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 [1]. 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.

The clinical manifestations of both meningococcal meningitis and meningococcemia will be reviewed here. The microbiology, pathobiology, epidemiology, diagnosis, treatment, and prevention of N. meningitidis infection are discussed separately. (See "Microbiology and pathobiology of Neisseria meningitidis" and "Epidemiology of Neisseria meningitidis infection" and "Diagnosis of meningococcal infection" and "Treatment and prevention of meningococcal infection".)

MENINGITIS AND ACUTE MENINGOCOCCEMIA — Acute systemic meningococcal disease is most frequently manifest by three syndromes [2]:

●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].

In a case-controlled study evaluating risk factors associated with systemic meningococcal infection in France from 2012 to 2017, the strongest associations were found with congenital immunodeficiency (odds ratio [OR] 39.1 [95% CI 5.1-299]), acquired immunodeficiency (OR 10.3 [95% CI 4.5-24.0]), and asplenia/hyposplenia (OR 6.7 [95% CI 3.7-14.7]) [4]. Other factors associated with invasive meningococcal disease included autoimmune diseases, chronic respiratory infections, and hemophilia, as well as low household income.

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 [5]. The classic triad is much more common in pneumococcal meningitis (58 percent in the same cohort study) [6]. (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 or caregivers 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 [7].

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 or caregivers 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 [7]:

●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 [2,8]. 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 [9].

Disseminated intravascular coagulation — Probably the most dramatic consequence of this clinical problem is the presence of disseminated intravascular coagulation [10,11].

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 [12]. 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 [13-15] (see "Protein C deficiency"). Protein C appears to play a role in anticoagulation but also in modifying inflammation [14]. One study examined vascular endothelial integrity, endothelial protein C receptor (EPCR), 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 [16]. 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. Studies have also shown that A Disintegrin and Metalloproteinase- 10 mediated shedding of EPCR on endothelial cells induced by the meningococcal interaction with endothelial cells was responsible for an impaired activation of protein C [17]. 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 [18], occurring in approximately 15 to 25 percent of those with meningococcemia [19,20]. 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 [18].

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 [21]. 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 [22]. The cause of death appears to be related to toxins such as lipo-oligosaccharides (LOS) produced by the organism or to the secondary effects of cerebral edema on the vital centers in the midbrain region [22-24].

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 [25,26]. 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 [27].

More than 50 percent of patients who die of meningococcal disease have myocarditis of varying degrees of severity detected on postmortem examination [23,28]. 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) [29].

Infective endocarditis due to N. meningitidis is a very rare occurrence in the antibiotic era [30]. Management is based on the clinical manifestations of the patient and the antimicrobial sensitivity of the organism isolated.

Acute abdomen — In a case series of invasive meningococcal disease in France, 105 patients presented with abdominal pain and gastroenteritis. There has been an increase in this presentation since 2000 [31].

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 complex–associated 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 [21,32-39].

Association between lipo-oligosaccharide levels and prognosis — The principal toxin associated with meningococcal infection is the outer membrane glycolipid, LOS [40-45] (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 [42]. 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 [41]. 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 [45]. 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 [5,46]. A retrospective population-based analysis of meningococcal disease mortality in the United States during 1990 to 2002 identified 3335 meningococcal deaths [47]. 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 [48].

CHRONIC MENINGOCOCCEMIA — Chronic meningococcemia and chronic gonococcemia cannot be differentiated except by the isolation of the causative organism [49-52]. 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 [50]. 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 [51]. 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 [52].

ARTHRITIS — Primary purulent arthritis caused by N. meningitidis is a rare event when compared with arthritis due to immune complexes. In contrast with immune complex–based 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 [53].

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 [33]. This form of pericarditis, which has an incidence as high as 19 percent [36], is thought to have an immunologic etiology. Both the infectious and immunological forms of meningococcal pericarditis can cause massive tamponade and be life threatening [37]. (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 [54].

While the ability of the meningococcus to cause pneumonia has been appreciated for many years [55-58], 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 [56], 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 [56].

More than 50 percent of patients in this large series had a history of cough, chest pain, chills, and previous upper respiratory infection [56]. Almost all of the patients had crackles 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 [59].

A symptomatic pharyngitis due to N. meningitidis has been described in contacts of patients with other meningococcal infection [60]. As noted above, pharyngitis is also a common symptom preceding other symptoms and signs in cases of serious meningococcal disease [61].

URETHRITIS AND ASCENDING INFECTIONS — Meningococci have been isolated from the urethra and can be the etiologic agent in some cases of urethritis [62-66]. Although it is uncommon, meningococcal urethritis appears to have increased in frequency since the 1970s [66]. A meningococcal uropathic nonencapsulated clone (clonal complex 11, lineage 11.2) has been identified with increased frequency as a cause of meningococcal urethritis in men who have sex with men [67,68].

Meningococcal urethritis occurs in both males and females and its presentation can be indistinguishable from acute gonococcal urethritis [65,66]. It can cause ascending infection, including epididymitis in males and pelvic inflammatory disease in females. In a surveillance study of a population of 383 men who have sex with 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) [64]. 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 complex–associated 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 [69].

OCCULT BACTEREMIA — Meningococcal bacteremia rarely occurs without sepsis [2,8]. 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 [70].

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 complex–associated 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.)