sign in sign up
<<
Home , Brazilian purpuric fever, Moraxella catarrhalis

The Other Siblings: Respiratory Caused by catarrhalis and influenzae

Larry Lutwick, MD, and Laila Fernandes, MD

Corresponding author Larry Lutwick, MD Infectious Diseases (IIIE), VA Medical Center, 800 Poly Place, Bacteriology Brooklyn, NY 11219, USA. M. catarrhalis is a Gram negative, aerobic E-mail: [email protected] that was initially described by Anton Ghon and Rich- Current Infectious Disease Reports 2006, 8:215–221 ard Pfeiffer as Micrococcus catarrhalis at the end of the Current Science Inc. ISSN 1523-3847 19th century. For most of the first century of its rec- Copyright © 2006 by Current Science Inc. ognition, M. catarrhalis is considered to be a human mucosal commensal organism based on its common finding as an inhabitant of the oropharynx of healthy Respiratory infections remain substantial causes of mor- adults. During a significant amount of this time, based bidity and mortality globally. In this paper, two substantial on phenotypic characteristics as well as microbiologic players in bacterial-associated respiratory disease are colony appearances, the diplococcus was referred to assessed as to their respective roles in children and adults as catarrhalis. Of note, in 1963, N. catarrhalis and in the developed and developing world. Moraxella was found to contain two distinct species, catarrhalis catarrhalis, although initially thought to be a nonpathogen, and cinerea [1]. continues to emerge as a cause of upper respiratory Reclassification of the genus of this microorganism disease in children and in adults. No occurred in 1970 when significant phylogenetic dispari- is currently available to prevent M. catarrhalis . ties between N. catarrhalis and the generally considered Haemophilus influenzae type b, originally thought to be the “true” Neisseria species (such the meningococcus and cause of influenza, has now been limited epidemiologically gonococcus) were elucidated. These findings resulted in in the developed world due to an effective the movement of the organism into the newly created but it continues to be a major player in the developing genus of [2]. This genus was to honor Sara world. Nonencapsulated strains of H. influenzae still Branham whose pioneering work on N. meningitidis and remain as significant causes of respiratory infections in influenza virus helped introduce the importance of the the developing world especially in exacerbation of chronic bacteriology into public health. obstructive disease. Finally, and in brief, the spectrum Fourteen years later, the of this organism of due to a specific biotype of (neé Micrococcus) changed once more with its reassign- H. influenzae is discussed. ment into the genus Moraxella [3] based on DNA-DNA hybridization, rRNA-DNA hybridization, and 16S ribosomal DNA sequence and wall fatty acid com- Introduction parisons. This genus therefore contained the diplococcus Certainly Streptococcus pneumoniae is recognized as the “big M. catarrhalis and other moraxellae such as osloensis that brother” of respiratory infections, especially pneumonia. is bacillary in shape. Many other pyogenic like the pneumococcus, In blood agar, the organism produces nonhemolytic, however, are primary respiratory pathogens. This paper round, opaque, grayish-white colonies that remain intact addresses two of the other major bacterial causes of respi- when pushed across the surface of the agar [4••]. On Gram ratory infections throughout the world after Streptococcus stain, M. catarrhalis appears as a standard Neisseria organ- pneumoniae, Moraxella catarrhalis and Haemophilus influenzae, ism does, as a Gram negative diplococcus with adjacent the other siblings in the respiratory infection family. flattened sides. In addition to being oxidase positive, the 216 Pleuropulmonary and Bronchial Infections organism is generally DNase, nitrate and nitrite reduction, nary respiratory involvement with this organism has been and tributyrin hydrolysis positive [4••]. described. Not only cases of and have been described in children [4••], but also the diplococcus Carriage has been linked to cases of and tracheobronchitis, An inverse relationship between age and healthy carriage the latter often associated with an exacerbation of chronic rate is found with this organism. Up to 75% of children obstructive pulmonary disease (COPD). can be colonized with M. catarrhalis [4••] whereas the An association of laryngitis in the adult with Morax- carriage rate in healthy adults is generally regarded to ella has been made by Hol et al. [14] in the Netherlands. be 1% to 5% [4••,5••]. Carriage rates of the organism The group had previous observed that the organism appear to be higher during the fall and winter months. could be isolated from more than 50% of 40 cases of lar- Murphy [5••] states that colonization rates appear to be yngitis and none of 40 controls but it was not clear if the higher in