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Clinical manifestations of meningococcal infection

INTRODUCTION Neisseria meningitidis is the leading cause of bacterial meningitis


in children and young adults in the United States, with an overall mortality rate of 13
percent, and it is the second most common cause of community-acquired adult bacterial
meningitis. The clinical manifestations of meningococcal disease can be quite varied,
ranging from transient fever and bacteremia to fulminant disease with death ensuing
within hours of the onset of clinical symptoms.

MENINGITIS AND ACUTE MENINGOCOCCEMIA Acute systemic


meningococcal disease is most frequently manifest by three syndromes

Meningitis

Meningitis with accompanying meningococcemia

Meningococcemia without clinical evidence of meningitis

In a multicenter surveillance study of invasive meningococcal infection in children that


identified 159 cases between January 2001 and March 2005, meningitis accounted for
112 cases (70 percent) and bacteremia without meningitis for 43 cases (27 percent) [3].

Clinical manifestations The typical initial presentation of meningitis due to N.


meningitidis consists of the sudden onset of fever, nausea, vomiting, headache,
decreased ability to concentrate, and myalgias in an otherwise healthy patient. In a
prospective observational cohort study, the classic meningitis triad of fever, neck
stiffness, and altered mental status was present in 70 of the 258 patients (27 percent)
with meningococcal meningitis; when rash was added, 89 percent of patients had at
least two of these four signs [4]. The classic triad is much more common in
pneumococcal meningitis (58 percent in the same cohort study) [5]. (See "Clinical
features and diagnosis of acute bacterial meningitis in adults", section on 'Presenting
manifestations'.)

Myalgias may be an important differential sign, and occasionally the pain is quite
intense. These are generally more painful than myalgias seen in viral influenza. Disease
progression is usually quite rapid with transition from health to severe disease in a
matter of hours.

Because of the trend for endemic meningococcal infection to occur during the late
winter when concurrent influenza virus is in the community, many cases of
meningococcal disease are mistaken initially for severe "flu." It is also not uncommon
for other cases to have been reported in the region or for the patient to have been a
contact of a previously diagnosed case.

Alternatively, preceding symptoms of pharyngitis, which in meningococcal meningitis


is nonsuppurative, can lead to a preliminary misdiagnosis of streptococcal pharyngitis.
However, patients with meningococcal meningitis either present with, or soon develop,
a degree of illness that is much too severe to warrant this diagnosis. The patient will
frequently tell the physician that this is the sickest they have ever felt; many express the
feeling that they are going to die. With infants, the parents are frequently more worried
than the early symptoms may warrant.

The clinical expression of this infection ranges widely, and, thus, a high index of
suspicion and a careful search for clues of disease are required to make a diagnosis,
particularly in the absence of an epidemic. (See "Epidemiology of Neisseria
meningitidis infection".)

The difficulty in identifying meningococcal disease is due, in part, to the fact that
clinicians in the community see so few cases in their lifetime and that the classic clinical
features of meningococcal disease (eg, hemorrhagic rash, meningismus, and impaired
consciousness) appear late in the illness. The critical need for diagnosis as early as
possible, because of the narrow time window between progression from initial
symptoms to death, prompted a systematic study of the occurrence of symptoms before
admission to the hospital in children and adolescents (aged 16 years) with
meningococcal disease [6].

Data were obtained from questionnaires answered by patients and primary care
physician records of the clinical symptoms and signs of infection before admission to
the hospital in 448 children (103 fatal and 345 nonfatal). The following findings were
noted:

The median time between onset of symptoms and admission to the hospital was 22
hours:

22 hours in those children aged 15 to 16 years

20 hours in those children aged 5 to 14 years

14 hours in those children aged 1 to 4 years

13 hours in those younger than 1 year

Nonspecific symptoms common to many self-limiting viral illnesses (eg, fever,


headache, loss of appetite, nausea, vomiting, and upper respiratory symptoms, such as
sore throat and coryza) were the earliest clinical symptoms.

