See CDC

Introduction:

Pneumococcal disease is a name for any infection caused by bacteria called Streptococcus pneumoniae or pneumococcus. Bacteria called Streptococcus pneumoniae, or pneumococcus, can cause many types of infections. Some of these infections like pneumonia below can be life threatening. Today, the pneumococcus is thought to be responsible for at least half of all community-acquired pneumonia and otitis media and remains a significant cause of bacteremia and meningitis (together referred to as invasive pneumococcal disease [IPD])

Pneumococcal infections are casued by Streptococcus pneuonia (pneumococcus), a gram-positive, facultative anaerobic bacterium. Pneumococcus can colonize the upper respiratory tract, most commonly in young children, and is transmitted to others through contact with respiratory droplets from a person with pneumococcal colonization in the upper respiratory tract. Certain persons with pneumococcal colonization might develop invasive pneumococcal disease (IPD). IPD is infection of normally sterile sites, including pneumonia with bacteremia, meingitis, osteomyelitis, septic arthritis and bacteremica without a focus of infection. Examples of noninvasive disease include pneumonia without bacteremia, sinusitits, or otitis mediate. In adults, pneumococccal pneumonia is the most common type of pneumococcal disease, and pneumococccus is the most common bacterial cause of pneumonia that resutls in hospitalizaiton. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).

In adults, the risk for pneumococcal disease increased with age. Pneumococcal pneumonia is the most common form of pneumococcal disease in adults and is estimated to account for about 10% of hospitalized community acquired pneumonia. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).

In 2020, a decline in IPD incidence was observed globally and the decline is thought to be a result of the introduciton of nonpharmaceutical interventions to contain COVID-19 such as mask wearing and restrictions on indoor gathering whic

Biochemical and Morphological Characteristics

Streptococcus pneumonia (S.p.) or pneumococcus is a gram-positive, alpha-hemolytic member of the genus Streptococcus.

Pneumococci are classified into seroptyes depending on their capsular polysaccharide, which is a main virulence factor for pneumococcus. At least 100 pneumococcal serotypes were documeted as of 2020. During 2018-2019, about 60-75% of all IPD in adults was caused by the 24 pneumococcal serotyeps that were included in formulations of commercially available polysaccharide conjugate vaccine (PCV) or pneumococcal polysaccharide vaccine (PPSV) vaccines (i.e., PCV13, PCV15, PCV20, and PPSV23). Current pneumococcal vaccines use the pneumococcal capsular polysaccharides as antigens to generate serotype specific antibodies, which facilitate serotype specific clearance of pneumococci through opsonophagocytosis. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).

What it causes

It is an important human pathogen that colonizes the upper respiratory tract. S pneumoniae is the most common etiologic agent in community acquired pneumonia, as well as bacterial meningitis, otitis media and sepsis. It is responsible for more than 500k cases of lower respiratory tract infection in the US each year. Despite the widespread use of antibiotics, the mortality rate from S.p remains highest during the first 48 hours of hospitalization and has not decreased appreciably over the past 30 years. Successful treatment has been hampered by the increasing prevalence of antibiotic resistant strains worldwide. The earliest stage is seldom recognized and is most likely to be found in patients who die after illness lasting only a short time period because of the very rapid progress of the disease.

Acute Otitis Media (Ear Infection):

Although the middle ear normally has no biota, bacteria can migrate along the eustachian tube form the upper respiratory tract. Wehn bacterai encounter mucus and fluid buildup in the middle ear, they multiply rapidy. Their presence increases the inflammatory response, leading to pus production and continued fluid secretion. Another condition, known as chronic otitis media occurs when fluid reamins in the middle ear.

The single most common bacterium seen in acute otitis media is Streptococcus pneumoniae, although new dat suggest that it is caused by a mixed biofilm of bacteria which are also less usceptible to antibiotics.

Pneumonia

Pneumonia is an inflammatory condition of the lung in which fluid fills the alveoli. It can be caused by a wide variety of different microorganisms but S pneumoniae accounts for up to 40% of community-acquired bacterial pneumonia cases.

