Читать книгу Cases in Medical Microbiology and Infectious Diseases - Melissa B. Miller - Страница 61

1. Based on his physical findings of productive cough with purulent sputum, shortness of breath, fever, and bibasilar fine crackles on chest auscultation in the left lower lung, coupled with left lower lobe infiltrates on radiographic imaging, this patient had a lower respiratory tract infection most consistent with bacterial pneumonia. Because this patient was at home at the time of disease onset, he would be considered to have community-acquired pneumonia.

Two clinical prediction models are widely used to determine if patients with community-acquired pneumonia should be admitted to the hospital. Having metrics for this purpose is valuable because patients do not wish to be hospitalized. There are several reasons for this: they get better faster at home; they are not exposed to nosocomial risks, including infections; and it is more cost-efficient. These two models allow for a rational approach to this process. The pneumonia prediction rule is a scoring system based on demographics; coexisting conditions; and physical, laboratory, and radiographic findings. Because of its complexity, it is more of a research tool with limited practical application. The second system is CRB-65, a modification of CURB-65. CRB-65 is simple to use, as it has four criteria that can be easily determined: C, presence or absence of confusion; R, respiratory rate of >30 per minute; B, low systolic (≤90 mm Hg) or diastolic (≤60 mm Hg) blood pressure; and age >65 years. Patients are ranked on a scale of 0 to 4; those with a score of 3 or 4 are judged to have severe disease, with frequent admission to the intensive care unit and 30-day mortality of >40%. This patient had a CRB-65 score of 0. Patients with that score are usually not admitted to the hospital, as their 30-day mortality is 0%. However, CRB-65 is a simple system that does not take into account certain complexities in this patient. This patient was immunocompromised due to his history of head and neck carcinoma. He also had a long-term smoking history, which put him at increased risk for respiratory infections. Finally, he had previous episodes of respiratory infection, which were concerning to his physician; thus the decision to admit him.

2. In patients who are suspected of having bacterial pneumonia, attempts are made to determine the etiologic agent so that management can be directed toward a specific agent. In lobar pneumonia, as was seen on physical and radiographic examination of this patient, the most common etiologic agent is Streptococcus pneumoniae. Three approaches are widely used to determine if a patient is infected with this organism: sputum examination, blood culture, and pneumococcal urinary antigen detection. The organism isolated from this patient’s positive blood culture was a catalase-negative, Gram-positive diplococcus (Fig. 8.2). It was alpha-hemolytic on sheep blood agar and was susceptible to the copper-containing compound optochin (ethylhydrocupreine hydrochloride). These phenotypic characteristics are consistent with S. pneumoniae. Approximately one-third of patients with pneumococcal pneumonia will have a positive blood culture, so the finding in this patient was consistent with this diagnosis. Pneumococcal pneumonia can often be diagnosed by its characteristic Gram stain, in which stained sputum demonstrates numerous polymorphonuclear cells and the presence of many lancet-shaped, Gram-positive diplococci. However, it requires a high-quality specimen, which is defined as one where there are ≥25 neutrophils and <10 squamous epithelial cells per low-power field. In patients with high-quality specimens who have not received antimicrobials prior to specimen collection and have characteristic Gram-positive diplococci, Gram stain has a sensitivity of 80%. However, in the clinical setting, it is not uncommon to receive poor-quality sputum specimens that are unable to be analyzed, as was the case for this patient. Poor-quality specimens typically have high numbers of squamous epithelial cells because of contamination of the specimen with oropharyngeal secretions. Oropharyngeal secretions contain high numbers of squamous epithelial cells. Because the pneumococcus can be part of the resident microbiota of the oropharynx, the finding of this organism in a poor-quality sputum specimen cannot be reliably associated with the diagnosis of pneumococcal pneumonia. Such a finding may be a false positive.

