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Meningococcal pneumonia
Vaccine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Meningococcal pneumonia Matthias Vossen a, Dieter Mitteregger b, Christoph Steininger a,⇑ a b
Department of Medicine I, Div. of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria Department of Laboratory Medicine, Div. of Clinical Microbiology, Medical University of Vienna, Vienna, Austria
a r t i c l e
i n f o
Article history: Received 31 March 2016 Received in revised form 7 July 2016 Accepted 11 July 2016 Available online xxxx Keywords: Neisseria meningitidis Pneumonia Invasive meningococcal disease
a b s t r a c t Neisseria meningitidis remains the most important cause of bacterial meningitis worldwide, particularly in children and young adults. The second most common and a potentially severe end-organ manifestation of invasive meningococcal disease (excluding systemic sepsis) is meningococcal pneumonia. It occurs in between 5% and 15% of all patients with invasive meningococcal disease and is thus the second most common non-systemic end-organ manifestation. To establish the diagnosis requires a high level of clinical awareness – the incidence is therefore very likely underreported and underestimated. This review of 344 meningococcal pneumonia cases reported in the Americas, Europe, Australia, and Asia between 1906 and 2015 presents risk factors, pathogenesis, clinical manifestations, diagnostic approaches, treatment, and prognosis of meningococcal pneumonia. Ó 2016 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis of meningococcal pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Meningococcal pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk factors for meningococcal pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and radiological diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microbiological diagnosis of meningococcal pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prophylaxis by vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. Search strategy and selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Invasive meningococcal disease (IMD) is feared for its rapid progression from health to death or permanent disability within as little as 24 h [1]. The disease is caused by infection with a Gram-negative diplococcus, Neisseria meningitidis (meningococcus), member of the phylum ß-proteobacteria and of the bacterial family Neissericaceae. IMD occurs worldwide and year-round. The annual incidence of IMD varies between 0.4 and 1000 cases/100, ⇑ Corresponding author at: Medical University Vienna, Department of Medicine I, Währinger Gürtel 18-20, 1090 Vienna, Austria. E-mail address: [email protected] (C. Steininger).
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000 population with low rates in North America and Europe and epidemics occurring particularly in sub-Saharan Africa [2–5]. IMD may, however, be underreported as well as underdiagnosed even in European countries [6]. The majority of cases are noted during winter and early spring and in children and teenagers although all age-groups may be affected [7]. The rates of disease are highest among infants in whom protective antibodies have not yet developed; the rates drop after infancy and then increase again during adolescence and early adulthood [7]. In these two age groups, meningococcal meningitis is the leading cause of bacterial meningitis, and in adults, it is the second most common cause of community-acquired bacterial meningitis [2,8]. In a survey conducted in the Netherlands between June 1999 and 2011
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M. Vossen et al. / Vaccine xxx (2016) xxx–xxx
only 8% (69 of 874) of all cases were reported in patients aged P65 years [9]. In the pre-antibiotic era, the mortality of meningococcal infection was 70–90% [10]. The prognosis of the disease improved dramatically with the advent of antimicrobial treatment options. Still, overall case-fatality rates decreased only to 10–15% percent by the late 1960s and remained at this level despite further major advancements in supportive care [2,11,12]. Moreover, 11–19% of survivors have long-term sequelae including neurologic disability, limb or digit loss, and hearing loss [13,14]. Meningitis is one of the most severe manifestations of IMD, particularly in children and young adults, and affects about 50% of patients [7,15]. At the onset of symptoms, clinical manifestations may be difficult to distinguish from other acute neurological diseases. Symptoms include sudden onset of fever, nausea, vomiting, headache, decreased ability to concentrate, neck stiffness, and myalgias in an otherwise healthy patient. In severe cases, purpura fulminans, disseminated intravascular coagulopathy, or vasculitis may be noted. IMD may also present clinically without neurological involvement as bacteremia, arthritis, pericarditis, pharyngitis, urethritis, conjunctivitis, or immune complex disease. Nevertheless, the second most common end-organ disease of IMD remains widely neglected despite accounting for 5–15% of cases – meningococcal pneumonia [15–17]. This review aims to highlight the clinical relevance, as well as the diagnostic and management challenges related to this disease. Increasing awareness for meningococcal pneumonia may result in more frequent diagnosis of the disease, earlier institution of targeted therapies, and improved prognosis. 2. Pathogenesis of meningococcal pneumonia Meningococci may invade the lower respiratory tract hypothetically via three different modes of infection. First, N. meningitidis colonizes the nasopharyngeal mucosa of 4–10% of young, asymptomatic adults and carriage rates may range in selected cohorts between 4% and 59% [18–22]. Invasion of the loco-regional blood supply results in bacteremia and secondary dissemination of the bacterial pathogen from the oropharynx to multiple body sites, including the lungs, where a favorable micro-environment sustains bacterial replication. In concordance with a clinical significance of this pathway, 23% (10 of 44) of patients with blood cultures that are positive for N. meningitidis also have an infiltrate evident on a chest radiograph [7,23]. In these cases, meningococci may have entered the lungs via the blood stream [7]. Second, large airborne droplets that are generated during coughing and contaminated with microbial nuclei may be inhaled. Third, meningococci colonizing the oropharynx may be transmitted to the lower respiratory tract by microaspiration following biofilm formation. N. meningitidis infection in the oropharynx requires adherence of bacteria as microcolonies on nonciliated nasopharyngeal epithelial cells. Consecutively, re-organization of host cell actin and formation of membrane protrusions by bacterial mechanisms protect bacteria from shear stress by biofilm formation. Post-translational modification of bacterial pilin lead to the disassembly of bacteria and spread to other sites such as the lungs [24,25]. Viral or other bacterial infections may further reduce resistance to meningococcal infection of the lower respiratory tract as well-documented for IMD [26,27]. 3. Meningococcal pneumonia In 1907, Jacobitz described for the first time cases of meningococcal pneumonia that could be diagnosed by demonstration of N. meningitidis in sputum samples [28]. In this case series, thirteen
soldiers living in the same barracks suffered from IMD. Four of these soldiers had meningitis and pneumonia and seven had a respiratory tract infection only including two with mixed infection by meningococci and pneumococci. The source of infections could be traced back to a single index patient who presumably had contracted the disease in the nearby town of Colmar, where IMD was endemic. Jacobitz noted already more than a century ago that asymptomatic individuals may also carry N. meningitidis in their oropharynx, and hence, demonstration of the pathogen in these samples does not confirm the clinical diagnosis [28]. Large outbreaks of meningococcal pneumonia were noted during the 1918–19 influenza pandemic [29]. In 1948 the first two cases of meningococcal pneumonia in the antibiotic era were systematically studied and previous case series reviewed [30]. Brick noted in this analysis that ‘‘It has been known for some time that extrameningeal meningococcal infections are not uncommon, but the attention directed to the respiratory phase of such infections is very scant”[30]. Based on a review of contemporary evidence Putsch et al. suspected in 1970 a significant role of Neisseria meningitis in community-acquired pneumonia [31]. Since then, multiple reports of individual cases and case series indicated the clinical relevance of IMD of the respiratory tract (Table 1) [32]. We could identify a total of 344 cases of meningococcal pneumonia that were observed in the Americas, Europe, Australia, and Asia and published over a period of more than a century (1906–2015). The largest proportion of meningococcal isolates (142 cases) identified in this review of published IMD cases were of serogroup Y (Table 1). National surveys on the incidence of IMD indicate that meningococcal pneumonia is the most common non-neurological endorgan disease of IMD and occurs in about 17% (61 of 364) of patients (Table 1). This is consistent with the previously published range of 5–15% [15–17,23,33–35]. Still, the incidence of meningococcal pneumonia is very likely underestimated as discussed in more detail in ‘‘Microbiological diagnosis of meningococcal pneumonia” below.
