, uvula, and soft palate. The nasopharynx (NP) of healthy children is generally colonized by relatively non-pathogenic aerobic and anaerobic organisms, [1] some of which possess the ability to interfere with the growth of potential pathogen [2 /4]. Conversely, carriage of potential respiratory aerobic pathogen such as Streptococcus pneumoniae , Haemophilus
*Tel.: /1-301-295-2698; fax: /1-646-390-2494. E-mail address: [email protected] (I. Brook).
influenzae and Moraxella catarrhalis , as well as some anaerobic bacteria (Peptostreptococcus , Fusobacterium and Prevotella spp.) increases during NPT [5,6]. The development of purulent NPT in children is associated with the pre-existing colonization by potential pathogens and the absence of interfering organisms in the NP. Controversy exists regarding the management of NPT as no conclusive evidence exists to date that the administration of antimicrobials will shorten the illness. The purpose of this review is to present the microbiological and therapeutic studies that investigated the management of NPT.
2. Bacterial interference Competitive interactions between micro-organisms take place in the process of the colonization
0165-5876/03/$ - see front matter. Published by Elsevier Ireland Ltd. doi:10.1016/S0165-5876(03)00203-9
1048
of mucus membranes, as well as in clinical infections. Bacteria interact with each other when they attempt to establish themselves and dominate their environment [7]. Some of these interactions are synergistic while others are antagonistic, as organisms can interfere with each other’s growth and compete for their ecological space. Bacterial interference (BI) may play a major role in the maintenance of the normal flora of skin and mucous membranes, by preventing invasion by potentially exogenous pathogens. This may be one of the important mechanisms that prevent certain infectious disease. BI is expressed through several mechanisms. These includes the production of antagonistic substances, changes in the bacterial microenvironment and reduction of needed nutritional substances [8,9]. The mediators of BI vary and include the production of complex materials such as bacteriocins, bacteriophages, or bacteriolytic enzymes, and less complex molecules such as hydrogen peroxide, lactic or fatty acids and ammonia [8,9]. Bacteria that are part of the normal flora that possess interfering capability with potential pathogens include aerobic and facultative bacteria (alpha and gamma-hemolytic streptococci [10] and Lactobacillus spp. [11]) and the anaerobic bacteria (pigmented Prevotella , Prevotella oralis , Bacteroides fragilis , and Peptostreptococcus anaerobius ) [12]. Several studies demonstrated that interfering aerobic organisms (Streptococcus mitis and Streptococcus sanguis , both alpha-hemolytic streptococci streptococci) were less often recovered from the tonsils of children with recurrent streptococcal tonsillitis [13,14], the adenoids [15] and the NP [4,16] of children with recurrent otitis or sinusitis [17], as compared to children without such a history. In contrast children with recurrences of these infections were more often colonized by potential pathogens as compared with children who do not suffer from recurrent respiratory infections. It is possible that the absence of interfering organisms contributes to colonization by these pathogens. Overuse of antibiotics that can reduce the rate of colonization by some members of the normal flora might have contributed to these findings [18]. The ability of the indigenous normal NP flora to inhibit colonization with potential pathogens has been studied [2 /4,19,20]. Alpha hemolytic streptococci were found to inhibit the colonization in patients and in vitro growth of a variety of pathogenic bacteria. These include S. pneumoniae , GABHS and S. aureus . Brook and Gober [21]
I. Brook
studied children seen consecutively in the pediatric clinic for acute nasal discharge (ND). They illustrated that the development to a purulent discharge in NPT is associated with prior colonization by potential pathogens and the absence of organisms with interfering capabilities in the NP of the patients (Table 1). However, patients who are not colonized with potential respiratory pathogens but are colonized with interfering bacteria, or non pathogens such as P. acnes and Corynebacterum spp. were not prone to develop purulent NPT.
3. Microbiological studies Most cases of NPT are caused by viral infections. The commonest viral causes of NPT are adeno (types 1 /7, 7a, 9, 14 and 15), influenza and parainfluenza viruses [22]. Although rhino and respiratory syncytial viral infections are common in children and both always have nasal manifestations (rhinitis), the occurrence of pharyngeal manifestations is uncommon [23]. S. pneumoniae , H. influenzae , Staphylococcus aureus , and GABHS were recovered in over 75% of patients with purulent ND and Corynebacterium diphtheriae and Neisseria meningitidis are rarely recovered [6,24 /27]. The role of anaerobic bacteria, however, was not investigated in these studies. Todd et al. [28] who evaluated 144 children with purulent NPT isolated grew S. pneumoniae , in 46%; H. influenzae type-b in 21%; and GABHS in 8% of the patients. Nasal crusting was significantly associated with the growth of S. pneumoniae or H. influenzae type-b. Cisse et al. [29] recovered S. pneumoniae (in 60% of the children), streptococci group C (in 41%), H. influenzae (in 33%), GABHS (in 20%), and M. catarrhalis (in 13%) in the NP of children with NPT in Senegal. We studied the aerobic and anaerobic microbiology of purulent NPT [6] by processing specimens from the inferior nasal meatus of 25 children with purulent NPT and from 25 controls (Table 2). A total of 98 isolates (3.9/patient), 45 aerobes (1.8/ patient) and 53 anaerobes (2.1/patient) were isolated in patients with purulent NPT. Seventythree isolates (2.9/patient) were found in the controls, 47 aerobes (1.9/patient) and 26 aerobes (1.0/patient). The organisms recovered in statistically significantly higher numbers in patients with NPT were S. pneumoniae, Haemophilus spp., Peptostreptococcus spp., Fusobacterium spp., and Bacteroides spp. The organism recovered in significantly higher numbers in controls was Propionibactrium acnes .