Another test for invasive pneumococcal disease is a urinary antigen test. This test is most likely to be positive in patients with bacteremic pneumococcal pneumonia, the exact clinical situation seen in this patient. This test is most useful in a setting where antimicrobials have already been given, making it much less likely that organisms will be detected either by blood or sputum culture. Urinary antigen tests should not be used in children, especially in the winter months, since false positives due to high colonization rates may occur.

3. Many different patient populations are at increased risk for invasive pneumococcal disease—pneumonia, bacteremia, and meningitis. Patient populations in whom rates of pneumococcal invasive disease are increased include AIDS patients; patients who are anatomically or functionally asplenic (including patients with sickle-cell disease); patients with cardiovascular, liver, or kidney diseases; individuals with diabetes or malignancies; and individuals who are receiving immunosuppressive agents because of connective tissue disease or organ transplantation. Prevention strategies that target these populations are discussed in the answer to question 5.

4. The polysaccharide capsule is the major virulence factor of S. pneumoniae. More than 90 antigenically different capsular polysaccharides have been recognized, with 7 types—4, 6B, 9V, 14, 18C, 19F, and 23F—being responsible for 80 to 90% of cases of invasive pneumococcal disease. Animal experiments done in the first part of the 20th century established the importance of capsule in the organism’s ability to cause disease. It is well recognized that the capsular polysaccharide allows the pneumococcus to evade phagocytosis.

The second virulence factor is the cholesterol-dependent cytolysin, pneumolysin. Pneumolysin acts on both alveolar epithelial cells and pulmonary endothelial cells. Pneumolysin may contribute to fluid accumulation and hemorrhage by directly damaging these two cell types. Animal studies of pneumococcal pneumonia indicate that pneumolysin plays a primary role in the inflammation, fluid accumulation, and hemorrhage that occurs in the alveoli during lobar pneumococcal pneumonia. The inflammatory response is due at least in part to pneumolysin upregulating the synthesis of both tumor necrosis factor-α and interleukin-1 in the airways.

5. Currently, there are two vaccines licensed for prevention of pneumococcal disease, a 23-valent polysaccharide vaccine and a 13-valent conjugate vaccine. The 23-valent vaccine is used in adults, while the 13-valent conjugated vaccine was developed for use in children <2 years of age. Young children are not able to reliably mount a T-cell-independent immune response, the type of immune response necessary to produce antibodies against polysaccharide antigens. However, they are able to mount a T-cell-dependent immune response.

The 13-valent pneumococcal vaccine is also recommended for adults, especially immunocompromised individuals. Currently, many clinicians are still using the 23-valent vaccine in adults >60 years. In adults, the 23-valent polysaccharide vaccine has been used successfully for many years. The efficacy of the 23-valent vaccine in adults is not as high (efficacy ranges from 50 to 90% in different populations) as that of the 13-valent conjugate vaccine in children.

A conjugate vaccine is one in which a polysaccharide antigen is coupled to a carrier protein. The coupling of a polysaccharide antigen to a protein creates a “new” antigen. This new antigen stimulates a T-cell-dependent immune response (see case 45 for further details). Therefore, the conjugated pneumococcal vaccine results in a protective immune response to capsular types present in the vaccine and perhaps to other related serotypes in children <2 years old. It has been shown to be highly efficacious (>95%) in preventing invasive pneumococcal disease in this age group. It has been less effective in preventing a common pneumococcal infection in this age group, otitis media. The conjugated pneumococcal vaccine is now recommended for use in all children <2 years of age.

The widespread use of the 13-valent conjugated pneumococcal vaccine in children has resulted in declines in the two major populations with invasive pneumococcal disease: those <5 and those >65 years of age. Herd immunity clearly is playing a role in this decline and is discussed in greater detail in case 45.

An additional vaccine strategy that might be helpful in protecting this patient from pneumococcal disease would be to vaccinate him against influenza virus. Influenza infection has been recognized as being an important predisposing factor for the development of pneumococcal pneumonia.