4. Risk factors for meningococcal pneumonia Meningococcal pneumonia is considered to affect mostly older adults (>50 years) in contrast to meningococcal meningitis which affects predominantly children and teenagers, based on epidemiological surveys [16,32,34,36]. In patients aged >65 years, pneumonia is even the most common manifestation of IMD [34,36]. Nevertheless, recent reports and our present revision points to a bimodal age distribution of cases with peaks in incidence in patients aged <30 years and those aged >60 years [32]. Accordingly, factors other than patient age or serogroup may contribute more significantly to a predisposition for meningococcal pneumonia. The second relevant predictor for respiratory disease in IMD may be the infecting bacterial strain type. Several outer membrane components have been linked to meningococcal virulence, such as outer membrane proteins and lipooligosaccharid subtype; the capsular polysaccharides, however, are the major virulence factor of N. meningitidis and the main target of humoral immunity [1,37]. Genetic differences within the gene coding for capsular polysaccharides of N. meningitidis translate into antigenic differences that allowed differentiation between thirteen meningococcal serogroups so far. More recently, genomic typing, i.e. multilocus sequence typing (MLST) and whole-genome sequencing have allowed for grouping of meningococcal strains with even higher discriminatory power [38]. These analyses revealed that five N. meningitidis serogroups (A, B, C, W, and Y) are responsible for the majority of meningitis cases. In contrast to meningococcal meningitis, pneumonia is caused mostly by otherwise rare serogroups – particularly serogroup Y followed by serogroup W
Please cite this article in press as: Vossen M et al. Meningococcal pneumonia. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.07.013
Observational period of study
Country
Total number of meningococcal cases
Meningococcal pneumonia No.
% of total
Data source
2010–2013 2008–2009 2012 2007-2009 2009 2006 2001–2003 2003 2001 1999–2002 1999 1974–1998
UK India UK UK France USA Taiwan Spain Australia / Japan France UK USA
129 110 1 65 1 1 88 1 1 33 3 8
15 8 1 19 1 1 6 1 1 33 3 8
12 7 100 29 100 100 7 100 100 100 100 100
National surveillance system Patient cluster Individual patient National surveillance system Individual patient Individual patient National surveillance system Individual patient Individual patient Patient cluster Individual patient Patient cluster
1998 1998 1998 1997 1989–1995 1996 1988–1993 1995 1995 1995 1994 1994 1993 1991 1987–1989 1987 1986 1986 1985 1984 1982 1981 1976–1981 1981 1981 1977–1979 1980 1979 1979 1971–1974
Taiwan UK Spain UK France Japan USA, Atlanta Australia Spain Spain Spain Spain Spain USA France USA USA USA UK Switzerland USA USA USA USA USA USA Canada USA USA USA
1 1 1 3 15 1 44 1 1 1 1 1 1 1 38 1 1 1 1 4 2 3 5 4 2 34 1 1 1 88
1 1 1 3 15 1 10 1 1 1 1 1 1 1 11 1 1 1 1 4 2 3 2 1 2 6 1 1 1 68
100 100 100 100 100 100 23 100 100 100 100 100 100 100 29 100 100 100 100 100 100 100 40 25 100 18 100 100 100 77
Individual patient Individual patient Individual patient Patient cluster National surveillance system Individual patient National surveillance system Individual patient Individual patient Individual patient Individual patient Individual patient Individual patient Individual patient National surveillance system Individual patient Individual patient Individual patient Individual patient Patient cluster Individual patient Patient cluster Patient cluster Patient cluster Individual patient Patient cluster Individual patient Individual patient Individual patient Patient cluster
1978 1976 1975 1975 1975 1975
Finland Germany USA USA USA USA
1 1 1 1 3 1
1 1 1 1 3 1
100 100 100 100 100 100
Individual patient Individual patient Individual patient Individual patient Patient cluster Individual patient
Material used for microbiological diagnosis of meningococcal pneumonia
Range of patient age (years)
% female
Sterile n.a. sterile Sterile n.a. Sterile Sterile n.a. Sterile Sterile Sterile Sterile and sputum/BAL n.a. Sterile
n.a. Average 848 80 <5 to >85 n.a. 14 <1 to >55 n.a. 62 40 to >70 64, 83 and 85 17–86
n.a. 382 100 n.a. n.a. 100 n.a. n.a. 0 27 100 38
n.a. 91
n.a. 100
Sterile Sputum/BAL Sputum/BAL Sterile n.a. n.a. Sterile Sputum/BAL n.a. n.a. Sterile Sterile Sterile Sterile Sterile n.a. Sterile Sterile Sputum BAL Sterile Sterile Sputum/BAL Sterile Sterile Sterile Sterile Sterile and sputum/BAL Sterile Sterile Sterile Sputum/BAL Sputum/BAL Sterile
19, 50, 88 1–94 22 >18 19 months n.a. n.a. n.a. >18 n.a. 29 4 months – 86 67 4 1/3 82 72 5–12 59, 75 56, 65, 82 19, 62 n.a. 69, 87 n.a. 66 16 52 17–24
33 60 n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. 0 n.a. 100 100 100 100 100 100 66 50 n.a. 0 n.a. 100 100 0 0
n.a. 16 43 34 16, 17, 19 24
0 0 100 0 33 0
Meningococcal serogroup in pneumonia cases (% of total) A
B
C
W
X
Y
Ref. Z
100 100 100 100 100 83 100 Unknown 6 27 55 3 9 75 25 Unknown, 25 identified as Group Y Unknown 100 Unknown 33 33 26 20 Unknown 30 10
33 40 20
30 100
Unknown Unknown Unknown 100 100 100 100 100 100 100 100 66 100 100
33
100 3 100 100 100 100 100 100 100 100 100 100
Ladhani et al. [33] Dass Hazarika et al. [64] Chan et al. [65] Ladhani et al. [34] Seiberras and Fourmaux [66] Glikman et al. [67] Wang et al. [39] Pérez et al. [68] Shiraishi et al. [69] Vienne et al. [36] Weightman et al. [47] Winstead et al. [32] Tsai [70] Cadwgan et al. [71] González et al. [72] Jones et al. [48] Angelini et al. [73] Ootaki et al. [74] Stephens et al. [23] Goldwater and Rice [75] Gutiérrez-Guisado et al. [76] Nicolás-Sánchez et al. [77] Arrate et al. [78] Naya Manchado et al. [79] Alberte et al. [80] Winters et al. [81] Le Bastard et al. [82] Bergmann and Gleckman [83] Burns et al. (1986) Sacks (1986) Hanson and Lawson (1985) Llorens-Terol et al. (1984) Witt et al. (1982) Darnell et al. (1981) Brandstetter et al. (1981) Salit [62] Rose et al. (1981) Haburchak (1981) Richter (1981) Hersh et al. (1979) Cohen et al. (1979) Koppes et al. [46]
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Table 1 Reported cases of meningococcal pneumonia from 1906 to 2015, reports without radiological or post-mortem diagnosis of pneumonia was excluded, duplicate cases were removed. Material ‘‘sterile” refers to culture material obtained from normally sterile body site (Peripheral blood, pleural effusion fluid). CSF, cerebrospinal fluid.