Worldwide more children under the age of 5 die from pneumonia than any other infectious disease. In the US there are 2-3 million cases of pneumonia and more than 45,000 deaths eacy year. It is much more common in the winter.

Symptoms: 

Histologically, the initial phase of pneumococcal pneumonia is characterized by acute lung injury (ALI) which is an inflammatory disorder of the lung, characterized by hypoxemia, diffuse biolateral infiltrate on chest radiograph and absence of atrial hypertension. Although numerous bacterial are present, few inflammatory cells are seen in serous exudates of these lesions because leukocytes have not had time to reach the alveoli in the advance edema zone.

Etiology: 

Following adherence and colonization, Sp will infrequently cause more invasive disease such as pneumonia. The pneumococcus can gain access to the alveolar space and set in motion a series of events leading to inflammation and clinical pneumonia. Although the pneumococcus can bind to many epithelial cell types in the nasopharynx, it cannot adhere to the cilated epithelium lining the tracheo-bronchial tree and ultizes an entirely different set of cell surface receptors in the alveolus. How the pneumococcus changes from a passive colonizing agent in the nasopharynx to a destructive invader of the lower respiratory tract is incompletely understood.  (McCullers, “Molecular Pathogenesis of Pneumococcal Pneumonia, Frontiers in Bioscience, 6, 2001).

1. Virulence Factors

pneumolysis (PLY), a 53 kDa protein produced by virtually all clinical isolates of Sp, plays an important role in mortality by inducing hemorrhage. PLY is a member of a family of cholesterol-binding toxins (CBTs, known as cholesterol-dependent cytolysin), which also includes numerous toxins from four general of Gram-positive bacteria.

2. Protecting Factors:

CYLD: Studies have also shown that a deficiency of the deubiquitinating enzyme CYLD protects mice from Sp pneumonia pneumolysis induced ALI and lethality. CYLD was initially identified as a tumor suppressor because loss of its activity causes a benign human syndrome called cylindromatosis. In vitro studies have indicated that CYLD is a member of the deubiquitinating (cleavage of ubiquitin from protein) enzyme family. Transfection studies have that CYLD deubiquitinates TRAF2and TRAF6 and acts as a negative regulator for activation of NF-?B by tumor necrosis factor receptor and Toll-like receptor.

Type-1 plasminogen activator inhibitor-1 (PAI-1) deficient mice are hyper-susceptible to several Sp infection and exogenous administration of PAI-1 protects against alveolar hemorrhage and early lethality in mice (WO 2009/018010). PAI-1 is a principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis (the physiological breakdown of blood clots). CYLD (above) has been shown to act as a negative regulator for PAI-1 expression. CYLD, highly induced by pneumolysin, negatively regulates MKK3-p38 MAPK-dependent expression of PAI-1 in lung tissue, which in turn leads to potentiation of lung hemorrhage and increased mortality.

Capsule: Streptococcus pneumoniae (the pneumococcus) virulence is largely due to its polysaccharide capsule, which shields it from the host immune system. Capsular PS is critical to pneumococcal survival by shielding the organism from complement and subsequent phagocytic killing. It is the virulence factor most necessary for invading the host and causing disease. Most protective antibodies are specific to serotypes or serogroups, and because of this, the famous immunologist Charles Janeway, Jr., stated, “from the point of view of the adaptive immune system, each serotype of S. pneumoniae represents a distinct organism”.  Not all capsule types appear to be equally effective in shielding. Only 20 to 30 serotypes of the more than 90 show significant invasiveness. Most pneumococcal capsules are anionic which is thought to help prevent clearance by mucus. CAs pneumococcal vaccines provide serotype-specific protection, it is important that vaccines prevent disease caused by the most clinically relevant serotypes.

