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Pneumococcal Pneumonia: History
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Subjects: Others
Contributor: Rudolf Lucas

Pneumococcal infection can have serious implications in pneumonia and sepsis. Patients with SCD who have functional asplenia and increased oxidative stress in the vasculature, are at great risk for pneumococcal infections from infancy through to their adult lives.

  • Pneumococcal Pneumonia
  • Streptococcus pneumoniae
  • Sickle Cell Disease
  • Acute Chest Syndrome

1. Introduction

Sickle cell disease (SCD) arises from homozygous single nucleotide polymorphisms (SNP) in the sixth codon of the β-globin gene (HbSS) on chromosome 11 which causes substitution of a single valine (Val) residue for glutamic acid (Glu) [1]. As a consequence, HbSS can polymerize under deoxygenation and mediates the sickling of erythrocytes [2].

SCD represents one of the most common autosomal recessive disorders in the world. In the US, 8% of African Americans are heterozygous and have the sickle cell trait, whereas 1 in 600 is homozygous and has sickle cell disease [3]. A leading cause of death and hospitalization in patients with SCD is the acute chest syndrome (ACS) [4] characterized by abnormal interactions between sickle erythrocytes and/or platelets and the vascular endothelium [5].

Although both infectious and non-infectious causes for ACS have been suggested, the pathophysiology of the disease remains elusive and is often ill-defined, even at autopsy. [6] There are multiple identified etiologies associated with the development of ACS, but bacterial and viral infection represents the main cause. Standard therapy of ACS remains supportive and includes transfusion (exchange or simple), use of bronchodilators and mechanical ventilation.

1.1. Streptococcus pneumoniae: A Prominent Etiological Agent of Severe Pneumonia

Infections of the lower respiratory tract represent the most common cause of infectious disease mortality and the fifth highest cause of death overall. With 294,000 deaths in infants under 5 years old in 2015, Spn represents the leading cause of death in infants worldwide [7] and is the major etiologic agent of community-acquired pneumonia. Elderly and immunocompromised patients are also more susceptible to Spn [8]. Spn is a facultative anaerobe Gram-positive bacterium that colonizes the upper respiratory tract as a commensal bacterium in healthy individuals. This asymptomatic carriage phase is considered a prerequisite for subsequent development of pneumonia, which can occur once the pathogen migrates into the lungs. A retrospective study showed that Spn was the most common bacterial co-infection in COVID-19 patients [9].

1.2. Increased Susceptibility to Pneumococcal Infections in SCD Patients

Patients with SCD, especially children, are particularly prone to invasive infections [10] and this can promote ACS. SCD patients with pneumococcal pneumonia are sicker than non-SCD patients with a similar infection, as demonstrated by longer duration of fever and hospitalization, an increased need for red blood cell transfusion and the presence of pleural effusions [11]. Children and infants with SCD are extremely susceptible to bacteremia, pneumonia and meningitis caused by Spn and have a 100-times higher rate of Spn infection than non-SCD infants and children. This vulnerability is at least partially due to functional asplenia in infants with SCD [12]. Other contributions of increased susceptibility to pneumococcal disease in children and adults with SCD are a dysfunctional IgG and IgM antibody response, a lack of splenic clearance and defects in alternative pathway fixation of complement and opsonophagocytic dysfunction. All of these contribute to the susceptibility of infection from all polysaccharide-encapsulated bacteria including pneumococci, Neisseria meningitides and Hemophilus influenzae [10][13]. Spn was responsible for about half of the episodes of pneumonia in SCD patients prior to prophylactic penicillin in children and application of the pneumococcal vaccines at all ages [14].
At initial diagnosis, a case of pneumococcal pneumonia is often indistinguishable in the sickle cell patient and the patient that has normal immunity. However, the patient with SCD may soon develop ACS, defined as a new pulmonary infiltrate, often accompanied by fever, chest pain, cough, wheezing and tachypnea. A published case study, which points out the vulnerability of a patient with SCD and functional asplenia with decreased immunity, reports on a 22-year old African American male with hemoglobin SD disease (a type of SCD) admitted to the hospital with Gram-positive meningitis, sepsis, pneumonia, and vaso-occlusive pain crisis. He was initially diagnosed and treated for meningitis with powerful antibiotics, ceftriaxone, and vancomycin. Four days after admission his respiratory status progressively worsened and he was diagnosed with pneumonia due to Spn. His vaccine status was up-to-date, and it was suspected that he could have an immune deficiency or inadequate specific IgG levels against some strains of the pneumococcal polysaccharide vaccine 23 (PPSV23). Two months after his hospitalization he received his fourth PPSV23 booster, which produced normal protective levels of IgG. This case highlights the uncertainty about the effectiveness of pneumococcal vaccination and more specifically in patients with functional asplenia, as can occur in SCD [15].
An early study by Overturf et al. reported mortality in a vaccinated (Pneumovax 14-valent vaccine) 37-month-old boy with SS (homozygous disease), who had sepsis and died within hours after the onset of symptoms. Spn, Type 6, was isolated from antemortem blood cultures. In this case, serum immunoglobulins were normal but titers to Type 6 were low [16]. Ahonkhai and colleagues published a two-case series of pediatric patients who contracted Spn and invasive pneumococcal disease (IPD) after vaccination with the 14-valent pneumococcal vaccine [17]. Later studies postulated that abnormalities of immunologic defense mechanisms, including synthesis of polyclonal IgG and IgM, the alternative complement pathway, opsonic activity and T and B cell interaction exist in the patient with SS genotype [18][19]. Another 10-case report evaluated IPD in vaccinated patients [20]. Among the cases was a 16-year-old male with SS disease, who had received two doses of PPSV23 and one dose of PCV7 (the precursor to PCV-13). He was admitted to the intensive care unit with hypotension and acute respiratory failure. In his case, as in the other nine cases, the severe illness was from serotypes of Spn not contained in the vaccines he received [20]. A 2016 study, evaluating the vaccine response in a single Sickle Cell Center, found that only 36% of patients had protective levels of anti-pneumococcal antibody titers at 37 months after vaccination. Among the group of patients who had sub-therapeutic titers, 64% demonstrated a vaccine response to less than 25% of the tested serotypes. The study team concluded that anti-pneumococcal immunity may not be optimal in the current vaccine strategy, leaving SCD patients vulnerable to IPD [21].
Vaccinated patients might carry a lower risk of infection, however, vaccination by itself should never allow a false sense of security [22]. The rapidity of an overwhelming pneumococcal strep infection is well known. When not recognized early or when the patient does not receive early and aggressive medical care, mortality rates can range from 50 to 70%. This mortality may however decrease to 10% if recognized early and treated aggressively [23]. In conclusion, irrespective of the vaccination status, SCD patients who all have functional asplenia and a potential pneumococcal infection of any type, including ACS, should receive immediate and aggressive care [23].

