The girl was diagnosed with Streptococcus pneumoniae (pneumococcus) infection. S. pneumoniae is a gram-positive, encapsulated bacterium, and an important and commonly encountered bacterial pathogen in humans. It is often found as a normal commensal in the nasopharynx of healthy adults and children. It does however have the potential to become pathogenic. In developing countries, including South Africa, pneumococcus remains the most common and important disease-causing organism in infants. Although exact numbers are difficult to obtain, it is estimated that pneumococcal infection is responsible for more than one million of the 2.6 million annual deaths due to acute respiratory infection in children younger than 5 years. Case fatality rates associated with invasive disease vary widely but can approach 50% and are greatest in patients who develop meningitis. The bacterium does so by escaping local host defenses and phagocytic mechanisms, and penetrates the CSF either through choroid plexus/subarachnoid space seeding from bacteraemia or through direct extension from sinusitis, otitis media or mastoiditis. Presently, it is the most common bacterial cause of meningitis, accounting for 47% of cases.
Most individuals who are colonised with pneumococcus carry only a single serotype at any given time. The duration of colonisation varies depending on bacterial characteristics such as serotype and host characteristics. Invasive disease is usually related to recent acquisition of a new serotype. However, in most healthy hosts, colonisation is not associated with symptoms or disease but allows for the continued presence of pneumococcus within the population. The bacterial capsule consists of repeating oligosaccharides and based on antigenic differences within these capsular polysaccharides, greater than 91 serotypes of pneumococcus have been identified. From these a heptavalent pneumococcal conjugate vaccine (PCV7 vaccine) has been designed which contains the 7 most common pneumococcal serotypes causing 70% of the invasive infections in children. With the implementation of childhood vaccinations (since 2000 in USA, 2009 in RSA) using this heptavalent conjugate vaccine (prevnar) for pneumococcus, colonisation rates have decreased in children receiving the vaccine. As a result, adults and other children living in the same household become less exposed and the incident cases of pneumoccocus are significantly reduced because of the phenomenon of herd immunity.
In this discussion we will explore the current understanding of how pneumococcus is able to colonise the nasopharynx, the ways in which the bacterium evades the innate immune system and how it is able to cause disease. With the aid of our graphics we will discuss the processes involved in various bacterial dissemination routes, such as to the middle ear and meninges, dissemination to the lungs and then via the bloodstream to the meninges or dissemination via a bacteraemia to the meninges. We will also go into a more detailed discussion of the strategies employed by the bacterium to evade the innate immune system. Pneumococcal vaccinations will not be discussed in any detail here, but will be detailed in a separate case study.
Colonisation of the upper respiratory tract
Pneumococcus is a commensal bacterium that is transmitted between humans via aerosols. In this way the bacteria colonise the nasopharynx, and typically do not cause any disease in healthy individuals. However, amongst children younger then 5 years, the elderly and immunocompromised individuals, especially those who are HIV-infected, asplenic, have complement deficiencies, humoral immunity defects or neutrophil dysfunction, they are all at a greater risk of disease resulting in infections at more distant sites such as pneumonia, otitis media, meningitis, encephalitis and systemic bacteraemia.
A common dissemination route, particularly in young children, is the ascent of the bacteria via the Eustachian tube to the middle ear causing otitis media. Prolonged infection in this compartment can permit spread of bacteria directly into the CSF through the mastoid sinuses resulting in meningitis. This is the route through which our case study patient was repeatedly infected. In the case of our index patient we know that she cleared infection on every admission. We know that although she is HIV-positive, her immune system is most probably robust due to the viral suppressive effect of HAART (her viral load is undetectable) with a CD4 count in a normal range. We also know from our laboratory investigations that she did not develop a bacteraemia because her blood cultures were always negative therefore her recurrent infections into the meninges was due to direct access to CSF from the middle ear or mastoid sinuses.
Another common route of dissemination from the nasopharynx, particularly in adults, is seeding of the lower respiratory tract and invasion of the lungs resulting in pneumonia. Inflammation of the lungs can then permit escape of bacteria into the bloodstream. Entry of bacteria into the systemic blood system can result in bacteraemia, but can also lead to invasion of the CSF via the capillary networks that traverse the choroid plexus or subarachnoid space causing meningitis. Alternatively bacteria can penetrate the nasopharyngeal submucosa by translocation across the epithelium and subsequent translocation of capillary endothelial cells entering the blood stream and causing bacteraemia.
Once in the bloodstream, bacteria can cross endothelial cell barriers and enter the CSF through the blood vessels traversing the choroid plexus or subarachnoid spaces and cause meningitis. Endothelial cells of the blood-brain barrier can also be penetrated allowing bacterial spread into the CNS, resulting in encephalitis; but this occurs less often.
Now that we understand bacterial dissemination on a gross level we can take a closer look at how the bacteria cross the upper respiratory tract epithelium and translocate the capillary endothelium to gain access to the bloodstream.