Nikoskelainen et al. (1978) Berger (1976) Yee et al. (1975) Galpin et al. (1975) Irwin et al. (1975) Barnes et al. (1975) 3
(continued on next page)
Holm et al. [29] Jacobitz [28]
Unknown Unknown Unknown/one case Type I; six cases Type II 13 52 87 Unknown
100 100 100 100 100 100 Unknown Both cases Type I
A
B
C
W
X
Y
Z
Ref.
n.a. n.a. n.a. n.a. Sterile Sputum/BAL
100 100 100
100 100
17%
19 5 11
23 12
344 61
Patient cluster Patient cluster Patient cluster
25 100 100 100 100 100 100 100 3 1 14 1 1 1 1 2
Patient cluster Patient cluster
n.a. n.a. 0 n.a. n.a. n.a.
0 0 0 0 0 0 n.a. 0 20, 24 19 n.a. 22 20 16 n.a. 53, 56
Sterile Sterile Sterile Sterile Sterile Sputum/BAL Sputum/BAL Sterile and sputum/BAL n.a. n.a. Sterile Patient cluster Individual patient Patient cluster Individual patient Individual patient Individual patient Individual patient Individual patient
% of total No.
812 364 Total From national surveys
USA Germany 1918–1919 1906
23 12
France UK USA 1919 1919 1918
19 5 11
USA USA USA USA USA USA USA USA 1974 1974 1970–1972 1970 1968 1965 1945 1942
12 1 14 1 1 1 1 2
Meningococcal serogroup in pneumonia cases (% of total) % female
Range of patient age (years) Material used for microbiological diagnosis of meningococcal pneumonia Data source
Clinical presentation of meningococcal pneumonia is indistinguishable in most patients from community-acquired pneumonia caused by other infectious pathogens. The most common clinical symptoms reported by >50% of patients with meningococcal pneumonia are fever and chills, followed by pleuritic chest pain [16,32]. Productive cough (31%) and shortness of breath (23%) are clearly less common in these patients. A rash is noted frequently in association with septic features in patients with meningococcal pneumonia [23,46,47]. Complications such as lung abscesses, empyema, pleural effusions, or pericarditis are uncommon [23]. Despite being the main diagnostic criterion in previous studies on meningococcal pneumonia, meningococcemia is rarely an accompanying presentation of meningococcal pneumonia [32]. Blood chemistry and blood counts usually indicate an acute inflammatory process with leukocytosis and increased acute-phase protein levels such as C-reactive protein, procalcitonin, serum amyloid A, and erythrocyte sedimentation rate [32]. Abnormal chest radiographic imaging studies may be noted in most patients with meningococcal pneumonia. Bilateral infiltrations were observed in one-fifth (9 of 45) of patients and pleural effusions in 13% (6 of 45) of patients [32]. Radiological signs, however, do not allow to differentiate meningococcal pneumonia from community-acquired pneumonia caused by other bacterial agents [48]. 6. Microbiological diagnosis of meningococcal pneumonia
Country
Total number of meningococcal cases
Meningococcal pneumonia
[2,32,36,39–42]. In one case series, almost one-third of patients (42 of 53) with invasive serogroup Y infection suffered from pneumonia [32]. In another report from Taiwan, pneumonia was noted in 24% (5 of 21) of patients with invasive serogroup W infection [39]. Meningococcal pneumonia cases were also reported in conjunction with serogroups B and C although at rates much lower than serogroups Y and W [15,32]. The association of meningococcal pneumonia with different serogroups may indicate the influence of additional factors on the infection of the lower respiratory tract [12,34,42]. IMD is associated with multiple other, well-characterized hostassociated risk factors including smoking, deficiencies in the complement pathway, asplenia, lack of type-specific opsonising antibodies, deficiencies in mannose binding lectin and more specific genetic predispositions [12,13,43,44]. Currently, the significance of these risk factors for invasion of the lower respiratory tract by N. meningitidis is unclear. Smoking, however, is a major risk factor for invasive pneumococcal disease and it may be hypothesized accordingly that similar host-related mechanisms may also provide the grounds for other bacterial invasion [45]. 5. Clinical and radiological diagnosis
Observational period of study
Table 1 (continued)
Kinnicutt and Binger [85] Meader et al. [86] Fletcher [87]
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Smilack (1974) Jacobs et al. (1974) Ellenbogen et al. (1974) Ball and Young (1974) Hand et al. (1968) Paine et al. (1967) Roberg [84] Brick [30]
4
A reliable and rapid microbiological diagnosis is of high clinical and epidemiologic relevance as a single identified case of N. meningitidis disease may well be at the center of a small localized outbreak [49]. Racoosin [16] suspected two decades ago that meningococcal pneumonia was being under-diagnosed because the focus of diagnostic and clinical evaluations in patients with meningitis is on the devastating neurological disease. In addition, currently available diagnostic tools are limited by technical shortcomings and the characteristics of meningococcal infection. Blood is frequently cultured in febrile patients with community-acquired pneumonia in an attempt to identify a suspected pneumococcal strain. Blood culture may be helpful in establishing the diagnosis in cases of meningococcal meningitis as positivity rates of N. meningitidis are >50% in neurological patients [50]. In addition, isolation of bacteria from blood allows the
Please cite this article in press as: Vossen M et al. Meningococcal pneumonia. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.07.013
M. Vossen et al. / Vaccine xxx (2016) xxx–xxx
evaluation of N. meningitidis for antimicrobial susceptibility. Nevertheless, the diagnosis of respiratory pathogens with use of blood culture is in general very insensitive [51]. Positivity rates of blood cultures to detect for instance pneumococcal pneumonia range between 6% and 79% [32,46]. Accordingly, the prevalence of meningococcal pneumonia may be underestimated, as blood cultures were the main diagnostic tool used in epidemiological surveys and case series. The nucleic acid amplification tests commonly used on blood samples to identify the presence of infectious pathogens are both sensitive and specific, however they are currently unavailable for diagnosing N. meningitidis [52]. Isolation of N. meningitidis from respiratory samples might be misleading, because this organism is frequently part of the transient oropharyngeal flora of asymptomatic carriers [53,53,54]. Therefore diagnostic efforts should follow appropriate algorithms, as provided in several national and international guidelines like the Microbiology Procedures Quality Standards (MiQ) issued by the German Society for Hygiene and Microbiology, the UK Standards for Microbiology Investigations issued by the Standards Unit, Public Health England, the European Manual of Clinical Microbiology issued by the European Society of Clinical Microbiology and Infectious diseases [55]. Diagnostic algorithms aim to distinguish between contamination from normal or transient flora and presence of pathogenic microorganisms. They thus include evaluation of respiratory samples for inflammatory cells as well as quantitative assessment of the amount of meningococci in comparison to other bacterial elements. Reliable and rapid diagnostic tools for the diagnosis of meningococcal pneumonia are therefore urgently needed similarly to the situation in pneumococcal pneumonia before the advent of a specific urinary antigen test [56]. One of the major challenges of differentiating meningococcal pneumonia from other infectious causes of pneumonia therefore remains – the high level of clinical awareness required to initiate appropriate diagnostic procedures.