The first specific clinical symptoms were signs of sepsis in all age groups:

Leg pain (in 31 to 63 percent, excluding infants)

Cold hands and feet (in 35 to 47 percent)

Abnormal skin color such as pallor or mottling (in 17 to 21 percent)

The first classic symptom of meningococcal disease was rash, which sometimes
evolved from nonspecific to petechial to hemorrhagic over several hours (in 42 to 70
percent of cases).
Median time of onset of specific meningitis symptoms (eg, neck stiffness,
photophobia, bulging fontanelle) was approximately 12 to 15 hours after onset of
illness. Late signs of meningitis (eg, unconsciousness, delirium, or seizures) occurred at
a median of 15 hours in infants under 1 year of age and 24 hours in older children.

Most children (72 percent) had one of the three sepsis symptoms (eg, leg pain,
abnormal skin color, or cold hands and feet) at a median time of 8 hours after the onset
of illness, 11 hours sooner than the median time of hospital admission (19 hours).

The authors suggested that both clinicians and parents should be educated regarding the
frequency and importance of the early signs of sepsis (eg, leg pain, cold hands and feet,
and abnormal skin color) as potential warning signs of meningococcal disease. The
study was limited by retrospective data collection, recall bias, and the absence of similar
data collection for children with other illnesses to compare frequency of symptoms.

Worrisome signs Although initial clinical features of patients with meningococcal


disease are similar to many common, self-limiting viral illnesses seen in primary care,
signs of early sepsis should differentiate the patient who merits clinical monitoring.
Based on the retrospective review of 448 children with meningococcal disease cited
above, signs and symptoms suggesting early sepsis include [6]:

Leg pain

Cold hands and feet

Abnormal skin color (eg, pallor or mottling)

Physical examination The vital signs often show a low blood pressure with an
elevated pulse rate. The patient should be examined for postural hypotension as a sign
of early vascular instability. Diaphoresis is common. Patients will frequently respond to
intravenous infusions with transient rises in blood pressure and an improved sense of
wellbeing. This can be misleading and result in a delay in initiating definitive
antimicrobial and supportive therapy.

A careful physical examination should be performed. An intensive search for petechiae


and ecchymoses should be undertaken. The patient should be examined fully undressed.
Sites where pressure is applied to skin by belts and elastic straps are prime locations to
find petechiae. The physical examination should also include provocative tests for
meningeal irritability, such as the Kernig and Brudzinski signs. However, the absence of
signs of meningitis does not exclude the diagnosis of systemic meningococcal infection.

Rash The petechial rash appears as discrete lesions 1 to 2 mm in diameter, most


frequently on the trunk and lower portions of the body. The mucous membranes of the
soft palate, ocular, and palpebral conjunctiva must be carefully examined for signs of
hemorrhage. Over 50 percent of patients will have petechiae upon presentation [2,7].
Petechiae can coalesce into larger purpuric and ecchymotic lesions (picture 1). The
petechiae correlate with the degree of thrombocytopenia and clinically are important as
an indicator of the potential for bleeding complications secondary to disseminated
intravascular coagulopathy (DIC).
A maculopapular eruption resembling a wide variety of viral exanthems, particularly
rubella, can be an early finding in meningococcemia. This transient rash generally does
not persist for more than two days and has frequently disappeared hours after its first
observation; it is neither purpuric nor pruritic.

Shock The shock state is frequently dominant in the manifestations of


meningococcal meningitis. The patient is poorly responsive, and peripheral
vasoconstriction is maximal with cyanotic poorly perfused extremities. Arterial blood
gas analysis demonstrates evidence of acidosis and, depending on the degree of shock,
hypoxia may be manifest with arterial PO2 below 70 mmHg. In addition to the direct
effects of meningococcemia, adrenal infarction leading to adrenal insufficiency
(Waterhouse-Friderichsen syndrome) can contribute to the hypotension [8].