Microbial dynamics of purulent nasopharyngitis in children
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Table 1 Recovery of organisms with interference capability against Haemophilus influenzae , Streptococcus pneumoniae and Group A beta-hemolytic streptococci from the NP of children [21] Group 1 developed NPT purulent (n / Group 2 did not develop purulent NPT (n / 20) 20) HI
SP
GABHS
Alpha-hemolytic streptococci 1 Peptostreptococcus anaerobius 0 Prevotella melaninogenica 1
2 1 0
Total
3
2
HI
SP
GABHS
2 0 1
5 3 4
4 4 3
6 3 3
3
12
11
12
HI, Haemophilus influenzae ; SP, Streptococcus pneumoniae ; GABHS, Group A beta-hemolytic streptococci. Table 2 Bacteria isolated NP of 25 children with NPT and 25 controls [6] Isolates Aerobic and facultative Streptococcus pneumoniae Alpha-hemolytic streptococci Gamma-hemolytic streptococci Group A, beta-hemolytic streptococci Group C, beta-hemolytic streptococci Group F, beta-hemolytic streptococci Staphylococcus aureus Staphylococcus epidermidis Moraxella catarrhalis Haemopillus influenzae Haemophilus spp. Diphtheroid sp. Escherichia coli Proteus sp. Subtotal Anaerobic Peptostreptococcus spp. Microaerophilic streptococci Propionibacterium acnes Veillonella parvula Fusobacterium spp. Fusobacterium nucleatum Bacteroides spp. Pigmented Prevotella and Porphyromonas Prevotella oralis
NPT Controls 6a 6 5 2 1 / 3 1 8 5a 2 4 1 1 45
1 8 6 / / 1 8 5 7 1 / 7 2 1 47
17b 4 4 3 3 12c 2 3 3b / 6b 1 4b 1 11b 2 3
/
Subtotal
53
26
Total number of organisms
98
73
Key: statistically higher number of isolates than other group. aP B/0.05; bP B/0.001; cP B/0.01 (Stu-
Current data suggests that the presence of NPT is associated with an increase rate of isolation of an aerobic-anaerobic polymicrobial flora. However, the pathogenic role of these organisms in the inflammatory process is unknown.
4. Microbial dynamics of nasopharyngitis The ND in children with NPT is generally initially clear and watery; however, in cases that progress, it becomes viscous, opaque and discolored (white, yellow or green) in a mater of days. Usually the purulent discharge resolves or becomes watery again before disappearing without specific therapy [30]. Cherian et al. [31] evaluated 56 rural Indian children with persistent NPT, and 91 age-matched controls. Chronic ear discharge was noted in 6 (12%) of cases but in none of the controls (P / 0.007). S. pneumoniae was isolated from NP in 42/49 (86%) cases and 44/80 (55%) controls (P B/ 0.001) and H. influenzae from seven cases and five controls. S. pneumoniae was also isolated in all children with chronic ear discharge and H. influenzae was recovered from one child. A recent study characterizes the aerobic and anaerobic bacterial flora of ND obtained from children at different stages of uncomplicated NPT [21]. A correlation was made between the bacterial flora and the eventual course of the illness. It also investigated the relationship between colonization of the NP with organisms with interfering capability and the subsequent development of purulent NPT. Serial semi-quantitative NP and quantitative ND cultures were taken every 3 /5 days from 20 children who eventually developed purulent discharge (Group 1), and a single culture was obtained from a group of 20 who had only clear discharge (Group 2) (Table 3). Aerobic and anaerobic bacteria were isolated from all NP cultures. Bacterial growth was present in 8 (40%) ND of Group 2. Only 7 (35%) of the clear ND of Group 1 showed bacterial growth; the number increased to 14 (70%) at the mucoid stage, and 20 (100%) in the purulent stage. It declined to 6 (30%) at the final clear stage. The number of species and total number of organisms increased in the ND of Group 1. Group 1 patients had higher recovery rate of S. pneumoniae
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. Table 3
Microbiology of predominant isolates recovered from 40 children with ND [21] Children who developed purulent discharge (Group 1) (N / 20)
Type of ND
Clear
Mucoid
Purulent
Clear
Day of illness
1 /4
4 /7
6 /13
9 /15
NP
NP
Site cultural
NP
Positive culture 20 Average number of organisms/ml secretion log10 (9/S.D.) ND Organisms isolated Aerobic and facultative organisms Streptococcus pneumoniae Beta-hemolytic streptococci Staphylococcus aureus Moraxella catarrhalis Haemophilus influenzae , type b Haemophilus influenzae non type b Corynebacterium spp.
ND
NP
7 20 2.39/0.6 ND
8a 5 0 4b 2 7a 6
0 0 2 0 1 2 2
7a 15 10
Subtotal Anaerobic organisms Peptostreptococcus spp. Propionibacterium acnes Fusobacterium spp. Prevotella and Porphyromonas spp.
66
ND
14 20 4.89/0.9 ND
ND
ND
Children who did not develop purulent discharge (Group 2) (N /20)
1 /4 NP
ND
20 20 5.49/1.2 ND
6 20 2.69/0.9 ND
8 2.89/0.6
2 8a 7
2 3 3 1 1 3 3
8a 5 0 3 2 7a 7
6 5 3 3 2 6 2
6 3 0 2 1 6 8
2 1 0 0 0 2 2
2 0 5 1 1 2 14a
0 0 2 1 1 0 3
13
60
28
58
37
55
12
58
14
20 2 16 34
2 0 0 1
20 2 16 32
5 0 2 6
19 3 21 31
15 1 10 13
18 1 18 30
1 0 1 1
19 14* 16 30
2 2 0 1
Subtotal
79
3
77
16
80
43
71
3
86
6
Total
145 16
144
20
137 44
138 80
126 15
NP, nasopharynx; ND, nasal discharge; ND, not done. a P B/0.05 compared to NP in Group 2. b In parenthesis number of beta-lactamase-producing bacteria.