adults with chronic respiratory diseases. This organism had a pathogenic role in the disease. The find- asymptomatic carriage appears to be a dynamic one with ing that the laryngitis isolates had a higher proportion individuals eliminating one and then acquiring a (57%) of complement-resistant strains than did carrier genetically distinct strain later. strains from healthy 8- to 13-year-old school children (16%) with a P < 0.001 the finding of complement-resis- Respiratory disease in childhood tant (virulence-associated) phenotype in adults with As has been recognized to be the case with meningococcal acute laryngitis supports the theory of an active role of disease, pediatric longitudinal studies have revealed M. catarrhalis in the pathogenesis of acute laryngitis. that newly acquired nasopharyngeal colonization with Just as the pneumococcus and H. influenzae (especially a strain of M. catarrhalis precedes the development of nontypeable strains) have been associated with acute exac- infection due to this strain [6]. Systemic infections such erbations of COPD with increasing amount and purulence as and/or bacteremia do occur (especially in of respiratory secretions, M. catarrhalis is now linked as the immunoincompetent individual [7] but are rare. In well. Murphy [5••] presents a number of lines of evidence cases of bacteremia as many as 50% of them may develop to link this organism to COPD exacerbations: a rash which can resemble that in meningococcemia [8]. Most cases of M. catarrhalis infection in children are 1. Some patients with exacerbations of COPD will represented by upper respiratory infections such as otitis have Gram stains of the expectorated media, bacterial sinusitis, and /tracheitis. revealing the predominant organism being a Gram Bacteriologically, Moraxella accounts for about 20% negative kidney bean-shaped diplococcus with of acute or subacute sinus infections in children with significant growth of the organism upon culture. Haemophilus influenzae also causing 20% and Streptococcus 2. Pure cultures of the organism have been pneumoniae 40% [9]. Similar numbers have been generated obtained in some cases of exacerbation in secre- for pediatric otitis media [10]. Verduin et al. [4••] suggest tions obtained through transtracheal aspiration that the incidence of M. catarrhalis causing these infec- to avoid the contamination of oral flora. tions may well be higher as it is not easily isolated from 3. Improvement of symptoms may occur only when, relatively low redox potential (anaerobic) environments. since most M. catarrhalis strains produce a beta- Studies have been published that suggest that the severity lactamase, antimicrobial treatment is modified to of symptoms and the bacterial load in the middle ear fluid a drug resistant to bacterial beta-lactamase. are lower for Moraxella infections as compared with the 4.. may develop to the homologous strain other common bacterial causes of otitis media [11]. of the organism that was isolated during the event. due to this organism has been felt to be relatively uncommon with most of them Pneumonia due to this organism certainly appears occurring in pediatric patients younger than 1 year of to be more common in the elderly than in the pediat- age [12]. The co-morbidity of bronchopulmonary dys- ric cohort. One study from Belgium done prospectively plasia appears to be a predisposing problem in pediatric regarding community-acquired pneumonia in the elderly M. catarrhalis pneumonia [13]. Although uncommon reported that 8% of in those older than 60 in most studies, good documentation of the diagnosis years of age were caused by this diplococcus [15]. The has been made by the isolation of the organism in pure same group reported that the asymptomatic carriage rate culture from tracheal aspirates as well as finding the appeared to increase in those older than 60 years of age organism in blood culture. to about 25% from 5% in those adults younger than 60 years of age. Most of the older individuals who develop Respiratory disease in adults M. catarrhalis pneumonia have, as many with other Although occasional extrarespiratory infections with bacterial pneumonias, significant co-morbidities [16,17]. M. catarrhalis occur in the adult including endocarditis, most These cofactors include COPD, congestive heart failure, and infections are related to the . Nonpulmo- diabetes mellitus. In the study by Wright et al. [16], 55% of Respiratory Infections Caused by M. catarrhalis and H. influenzae Lutwick and Fernandes 217 the patients were older than 65 years of age and 98% had testing suggests its utility unless it is clear that the organ- COPD or other serious underlying co-morbidity. Eighty- ism is not a beta-lactamase producer. eight percent of the cases occurred from October to April. Infections due to M. catarrhalis, if mild enough, can It has been observed that, while the pneumonia due be treated with a variety of antimicrobial