Disseminated intravascular coagulation Probably the most dramatic consequence of


this clinical problem is the presence of disseminated intravascular coagulation [9,10].

The pathogenesis of this problem in patients with meningococcal sepsis may be related
in part to high levels of circulating microparticles that originate from platelets or
granulocytes and have procoagulant activity. In one report, those with the most severe
manifestations had microparticles which, when added to normal plasma in vitro,
generated a substantial amount of thrombin [11]. Clinical evidence of DIC becomes
apparent with extension of subcutaneous hemorrhages, gastric or gingival bleeding, or
oozing at the sites of venipuncture or intravenous infusions.

A number of studies have shown that patients with DIC and purpura fulminans,
especially children, have low levels of protein C [12-14] (see "Protein C deficiency").
Protein C appears to play a role in anticoagulation but also in modifying inflammation
[13]. One study examined vascular endothelial integrity, endothelial protein C receptor,
and plasma thrombomodulin in children with meningococcal sepsis and found intact
endothelial cells in both thrombosed and unaffected vessels in skin biopsy specimens
but decreased expression of endothelial thrombomodulin and protein C receptor [15].
Plasma thrombomodulin was higher in patients with meningococcal sepsis compared
with healthy controls. The authors concluded that protein C activation in endothelial
cells might be disordered in patients with severe meningococcal sepsis. Protein C
replacement is being investigated as a possible therapeutic agent. (See "Treatment and
prevention of meningococcal infection".)

Purpura fulminans Purpura fulminans is a severe complication of meningococcal


disease [16], occurring in approximately 15 to 25 percent of those with
meningococcemia [17,18]. It is characterized by the acute onset of cutaneous
hemorrhage and necrosis due to vascular thrombosis and disseminated intravascular
coagulopathy. Initially, there is cutaneous pain followed by erythema and petechiae.
Ecchymoses develop and these lesions, if the course is not altered with therapy, evolve
into painful indurated, well-demarcated purple papules with erythematous borders.
These areas progress to necrosis with formation of bullae and vesicles. Gangrenous
necrosis can follow with extension into the subcutaneous tissue and occasionally
involves muscle and bone [16].

Neurologic manifestations In contrast with purulent meningitis due to Haemophilus


influenzae or Streptococcus pneumoniae, focal neurologic signs and seizures are less
common in meningococcal meningitis [19]. Evidence of meningeal irritation is common
in meningococcal meningitis except in the very young and old, and the degree of
alteration in the level of consciousness is very similar in cases caused by any of the
three bacteria. (See "Neurologic complications of bacterial meningitis in adults" and
"Bacterial meningitis in children: Neurologic complications".)

The absence of focality in the clinical presentation of meningococcal meningitis


correlates with postmortem findings in which focal cerebral involvement is unusual
[20]. The cause of death appears to be related to toxins such as lipopolysaccharides
produced by the organism or to the secondary effects of cerebral edema on the vital
centers in the midbrain region [20-22].

Myocardial involvement A number of investigators have stressed myocardial


manifestations associated with meningococcal meningitis, including heart failure with
pulmonary edema and high central venous pressures accompanying signs of poor
peripheral perfusion [23,24]. Treatment of myocardial failure can ameliorate the
situation. Increased levels of interleukin 6 may be a mediator of myocardial depression
in septic shock due to meningococcal infection [25].

More than 50 percent of patients who die of meningococcal disease have myocarditis of
varying degrees of severity detected on postmortem examination [21,26]. In one series
of 12 children with meningococcemia, those with evidence of myocardial dysfunction
on serial echocardiograms had a higher incidence of fatal outcomes (three of seven
children versus zero of five) [27].

Infective endocarditis due to N. meningitidis is a very rare occurrence in the antibiotic


era [28]. Management is based on the clinical manifestations of the patient and the
antimicrobial sensitivity of the organism isolated.