I. Brook
Microbial dynamics of purulent nasopharyngitis in children
and H. influenzae in their NP cultures than those in Group 2 (P B/0.05). During the purulent stage, Peptostreptococcus spp. was isolated in 15 (75%), Prevotella spp. in 9 (45%), Fusobacterium spp. in 8 (40%), H. influenzae in 8 (40%), S. pneumoniae in 6 (30%), and beta-hemolytic streptococci in 5 (25%) of ND of Group 1. This was higher than their recovery in the clear stages of both groups and the mucoid stage of Group 1. A total of eight organisms with interfering capability of the growth of potential pathogens were isolated from the NP of Group 1, as compared to 35 from Group 2 (P B/ 0.001) (Table 1). This study illustrated that the development of purulent NPT is associated with the pre-existing presence in the NP of potential pathogens and the absence of interfering organisms. The potential oropharyngeal pathogens S. pneumoniae , H. influenzae and beta-hemolytic streptococci were recovered in the purulent ND of over 3/4 of patients. In contrast these organisms were rarely recovered in patients who did not develop purulent NPT. Children who are not colonized with potential respiratory pathogens but harbor interfering bacteria, or non pathogens such as P. acnes and Corynebacterum spp. may not be prone to develop purulent ND. It is most likely that the initial inflammation in the NP is viral in nature that becomes bacterial in those patients who are colonized with potential respiratory pathogens and do not harbor interfering bacteria. Since no viral cultures were taken, the etiology of NPT in this study was not completely determined. However, the recovery of several aerobic and anaerobic bacteria not generally found as part of the nasal flora, in patients with purulent NPT, may signify their potential pathogenic role. The concomitant presence of these organisms in the inflamed pharynx supports the concept of a generalized inflammation that also involves the nasal spaces.
5. Therapeutic implications Controversy exists regarding the management of NPT. Some clinicians regard it as a self-limited phase of viral infection, which does not require specific therapy, while others recommend performing nasal culture to detect GABHS and initiation of antimicrobial therapy if the ND continues for more than 10 days [32]. Cohen [33] enrolled 700 pediatricians in France and evaluated their use of antimicrobials in patients with uncomplicated NPT. Antimicrobials were used in 59% of patients. Criteria considered
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as the most important for deciding to use antimicrobials included purulent secretions, congestion of both tympanic membranes, cough, fever greater than 39 8C, and a history of otitis media. Schwartz et al. [34] surveyed all 450 pediatricians (PD) and family practitioners (FP) in northern Virginia about their use of antibiotics for NPT. They found that most infants and children with NPT of short duration were treated with antibiotics despite the physicians concerns over the spread of bacterial resistance; the practice was more prevalent among FP. Seventy-one percent of FP and 53% of PD immediately prescribed antibiotics for infants NPT of one day duration. Over 94% of all participants prescribed antibiotics immediately for infants with NPT who attended day care and 86% of FP and 78% of PD treated without delay otitis-prone children who were not in day care. The reasons given for prompt use of antibiotic therapy were: the belief that many untreated patients would develop persistent purulent nasal drainage; concern that acute otitis media would develop; pressure from mothers to prescribe an antibiotic and/ or the desire to allow parents to return to work earlier. Todd et al. [28] attempted to modify the progress of purulent NPT by using cephalexin. Although some bacterial strains susceptible to cephalexin were identified, the clinical outcome was not affected. However, since the antibacterial spectrum of cephalexin is limited, these researchers suggested the need for further studies to investigate the therapy of NPT with antimicrobial agents with wider spectra of activity. Wald [32] reported a small study of 13 patients with purulent ND who were either treated with amoxicillin-clavulanate or placebo. Five of the six given the antimicrobial completely resolved their infection within 10 days compared to only two of the seven on placebo (P B/0.05). Kaiser et al. [35] studied the efficacy of amoxicillin-clavulanate compared to placebo in 300 adults with nasal congestion and rhinorrhoea. They found that among the 61 who were culture positive for S. pneumoniae , H. influenzae and M. catarrhalis , the antimicrobial therapy produced a significant clinical response. In contrast, no difference was noted in the response of the patients without these organisms. The authors concluded that these potential pathogens were the cause of the symptoms in this subgroup of patients. In a commentary to that study, Wise [36] cautioned clinicians from routinely administering antimicrobials to patients with common cold, as such an approach would only increase the resistance to
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antimicrobial agents in the community, and provides only minimal benefit to the patients. Even though an association was found in the study by Brook and Gober [21], between the preexisting NP colonization with potential pathogens and the subsequent development of NPT, no conclusive evidence exists to date that the administration of antimicrobials directed at these pathogens will shorten the illness. Use of antimicrobial therapy may on the other hand generate emergence of antimicrobial resistance, increase cost and untoward side effects. Further studies are needed to explore whether prevention of colonization with pathogens by vaccination, active colonization of the oropharynx by interfering organisms, or utilization of antimicrobials can provide the patients with clinical benefit, and prevent complications.
References [1] P.A. Mackowiak, The normal flora, N. Engl. J. Med. 307 (1982) 83 /93. [2] S.S. Sanders, G.E. Nelson, W.E. Sanders, Jr., Bacterial interference IV. Epidemiological determinants of the antagonistic activity of the normal flora against Group A streptococci , Infect. Immunol. 16 (1977) 599 /606. [3] K. Sprunt, W. Redman, Evidence suggesting importance of role of interbacterial inhibition in maintaining a balance of normal flora, Ann. Inter. Med. 68 (1968) 579 /587. [4] J.M. Bernstein, S. Sagahtaheri-Altaie, D.M. Dryjd, et al., Bacterial interference in nasopharyngeal bacterial flora of otitis-prone and non-otitis-prone children, Acta oto-rhinolaryngologica Belg. 48 (1994) 1 /9. [5] H. Faden, M.J. Zaz, J.M. Bernstein, et al., Nasopharyngeal flora in the first three years of life in normal and otitisprone children, Ann. Oto. Rhinol. Laryn. 100 (1991) 612 / 615. [6] I. Brook, Aerobic and anaerobic bacteriology of purulent nasopharyngitis in children, J. Clin. Microbiol. 26 (1988) 592 /594. [7] I. Brook, Bacterial interference, Crit. Rev. Microbiol. 25 (1999) 155 /172. [8] L.W. Wannamaker, Bacterial interference and competition, Scand. J. Infect. Dis. Suppl. 24 (Suppl) (1980) 82 /85. [9] H. Smith, The revival of interest in mechanisms of bacterial pathogenicity, Biol. Rev. 70 (1995) 277 /316. [10] A.S. Dajani, M.C. Tom, D.J. Law, Viridins, enteriocins of alpha-hemolytic streptococci: isolation, characterization, and partial purification, Antimicrob. Agents Chemother. 9 (1976) 81 /88. [11] G. Reid, A.W. Bruce, R.L. Cook, Examination of strains of lactobacilli for properties that may influence bacterial interference in the urinary tract, J. Urol. 138 (1987) 330 / 335. [12] P.R. Murray, J.E. Rosenblatt, Bacterial interference by oropharyngeal and clinical isolates of anaerobic bacteria, J. Infect. Dis. 134 (1976) 281 /285. [13] E. Grahn, S.E. Holm, K. Roos, et al., Interference of alphahemolytic streptococci isolated from tonsillar surface, on beta-hemolytic streptococci, Streptococcus pyogenes : a methodological study, Zentralbl. Microbiol. 254 (1983) 459 /468.