Thus, vaccines provide the greatest impetus for recognizing capsular diversity and serotype epidemiology. See Geno

Using unencapsulated serotype 2 and 4S. pneumoniaemutants, Hyams have confirmed that the capsule has several effects on complement activity. The capsule impaired bacterial opsonization with C3b/iC3b by both the alternative and classical complement pathways and also inhibited conversion of C3b bound to the bacterial surface to iC3b. There was increased binding of the classical pathway mediators immunoglobulin G (IgG) and C-reactive protein (CRP) to unencapsulatedS. pneumoniae, indicating that the capsule could inhibit classical pathway complement activity by masking antibody recognition of subcapsular antigens, as well as by inhibiting CRP binding. Cleavage of serum IgG by the enzyme IdeS reduced C3b/iC3b deposition on all of the strains, but there were still marked increases in C3b/iC3b deposition on unencapsulated TIGR4 and D39 strains compared to encapsulated strains, suggesting that the capsule inhibits both IgG-mediated and IgG-independent complement activity againstS. pneumoniae. Unencapsulated strains were more susceptible to neutrophil phagocytosis after incubation in normal serum, normal serum treated with IdeS, complement-deficient serum, and complement-deficient serum treated with IdeS or in buffer alone, suggesting that the capsule inhibits phagocytosis mediated by Fcγ receptors, complement receptors, and nonopsonic receptors. Overall, these data show that theS. pneumoniaecapsule affects multiple aspects of complement- and neutrophil-mediated immunity, resulting in a profound inhibition of opsonophagocytosis. See Hyams

Prevention and Treatment:

Vaccination:

Before October 2024, the Advisory Committee on Immunization Practices (ACIP) recommended use of a pneumococcal conjugate vaccine (PCV) for all adults aged ≥65 years, as well as for those aged 19–64 years with risk conditions for pneumococcal disease who have not received a PCV or whose vaccination history is unknown. Options included either 20-valent PCV (PCV20; Prevnar20; Wyeth Pharmaceuticals) or 21-valent PCV (PCV21; CAPVAXIVE; Merck Sharp & Dohme) alone or 15-valent PCV (PCV15; VAXNEUVANCE; Merck Sharp & Dohme) in series with 23-valent pneumococcal polysaccharide vaccine (PPSV23; Pneumovax23; Merck Sharp & Dohme). On October 23, 2024, ACIP recommended a single dose of PCV for all PCV-naïve adults aged ≥50 years. See CDC

Widespread use of pneumococcal conjugate vaccine (PCV) in children reduced the incidence of pneumococcal disease, both among children through direct effects and among older children and adults who have not received PCV through indirect effects (i.e., reduction in disease incidence in the population because of decreased transmission of pneumococcus from children).

The PPSV and PCV vaccines induce immune responses in different ways. Studies in mice have found that the polysaccharide vaccine induces a T cell independent immune response and stimulated immediate B cell resposes. As a result, B cells differentiate to plasma cells that produce antibodies. However, a T cell independent immune response does not result in creation of serotope specific memory cells. On the other hand, conjugate vaccines induce a T cell dependent response. The polysaccharide antigen binds to the B cells, and the peptides form the carrier protein are presented to carrier peptide specific helper T cells which enhance the immune response by the B cells and memory Beclls are also created. All PCVs use CRM197 (genetically detoxified diphteria toxin) as a carrier protein. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).

Use of azithromycin, benzathine penicillin G, amoxicillin or levofloxacin has been reported in recent outbreaks to prevent additional cases. If an exposed person has received vaccines that contain the serotype of the circulating pneumococcus, they are expected to have longer term proteion against pneumococcal diasese than if they were to receive antimicrobial chemoprophylaxis. PCVs have advantages ofver PPSV23 because these vaccines can induce high levels of serotype specific iIgG to help protect vaccinated persons from vaccine type pneumococcal carriage. (Kabayashi, “Pneumococcal vaccine for adults aged > 18 years: Recommendations of the advisory committe on immunization practices, United States, 2023”).

Treatment:

The current treatment recommendation for uncomplicated acute otitis media with a fewer below 104F is “watchful waiting” for 72 hours to allow the body to clear the infection, avoiding the use of antibiotics.

Since the introduction of sulfonamides and penicilin in the first half of the 20th century, antibiotic therpay has been the primary treatment. However, antibotic resistance could be detected in clinical isolates as early as 1941, 12 years after the discvoery of penicillin.