Complications A number of complications have been documented in patients with


meningococcal meningitis either at the time of presentation or, more commonly, later in
the recovery phase of illness. These include immune complexassociated complications
such as arthritis without the recovery of organisms, pleurisy, vasculitis, and pericarditis
(see below). Epiglottitis, conus medullaris syndrome, and cranial nerve dysfunctions,
especially sixth, seventh, and eighth, can also occur [19,29-36].

Association between lipooligosaccharide levels and prognosis The principal toxin


associated with meningococcal infection is the outer membrane glycolipid,
lipooligosaccharide (LOS) [37-42] (see "Microbiology and pathobiology of Neisseria
meningitidis"). Investigators have measured LOS in the plasma and cerebrospinal fluid
(CSF) of infected patients and have shown that there is a close correlation between LOS
levels and prognosis [39]. Patients with septicemia without meningitis, for example, had
high LOS levels in plasma and low levels in CSF. By contrast, LOS levels were higher
in CSF in patients with meningitis, even without clinical evidence of shock (18 of 19
patients had detectable LOS in the CSF versus 3 of 19 with detectable levels in plasma).

Meningococcal LOS is present in plasma as a component of bacterial membranes either


released from lysed bacteria or by the meningococcal blebbing process (see
"Microbiology and pathobiology of Neisseria meningitidis"). Bacterial outer membrane
fragments have been found in the plasma of three patients; in one of these patients,
plasma contained a bacterium covered with multiple, long membrane protrusions,
indicating that surplus outer membrane (blebbing) occurs in vivo [38]. Mass
spectrometric analysis indicated that the endotoxin from patients with meningococcal
sepsis was of meningococcal origin rather than arising from the gastrointestinal tract
due to increased permeability during infection [42]. The release of LOS from the
surface of the meningococcus in the form of copious amounts of outer membrane blebs
is now considered to be the principal factor associated with the high endotoxin levels
observed in meningococcal sepsis.

Mortality Mortality rates in patients with meningococcal meningitis are


approximately 10 to 15 percent despite antibiotic treatment [4,43]. A retrospective
population-based analysis of meningococcal disease mortality in the United States
during 1990 to 2002 identified 3335 meningococcal deaths [44]. The following findings
were noted:

The crude and age-adjusted mortality rates were 0.10 deaths per 100,000 population
per year

The majority of deaths occurred among persons <25 years of age (58 percent)

Mortality was highest in infants (crude mortality rate 0.95 per 100,000 population)

Age-adjusted mortality rates were significantly higher among African Americans (0.13
per 100,000 population) compared with other racial or ethnic groups

Mortality rates were higher in winter compared with summer months

Mortality rates increased from 1990 to 1997 and decreased from 1998 to 2002
(primarily due to declining mortality in children <5 years and infants)

In the multicenter surveillance study of invasive meningococcal infection in children


noted above, mortality was greatest for children 11 years of age (21 percent compared
with 5 percent in those <11 years) [3].

In a subsequent survey, the age-adjusted average annual meningococcal disease


mortality rate in the United States between 2002 and 2006 was 0.05 per 100,000 person-
years, which was significantly lower than the rate observed from 1990 to 2002 [45].

CHRONIC MENINGOCOCCEMIA Chronic meningococcemia and chronic


gonococcemia cannot be differentiated except by the isolation of the causative organism
[46-49]. Joint involvement, tenosynovitis, and the distribution and appearance of
cutaneous lesions in chronic meningococcemia are indistinguishable from chronic
gonococcemia. (See "Disseminated gonococcal infection".)

The frequency of the meningococcus as a causative agent in the acute arthritis-


dermatitis syndrome may actually be increasing [47]. In a study comparing the isolation
of the gonococcus and meningococcus from blood or synovial fluid from 1970 to 1972
to the years 1980 to 1983, meningococcal isolates became more common with a ratio of
5 to 9 compared with 1 to 15 in the earlier time period [48]. Based upon this
observation, the suspicion for systemic meningococcal infection should be higher in
patients with the acute arthritis-dermatitis syndrome. Other studies have indicated that
patients with deficiencies in the late components of the complement system are also at
increased risk for chronic meningococcemia [49].