I. Brook [14] I. Brook, A.E. Gober, Bacterial interference by aerobic and anaerobic bacteria in children with recurrent Group A beta-hemolytic streptococcal tonsillitis, Arch. Otolaryngol. Head Neck Surg. 125 (1999) 552 / 554. [15] I. Brook, P. Yocum, Bacterial interference in the adenoids of otitis media prone children, Ped. Inf. Dis. J. 18 (1999) 835 /837. [16] I. Brook, A. Gober, Bacterial interference in the nasopharynx of otitis media prone and not otitis media prone children, Arch. Otol. Head Neck Surg. 126 (2000) 1011 / 1013. [17] I. Brook, A. Gober, Bacterial interference in the nasopharynx and nasal cavity of sinusitis prone and not sinusitis prone children, Acta Otolaryngol. 119 (1999) 832 / 836. [18] I. Brook, A.E. Gober, Bacterial interference in the nasopharynx following antimicrobial therapy of acute otitis media, J. Antimicrob. Chemother. 41 (1998) 489 /492. [19] A. Raza, H.I. Maibach, H.R. Shinefield, A. Mandel, W.G. Strauss, Bacterial interference among strains of Staphylococcus aureus in man, J. Infect. Dis. 129 (1974) 720 /724. [20] I. Brook, A.E. Gober, Role of bacterial interference and b-lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococcal pharyngotonsillitis, Arch. Otolaryngol. Head Neck Surg. 121 (1995) 1405 /1409. [21] I. Brook, A.E. Gober, Dynamics of nasopharyngitis in children, Otolaryngol. Head Neck Surg. 122 (2000) 696 / 700. [22] J.P. Engel, Viral upper respiratory infections, Semin. Respir. Infect. 10 (1995) 3 /13. [23] A. Heald, R. Auckenthaler, F. Borst, et al., Adult bacterial nasopharyngitis: a clinical entity?, J. Gen. Intern. Med. 8 (1993) 667 /673. [24] G.C. Hays, J.E. Mullard, Can nasal bacteria flora be predicted from clinical findings?, Pediatrics 49 (1972) 596 /599. [25] A. Freijd, S. Bygdeman, B. Rynnel-Dagoo, The nasopharyngeal microflora of otitis-prone children, with emphasis on H. influenzae , Acta Otolaryngol. 97 (1984) 117 /126. [26] H.R. Jousimies-Somer, S. Savolainen, J.S. Ylikoski, Comparison of the nasal bacterial floras in two groups of healthy subjects and in patients with acute maxillary sinusitis, J. Clin. Microbiol. 27 (1989) 2736 /2743. [27] A. Heald, R. Auckenthaler, F. Borst, Adult bacterial nasopharyngitis: a clinical entity?, J. Gen. Intern. Med. 8 (1993) 667 /673. [28] J.K. Todd, N. Todd, J. Damato, et al., Bacteriology and treatment of purulent nasopharyngitis: a double-blind placebo-controlled evaluation, Pediatr. Infect. Dis. 3 (1984) 226 /232. [29] M.F. Cisse, A.I. Sow, C. Thiaw, et al., Bacteriological study of purulent nasopharyngitis in children in Senegal, Arch. Pediatr. 4 (1997) 1192 /1196. [30] R.S. Gohd, The common cold, N. Engl. J. Med. 250 (1954) 687 /691. [31] T. Cherian, S. Bhattacharji, K.N. Brahmadathan, et al., Persistent rhinorrhoea in rural Indian children: prevalence and consequences, J. Trop. Pediatr. 46 (2000) 365 /367. [32] E.R. Wald, Purulent nasal discharge, Pediatr. Infect. Dis. J. 10 (1991) 329 /333.
Microbial dynamics of purulent nasopharyngitis in children [33] R. Cohen, A survey on the criteria of prescription antibiotic therapy in nasopharyngitis in pediatric practice, Ann. Pediatr. (Paris) 39 (1992) 195 /201. [34] R.H. Schwartz, B.J. Freij, M. Ziai, et al., Antimicrobial prescribing for acute purulent rhinitis in children: a survey of pediatricians and family practitioners, Pediatr. Infect. Dis. J. 16 (1997) 185 /190.
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[35] L. Kaiser, D. Lew, B. Hirschel, et al., Effects of antibiotic treatment in the subset of common-cold patients who have bacteria in nasopharyngeal secretions, Lancet 347 (1996) 1507 / 1510. [36] R. Wise, Antibiotics for the uncommon cold, Lancet 347 (1996) 1499.
www.elsevier.com/locate/ijporl
REVIEW ARTICLE
Microbial dynamics of purulent nasopharyngitis in children Itzhak Brook* Department of Pediatrics, Georgetown University School of Medicine, 4431 Albemarle St. NW, Washington, DC 20016, USA Received 20 March 2003; received in revised form 11 June 2003; accepted 17 June 2003
KEYWORDS Nasopharyngitis; Anaerobic bacteria; Interference; Haemophilus influenzae ; Streptococcus pneumoniae ; Streptococcus pyogenes
Summary This review presents the microbiological dynamic and therapeutic options in the management of purulent nasopharyngitis (NPT). The nasopharynx (NP) of healthy children is generally colonized by relatively non-pathogenic aerobic and anaerobic organisms, some of, which possess the ability to interfere with the growth of potential pathogens. Conversely, carriage of potential respiratory aerobic pathogen such as Streptococcus pneumoniae , Haemophilus influenzae and Moraxella catarrhalis , as well as some anaerobic bacteria (Peptostreptococcus , Fusobacterium and Prevotella spp.) increases during purulent NPT. The development of purulent NPT in children is associated with the pre-existing colonization by potential pathogens and the absence of interfering organisms in the NP. Controversy exists regarding the management of NPT as no conclusive evidence exists to date that the administration of antimicrobials will shorten the illness. Published by Elsevier Ireland Ltd.