7. Treatment and prognosis Therapy of IMD has dramatically changed over the past 25 years. Penicillin antibiotics were the mainstay of antimicrobial therapy until 1991. Due to the considerable lethality of untreated IMD, the emergence of penicillin-resistant strains, however, also changed treatment practice thereafter. According to EUCAST (European Committee on Antimicrobial Susceptibility testing), about 95% of N. meningitidis isolates are susceptible to benzylpenicillin in Europe (http://mic.eucast.org/Eucast2/regShow.jsp?Id=3967, accessed 03/27/2016). Today, the standard empirical treatment for IMD is accordingly third-generation cephalosporins. In the case of penicillin-susceptible meningococci as confirmed by antimicrobial susceptibility testing, therapy may be switched to high-dose penicillin or continued with third-generation cephalosporins given the excellent efficacy, convenient dosing, and affordability of these agents [57]. The optimum treatment regime for meningococcal pneumonia has yet to be defined but may very likely be similar to that of meningococcal meningitis. Third-generation cephalosporins are also excellent treatment options in bacterial pneumonia caused by other, susceptible pathogens in general and efficacy may also be expected in meningococcal pneumonia [58]. Indeed, 80% of reported meningococcal pneumonia cases received penicillin before 1991 and mostly cephalosporin antibiotics thereafter [32]. Glucocorticoids are indicated for the treatment of known or suspected pneumococcal meningitis but are of no benefit in meningococcal meningitis and should be discontinued once this diagnosis is established [59]. In community-acquired pneumonia, evidence for the use of glucocorticoids is conflicting and not generally recom-
5
mended so far [60,61]. Accordingly, glucocorticoid-treatment of meningococcal pneumonia may also not be recommended. Meningococcal pneumonia has a somewhat higher case-fatality ratio than meningococcal meningitis (16% and 9–14%, respectively) [2,15]. Prognosis of meningococcal pneumonia is associated with age of the patient, meningococcal serogroup, and underlying diseases similar to other infectious diseases of the lower respiratory tract. Case-fatality rate is highest among patients older than 65 years of age (23%) and decreases with lower age [15,32,46]. Case-fatality ratio was highest among cases caused by serogroup W (16%) and lower among cases caused by serogroup B strains (9%) [15]. Secondary cases of meningococcal infections following exposure to patients with meningococcal pneumonia have been reported but are uncommon [32,62]. Recommendations for the prevention of secondary cases in the health care setting have been published and focus mainly on droplet precautions [63]. The risk of N. meningitidis transmission might be somewhat higher in patients with meningococcal pneumonia due to the generations of aerosols by coughing but may also be controlled by droplet precautions. 8. Prophylaxis by vaccination Active immunization is recommended to provide pre-exposure immunity to populations at high risk for meningococcal infection and disease [2]. Currently available vaccines and combinations thereof may protect from serogroups A, C, Y, W and as of late from serogroup B. Vaccines are the most effective intervention for the prevention of IMD and very likely also of meningococcal pneumonia. Antigens of the meningococcal serogroups predominantly associated with cases of pneumonia are included in available vaccines. Routine vaccination programs may reduce the incidence of IMD as well as carriage but related costs interfere with broad implementation of life-saving vaccination programs [53]. Of note, even immunized close contacts should still receive chemoprophylaxis, because the vaccines do not confer sterilizing immunity in all vaccinees and immunity wanes with time [2]. Routine vaccination is currently not recommended for adults except for those with underlying diseases, certain traveling destinations or exposure in the health-care setting. Nevertheless, meningococcal pneumonia has a peak in incidence in the age group of >65 years. Perhaps, these recommendations may have to be adapted with a better understanding of the epidemiology and pathogenesis of meningococcal pneumonia. 9. Conclusions The present review highlights multiple aspects related to the diagnosis and treatment of meningococcal pneumonia. Meningococcal pneumonia is the most common non-neurological endorgan manifestation of IMD [36]. In patients aged >65 years, meningococcal serogroup Y disease manifests even more frequently as pneumonia than as meningitis and clearly increased in incidence during the past two decades [34]. Meningococcal pneumonia is difficult to diagnose because of frequent asymptomatic oro-pharyngeal carriage of N. meningitidis and generally short periods of bacteremia in patients with respiratory infections but without sepsis. The incidence of meningococcal pneumonia may be underestimated and a high level of clinical awareness is required to initiate early and effective diagnostic and therapeutic procedures. 9.1. Search strategy and selection criteria References for this review were identified through searches of PubMed for articles published globally from January, 1906, to April,
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2015, by use of the terms ‘‘Meningococcal AND pneumonia”, ‘‘Neisseria meningitidis”. All articles resulting from these searches and relevant references cited in those articles were reviewed. All articles published in English, French, and German were included without exception.
Conflict of interest All authors have no conflict of interest to declare References [1] Stephens DS, Greenwood B, Brandtzaeg P. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet 2007 Jun 30;369 (9580):2196–210. [2] Cohn AC, MacNeil JR, Clark TA, et al. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013;62(RR-2):1–28. [3] Stefanelli P, Fazio C, Neri A, Boros S, Renna G, Pompa MG. Changing epidemiology of Infant Meningococcal Disease after the introduction of meningococcal serogroup C vaccine in Italy, 2006–2014. Vaccine 2015;33 (31):3678–81. [4] Gabutti G, Stefanati A, Kuhdari P. Epidemiology of Neisseria meningitidis infections: case distribution by age and relevance of carriage. J Prev Med Hyg 2015;56(3):E116–20. [5] Cohn A, MacNeil J. The changing epidemiology of meningococcal disease. Infect Dis Clin North Am 2015;29(4):667–77. [6] Azzari C, Nieddu F, Moriondo M, et al. Underestimation of invasive meningococcal disease in Italy. Emerg Infect Dis 2016;22(3). [7] Rosenstein NE, Perkins BA, Stephens DS, Popovic T, Hughes JM. Meningococcal disease. N Engl J Med 2001;344(18):1378–88. [8] Okike IO, Ribeiro S, Ramsay ME, Heath PT, Sharland M, Ladhani SN. Trends in bacterial, mycobacterial, and fungal meningitis in England and Wales 2004– 11: an observational study. Lancet Infect Dis 2014;14(4):301–7. [9] Stoof SP, Rodenburg GD, Knol MJ, et al. Disease burden of invasive meningococcal disease in The Netherlands between June 1999 and June 2011: a subjective role for serogroup and clonal complex. Clin Infect Dis 2015;61(8):1281–92. [10] Flexner S. The results of the serum treatment in thirteen hundred cases of epidemic meningitis. J Exp Med 1913;17(5):553–76. [11] Andersen BM. Mortality in meningococcal infections. Scand J Infect Dis 1978;10(4):277–82. [12] Brouwer MC, Read RC, van de Beek D. Host genetics and outcome in meningococcal disease: a systematic review and meta-analysis. Lancet Infect Dis 2010;10(4):262–74. [13] Edwards MS, Baker CJ. Complications and sequelae of meningococcal infections in children. J Pediatr 1981;99(4):540–5. [14] Kirsch EA, Barton RP, Kitchen L, Giroir BP. Pathophysiology, treatment and outcome of meningococcemia: a review and recent experience. Pediatr Infect Dis J 1996;15(11):967–78. [15] Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998–2007: implications for prevention of meningococcal disease. Clin Infect Dis 2010;50(2):184–91. [16] Racoosin JA, Whitney CG, Conover CS, Diaz PS. Serogroup Y meningococcal disease in Chicago, 1991–1997. JAMA 1998;280(24):2094–8. [17] Griffiss JM, Yamasaki R, Estabrook M, Kim JJ. Meningococcal molecular mimicry and the search for an ideal vaccine. Trans R Soc Trop Med Hyg 1991;85(Suppl. 1):32–6. [18] Caugant DA, Tzanakaki G, Kriz P. Lessons from meningococcal carriage studies. FEMS Microbiol Rev 2007;31(1):52–63. [19] Delbos V, Lemee L, Benichou J, Berthelot G, Taha MK, Caron F. Meningococcal carriage during a clonal meningococcal B outbreak in France. Eur J Clin Microbiol Infect Dis 2013;32(11):1451–9. [20] Andersen J, Berthelsen L, Bech JB, Lind I. Dynamics of the meningococcal carrier state and characteristics of the carrier strains: a longitudinal study within three cohorts of military recruits. Epidemiol Infect 1998;121(1):85–94. [21] Ala’Aldeen DA, Oldfield NJ, Bidmos FA, et al. Carriage of meningococci by university students, United Kingdom. Emerg Infect Dis 2011;17(9):1762–3. [22] Rodriguez P, Alvarez I, Torres MT, et al. Meningococcal carriage prevalence in university students, 1824 years of age in Santiago, Chile. Vaccine 2014;32 (43):5677–80. [23] Stephens DS, Hajjeh RA, Baughman WS, Harvey RC, Wenger JD, Farley MM. Sporadic meningococcal disease in adults: results of a 5-year population-based study. Ann Intern Med 1995;123(12):937–40. [24] Corbett A, Exley R, Bourdoulous S, Tang CM. Interactions between Neisseria meningitidis and human cells that promote colonisation and disease. Expert Rev Mol Med 2004;6(14):1–14. [25] Trivedi K, Tang CM, Exley RM. Mechanisms of meningococcal colonisation. Trends Microbiol 2011;19(9):456–63. [26] Virji M. Pathogenic neisseriae: surface modulation, pathogenesis and infection control. Nat Rev Microbiol 2009;7(4):274–86.