ARTHRITIS Primary purulent arthritis caused by N. meningitidis is a rare event


when compared with arthritis due to immune complexes. In contrast with immune
complexbased arthritis, which is frequently polyarticular, purulent arthritis is generally
monoarticular. The management is the same for both types of meningococcal arthritis
and consists primarily of treatment with antibiotics (eg, ceftriaxone or high-dose
penicillin G) and aspiration of the affected joint [50].

PERICARDITIS Purulent pericarditis due to N. meningitidis is a rare infection,


which can either arise in association with bacteremia and other evidence of
meningococcemia or as an isolated event without evidence of systemic meningococcal
infection. However, pericardial involvement in the convalescent stage of appropriately
treated meningococcal disease is more common, particularly in serogroup C infections
[30]. This form of pericarditis, which has an incidence as high as 19 percent [33], is
thought to have an immunologic etiology. Both the infectious and immunological forms
of meningococcal pericarditis can cause massive tamponade and be life threatening
[34]. (See "Purulent pericarditis".)

PNEUMONIA AND PHARYNGITIS Meningococcal pneumonia is uncommon. In


one study of 162 cases of community-acquired pneumonia in Finland, N. meningitidis
was implicated as the causative agent in only 6 [51].

While the ability of the meningococcus to cause pneumonia has been appreciated for
many years [52-55], it is difficult to establish the diagnosis from a sputum culture since
nasopharyngeal carriage of the organism is common. Unlike the situation with the
pneumococcus, the incidence of bacteremia in meningococcal pneumonia appears to be
quite low [53], which means that blood cultures probably do not assist in making the
diagnosis. In a group of 68 Air Force recruits with group Y meningococcal pneumonia,
transtracheal aspiration and culture were used to confirm the etiology [53].

More than 50 percent of patients in this large series had a history of cough, chest pain,
chills, and previous upper respiratory infection [53]. Almost all of the patients had rales
and fever; an accompanying pharyngitis occurred in over 80 percent. Forty percent of
patients had involvement of more than one lobe on chest radiography; the right lower
and middle lobes were the most frequently affected. No deaths occurred in this study.

Meningococcal pneumonia has been linked to a preceding viral respiratory infection,


especially influenza. As an example, most patients had serologic evidence of recent
influenza in one outbreak of meningococcal infection in older adults [56].

A symptomatic pharyngitis due to N. meningitidis has been described in contacts of


patients with other meningococcal infection [57]. As noted above, pharyngitis is also a
common symptom preceding other symptoms and signs in cases of serious
meningococcal disease [58].

URETHRITIS AND ASCENDING INFECTIONS Meningococci have been isolated


from the urethra and can be the etiologic agent in some cases of urethritis [59-63].
Although it is uncommon, meningococcal urethritis appears to have increased in
frequency since the 1970s [63]. It occurs in both men and women and its presentation
can be indistinguishable from acute gonococcal urethritis [62,63]. In both sexes, it can
cause ascending infection, including epididymitis in men and pelvic inflammatory
disease in women.

In a surveillance study of a population of 383 homosexual men, the organism was


isolated from 35 percent, but 94 percent of these positive isolates were from the
pharynx; positive cultures from the rectum or urethra were infrequent (6 and 1 percent,
respectively) [61]. A possibility was raised in this study that urethral acquisition of the
organism occurred following orogenital sex.

IMMUNE COMPLEX DISEASE A number of complications in the convalescent


phase of meningococcal disease are associated with immune complexes (see 'Arthritis'
above and 'Pericarditis' above). A publication describing children recovering from
meningococcal sepsis reported that 15.3 percent had an immune complexassociated
complication while convalescing. These included vasculitis (8.4 percent), pleurisy (3.8
percent), and arthritis (13.8 percent). In this population, these complications occurred 4
to 10 days after systemic disease and were generally associated with a recrudescence of
fever and increasing white blood count [64].