agents. These to M. catarrhalis can cause a significant degree of mor- agents include the fixed combination of bidity, fulminating pneumonia as can be seen with the and sulfamethoxazole, , the fluoroquinolones pneumococcus is uncommon [5••]. Although attribut- such as ciprofloxacin, the newer macrolide type medica- able mortality may be low, as many as 45% of patients tions and , beta-lactamase had died of any cause within 3 months of admission dem- stable , and -clavulanate. The onstrating the severity of underlying disease. Other than beta-lactamase resistant such as methicillin and the Gram stain of a good deeply expectorated sputum, are not active. Intravenous forms of these med- which can show many polymorphonuclear leukocytes ications, as available, can be used for serious infections. and Gram negative diplococcus, which may be extra- or intracellular, the clinical signs of pneumonia due to this Prevention organism is not specific. The picture is one of a febrile There is no current commercially available vaccine for M. individual (to as high as 40°C or greater) with cough, catarrhalis. Since the organism has no secreted exotoxin purulent sputum, and dyspnea. Chest x-rays may show and no isolated fimbriae or capsule, other must lobar or, more commonly, patchy bronchoalveolar infil- be sought as potential vaccine targets [23]. These targets trates. Uncomplicated or complicated pleural effusions include those involved in adhesion, in nutrient acquisi- are uncommon. The Gram stain as described can also tion, and for virulence. A recent article by Murphy [24] be due to pneumonia due to [18], has summarized the progress that has been made, where the meningococcus, which is a more uncommon cause of work has stalled, and what should be done to bring a pneumonia in the elderly but may be more common in vaccine to prevent this important pathogen to fruition. the child or younger adult. Another aspect of respiratory infection with M. catarrhalis that merits notation is nosocomial (hospital acquired) Haemophilus influenzae, Type b disease. One outbreak reported by Patterson et al. [19] was Bacteriology confirmed to be a clonal origin by the use of DNA restric- Pfeiffer’s bacillus, H. influenzae, was originally found tion endonuclease analysis. This outbreak, in a respiratory in 1892 and was initially thought to be the agent of care unit, involved five patients and two staff members. epidemic influenza. It is a small pleomorphic Gram Other reports have found that substantial contamination negative organism that exhibits bacillary and cocco- of the environment can occur with this organism [20]. bacillary forms. This is important to recognize when Verduin et al. [4••] state that person-to-person and environ- comparing Gram stains of this organism with those mentally spread nosocomial infection with this organism of the pneumococcus (Streptococcus pneumoniae) and has been inferred but that important questions regarding M. catarrhalis. Confusion is much more likely to occur spread still occur. Of note, the organism may survive in spu- between H. influenzae and the pneumococcus when the tum obtained from patients for several weeks [21]. Outside stain is under- or overdecolorized since the morphology the hospital environment, nursery schools and day care is similar between them (coccobacillary forms of the centers may function as places where spread from child to former and lancet shaped diplococcus of the latter). An child can occur as it does with other respiratory and gastro- important observation regarding underdecolorization intestinal bacteria and viruses. Intrafamily transmission of of the Gram stain is whether the nuclei of the poly- the organism has also been well documented [22]. morphonuclear leukocytes are Gram-positive staining, if so there is undercolorization and any H. influenzae Treatment may be Gram positive. There should be no problem in The first strains of this organism to be found to produce distinguishing Haemophilus from Moraxella since their beta-lactamase and therefore be resistant to and morphologies are quite distinct. were identified in 1977, initially in France. The H. influenzae is a fastidious bacterium; a facultative frequency of these strains increased in the last quarter of organism, it requires factor X (hematin) and factor V (nico- the 20th century so that, at present, 90% of the strains tinamide adenine dinucleotide [NAD]) for growth. These produce this enzyme. As reviewed by Murphy [5••], the factors are supplied by but not blood agar beta-lactamase activity is inducible, cell-associated, and (absence of available factor V). Factor V can be supplied by can be inhibited by the two commercially available beta- Staphylococcus aureus growing on the blood agar and colonies lactamase inhibitors, clavulanic acid and sulbactam. It is of H. influenzae may be seen growing around the larger S. important to note, as stressed by Murphy [5••], that the aureus colonies demonstrating a phenomenon called satel- effect in vitro is inoculum dependent. Therefore, ampi- litism. The different species of the Haemophilus genus can, in cillin should not be used clinically even if susceptibility part, be distinguished by the dependence of factors X and V. 218 Pleuropulmonary and Bronchial Infections