1. Introduction Purulent nasopharyngitis (NPT) is common in children, especially in the fall, winter, and early spring. This infection is often part of an inflammatory response of the upper respiratory tract that also involves the tonsils, adenoids, uvula, and soft palate. The nasopharynx (NP) of healthy children is generally colonized by relatively non-pathogenic aerobic and anaerobic organisms, [1] some of which possess the ability to interfere with the growth of potential pathogen [2 /4]. Conversely, carriage of potential respiratory aerobic pathogen such as Streptococcus pneumoniae , Haemophilus
*Tel.: /1-301-295-2698; fax: /1-646-390-2494. E-mail address: [email protected] (I. Brook).
influenzae and Moraxella catarrhalis , as well as some anaerobic bacteria (Peptostreptococcus , Fusobacterium and Prevotella spp.) increases during NPT [5,6]. The development of purulent NPT in children is associated with the pre-existing colonization by potential pathogens and the absence of interfering organisms in the NP. Controversy exists regarding the management of NPT as no conclusive evidence exists to date that the administration of antimicrobials will shorten the illness. The purpose of this review is to present the microbiological and therapeutic studies that investigated the management of NPT.
2. Bacterial interference Competitive interactions between micro-organisms take place in the process of the colonization
0165-5876/03/$ - see front matter. Published by Elsevier Ireland Ltd. doi:10.1016/S0165-5876(03)00203-9
1048
of mucus membranes, as well as in clinical infections. Bacteria interact with each other when they attempt to establish themselves and dominate their environment [7]. Some of these interactions are synergistic while others are antagonistic, as organisms can interfere with each other’s growth and compete for their ecological space. Bacterial interference (BI) may play a major role in the maintenance of the normal flora of skin and mucous membranes, by preventing invasion by potentially exogenous pathogens. This may be one of the important mechanisms that prevent certain infectious disease. BI is expressed through several mechanisms. These includes the production of antagonistic substances, changes in the bacterial microenvironment and reduction of needed nutritional substances [8,9]. The mediators of BI vary and include the production of complex materials such as bacteriocins, bacteriophages, or bacteriolytic enzymes, and less complex molecules such as hydrogen peroxide, lactic or fatty acids and ammonia [8,9]. Bacteria that are part of the normal flora that possess interfering capability with potential pathogens include aerobic and facultative bacteria (alpha and gamma-hemolytic streptococci [10] and Lactobacillus spp. [11]) and the anaerobic bacteria (pigmented Prevotella , Prevotella oralis , Bacteroides fragilis , and Peptostreptococcus anaerobius ) [12]. Several studies demonstrated that interfering aerobic organisms (Streptococcus mitis and Streptococcus sanguis , both alpha-hemolytic streptococci streptococci) were less often recovered from the tonsils of children with recurrent streptococcal tonsillitis [13,14], the adenoids [15] and the NP [4,16] of children with recurrent otitis or sinusitis [17], as compared to children without such a history. In contrast children with recurrences of these infections were more often colonized by potential pathogens as compared with children who do not suffer from recurrent respiratory infections. It is possible that the absence of interfering organisms contributes to colonization by these pathogens. Overuse of antibiotics that can reduce the rate of colonization by some members of the normal flora might have contributed to these findings [18]. The ability of the indigenous normal NP flora to inhibit colonization with potential pathogens has been studied [2 /4,19,20]. Alpha hemolytic streptococci were found to inhibit the colonization in patients and in vitro growth of a variety of pathogenic bacteria. These include S. pneumoniae , GABHS and S. aureus . Brook and Gober [21]
I. Brook
studied children seen consecutively in the pediatric clinic for acute nasal discharge (ND). They illustrated that the development to a purulent discharge in NPT is associated with prior colonization by potential pathogens and the absence of organisms with interfering capabilities in the NP of the patients (Table 1). However, patients who are not colonized with potential respiratory pathogens but are colonized with interfering bacteria, or non pathogens such as P. acnes and Corynebacterum spp. were not prone to develop purulent NPT.
3. Microbiological studies Most cases of NPT are caused by viral infections. The commonest viral causes of NPT are adeno (types 1 /7, 7a, 9, 14 and 15), influenza and parainfluenza viruses [22]. Although rhino and respiratory syncytial viral infections are common in children and both always have nasal manifestations (rhinitis), the occurrence of pharyngeal manifestations is uncommon [23]. S. pneumoniae , H. influenzae , Staphylococcus aureus , and GABHS were recovered in over 75% of patients with purulent ND and Corynebacterium diphtheriae and Neisseria meningitidis are rarely recovered [6,24 /27]. The role of anaerobic bacteria, however, was not investigated in these studies. Todd et al. [28] who evaluated 144 children with purulent NPT isolated grew S. pneumoniae , in 46%; H. influenzae type-b in 21%; and GABHS in 8% of the patients. Nasal crusting was significantly associated with the growth of S. pneumoniae or H. influenzae type-b. Cisse et al. [29] recovered S. pneumoniae (in 60% of the children), streptococci group C (in 41%), H. influenzae (in 33%), GABHS (in 20%), and M. catarrhalis (in 13%) in the NP of children with NPT in Senegal. We studied the aerobic and anaerobic microbiology of purulent NPT [6] by processing specimens from the inferior nasal meatus of 25 children with purulent NPT and from 25 controls (Table 2). A total of 98 isolates (3.9/patient), 45 aerobes (1.8/ patient) and 53 anaerobes (2.1/patient) were isolated in patients with purulent NPT. Seventythree isolates (2.9/patient) were found in the controls, 47 aerobes (1.9/patient) and 26 aerobes (1.0/patient). The organisms recovered in statistically significantly higher numbers in patients with NPT were S. pneumoniae, Haemophilus spp., Peptostreptococcus spp., Fusobacterium spp., and Bacteroides spp. The organism recovered in significantly higher numbers in controls was Propionibactrium acnes .