Pneumococcus interferes with the secretory antibody pathway of the upper respiratory track. Anti-capsular antibodies play an important role in control of pneumococcal infections. B lymphocytes in the submucosa secrete IgM and dimeric IgA which is transported across the mucosal epithelium of the upper respiratory tract by transcytosis. The polymeric immunoglobulin receptor (PigR), expressed on the basolateral membrane of epithelial cells, binds to the J chain of IgM and dimericIgA. The bound antibodies are then transported in a vesicle through the cell and released at the apical membrane. Here proteosomal cleavage of the receptor at the membrane surface releases the antibody keeping the secretory component attached.
The pneumococcus, which is found in the upper respiratory tract on the apical side, the mucosal epithelium expresses its own surface protein known as PspC. This protein facilitates translocation of bacteria by reverse transcytosis through the upper respiratory epithelial cells. This is achieved by PspC essentially hijacking the polymeric immunoglobulin receptor (PigR) which normally transports IgM and dimeric IgA to the mucosal surface. Although primarily expressed at the epithelial basolateral cell surface, PigR is found at a low level on the apical membrane. Binding of bacterial PspC to the secretory component of PigR induces reverse transcytosis and in this way delivers intact bacteria into the submucosa. PigR is not expressed in the lower respiratory tract and therefore does not play a role in lung disease.
Once in the submucosa the bacteria can further translocate across the capillary endothelium to gain access to the bloodstream. This is achieved via the presence of another cell surface protein expressed by pneumococcus known as ChoP, a phosphorylcholine protein. The bacterium takes advantage of the immune response triggered by its presence in the submucosa of the upper respiratory tract. When inflammatory cytokines are released they upregulate the expression of cell surface receptors on the basolateral surface of the capillary endothelial cells. One of these receptors is the platelet activating factor receptor (PafR).ChoP is able to bind to this receptor and on engagement PafR triggers clathrin-dependent endocytosis of the receptor-complex which facilitates internalisation of the bound bacteria. In this way the bacteria are able to invade the bloodstream from the submucosa via escape at the apical membrane of the endothelial cell into the capillary lumen.
The classic triad of meningitis consists of fever, nuchal rigidity, and altered mental status, but not all patients have all 3, and almost all patients have headache. Altered mental status can range from irritability to somnolence, delirium, and coma. The examination reveals no focal neurologic deficits in the majority of cases. Furthermore, the majority of patients with bacterial meningitis have a stiff neck, but the meningeal signs are insensitive for diagnosis of meningitis. 
Acute bacterial meningitis in otherwise healthy patients who are not at the extremes of age presents in a clinically obvious fashion. In contrast, most patients with subacute bacterial meningitis pose a diagnostic challenge. Systemic examination occasionally reveals a pulmonary or otitis media coinfection.
Systemic findings can also be present. Extracranial infection (eg, sinusitis, otitis media, mastoiditis, pneumonia, or urinary tract infection [UTI]) may be noted. Endotoxic shock with vascular collapse is characteristic of severe N meningitidis (meningococcal) infection.
General physical findings in viral meningitis are common to all causative agents, but some viruses produce unique clinical manifestations that help focus the diagnostic approach. Enteroviral infection is suggested by the presence of the following:
Symptoms of pericarditis, myocarditis, or conjunctivitis
Syndromes of pleurodynia, herpangina, and hand-foot-and-mouth disease
Increased blood pressure with bradycardia can also be present. Vomiting occurs in 35% of patients.
Nonblanching petechiae and cutaneous hemorrhages may be present in meningitis caused by N meningitidis (50%), H influenzae, S pneumoniae, or S aureus.  Arthritis is seen with meningococcal infection and with M pneumoniae infection but is less common with other bacterial species.
Infants may have the following:
Bulging fontanelle (if euvolemic)
Paradoxic irritability (ie, remaining quiet when stationary and crying when held)
In infants, the clinicians should examine the skin over the entire spine for dimples, sinuses, nevi, or tufts of hair. These may indicate a congenital anomaly communicating with the subarachnoid space.
Focal neurologic signs
Focal neurologic signs include isolated cranial nerve abnormalities (principally of cranial nerves III, IV, VI, and VII), which are present in 10-20% of patients. These result from increased intracranial pressure (ICP) or the presence of exudates encasing the nerve roots. Focal cerebral signs are present in 10-20% of patients and may develop as a result of ischemia from vascular inflammation and thrombosis.
Papilledema is a rare finding (< 1% of patients) that also indicates increased ICP, but it is neither sensitive nor specific: it occurs in only one third of meningitis patients with increased ICP and is present not only in meningitis but also in brain abscess and other disorders.
Signs of meningeal irritation
For more than 100 years, clinicians have relied on meningeal signs (nuchal rigidity, Kernig sign, and Brudzinski sign) to evaluate patients with suspected meningitis and help determine who should undergo a lumbar puncture (LP). However, a prospective study of 297 adults with suspected meningitis documented very low sensitivities for these signs: 5% for the Kernig sign, 5% for the Brudzinski sign, and 30% for nuchal rigidity.  Thus, the absence of the meningeal signs should not defer the performance of the LP.