In 1931, Pittman characterized the six capsular types and must be watched for although the larger airway of of this organism, designating them a, b, c, d, e, and f. adults may be less often fully obstructed. Care must Similar to Lancefield’s typing scheme for beta-hemolytic be taken in examining the epiglottis, which may be streptococci, each capsular type is antigenically distinct. visible as a red, swollen mass posterior to the tongue An overwhelming majority of clinically significant iso- as obstruction may follow the exam. For whatever rea- lates of H. influenzae are type b and pathogenic strains of son, in developing areas of the world there has always the other capsular types are quite uncommon. been a low incidence of epiglottitis despite meningeal infection and pneumonia being common [31••]. Carriage Bacteremic and nonbacteremic Hib pneumonia occurs This organism is not found in nature outside its human in the developed and developing world but most studies , colonizing the nasopharynx of its healthy host. underestimate its incidence since nonbacteremic cases are Much of the colonization is with unencapsulated strains undercounted. Typically, the child with Hib pneumonia is but in the preimmunization era, type b could be found younger than 4 years of age and develops signs of pneu- in the nasopharynx of 2% to 4% of children [25]. This monia during the winter or spring. It has been stated that has dropped to less than 1% in children vaccinated Hib pneumonia may develop somewhat more insidiously against type b with a conjugate vaccine. Non b typeable than that due to the pneumococcus. H. influenzae pneumo- strains can be found in 1% to 2% of children and, not nia is, however, quite common in parts of the developing unexpectedly, has not changed in the vaccine era. As with world, especially Papua New Guinea and Gambia. Annual M. catarrhalis, colonization is a dynamic process with incidence rates as high as 2850 cases per 100,000 children genetically distinct strains (usually unencapsulated ones) under the age of 4 years have been reported from Papua coming and going in the nasopharynx [26]. New Guinea [32], a rate 10 times higher than the Austra- lian native population and four to five times higher than Respiratory disease in children Alaskan Inuits [31••]. That Hib is an important cause Although a pathogen causing otitis media, of pneumonia in the developing world can be further sinusitis, epiglottitis, and pneumonia, H. influenzae type b underscored by the observation that 25% of severe life- (Hib) has been well recognized as an invasive pathogen threatening childhood pneumonia was decreased after a causing meningitis, , primary bacteremia, Hib vaccine initiative [33]. and a clinically characteristic facial cellulitis with a violet- As summarized by Shann [34], quite amount of colored hue. The incidence of each of these manifestations variability exists in the reports of the distribution of of Hib disease has dramatically decreased in areas where Hib and nontypeable strains and even non-b capsular Hib of children is widespread. Adult invasive types found. He reported that by lung aspiration in infection with Hib is quite uncommon but has decreased Papua New Guinea and Gambia, a majority of strains somewhat with childhood immunization for Hib as the were nontypeable but 21% to 63% were type b. Addi- reservoir for the bacterium has diminished. Additionally, tionally, by blood culture in Pakistan, the Philippines, adults are much less susceptible to Hib since most have and Papua New Guinea, most cultures were type b. specific against the capsule polysaccharide and This is not surprising since type b is much more likely against other bacterial antigens that developed from colo- to be bacteremic. nization in childhood [27]. Another invasive infection due to Hib is postsplenectomy , a rapidly fulminating Respiratory disease in the adult bacteremic infection in asplenic or hyposplenic individu- As mentioned in the above section, respiratory infec- als due to encapsulated bacteria [28]. Usually due to the tions due to Hib are uncommon in adults as most of the pneumococcus, Hib has been, in the prevaccine era, the infections are nontypeable strains. However, occasionally second most common cause. otitis, sinusitis, epiglottitis, and pneumonia as well as Hib has been the most common organism associ- more invasive bacteremic infections can occur [35]. ated with epiglottitis, an infection causing prominent swelling due to local edema of the epiglottic area Treatment with the potential for acute respiratory obstruction. As with M. catarrhalis, at one point