2. Prevention and Treatment of Pneumococcal Pneumonia

Health maintenance of children with SCD includes the pneumococcal vaccines and prophylactic antibiotics such as amoxicillin for pneumococcal infection until the child is five years old and azithromycin or clarithromycin for ages over five [24]. Recent data from murine models, however, suggest that antibiotic therapy needs to be initiated prior to breakdown of the alveolar-capillary barrier and systemic inflammation in pneumococcal pneumonia [25].

Currently, two main types of vaccines have been developed to reduce or eliminate the burden of pneumococcal infections: the unconjugated 23-valent polysaccharide vaccine and the 10- or 13-valent conjugated polysaccharide vaccine. Their coverage of all serotypes is however not universal, and they fail to affect non-capsulated pneumococci. Treatment of pneumococcal pneumonia in susceptible populations, such as SCD patients, is problematic as strains of pneumococci have become increasingly resistant and difficult to treat with the traditional antibiotic treatment, such as penicillin. Multidrug-resistant strains of pneumococci have become increasingly established due to the widespread availability and overuse of antibiotics; consequently pneumococcal infections remain a worldwide public health problem [26]. There is growing concern that a major problem in the treatment of Spn in ACS is the further evolution of antibiotic resistant strains. The high death rate associated with pneumococcal disease and the emergence of antibiotic resistance and the problems associated with current vaccines have stimulated interest in the mechanisms of virulence.

Universal immunization of infants and toddlers against pneumococcus has dramatically altered the landscape of pneumococcal disease and there is a decrease in invasive pneumococcal disease [27]. However children with any comorbid conditions have higher rates of pneumococcal disease and increased case fatality rates compared with otherwise healthy children [27]. Protection will continue to require strategies to address the increased susceptibility in these children.

3. Conclusions

Pneumococcal infection can have serious implications in pneumonia and sepsis. Patients with SCD who have functional asplenia and increased oxidative stress in the vasculature, are at great risk for pneumococcal infections from infancy through to their adult lives. A major virulence factor of pneumococcal infection, PLY is a major contributor of pathogenicity. PLY is released early in infection and during antibiotic therapy contributing to the formidable morbidity and mortality of this disease. Pneumococcal vaccines are recommended in SCD patients, but their highly increased vulnerability to pneumococcal disease stresses the need for early diagnosis and intervention. Future studies should further address mechanisms that account for increased susceptibility of SCD patients to pneumococcal pneumonia-associated ACS and the role of pneumococcal virulence factors, mainly PLY and H2O2, in this process.

This entry is adapted from the peer-reviewed paper 10.3390/toxins13020157

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