Alternatively, prophylactic antimicrobials have been used in selected populations, such as sickle-cell patients with a history of recurrent invasive pneumococcal infections. Given the problem of emerging drug resistance in the pneumococci (see below), this is probably a preventive strategy that is becoming less efficacious.

The intense interest in pneumococcal vaccine is being driven to a significant degree by an alarming increase in the numbers of multidrug-resistant pneumococcal isolates being recovered from patients with invasive disease. Prior to 1990, pneumococcal isolates that were resistant to penicillin were quite unusual in the United States, as was the recovery of isolates that were resistant to other classes of antimicrobials. Beginning in the 1990s, pneumococcal isolates resistant to multiple antibiotics, including penicillin, macrolides, and trimethoprim-sulfamethoxazole, became increasingly common. Rates of resistance accelerated in the late 1990s. Some of this increase was due to the dissemination of selected clones of multidrug-resistant pneumococci, including the international dissemination of a multidrug-resistant type 23 strain. However, a common theme in the increasing drug resistance in this organism is the inappropriate use of antimicrobial agents. Several studies have been able to link increased use of specific antimicrobials, such as the macrolides and fluoroquinolones, with increased resistance. Because multidrug-resistant organisms are being seen with increasing frequency in invasive pneumococcal disease, it is clear that these multidrug-resistant strains have maintained their virulence, unlike some drug-resistant strains of other organisms that appear to be less virulent than nonresistant ones. Prevention of invasive infection with multidrug-resistant organisms by the two vaccines may be possible because >90% of multidrug-resistant pneumococcal serotypes are either present in the vaccines or likely to cross-react with antibodies to the vaccine serotypes. It should be noted that in the pre-antibiotic era, mortality from invasive pneumococcal disease was 80%. It now stands at between 10 and 20%. With increasing resistance limiting the efficacy of antimicrobials, will mortality due to invasive pneumococcal disease begin to increase?

6. There are four potential explanations for why patients can have repeated episodes of infection with the same serotype. The first three fall under the category of inadequate treatment; the fourth involves reinfection.

In terms of inadequate treatment, the patient may have been treated with an antimicrobial to which the infecting organism was not susceptible. Given the increasing trend of multidrug resistance in pneumococci, this is a reasonable explanation. Susceptibility testing of this organism revealed it to be pan-sensitive, meaning it was susceptible to all antimicrobials against which it was tested, including the antimicrobial with which he was treated. The second explanation is that the patient did not receive antimicrobials for a sufficient period of time to eliminate the organism. If hospitalized, it is likely that the patient would receive appropriate antimicrobial therapy during his stay. However, in the managed care era, hospital stays are becoming shorter and shorter. Our patient received 4 days of intravenous antimicrobials in the hospital and then oral antibiotics prescribed for use after discharge. If he failed to take his oral antibiotics, i.e., was noncompliant, his infection may have been inadequately treated, contributing to a relapse. A third possibility is that he had an undrained focus of infection that the antimicrobials did not adequately penetrate. In pneumococcal pneumonia, highly viscous pleural exudates may form that antimicrobials cannot penetrate. Removal of these exudates by drainage may be required for treatment of severe infections. Occasionally, drainage of exudates is not possible percutaneously. In these cases, a surgical procedure may be necessary to remove this focus of infection.

The fourth possible explanation is reinfection with the same serotype. Serotype 23 is one of the most common serotypes of S. pneumoniae, being responsible for 7% of invasive pneumococcal infections in a recent U.S. survey. It is possible that he was carrying the organism in his nasopharynx and became reinfected in that manner, since it has been shown that antimicrobial therapy does not reliably eliminate nasopharyngeal colonization of pneumococci. What is more difficult to understand is why his original infection did not result in his mounting a protective immune response to this organism. A possible explanation is that his immunosuppressed state due to the carcinoma blunted his immune response. It is uncertain if vaccination would be an effective preventive strategy in this patient given the observation that he had three infections in a month with S. pneumoniae serotype 23, which is present in the vaccine.