Hib isolates were Most common in childhood from age 2 to 7 and often universally sensitive to ampicillin. In 1973, however, under 4, the disease may occur in adults and can be beta-lactamase producing strains of Hib were found in due to Hib but may be related to other pathogens. As the United States and the frequency of these ampicillin- with other invasive Hib infections it has diminished resistant strains has increased. Infections due to Hib, if in areas where Hib vaccination is widespread [29,30], mild enough, can be treated with a variety of antimicro- but with less of an effect on individuals over the age of bial agents. These agents include the fixed combination 15 years. The disease usually, but not always, is quite of trimethoprim and sulfamethoxazole, tetracycline, the abrupt with sore throat, fever, and shortness of breath. fluoroquinolones such as ciprofloxacin, the newer macro- Airway obstruction can occur at any time and any age lide type medications azithromycin and clarithromycin, Respiratory Infections Caused by M. catarrhalis and H. influenzae Lutwick and Fernandes 219 beta-lactamase stable cephalosporins and amoxicillin- Haemophilus influenzae, Nontypeable clavulanate. Intravenous forms of these medications, as As reviewed succinctly by Shann [34], 75% to 95% of the available, can be used for serious infections. H. influenzae carriage strains are unencapsulated (non- serotypeable) strains that colonize between 10% and Prevention 100% of healthy children. When H. influenzae infection Chemoprophylaxis against invasive Hib disease is an is caused by direct spread from the nasopharynx as might important part of management for unimmunized or occur in otitis media or sinusitis, most of these cases are inadequately immunized contacts of cases of invasive caused by nontypeable strains of the bacillus. This is in Hib disease [36]. In the absence of prior immunization, contradistinction to the bloodborne infections described household contacts younger than 4 years of age with above which are almost always due to type b strains. It individuals with invasive Hib infection have a substantial is important to understand that most unencapsulated incidence of disease. In the month after onset of dis- strains of H. influenzae are not strains of capsulated origin ease in the index case, the attack rate is estimated to be that have lost their ability to produce capsule. Indeed, the 3.8% among children younger than 2 years of age, 1.5% nontypeable isolates are clearly different genetically. among children 2 to 3 years of age, 0.1% among those 4 Adherence of these strains appears to be related to the to 5 years of age, and 0% among those older than 6 years outer membrane P2 and P5 [38]. P2 is primarily of age. Rifampin dosed at 20 mg/kg once daily (600 mg the most abundant of the outer membrane proteins and can maximum) for 4 days has eradicated the carrier state in form a trimer that has activity. P2 is a major target for approximately 95% of carriers and significantly reduced an antibody response but exhibits substantial strain-specific the incidence of secondary cases in household members. variability which limits its potential as a vaccine target. Rifampin prophylaxis is recommended for all household The same peri-nasopharyngeal spread occurring members, including adults (except pregnant women), a in otitis media and sinusitis appears to be significant contact younger than 48 months of age whose immuni- in the cause of H. influenzae bacterial pneumonia. In zation status with the conjugate vaccine is incomplete, or children with pneumonia in the developing world that an immunocompromised child of any age. A contact is were diagnosed by lung aspirate [39–41], cumulatively defined as a child who is either a household member or 41% of H. influenzae strains were nontypeable. Simi- who is spending 4 or more hours daily with the index case larly, 43% of the bacteremic H. influenzae cases were for at least 5 of the 7 days preceding the day the index case nontypeable strains [34]. was hospitalized. Rifampin prophylaxis, at the same dose Since the colonization rate with nontypeable schedule, is also indicated for all attendees and person- H. influenzae is high in children and remains high into nel at a daycare center or nursery when two or more cases adulthood, it is not surprising that infectious exacer- of invasive Hib disease have occurred within 60 days if bations of COPD may be associated with nontypeable incompletely immunized children attend the facility. strains of H. influenzae [42]. In this study, 11 of 35 The original vaccine to prevent Hib disease was puri- (31.4%) exacerbations of COPD were associated with fied type B capsule but, as a polysaccharide , it was the development of new serum IgG to homologous non- ineffective in children under 24 months and did not pro- typeable strains of H. influenzae. An additional 37.2% of duce immunologic memory. Subsequently, for cases