OCCULT BACTEREMIA Meningococcal bacteremia rarely occurs without sepsis


[2,7]. Patient admission in this entity is for an upper respiratory illness or viral
exanthem. Patients recover without specific antimicrobial therapy and only later are
blood cultures reported as positive for N. meningitidis. One case report noted three
children with such occult bacteremia who recovered from meningococcal bacteremia
spontaneously without antibiotics; the level of bacteremia in these children was low
[65].

SOCIETY GUIDELINE LINKS Links to society and government-sponsored


guidelines from selected countries and regions around the world are provided
separately. (See "Society guideline links: Bacterial meningitis in adults" and "Society
guideline links: Meningococcal infection" and "Society guideline links: Bacterial
meningitis in infants and children".)

SUMMARY

Neisseria meningitidis is the leading cause of bacterial meningitis in children and


young adults in the United States, with an overall mortality rate of 13 percent, and it is
the second most common cause of community-acquired adult bacterial meningitis. The
clinical manifestations of meningococcal disease can be quite varied, ranging from
transient fever and bacteremia to fulminant disease with death ensuing within hours of
the onset of clinical symptoms. (See 'Introduction' above.)

Acute systemic meningococcal disease is most frequently manifest by three


syndromes: meningitis alone, meningitis with accompanying meningococcemia, and
meningococcemia without clinical evidence of meningitis. (See 'Meningitis and acute
meningococcemia' above.)
The typical initial presentation of meningitis due to N. meningitidis consists of the
sudden onset of fever, nausea, vomiting, headache, decreased ability to concentrate, and
myalgias in an otherwise healthy patient. (See 'Clinical manifestations' above.)

Myalgias may be an important differential sign, and occasionally the pain is quite
intense. These are generally more painful than myalgias seen in viral influenza. Disease
progression is usually quite rapid with transition from health to severe disease in a
matter of hours. (See 'Clinical manifestations' above.)

Preceding symptoms of pharyngitis, which in meningococcal meningitis is


nonsuppurative, can lead to a preliminary misdiagnosis of streptococcal pharyngitis.
However, patients with meningococcal meningitis either present with, or soon develop,
a degree of illness that is much too severe to warrant this diagnosis. (See 'Clinical
manifestations' above.)

The clinical expression of this infection ranges widely, and, thus, a high index of
suspicion and a careful search for clues of disease are required to make a diagnosis,
particularly in the absence of an epidemic. (See 'Clinical manifestations' above.)

Although initial clinical features of patients with meningococcal disease are similar to
many common, self-limiting viral illnesses seen in primary care, signs of early sepsis
should differentiate the patient who merits clinical monitoring. (See 'Worrisome signs'
above.)

The vital signs often show a low blood pressure with an elevated pulse rate. An
intensive search for petechiae and ecchymoses should be undertaken. The physical
examination should also include provocative tests for meningeal irritability, such as the
Kernig and Brudzinski signs. However, the absence of signs of meningitis does not
exclude the diagnosis of systemic meningococcal infection. (See 'Physical examination'
above.)

Meningococcal meningitis and meningococcemia often result in shock, disseminated


intravascular coagulation, and purpura fulminans. (See 'Meningitis and acute
meningococcemia' above.)

A number of complications have been documented in patients with meningococcal


meningitis either at the time of presentation or, more commonly, later in the recovery
phase of illness. These include immune complexassociated complications such as
arthritis without the recovery of organisms, pleurisy, vasculitis, and pericarditis. (See
'Complications' above.)

Mortality rates in patients with meningococcal meningitis are approximately 10 to 15


percent despite antibiotic treatment. (See 'Mortality' above.)