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Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Meningococcal pneumonia Matthias Vossen a, Dieter Mitteregger b, Christoph Steininger a,⇑ a b
Department of Medicine I, Div. of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria Department of Laboratory Medicine, Div. of Clinical Microbiology, Medical University of Vienna, Vienna, Austria
a r t i c l e
i n f o
Article history: Received 31 March 2016 Received in revised form 7 July 2016 Accepted 11 July 2016 Available online xxxx Keywords: Neisseria meningitidis Pneumonia Invasive meningococcal disease
a b s t r a c t Neisseria meningitidis remains the most important cause of bacterial meningitis worldwide, particularly in children and young adults. The second most common and a potentially severe end-organ manifestation of invasive meningococcal disease (excluding systemic sepsis) is meningococcal pneumonia. It occurs in between 5% and 15% of all patients with invasive meningococcal disease and is thus the second most common non-systemic end-organ manifestation. To establish the diagnosis requires a high level of clinical awareness – the incidence is therefore very likely underreported and underestimated. This review of 344 meningococcal pneumonia cases reported in the Americas, Europe, Australia, and Asia between 1906 and 2015 presents risk factors, pathogenesis, clinical manifestations, diagnostic approaches, treatment, and prognosis of meningococcal pneumonia. Ó 2016 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7. 8. 9.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis of meningococcal pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Meningococcal pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk factors for meningococcal pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and radiological diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microbiological diagnosis of meningococcal pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prophylaxis by vaccination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. Search strategy and selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Invasive meningococcal disease (IMD) is feared for its rapid progression from health to death or permanent disability within as little as 24 h [1]. The disease is caused by infection with a Gram-negative diplococcus, Neisseria meningitidis (meningococcus), member of the phylum ß-proteobacteria and of the bacterial family Neissericaceae. IMD occurs worldwide and year-round. The annual incidence of IMD varies between 0.4 and 1000 cases/100, ⇑ Corresponding author at: Medical University Vienna, Department of Medicine I, Währinger Gürtel 18-20, 1090 Vienna, Austria. E-mail address: [email protected] (C. Steininger).
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000 population with low rates in North America and Europe and epidemics occurring particularly in sub-Saharan Africa [2–5]. IMD may, however, be underreported as well as underdiagnosed even in European countries [6]. The majority of cases are noted during winter and early spring and in children and teenagers although all age-groups may be affected [7]. The rates of disease are highest among infants in whom protective antibodies have not yet developed; the rates drop after infancy and then increase again during adolescence and early adulthood [7]. In these two age groups, meningococcal meningitis is the leading cause of bacterial meningitis, and in adults, it is the second most common cause of community-acquired bacterial meningitis [2,8]. In a survey conducted in the Netherlands between June 1999 and 2011
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M. Vossen et al. / Vaccine xxx (2016) xxx–xxx
only 8% (69 of 874) of all cases were reported in patients aged P65 years [9]. In the pre-antibiotic era, the mortality of meningococcal infection was 70–90% [10]. The prognosis of the disease improved dramatically with the advent of antimicrobial treatment options. Still, overall case-fatality rates decreased only to 10–15% percent by the late 1960s and remained at this level despite further major advancements in supportive care [2,11,12]. Moreover, 11–19% of survivors have long-term sequelae including neurologic disability, limb or digit loss, and hearing loss [13,14]. Meningitis is one of the most severe manifestations of IMD, particularly in children and young adults, and affects about 50% of patients [7,15]. At the onset of symptoms, clinical manifestations may be difficult to distinguish from other acute neurological diseases. Symptoms include sudden onset of fever, nausea, vomiting, headache, decreased ability to concentrate, neck stiffness, and myalgias in an otherwise healthy patient. In severe cases, purpura fulminans, disseminated intravascular coagulopathy, or vasculitis may be noted. IMD may also present clinically without neurological involvement as bacteremia, arthritis, pericarditis, pharyngitis, urethritis, conjunctivitis, or immune complex disease. Nevertheless, the second most common end-organ disease of IMD remains widely neglected despite accounting for 5–15% of cases – meningococcal pneumonia [15–17]. This review aims to highlight the clinical relevance, as well as the diagnostic and management challenges related to this disease. Increasing awareness for meningococcal pneumonia may result in more frequent diagnosis of the disease, earlier institution of targeted therapies, and improved prognosis. 2. Pathogenesis of meningococcal pneumonia Meningococci may invade the lower respiratory tract hypothetically via three different modes of infection. First, N. meningitidis colonizes the nasopharyngeal mucosa of 4–10% of young, asymptomatic adults and carriage rates may range in selected cohorts between 4% and 59% [18–22]. Invasion of the loco-regional blood supply results in bacteremia and secondary dissemination of the bacterial pathogen from the oropharynx to multiple body sites, including the lungs, where a favorable micro-environment sustains bacterial replication. In concordance with a clinical significance of this pathway, 23% (10 of 44) of patients with blood cultures that are positive for N. meningitidis also have an infiltrate evident on a chest radiograph [7,23]. In these cases, meningococci may have entered the lungs via the blood stream [7]. Second, large airborne droplets that are generated during coughing and contaminated with microbial nuclei may be inhaled. Third, meningococci colonizing the oropharynx may be transmitted to the lower respiratory tract by microaspiration following biofilm formation. N. meningitidis infection in the oropharynx requires adherence of bacteria as microcolonies on nonciliated nasopharyngeal epithelial cells. Consecutively, re-organization of host cell actin and formation of membrane protrusions by bacterial mechanisms protect bacteria from shear stress by biofilm formation. Post-translational modification of bacterial pilin lead to the disassembly of bacteria and spread to other sites such as the lungs [24,25]. Viral or other bacterial infections may further reduce resistance to meningococcal infection of the lower respiratory tract as well-documented for IMD [26,27]. 3. Meningococcal pneumonia In 1907, Jacobitz described for the first time cases of meningococcal pneumonia that could be diagnosed by demonstration of N. meningitidis in sputum samples [28]. In this case series, thirteen