were associated with nontypeable H. influenzae in the prevention of Hib where the type b capsule was con- conjunction with respiratory viruses. jugated to a backbone were produced are shown In addition to the involvement of nontypeable strains to be highly effective. Vaccination reduces or eliminates in purulent exacerbations of COPD in adults, pneumo- carriage of Hib strains which plays an important role nia in adults may occur in adults as well as in children. in the effectiveness of the vaccine. With widespread use The adult pneumonias occur primarily in those with of conjugate vaccines the incidence of reported invasive underlying pulmonary disease with or without other disease in children under the age of 5 years has declined significant co-morbidities. The clinical manifestations from an estimated 100 cases per 100,000 to 0.3 in the of pneumonia due to these H. influenzae strains are not United States [37]. distinguishable from pneumonias of other etiologies. Although certain populations in the United States, These features include fever, cough, and several days of including those of native American and native Alaskan increasingly purulent sputum with a chest radiograph children, show a persistently elevated rate of infection showing patchy or lobar infiltrates. A Gram stain of even with widespread vaccination, the vaccine has been appropriately obtained respiratory secretions will show effective throughout the developed world where vac- polymorphonuclear leukocytes and a predominance of cination incidence is high. However, the overall world small, pleomorphic Gram negative coccobacilli. impact has been far less impressive because of inadequate As with Hib, unencapsulated strains may produce vaccination schedules. It is estimated that, currently a beta-lactamase making them resistant to ampicillin worldwide, approximately 2% of cases of invasive Hib but at this point less ampicillin resistance is thought to infections are prevented by the vaccines [31••]. exist than with Hib. Agents with activity include trim- 220 Pleuropulmonary and Bronchial Infections ethoprim-sulfamethoxazole, amoxicillin-clavulante, the be detected in non-BPF biogroup aegyptius strains or in fluoroquinolones, the newer macrolides and the extended nontypeable or typeable H. influenzae strains [48]. This spectrum cephalosporins. Intravenous equivalents of genetic island could be important in characterizing the such coverage can be used if oral therapy is inadvisable. differences between BPF and non-BPF strains. Of note, Since the nontypeable strains are unencapsulated, a antibodies against the LOS of the clone were neither vaccine similar to that used for the encapsulated type b bacteriocidal nor protective in a rat model [49]. H. influenzae strain. One technique to prevent infection with nontypeable strains is to use a vaccine utilizing a lipooligosaccharide (LOS) based conjugate vaccine Conclusions [43]. Using a vaccine conjugated to tetanus toxoid in Moraxella catarrhalis and Haemophilus influenzae type b both adults, antibodies against LOS developed but the con- remain prominent causes of respiratory infections, both in jugate-induced antibodies did not produce significant the upper and lower aspects of the tract. Both have evolved bacteriocidal activity in vitro. Since the infections due to produce beta-lactamase which has changed the thera- to nontypeable H. influenzae are mucosal-based, vac- peutic approach to these bacteria. The availability of an cines to stimulate mucosal immunity have also been effective vaccine to prevent H. influenzae type b infections studied. Sabirov et al. [44] studied the outer mem- has changed the epidemiology in the developed world. A brane protein P6, an antigen common to nontypeable parallel vaccine in the nonencapsulated M. catarrhalis is not strains, with a mucosal adjuvant and demonstrated that yet available. The nonencapsulated H. influenzae strains, sinus clearance of nontypeable strains were increased. however, remain a significant problem. This increase occurred in both sinuses despite the uni- lateral administration of the immunogen. Systemic administration of the vaccine did not affect clearance References and Recommended Reading of the bacteria. More studies of these or other potential Papers of particular interest, published recently, vaccines are warranted. have been highlighted as: • Of importance •• Of major importance Haemophilus influenzae Biogroup aegyptius 1. Berger U: Die anspruchslosen Neisserien. Ergeb Microbiol Nontypeable Haemophilus influenzae has been known to Immunitaetforsh 1963, 36:97–167. be a significant etiologic agent in purulent . 2. Catlin BW: Transfer of the organism named Neisseria Of importance, it has been recognized that, unlike the catarrhalis to Branhamella gen. nov. Int J Syst Bacteriol relatively sporadic nature of most H. influenzae infections, 1970, 20:150–159. 