Microbial dynamics of purulent nasopharyngitis in children
1049
Table 1 Recovery of organisms with interference capability against Haemophilus influenzae , Streptococcus pneumoniae and Group A beta-hemolytic streptococci from the NP of children [21] Group 1 developed NPT purulent (n / Group 2 did not develop purulent NPT (n / 20) 20) HI
SP
GABHS
Alpha-hemolytic streptococci 1 Peptostreptococcus anaerobius 0 Prevotella melaninogenica 1
2 1 0
Total
3
2
HI
SP
GABHS
2 0 1
5 3 4
4 4 3
6 3 3
3
12
11
12
HI, Haemophilus influenzae ; SP, Streptococcus pneumoniae ; GABHS, Group A beta-hemolytic streptococci. Table 2 Bacteria isolated NP of 25 children with NPT and 25 controls [6] Isolates Aerobic and facultative Streptococcus pneumoniae Alpha-hemolytic streptococci Gamma-hemolytic streptococci Group A, beta-hemolytic streptococci Group C, beta-hemolytic streptococci Group F, beta-hemolytic streptococci Staphylococcus aureus Staphylococcus epidermidis Moraxella catarrhalis Haemopillus influenzae Haemophilus spp. Diphtheroid sp. Escherichia coli Proteus sp. Subtotal Anaerobic Peptostreptococcus spp. Microaerophilic streptococci Propionibacterium acnes Veillonella parvula Fusobacterium spp. Fusobacterium nucleatum Bacteroides spp. Pigmented Prevotella and Porphyromonas Prevotella oralis
NPT Controls 6a 6 5 2 1 / 3 1 8 5a 2 4 1 1 45
1 8 6 / / 1 8 5 7 1 / 7 2 1 47
17b 4 4 3 3 12c 2 3 3b / 6b 1 4b 1 11b 2 3
/
Subtotal
53
26
Total number of organisms
98
73
Key: statistically higher number of isolates than other group. aP B/0.05; bP B/0.001; cP B/0.01 (Stu-
Current data suggests that the presence of NPT is associated with an increase rate of isolation of an aerobic-anaerobic polymicrobial flora. However, the pathogenic role of these organisms in the inflammatory process is unknown.
4. Microbial dynamics of nasopharyngitis The ND in children with NPT is generally initially clear and watery; however, in cases that progress, it becomes viscous, opaque and discolored (white, yellow or green) in a mater of days. Usually the purulent discharge resolves or becomes watery again before disappearing without specific therapy [30]. Cherian et al. [31] evaluated 56 rural Indian children with persistent NPT, and 91 age-matched controls. Chronic ear discharge was noted in 6 (12%) of cases but in none of the controls (P / 0.007). S. pneumoniae was isolated from NP in 42/49 (86%) cases and 44/80 (55%) controls (P B/ 0.001) and H. influenzae from seven cases and five controls. S. pneumoniae was also isolated in all children with chronic ear discharge and H. influenzae was recovered from one child. A recent study characterizes the aerobic and anaerobic bacterial flora of ND obtained from children at different stages of uncomplicated NPT [21]. A correlation was made between the bacterial flora and the eventual course of the illness. It also investigated the relationship between colonization of the NP with organisms with interfering capability and the subsequent development of purulent NPT. Serial semi-quantitative NP and quantitative ND cultures were taken every 3 /5 days from 20 children who eventually developed purulent discharge (Group 1), and a single culture was obtained from a group of 20 who had only clear discharge (Group 2) (Table 3). Aerobic and anaerobic bacteria were isolated from all NP cultures. Bacterial growth was present in 8 (40%) ND of Group 2. Only 7 (35%) of the clear ND of Group 1 showed bacterial growth; the number increased to 14 (70%) at the mucoid stage, and 20 (100%) in the purulent stage. It declined to 6 (30%) at the final clear stage. The number of species and total number of organisms increased in the ND of Group 1. Group 1 patients had higher recovery rate of S. pneumoniae
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. Table 3
Microbiology of predominant isolates recovered from 40 children with ND [21] Children who developed purulent discharge (Group 1) (N / 20)
Type of ND
Clear
Mucoid
Purulent
Clear
Day of illness
1 /4
4 /7
6 /13
9 /15
NP
NP
Site cultural
NP
Positive culture 20 Average number of organisms/ml secretion log10 (9/S.D.) ND Organisms isolated Aerobic and facultative organisms Streptococcus pneumoniae Beta-hemolytic streptococci Staphylococcus aureus Moraxella catarrhalis Haemophilus influenzae , type b Haemophilus influenzae non type b Corynebacterium spp.
ND
NP
7 20 2.39/0.6 ND
8a 5 0 4b 2 7a 6
0 0 2 0 1 2 2
7a 15 10
Subtotal Anaerobic organisms Peptostreptococcus spp. Propionibacterium acnes Fusobacterium spp. Prevotella and Porphyromonas spp.
66
ND
14 20 4.89/0.9 ND
ND
ND
Children who did not develop purulent discharge (Group 2) (N /20)
1 /4 NP
ND
20 20 5.49/1.2 ND
6 20 2.69/0.9 ND
8 2.89/0.6
2 8a 7
2 3 3 1 1 3 3
8a 5 0 3 2 7a 7
6 5 3 3 2 6 2
6 3 0 2 1 6 8
2 1 0 0 0 2 2
2 0 5 1 1 2 14a
0 0 2 1 1 0 3
13
60
28
58
37
55
12
58
14
20 2 16 34
2 0 0 1
20 2 16 32
5 0 2 6
19 3 21 31
15 1 10 13
18 1 18 30
1 0 1 1
19 14* 16 30
2 2 0 1
Subtotal
79
3
77
16
80
43
71
3
86
6
Total
145 16
144
20
137 44
138 80
126 15
NP, nasopharynx; ND, nasal discharge; ND, not done. a P B/0.05 compared to NP in Group 2. b In parenthesis number of beta-lactamase-producing bacteria.