soldiers living in the same barracks suffered from IMD. Four of these soldiers had meningitis and pneumonia and seven had a respiratory tract infection only including two with mixed infection by meningococci and pneumococci. The source of infections could be traced back to a single index patient who presumably had contracted the disease in the nearby town of Colmar, where IMD was endemic. Jacobitz noted already more than a century ago that asymptomatic individuals may also carry N. meningitidis in their oropharynx, and hence, demonstration of the pathogen in these samples does not confirm the clinical diagnosis [28]. Large outbreaks of meningococcal pneumonia were noted during the 1918–19 influenza pandemic [29]. In 1948 the first two cases of meningococcal pneumonia in the antibiotic era were systematically studied and previous case series reviewed [30]. Brick noted in this analysis that ‘‘It has been known for some time that extrameningeal meningococcal infections are not uncommon, but the attention directed to the respiratory phase of such infections is very scant”[30]. Based on a review of contemporary evidence Putsch et al. suspected in 1970 a significant role of Neisseria meningitis in community-acquired pneumonia [31]. Since then, multiple reports of individual cases and case series indicated the clinical relevance of IMD of the respiratory tract (Table 1) [32]. We could identify a total of 344 cases of meningococcal pneumonia that were observed in the Americas, Europe, Australia, and Asia and published over a period of more than a century (1906–2015). The largest proportion of meningococcal isolates (142 cases) identified in this review of published IMD cases were of serogroup Y (Table 1). National surveys on the incidence of IMD indicate that meningococcal pneumonia is the most common non-neurological endorgan disease of IMD and occurs in about 17% (61 of 364) of patients (Table 1). This is consistent with the previously published range of 5–15% [15–17,23,33–35]. Still, the incidence of meningococcal pneumonia is very likely underestimated as discussed in more detail in ‘‘Microbiological diagnosis of meningococcal pneumonia” below.
4. Risk factors for meningococcal pneumonia Meningococcal pneumonia is considered to affect mostly older adults (>50 years) in contrast to meningococcal meningitis which affects predominantly children and teenagers, based on epidemiological surveys [16,32,34,36]. In patients aged >65 years, pneumonia is even the most common manifestation of IMD [34,36]. Nevertheless, recent reports and our present revision points to a bimodal age distribution of cases with peaks in incidence in patients aged <30 years and those aged >60 years [32]. Accordingly, factors other than patient age or serogroup may contribute more significantly to a predisposition for meningococcal pneumonia. The second relevant predictor for respiratory disease in IMD may be the infecting bacterial strain type. Several outer membrane components have been linked to meningococcal virulence, such as outer membrane proteins and lipooligosaccharid subtype; the capsular polysaccharides, however, are the major virulence factor of N. meningitidis and the main target of humoral immunity [1,37]. Genetic differences within the gene coding for capsular polysaccharides of N. meningitidis translate into antigenic differences that allowed differentiation between thirteen meningococcal serogroups so far. More recently, genomic typing, i.e. multilocus sequence typing (MLST) and whole-genome sequencing have allowed for grouping of meningococcal strains with even higher discriminatory power [38]. These analyses revealed that five N. meningitidis serogroups (A, B, C, W, and Y) are responsible for the majority of meningitis cases. In contrast to meningococcal meningitis, pneumonia is caused mostly by otherwise rare serogroups – particularly serogroup Y followed by serogroup W
Please cite this article in press as: Vossen M et al. Meningococcal pneumonia. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.07.013
Observational period of study
Country
Total number of meningococcal cases
Meningococcal pneumonia No.
% of total
Data source
2010–2013 2008–2009 2012 2007-2009 2009 2006 2001–2003 2003 2001 1999–2002 1999 1974–1998
UK India UK UK France USA Taiwan Spain Australia / Japan France UK USA
129 110 1 65 1 1 88 1 1 33 3 8
15 8 1 19 1 1 6 1 1 33 3 8
12 7 100 29 100 100 7 100 100 100 100 100
National surveillance system Patient cluster Individual patient National surveillance system Individual patient Individual patient National surveillance system Individual patient Individual patient Patient cluster Individual patient Patient cluster
1998 1998 1998 1997 1989–1995 1996 1988–1993 1995 1995 1995 1994 1994 1993 1991 1987–1989 1987 1986 1986 1985 1984 1982 1981 1976–1981 1981 1981 1977–1979 1980 1979 1979 1971–1974
Taiwan UK Spain UK France Japan USA, Atlanta Australia Spain Spain Spain Spain Spain USA France USA USA USA UK Switzerland USA USA USA USA USA USA Canada USA USA USA
1 1 1 3 15 1 44 1 1 1 1 1 1 1 38 1 1 1 1 4 2 3 5 4 2 34 1 1 1 88
1 1 1 3 15 1 10 1 1 1 1 1 1 1 11 1 1 1 1 4 2 3 2 1 2 6 1 1 1 68
100 100 100 100 100 100 23 100 100 100 100 100 100 100 29 100 100 100 100 100 100 100 40 25 100 18 100 100 100 77
Individual patient Individual patient Individual patient Patient cluster National surveillance system Individual patient National surveillance system Individual patient Individual patient Individual patient Individual patient Individual patient Individual patient Individual patient National surveillance system Individual patient Individual patient Individual patient Individual patient Patient cluster Individual patient Patient cluster Patient cluster Patient cluster Individual patient Patient cluster Individual patient Individual patient Individual patient Patient cluster
1978 1976 1975 1975 1975 1975
Finland Germany USA USA USA USA
1 1 1 1 3 1
1 1 1 1 3 1
100 100 100 100 100 100
Individual patient Individual patient Individual patient Individual patient Patient cluster Individual patient
Material used for microbiological diagnosis of meningococcal pneumonia
Range of patient age (years)
% female
Sterile n.a. sterile Sterile n.a. Sterile Sterile n.a. Sterile Sterile Sterile Sterile and sputum/BAL n.a. Sterile
n.a. Average 848 80 <5 to >85 n.a. 14 <1 to >55 n.a. 62 40 to >70 64, 83 and 85 17–86
n.a. 382 100 n.a. n.a. 100 n.a. n.a. 0 27 100 38
n.a. 91
n.a. 100
Sterile Sputum/BAL Sputum/BAL Sterile n.a. n.a. Sterile Sputum/BAL n.a. n.a. Sterile Sterile Sterile Sterile Sterile n.a. Sterile Sterile Sputum BAL Sterile Sterile Sputum/BAL Sterile Sterile Sterile Sterile Sterile and sputum/BAL Sterile Sterile Sterile Sputum/BAL Sputum/BAL Sterile
19, 50, 88 1–94 22 >18 19 months n.a. n.a. n.a. >18 n.a. 29 4 months – 86 67 4 1/3 82 72 5–12 59, 75 56, 65, 82 19, 62 n.a. 69, 87 n.a. 66 16 52 17–24
33 60 n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. 0 n.a. 100 100 100 100 100 100 66 50 n.a. 0 n.a. 100 100 0 0
n.a. 16 43 34 16, 17, 19 24
0 0 100 0 33 0
Meningococcal serogroup in pneumonia cases (% of total) A
B
C
W
X
Y
Ref. Z
100 100 100 100 100 83 100 Unknown 6 27 55 3 9 75 25 Unknown, 25 identified as Group Y Unknown 100 Unknown 33 33 26 20 Unknown 30 10
33 40 20
30 100
Unknown Unknown Unknown 100 100 100 100 100 100 100 100 66 100 100
33
100 3 100 100 100 100 100 100 100 100 100 100