3. Bovre K: The genus moraxella, In Bergey’s Manual of the conjunctivitis can occur in clusters. The organism Systematic Bacteriology, vol 1. Edited by , Krieg NR, Hold JG. associated with conjunctivitis had been given a separate Baltimore: Williams & Wilkins; 2000:296–303. speciation, H. aegyptius, but is now referred to as H. influ- 4.•• Verduin CM, Hol C, Fleer A, et al.: Moraxella catarrhalis: from emerging to established pathogen. Clin Microbiol Rev enzae biogroup aegyptius, sometimes referred to as the 2002, 15:125–144. Koch-Weeks bacillus. In 1984, a disease referred to as An excellent organized and well written review on clinical and Brazilian purpuric fever (BPF) was characterized as a ful- microbiologic aspects of M. catarrhalis by a group with a lot of experience with this pathogen. minant, often fatal childhood illness that began with a 5.•• Murphy TF: Branhamella catarrhalis: epidemiological purulent conjunctivitis [45]. This disease, which occurred and clinical aspects of a human respiratory tract patho- primarily in children from age 1 to 4, was caused by a gen. Thorax 1998, 53:124–128. A more succinct and focused review on this organism. Very well clonal strain or strains of this organism that had devel- thought out and, although an older citation than reference 4, one oped the ability to cause bacteremic disease associated to have on hand. with fever, a hemorrhagic rash and vascular collapse not 6. Faden H, Harabuchi Y, Hong JJ: Epidemiology of moraxella dissimilar to meningococcemia [46•]. The case fatality catarhalis in children during the first 2 years of live: rela- tionship to otitis media. J Infect Dis 1994, 169:1312–1317. rate was about 40%. Several hundred cases have been 7. Abuhammour WM, Abdel-Haq M, Asmar BI, Dajani AS: reported of BDP, almost all from Brazil but isolated cases Moraxella catarrhalis bacteremia: a 10-year experience. were diagnosed in Australia and the United States. South Med J 1999, 92:1071–1074. 8. Wallace MR, Oldfield C: Moraxella (Branhamella) This single clonal group, the BPF clone, was charac- catarrhalis bacteremia: a case report and literature terized by containing an about 24 megaDalton plasmid. review. Arch Intern Med 1990, 150:1332–1334. The plasmid, however, was subsequently found in non- 9. Blumer J: Clinical perspectives on sinusitis and otitis BPF strains and some BPF strains did not contain the media. Pediatr Infect Dis 1998, 17(Suppl 8):S68–S72. 10. Patel JA, Reisner B, Vizirinia N, et al.: Bacteriologic failure plasmid so that the virulence of the organism could of amoxicillin-clavulanate in the treatment of acute otitis not be explained by the BPF strain alone [47]. More media caused by nontypeable Haemophilus influenzae. recently, a chromosomal genomic island was identified J Pediatr 1995, 126:799–706. 11. Faden H, Bernstein L, Brodsky J, et al.: Effect of prior in a Haemophilus influenzae biogroup aegyptius BPF strain treatment on middle ear disease in children. which was also found in other BPF isolates, could not Ann Otol Rhinol Laryngol 1992, 101:87–91. Respiratory Infections Caused by M. catarrhalis and H. influenzae Lutwick and Fernandes 221

12. Boyle FM, Georghiou PR, Tilse MH, McCormack JG: Bran- 32. Lehmann D: Epidemiology of acute respiratory tract hamella (Moraxella) catarrhalis: pathogenic significance infections, especially those due to Haemophilus influ- in respiratory infections. Med J Aust 1991, 154:592–596. enzae, in Papua New Guinean children. J Infect Dis 1992, 13. Berg RA, Bartley DL: Pneumonia associated with 165:S185–S189. Branhamella catarrhalis in infants. Pediatr Infect Dis 1987, 33. Mulholland E, Alexander ER, Pepe M, et al.: Randomised 6:569–573. trial of Haemophilus influenze type-b tetanus protein 14. Hol C, Schalen C, Verduin CM, et al.: Moraxella catarrha- conjugate vaccine prevention of pneumonia and menin- lis in acute laryngitis: infection or colonization? J Infect igitis in Gambian infants. Lancet 1997, 349:1191–1197. Dis 1996, 174:636–668. 34. Shann F: Haemophilus influenzae pneumonia: type b or 15. Vaneechoutte M, Verschraegen G, Claeys G, et al.: Respi- non-type b? Lancet 1999, 354:1488–1490. ratory tract carrier rates of Moraxella (Branhamella) 35. Furrer M, Cottagnoud P, Muhlemann K: Haemophilus catarrhalis in adults and children and interpretation influenzae infections among hospitalized adult patients. of the isolation of M. catarrhalis from sputum. J Clin Infection 2000, 28:351–354. Microbiol 1990, 28:2674–2680. 36. American Academy of Pediatrics: Haemophilus influen- 16. Wright PW, Wallace RJ, Shepherd JR: A descriptive study zae infections. In Red Book: 2003 Report of the Committee of 42 cases of Branhamella catarrhalis pneumonia. on Infectious Diseases, edn 26. Edited by Pickering LK. Am J Med 1990, 88:2S–8S. Elk Grove Village, IL: American Academy of Pediatrics; 17. Hager H, Verghese A, Alvarez S, Berk SL: Branhamella 2003:296. catarrhalis respiratory infections. Rev Infect Dis 1987, 37. Bath S, Biskard K, Murphy T, et al.: Progress toward 9:1140–1149. elimination of Haemophilus influenzae type b invasive 18. Irwin RS, Woelk WK, Coudon WL: Primary meningococ- disease among infants and children-United States, 1998- cal pneumonia. Ann Intern Med 1975, 82:493–498. 