Systemic and extracranial findings
Systemic findings on physical examination may provide clues to the etiology of a patient’s meningitis. Morbilliform rash with pharyngitis and adenopathy may suggest a viral etiology (eg, Epstein-Barr virus [EBV], cytomegalovirus [CMV], adenovirus, or HIV). Macules and petechiae that rapidly evolve into purpura suggest meningococcemia (with or without meningitis). Vesicular lesions in a dermatomal distribution suggest VZV. Genital vesicles suggest HSV-2 meningitis.
Sinusitis or otitis suggests direct extension into the meninges, usually with S pneumoniae or, less often, H influenzae. Rhinorrhea or otorrhea suggests a cerebrospinal fluid (CSF) leak from a basilar skull fracture, with meningitis most commonly caused by S pneumoniae.
Hepatosplenomegaly and lymphadenopathy suggest a systemic disease, including viral (eg, mononucleosislike syndrome in EBV, CMV, and HIV) and fungal (eg, disseminated histoplasmosis). The presence of a heart murmur suggests infective endocarditis with secondary bacterial seeding of the meninges.
It is essential to perform careful general, systemic, and neurologic examinations, looking especially for the following:
Papilledema and tuberculomas during funduscopy
Cranial nerve palsies
The presentation of chronic tuberculous meningitis may be acute, but the classic presentation is subacute and spans weeks. Patients generally have a prodrome consisting of fever of varying degrees, malaise, and intermittent headaches. Cranial nerve palsies (III, IV, V, VI, and VII) often develop, suggesting basilar meningeal involvement.
Clinical staging of tuberculous meningitis is based on neurologic status, as follows:
Stage 1 - No change in mental function, with no deficits and no hydrocephalus
Stage 2 - Confusion and evidence of neurologic deficit
Stage 3 - Stupor and lethargy
The median incubation period before the appearance of symptoms in chronic syphilitic meningitis is 21 days (range, 3-90 days), during which time spirochetemia develops. Syphilitic meningitis usually occurs during the primary or secondary stage of syphilis, complicating 0.3-2.4% of primary infections during the first 2 years. Its presentation is similar to those of other types of aseptic meningitis, including headache, nausea, vomiting, and meningismus.
Meningovascular syphilis occurs later in the course of untreated syphilis, and the symptoms are dominated by focal syphilitic arteritis (ie, focal neurologic symptoms associated with signs of meningeal irritation) that spans weeks to months and results in stroke and irreversible damage if left untreated. Patients with concomitant HIV infection have an increased risk of accelerated progression.
Although rare during stage 1 of Lyme disease, central nervous system (CNS) involvement with meningitis may occur in Lyme disease–associated chronic meningitis and is characterized by the concurrent appearance of erythema migrans at the site of the tick bite. More commonly, aseptic meningitis syndrome occurs 2-10 weeks after the erythema migrans rash. This represents stage 2 of Lyme disease, or the borrelial hematogenous dissemination stage.
Headache is the most common symptom of Lyme disease–associated chronic meningitis, with photophobia, nausea, and neck stiffness occurring less frequently. Somnolence, emotional lability, and impaired memory and concentration may occur. Facial nerve palsy is the most common cranial nerve deficit. These symptoms of meningitis usually fluctuate and may last for months if left untreated.
Meningitis from C neoformans usually develops in patients with defective cell-mediated immunity (see CNS Cryptococcosis in HIV). It is characterized by the gradual onset of symptoms, the most common of which is headache.
Coccidioidal meningitis is the most serious form of disseminated coccidioidomycosis; it usually is fatal if left untreated. These patients may present with headache, vomiting, and altered mental function associated with pleocytosis, elevated protein levels, and decreased glucose levels. Eosinophils may be a prominent finding on CSF analysis.
Patients infected with B dermatitidis may present with an abscess or fulminant meningitis. Patients infected with H capsulatum may present with headache, cranial nerve deficits, or changes in mental status months before diagnosis.
Helminthic eosinophilic meningitis
After ingestion of A cantonensis larvae, which are found in raw or undercooked mollusks, most patients with symptomatic disease present with nonspecific and self-limited abdominal pain caused by larval migration into the bowel wall. On rare occasions, the larvae can migrate into the CNS and cause eosinophilic meningitis. Although A cantonensis is prevalent in Southeast Asia and tropical Pacific islands, infestations from this parasitic nematode have been reported in the United States and the Caribbean. 
In contrast to patients with bacterial meningitis, patients with aseptic meningitis syndrome usually appear clinically nontoxic, with no vascular instability. (See Aseptic Meningitis.) In many cases, a cause for meningitis is not apparent after initial evaluation, and the condition is therefore classified as aseptic meningitis. These patients characteristically have an acute onset of meningeal symptoms, fever, and CSF pleocytosis that is usually prominently lymphocytic.