Ladhani et al. [33] Dass Hazarika et al. [64] Chan et al. [65] Ladhani et al. [34] Seiberras and Fourmaux [66] Glikman et al. [67] Wang et al. [39] Pérez et al. [68] Shiraishi et al. [69] Vienne et al. [36] Weightman et al. [47] Winstead et al. [32] Tsai [70] Cadwgan et al. [71] González et al. [72] Jones et al. [48] Angelini et al. [73] Ootaki et al. [74] Stephens et al. [23] Goldwater and Rice [75] Gutiérrez-Guisado et al. [76] Nicolás-Sánchez et al. [77] Arrate et al. [78] Naya Manchado et al. [79] Alberte et al. [80] Winters et al. [81] Le Bastard et al. [82] Bergmann and Gleckman [83] Burns et al. (1986) Sacks (1986) Hanson and Lawson (1985) Llorens-Terol et al. (1984) Witt et al. (1982) Darnell et al. (1981) Brandstetter et al. (1981) Salit [62] Rose et al. (1981) Haburchak (1981) Richter (1981) Hersh et al. (1979) Cohen et al. (1979) Koppes et al. [46]
M. Vossen et al. / Vaccine xxx (2016) xxx–xxx
Please cite this article in press as: Vossen M et al. Meningococcal pneumonia. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.07.013
Table 1 Reported cases of meningococcal pneumonia from 1906 to 2015, reports without radiological or post-mortem diagnosis of pneumonia was excluded, duplicate cases were removed. Material ‘‘sterile” refers to culture material obtained from normally sterile body site (Peripheral blood, pleural effusion fluid). CSF, cerebrospinal fluid.
Nikoskelainen et al. (1978) Berger (1976) Yee et al. (1975) Galpin et al. (1975) Irwin et al. (1975) Barnes et al. (1975) 3
(continued on next page)
Holm et al. [29] Jacobitz [28]
Unknown Unknown Unknown/one case Type I; six cases Type II 13 52 87 Unknown
100 100 100 100 100 100 Unknown Both cases Type I
A
B
C
W
X
Y
Z
Ref.
n.a. n.a. n.a. n.a. Sterile Sputum/BAL
100 100 100
100 100
17%
19 5 11
23 12
344 61
Patient cluster Patient cluster Patient cluster
25 100 100 100 100 100 100 100 3 1 14 1 1 1 1 2
Patient cluster Patient cluster
n.a. n.a. 0 n.a. n.a. n.a.
0 0 0 0 0 0 n.a. 0 20, 24 19 n.a. 22 20 16 n.a. 53, 56
Sterile Sterile Sterile Sterile Sterile Sputum/BAL Sputum/BAL Sterile and sputum/BAL n.a. n.a. Sterile Patient cluster Individual patient Patient cluster Individual patient Individual patient Individual patient Individual patient Individual patient
% of total No.
812 364 Total From national surveys
USA Germany 1918–1919 1906
23 12
France UK USA 1919 1919 1918
19 5 11
USA USA USA USA USA USA USA USA 1974 1974 1970–1972 1970 1968 1965 1945 1942
12 1 14 1 1 1 1 2
Meningococcal serogroup in pneumonia cases (% of total) % female
Range of patient age (years) Material used for microbiological diagnosis of meningococcal pneumonia Data source
Clinical presentation of meningococcal pneumonia is indistinguishable in most patients from community-acquired pneumonia caused by other infectious pathogens. The most common clinical symptoms reported by >50% of patients with meningococcal pneumonia are fever and chills, followed by pleuritic chest pain [16,32]. Productive cough (31%) and shortness of breath (23%) are clearly less common in these patients. A rash is noted frequently in association with septic features in patients with meningococcal pneumonia [23,46,47]. Complications such as lung abscesses, empyema, pleural effusions, or pericarditis are uncommon [23]. Despite being the main diagnostic criterion in previous studies on meningococcal pneumonia, meningococcemia is rarely an accompanying presentation of meningococcal pneumonia [32]. Blood chemistry and blood counts usually indicate an acute inflammatory process with leukocytosis and increased acute-phase protein levels such as C-reactive protein, procalcitonin, serum amyloid A, and erythrocyte sedimentation rate [32]. Abnormal chest radiographic imaging studies may be noted in most patients with meningococcal pneumonia. Bilateral infiltrations were observed in one-fifth (9 of 45) of patients and pleural effusions in 13% (6 of 45) of patients [32]. Radiological signs, however, do not allow to differentiate meningococcal pneumonia from community-acquired pneumonia caused by other bacterial agents [48]. 6. Microbiological diagnosis of meningococcal pneumonia
Country
Total number of meningococcal cases
Meningococcal pneumonia
[2,32,36,39–42]. In one case series, almost one-third of patients (42 of 53) with invasive serogroup Y infection suffered from pneumonia [32]. In another report from Taiwan, pneumonia was noted in 24% (5 of 21) of patients with invasive serogroup W infection [39]. Meningococcal pneumonia cases were also reported in conjunction with serogroups B and C although at rates much lower than serogroups Y and W [15,32]. The association of meningococcal pneumonia with different serogroups may indicate the influence of additional factors on the infection of the lower respiratory tract [12,34,42]. IMD is associated with multiple other, well-characterized hostassociated risk factors including smoking, deficiencies in the complement pathway, asplenia, lack of type-specific opsonising antibodies, deficiencies in mannose binding lectin and more specific genetic predispositions [12,13,43,44]. Currently, the significance of these risk factors for invasion of the lower respiratory tract by N. meningitidis is unclear. Smoking, however, is a major risk factor for invasive pneumococcal disease and it may be hypothesized accordingly that similar host-related mechanisms may also provide the grounds for other bacterial invasion [45]. 5. Clinical and radiological diagnosis
Observational period of study
Table 1 (continued)
Kinnicutt and Binger [85] Meader et al. [86] Fletcher [87]
M. Vossen et al. / Vaccine xxx (2016) xxx–xxx
Smilack (1974) Jacobs et al. (1974) Ellenbogen et al. (1974) Ball and Young (1974) Hand et al. (1968) Paine et al. (1967) Roberg [84] Brick [30]
4
A reliable and rapid microbiological diagnosis is of high clinical and epidemiologic relevance as a single identified case of N. meningitidis disease may well be at the center of a small localized outbreak [49]. Racoosin [16] suspected two decades ago that meningococcal pneumonia was being under-diagnosed because the focus of diagnostic and clinical evaluations in patients with meningitis is on the devastating neurological disease. In addition, currently available diagnostic tools are limited by technical shortcomings and the characteristics of meningococcal infection. Blood is frequently cultured in febrile patients with community-acquired pneumonia in an attempt to identify a suspected pneumococcal strain. Blood culture may be helpful in establishing the diagnosis in cases of meningococcal meningitis as positivity rates of N. meningitidis are >50% in neurological patients [50]. In addition, isolation of bacteria from blood allows the
Please cite this article in press as: Vossen M et al. Meningococcal pneumonia. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.07.013
M. Vossen et al. / Vaccine xxx (2016) xxx–xxx