2000. Morbid Mortal Wkly Rep 2002, 51:234–237. 19. Patterson TF, Patterson JE, Masecar BL, et al.: A nosoco- 38. St. Geme JW: The pathogenesis of nontypable Haemophi- mail outbreak of Branhamella catarrhalis confirmed lus influenzae otitis media. Vaccine 2001, 19:S41–S50. by restriction endonuclease analysis. J Infect Dis 1988, 39. Shann F, Germer S, Hazlett D: Aetiology of pneumonia in 157:996–1001. children in Goroka Hospital, Papua New Guinea. Lancet 20. Ikram RB, Nixon M, Aitken J, Wells E: A prospective study 1984, 2:537–541. of isolation of Moraxella catarrhalis in a hospital during 40. Wall RA, Corrah PT, Mabey DCW, Greenwood BM: The the winter months. J Hosp Infect 1993, 25:7–14. etiology of in the Gambia. Bull World 21. Calder MA, Croughan MJ, McLeod DT, Ahmad F: The Health Org 1986, 64:553–558. incidence and antibiotic susuceptibility of Branha- 41. Adegbola RA, Falade AG, Sam BE, et al.: The etiology mella catarrhalis in respiratory infections. Drugs 1986, of pneumonia in malnourished and well-nourished 31(Suppl 3):11–16. Gambian children. Pediatr Infect Dis J 1994, 13:975–982. 22. Watanabe H, Hoshino K, Sugita R, et al.: Molecular 42. Bandi V, Jakubowycz M, Kinyon C, et al.: Infectious analysis of intrafamiliar transmission of Moraxella exacerbations of chronic obstructive pulmonary disease catarrhalis. Int J Med Microbiol 2005, 295:187–191. associated with respiratory viruses and non-typeable 23. McMichael JC: Vaccines for Moraxella catarrhalis. Vaccine Haemophilus influenzae. FEMS Immunol Med Microbiol 2001, 19:S101–S107. 2003, 37:69–75. 24. Murphy TF: Vaccine development for non-typeable Hae- 43. Gu X-X, Rudy SF, Chu C, et al.: Phase I study of a mophilus influenzae and Moraxella catarrhalis: progress lipooligosaccharide-based conjugate vaccine against and challenges. Expert Rev Vaccines 2005, 4:843–853. nontypeable Haemophilus influenzae. Vaccine 2003, 25. Turk DC: Clinical importance of Haemophilus influen- 21:2107–2114. zae. In Haemophilus Influenzae, Epidemiology, Immunology, 44. Sabirov A, Kodama S, Sabirova N, et al.: Intranasal immu- and Prevention of Disease. Edited by Sell SH, Wright PF. nization with outer P6 and Elsevier: New York; 1982:3–9. toxin induces sinus mucosal immunity and enhances 26. Samuelson A, Freijd A, Jonasson J, Lingberg AA: Turnover sinus clearance of nontypeable Haemophilus influenzae. of nonencapsulated Haemophilus influenzae in the Vaccine 2004, 22:3112–3121. nasopharynges of otitis-prone children. J Clin Microbiol 45. Brazilian Purpuric Fever Study Group: Brazilian purpuric 1995, 33:2027–2031. fever: epidemic fulminans associated with ante- 27. Anderson P, Johnston R, Smith DH: Human serum activi- cedent purulent conjunctivitis. Lancet 1987, 2:757–761. ties against Haemophilus influenzae type b. J Clin Invest 46.• Harrison LH, da Silva GA, Pittman M, et al.: Epidemiology 1972, 51:31–38. and clinical spectrum of Brazilian purpuric fever. J Clin 28. Lutwick LI: Infections in asplenic patients. In Mandell, Microbiol 1989, 27:599–604. Douglas and Bennett’s Perinciples and Practice of Infectious A well written summary of BPF. Diseases, edn 6. Edited by Mandell GL, Bennett JE, Dolin R. 47. Kroll JS, Farrant JL, Tyler S, et al.: Characterisation and Churchill Livingstone: Philadelphia; 2005:3524–3532. genetic organization of a 24-Mda plasmid from the Bra- 29. McVernon J, Slack MP, Ramsay ME: Changes in the zilian Purpuric Fever clone of Haemophilus influenzae epidemiology of epiglottitis following introduction of biogroup aegyptius. Plasmid 2002, 48:38–48. Haemophilus influenzae type b (Hib) conjugate vaccines 48. McGillivary G, Tomaras AP, Rhodes ER, Actis LA: Cloning in England: a comparison of two data sources. Epidemiol and sequencing of a genomic island found in the Brazil- Infect 2005, 17:1–3. ian purpuric fever clone of Haemophilus influenzae 30. Wood N, Menzies R, McIntyre P: Epiglottitis in Sydney biogroup aegyptius. Infect Immun 2005, 73:1927–1938. before and after the introduction of vaccination against 49. Peters VB, Rubim LG: Antibodies to lipoligosaccharide Haemophilus influenzae type b disease. Intern Med J of a Brazilian Purpuric Fever isolate of Haemophilus 2005, 35:530–535. influenzae biogroup aegyptius lack Bactericidal and 31.•• Peltola H: Worldwide Haemophilus influenzae type b protective activity. Infect Immun 1992, 60:3423–3427. disease at the beginning of the 21st century: global analysis of the disease burden 25 years after the use of the polysaccharide vaccine and a decade after the advent of conjugates. Clin Microbiol Rev 2000, 13:302–317. An excellent and comprehensive publication illustrating what an effective vaccine can produce in a population with access to it.