I. Brook
Microbial dynamics of purulent nasopharyngitis in children
and H. influenzae in their NP cultures than those in Group 2 (P B/0.05). During the purulent stage, Peptostreptococcus spp. was isolated in 15 (75%), Prevotella spp. in 9 (45%), Fusobacterium spp. in 8 (40%), H. influenzae in 8 (40%), S. pneumoniae in 6 (30%), and beta-hemolytic streptococci in 5 (25%) of ND of Group 1. This was higher than their recovery in the clear stages of both groups and the mucoid stage of Group 1. A total of eight organisms with interfering capability of the growth of potential pathogens were isolated from the NP of Group 1, as compared to 35 from Group 2 (P B/ 0.001) (Table 1). This study illustrated that the development of purulent NPT is associated with the pre-existing presence in the NP of potential pathogens and the absence of interfering organisms. The potential oropharyngeal pathogens S. pneumoniae , H. influenzae and beta-hemolytic streptococci were recovered in the purulent ND of over 3/4 of patients. In contrast these organisms were rarely recovered in patients who did not develop purulent NPT. Children who are not colonized with potential respiratory pathogens but harbor interfering bacteria, or non pathogens such as P. acnes and Corynebacterum spp. may not be prone to develop purulent ND. It is most likely that the initial inflammation in the NP is viral in nature that becomes bacterial in those patients who are colonized with potential respiratory pathogens and do not harbor interfering bacteria. Since no viral cultures were taken, the etiology of NPT in this study was not completely determined. However, the recovery of several aerobic and anaerobic bacteria not generally found as part of the nasal flora, in patients with purulent NPT, may signify their potential pathogenic role. The concomitant presence of these organisms in the inflamed pharynx supports the concept of a generalized inflammation that also involves the nasal spaces.
5. Therapeutic implications Controversy exists regarding the management of NPT. Some clinicians regard it as a self-limited phase of viral infection, which does not require specific therapy, while others recommend performing nasal culture to detect GABHS and initiation of antimicrobial therapy if the ND continues for more than 10 days [32]. Cohen [33] enrolled 700 pediatricians in France and evaluated their use of antimicrobials in patients with uncomplicated NPT. Antimicrobials were used in 59% of patients. Criteria considered
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as the most important for deciding to use antimicrobials included purulent secretions, congestion of both tympanic membranes, cough, fever greater than 39 8C, and a history of otitis media. Schwartz et al. [34] surveyed all 450 pediatricians (PD) and family practitioners (FP) in northern Virginia about their use of antibiotics for NPT. They found that most infants and children with NPT of short duration were treated with antibiotics despite the physicians concerns over the spread of bacterial resistance; the practice was more prevalent among FP. Seventy-one percent of FP and 53% of PD immediately prescribed antibiotics for infants NPT of one day duration. Over 94% of all participants prescribed antibiotics immediately for infants with NPT who attended day care and 86% of FP and 78% of PD treated without delay otitis-prone children who were not in day care. The reasons given for prompt use of antibiotic therapy were: the belief that many untreated patients would develop persistent purulent nasal drainage; concern that acute otitis media would develop; pressure from mothers to prescribe an antibiotic and/ or the desire to allow parents to return to work earlier. Todd et al. [28] attempted to modify the progress of purulent NPT by using cephalexin. Although some bacterial strains susceptible to cephalexin were identified, the clinical outcome was not affected. However, since the antibacterial spectrum of cephalexin is limited, these researchers suggested the need for further studies to investigate the therapy of NPT with antimicrobial agents with wider spectra of activity. Wald [32] reported a small study of 13 patients with purulent ND who were either treated with amoxicillin-clavulanate or placebo. Five of the six given the antimicrobial completely resolved their infection within 10 days compared to only two of the seven on placebo (P B/0.05). Kaiser et al. [35] studied the efficacy of amoxicillin-clavulanate compared to placebo in 300 adults with nasal congestion and rhinorrhoea. They found that among the 61 who were culture positive for S. pneumoniae , H. influenzae and M. catarrhalis , the antimicrobial therapy produced a significant clinical response. In contrast, no difference was noted in the response of the patients without these organisms. The authors concluded that these potential pathogens were the cause of the symptoms in this subgroup of patients. In a commentary to that study, Wise [36] cautioned clinicians from routinely administering antimicrobials to patients with common cold, as such an approach would only increase the resistance to
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antimicrobial agents in the community, and provides only minimal benefit to the patients. Even though an association was found in the study by Brook and Gober [21], between the preexisting NP colonization with potential pathogens and the subsequent development of NPT, no conclusive evidence exists to date that the administration of antimicrobials directed at these pathogens will shorten the illness. Use of antimicrobial therapy may on the other hand generate emergence of antimicrobial resistance, increase cost and untoward side effects. Further studies are needed to explore whether prevention of colonization with pathogens by vaccination, active colonization of the oropharynx by interfering organisms, or utilization of antimicrobials can provide the patients with clinical benefit, and prevent complications.