evaluation of N. meningitidis for antimicrobial susceptibility. Nevertheless, the diagnosis of respiratory pathogens with use of blood culture is in general very insensitive [51]. Positivity rates of blood cultures to detect for instance pneumococcal pneumonia range between 6% and 79% [32,46]. Accordingly, the prevalence of meningococcal pneumonia may be underestimated, as blood cultures were the main diagnostic tool used in epidemiological surveys and case series. The nucleic acid amplification tests commonly used on blood samples to identify the presence of infectious pathogens are both sensitive and specific, however they are currently unavailable for diagnosing N. meningitidis [52]. Isolation of N. meningitidis from respiratory samples might be misleading, because this organism is frequently part of the transient oropharyngeal flora of asymptomatic carriers [53,53,54]. Therefore diagnostic efforts should follow appropriate algorithms, as provided in several national and international guidelines like the Microbiology Procedures Quality Standards (MiQ) issued by the German Society for Hygiene and Microbiology, the UK Standards for Microbiology Investigations issued by the Standards Unit, Public Health England, the European Manual of Clinical Microbiology issued by the European Society of Clinical Microbiology and Infectious diseases [55]. Diagnostic algorithms aim to distinguish between contamination from normal or transient flora and presence of pathogenic microorganisms. They thus include evaluation of respiratory samples for inflammatory cells as well as quantitative assessment of the amount of meningococci in comparison to other bacterial elements. Reliable and rapid diagnostic tools for the diagnosis of meningococcal pneumonia are therefore urgently needed similarly to the situation in pneumococcal pneumonia before the advent of a specific urinary antigen test [56]. One of the major challenges of differentiating meningococcal pneumonia from other infectious causes of pneumonia therefore remains – the high level of clinical awareness required to initiate appropriate diagnostic procedures.
7. Treatment and prognosis Therapy of IMD has dramatically changed over the past 25 years. Penicillin antibiotics were the mainstay of antimicrobial therapy until 1991. Due to the considerable lethality of untreated IMD, the emergence of penicillin-resistant strains, however, also changed treatment practice thereafter. According to EUCAST (European Committee on Antimicrobial Susceptibility testing), about 95% of N. meningitidis isolates are susceptible to benzylpenicillin in Europe (http://mic.eucast.org/Eucast2/regShow.jsp?Id=3967, accessed 03/27/2016). Today, the standard empirical treatment for IMD is accordingly third-generation cephalosporins. In the case of penicillin-susceptible meningococci as confirmed by antimicrobial susceptibility testing, therapy may be switched to high-dose penicillin or continued with third-generation cephalosporins given the excellent efficacy, convenient dosing, and affordability of these agents [57]. The optimum treatment regime for meningococcal pneumonia has yet to be defined but may very likely be similar to that of meningococcal meningitis. Third-generation cephalosporins are also excellent treatment options in bacterial pneumonia caused by other, susceptible pathogens in general and efficacy may also be expected in meningococcal pneumonia [58]. Indeed, 80% of reported meningococcal pneumonia cases received penicillin before 1991 and mostly cephalosporin antibiotics thereafter [32]. Glucocorticoids are indicated for the treatment of known or suspected pneumococcal meningitis but are of no benefit in meningococcal meningitis and should be discontinued once this diagnosis is established [59]. In community-acquired pneumonia, evidence for the use of glucocorticoids is conflicting and not generally recom-
5
mended so far [60,61]. Accordingly, glucocorticoid-treatment of meningococcal pneumonia may also not be recommended. Meningococcal pneumonia has a somewhat higher case-fatality ratio than meningococcal meningitis (16% and 9–14%, respectively) [2,15]. Prognosis of meningococcal pneumonia is associated with age of the patient, meningococcal serogroup, and underlying diseases similar to other infectious diseases of the lower respiratory tract. Case-fatality rate is highest among patients older than 65 years of age (23%) and decreases with lower age [15,32,46]. Case-fatality ratio was highest among cases caused by serogroup W (16%) and lower among cases caused by serogroup B strains (9%) [15]. Secondary cases of meningococcal infections following exposure to patients with meningococcal pneumonia have been reported but are uncommon [32,62]. Recommendations for the prevention of secondary cases in the health care setting have been published and focus mainly on droplet precautions [63]. The risk of N. meningitidis transmission might be somewhat higher in patients with meningococcal pneumonia due to the generations of aerosols by coughing but may also be controlled by droplet precautions. 8. Prophylaxis by vaccination Active immunization is recommended to provide pre-exposure immunity to populations at high risk for meningococcal infection and disease [2]. Currently available vaccines and combinations thereof may protect from serogroups A, C, Y, W and as of late from serogroup B. Vaccines are the most effective intervention for the prevention of IMD and very likely also of meningococcal pneumonia. Antigens of the meningococcal serogroups predominantly associated with cases of pneumonia are included in available vaccines. Routine vaccination programs may reduce the incidence of IMD as well as carriage but related costs interfere with broad implementation of life-saving vaccination programs [53]. Of note, even immunized close contacts should still receive chemoprophylaxis, because the vaccines do not confer sterilizing immunity in all vaccinees and immunity wanes with time [2]. Routine vaccination is currently not recommended for adults except for those with underlying diseases, certain traveling destinations or exposure in the health-care setting. Nevertheless, meningococcal pneumonia has a peak in incidence in the age group of >65 years. Perhaps, these recommendations may have to be adapted with a better understanding of the epidemiology and pathogenesis of meningococcal pneumonia. 9. Conclusions The present review highlights multiple aspects related to the diagnosis and treatment of meningococcal pneumonia. Meningococcal pneumonia is the most common non-neurological endorgan manifestation of IMD [36]. In patients aged >65 years, meningococcal serogroup Y disease manifests even more frequently as pneumonia than as meningitis and clearly increased in incidence during the past two decades [34]. Meningococcal pneumonia is difficult to diagnose because of frequent asymptomatic oro-pharyngeal carriage of N. meningitidis and generally short periods of bacteremia in patients with respiratory infections but without sepsis. The incidence of meningococcal pneumonia may be underestimated and a high level of clinical awareness is required to initiate early and effective diagnostic and therapeutic procedures. 9.1. Search strategy and selection criteria References for this review were identified through searches of PubMed for articles published globally from January, 1906, to April,
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6
M. Vossen et al. / Vaccine xxx (2016) xxx–xxx
2015, by use of the terms ‘‘Meningococcal AND pneumonia”, ‘‘Neisseria meningitidis”. All articles resulting from these searches and relevant references cited in those articles were reviewed. All articles published in English, French, and German were included without exception.
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Please cite this article in press as: Vossen M et al. Meningococcal pneumonia. Vaccine (2016), http://dx.doi.org/10.1016/j.vaccine.2016.07.013