References [1] P.A. Mackowiak, The normal flora, N. Engl. J. Med. 307 (1982) 83 /93. [2] S.S. Sanders, G.E. Nelson, W.E. Sanders, Jr., Bacterial interference IV. Epidemiological determinants of the antagonistic activity of the normal flora against Group A streptococci , Infect. Immunol. 16 (1977) 599 /606. [3] K. Sprunt, W. Redman, Evidence suggesting importance of role of interbacterial inhibition in maintaining a balance of normal flora, Ann. Inter. Med. 68 (1968) 579 /587. [4] J.M. Bernstein, S. Sagahtaheri-Altaie, D.M. Dryjd, et al., Bacterial interference in nasopharyngeal bacterial flora of otitis-prone and non-otitis-prone children, Acta oto-rhinolaryngologica Belg. 48 (1994) 1 /9. [5] H. Faden, M.J. Zaz, J.M. Bernstein, et al., Nasopharyngeal flora in the first three years of life in normal and otitisprone children, Ann. Oto. Rhinol. Laryn. 100 (1991) 612 / 615. [6] I. Brook, Aerobic and anaerobic bacteriology of purulent nasopharyngitis in children, J. Clin. Microbiol. 26 (1988) 592 /594. [7] I. Brook, Bacterial interference, Crit. Rev. Microbiol. 25 (1999) 155 /172. [8] L.W. Wannamaker, Bacterial interference and competition, Scand. J. Infect. Dis. Suppl. 24 (Suppl) (1980) 82 /85. [9] H. Smith, The revival of interest in mechanisms of bacterial pathogenicity, Biol. Rev. 70 (1995) 277 /316. [10] A.S. Dajani, M.C. Tom, D.J. Law, Viridins, enteriocins of alpha-hemolytic streptococci: isolation, characterization, and partial purification, Antimicrob. Agents Chemother. 9 (1976) 81 /88. [11] G. Reid, A.W. Bruce, R.L. Cook, Examination of strains of lactobacilli for properties that may influence bacterial interference in the urinary tract, J. Urol. 138 (1987) 330 / 335. [12] P.R. Murray, J.E. Rosenblatt, Bacterial interference by oropharyngeal and clinical isolates of anaerobic bacteria, J. Infect. Dis. 134 (1976) 281 /285. [13] E. Grahn, S.E. Holm, K. Roos, et al., Interference of alphahemolytic streptococci isolated from tonsillar surface, on beta-hemolytic streptococci, Streptococcus pyogenes : a methodological study, Zentralbl. Microbiol. 254 (1983) 459 /468.
I. Brook [14] I. Brook, A.E. Gober, Bacterial interference by aerobic and anaerobic bacteria in children with recurrent Group A beta-hemolytic streptococcal tonsillitis, Arch. Otolaryngol. Head Neck Surg. 125 (1999) 552 / 554. [15] I. Brook, P. Yocum, Bacterial interference in the adenoids of otitis media prone children, Ped. Inf. Dis. J. 18 (1999) 835 /837. [16] I. Brook, A. Gober, Bacterial interference in the nasopharynx of otitis media prone and not otitis media prone children, Arch. Otol. Head Neck Surg. 126 (2000) 1011 / 1013. [17] I. Brook, A. Gober, Bacterial interference in the nasopharynx and nasal cavity of sinusitis prone and not sinusitis prone children, Acta Otolaryngol. 119 (1999) 832 / 836. [18] I. Brook, A.E. Gober, Bacterial interference in the nasopharynx following antimicrobial therapy of acute otitis media, J. Antimicrob. Chemother. 41 (1998) 489 /492. [19] A. Raza, H.I. Maibach, H.R. Shinefield, A. Mandel, W.G. Strauss, Bacterial interference among strains of Staphylococcus aureus in man, J. Infect. Dis. 129 (1974) 720 /724. [20] I. Brook, A.E. Gober, Role of bacterial interference and b-lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococcal pharyngotonsillitis, Arch. Otolaryngol. Head Neck Surg. 121 (1995) 1405 /1409. [21] I. Brook, A.E. Gober, Dynamics of nasopharyngitis in children, Otolaryngol. Head Neck Surg. 122 (2000) 696 / 700. [22] J.P. Engel, Viral upper respiratory infections, Semin. Respir. Infect. 10 (1995) 3 /13. [23] A. Heald, R. Auckenthaler, F. Borst, et al., Adult bacterial nasopharyngitis: a clinical entity?, J. Gen. Intern. Med. 8 (1993) 667 /673. [24] G.C. Hays, J.E. Mullard, Can nasal bacteria flora be predicted from clinical findings?, Pediatrics 49 (1972) 596 /599. [25] A. Freijd, S. Bygdeman, B. Rynnel-Dagoo, The nasopharyngeal microflora of otitis-prone children, with emphasis on H. influenzae , Acta Otolaryngol. 97 (1984) 117 /126. [26] H.R. Jousimies-Somer, S. Savolainen, J.S. Ylikoski, Comparison of the nasal bacterial floras in two groups of healthy subjects and in patients with acute maxillary sinusitis, J. Clin. Microbiol. 27 (1989) 2736 /2743. [27] A. Heald, R. Auckenthaler, F. Borst, Adult bacterial nasopharyngitis: a clinical entity?, J. Gen. Intern. Med. 8 (1993) 667 /673. [28] J.K. Todd, N. Todd, J. Damato, et al., Bacteriology and treatment of purulent nasopharyngitis: a double-blind placebo-controlled evaluation, Pediatr. Infect. Dis. 3 (1984) 226 /232. [29] M.F. Cisse, A.I. Sow, C. Thiaw, et al., Bacteriological study of purulent nasopharyngitis in children in Senegal, Arch. Pediatr. 4 (1997) 1192 /1196. [30] R.S. Gohd, The common cold, N. Engl. J. Med. 250 (1954) 687 /691. [31] T. Cherian, S. Bhattacharji, K.N. Brahmadathan, et al., Persistent rhinorrhoea in rural Indian children: prevalence and consequences, J. Trop. Pediatr. 46 (2000) 365 /367. [32] E.R. Wald, Purulent nasal discharge, Pediatr. Infect. Dis. J. 10 (1991) 329 /333.
Microbial dynamics of purulent nasopharyngitis in children [33] R. Cohen, A survey on the criteria of prescription antibiotic therapy in nasopharyngitis in pediatric practice, Ann. Pediatr. (Paris) 39 (1992) 195 /201. [34] R.H. Schwartz, B.J. Freij, M. Ziai, et al., Antimicrobial prescribing for acute purulent rhinitis in children: a survey of pediatricians and family practitioners, Pediatr. Infect. Dis. J. 16 (1997) 185 /190.
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[35] L. Kaiser, D. Lew, B. Hirschel, et al., Effects of antibiotic treatment in the subset of common-cold patients who have bacteria in nasopharyngeal secretions, Lancet 347 (1996) 1507 / 1510. [36] R. Wise, Antibiotics for the uncommon cold, Lancet 347 (1996) 1499.