Significant impact of pneumococcal conjugate vaccination on pediatric parapneumonic effusion: Italy 2006-2018.

Etiology and serotyping of parapneumonic effusion (PPE) and the impact of vaccination was evaluated over a 12-year period, before and after the PCV13 introduction (2011) for Italian children From 0 to 16 years of age. Five hundred and two children were evaluated; 226 blood and 356 pleural fluid samples were obtained and tested using Realtime-PCR and culture. In the pre-PCV13 era S. pneumoniae was the most frequent pathogen identified (64/90; 71.1%) with a large predominance of serotypes 1 (42.4%), 3 (23.7%), 7F (5.1%) and 19A (11.9%). The impact of vaccination, calculated on children 0-8 years of age, demonstrated a significant reduction of PPE: with an incidence rate of 2.82 (95%CL 2.32-3.41) in the pre-PCV13 era and an age-standardized rate (ASR) of 0.66 (95% CL 0.37-1.99) in the post-PCV13 era, p < 0.0001. No increase in non-PCV13 serotypes was recorded. S. pneumoniae remained the most frequent pathogen identified in the post-PCV13 era in unvaccinated children with an unchanged serotype distribution: respectively 26/66 (39.4%), 25/66 (37.9%), 5/66 (7.6%), and 4/66 (6.1%) for 1, 3, 7F and 19A. On the other hand 7F and 19A disappeared in vaccinated children and serotype 1 and 3 decreased by 91.8% and 31.5%, respectively. Realtime PCR was significantly more sensitive than culture both in pleural fluid (79.7% vs 12.5%) and in blood (17.8% vs 7.4%). In conclusion, our findings indicate that routine immunization with PCV13 has significantly reduced the burden of childhood PPE in vaccinated children, without increasing PPE due to other bacteria and without serotype shift. Moreover, the impact of PCV13 may be underestimated due to the increase in pneumococcal surveillance in Italy. Data has also shown that Real-time PCR is an essential tool to better define the etiology of PPE and to monitor vaccination plans. Longer studies will be necessary to evaluate the role of herd protection in PPE prevention.

Pediatric Complicated Pneumonia Caused by Streptococcus pneumoniae Serotype 3 in 13-Valent Pneumococcal Conjugate Vaccinees, Portugal, 2010-2015.

Despite use of 7-valent pneumococcal conjugate vaccine, incidence of pleural effusion and empyema (pediatric complicated pneumococcal pneumonia [PCPP]) is reportedly increasing globally. We cultured and performed PCR on 152 pleural fluid samples recovered from pediatric patients in Portugal during 2010-2015 to identify and serotype Streptococcus pneumoniae. We identified only 17 cases by culture, but molecular methods identified S. pneumoniae in 68% (92/135) of culture-negative samples. The most frequent serotypes were 3, 1, and 19A, together accounting for 62% (68/109) of cases. Nineteen cases attributable to 13-valent pneumococcal conjugate vaccine (PCV13) serotypes (mostly serotype 3) were detected among 22 children age-appropriately vaccinated with PCV13. The dominance of the additional serotypes included in PCV13 among PCPP cases in Portugal continues, even with PCV13 available on the private market (without reimbursement) since 2010 and with average annual coverage of 61% among age-eligible children. Our data suggest reduced effectiveness of PCV13 against serotype 3 PCPP.

A forgotten epidemic that changed medicine: measles in the US Army, 1917-18.

A US army-wide measles outbreak in 1917-18 resulted in more than 95,000 cases and more than 3000 deaths. An outbreak investigation implicated measles and streptococcal co-infections in most deaths, and also characterised a parallel epidemic of primary streptococcal pneumonia in soldiers without measles. For the first time, the natural history and pathogenesis of these diseases was able to be well characterised by a broad-interdisciplinary research effort with hundreds of military and civilian physicians and scientists representing disciplines such as internal medicine, pathology, microbiology, radiology, surgery, preventive medicine, and rehabilitation medicine. A clear conceptualisation of bronchopneumonia resulting from viral-bacterial interactions between pathogens was developed, and prevention and treatment approaches were developed and optimised in real time. These approaches were used in the 1918 influenza pandemic, which began as the measles epidemic waned. The outbreak findings remain relevant to the understanding and medical management of severe pneumonia.

Pneumonia research in Papua New Guinea: 1967-1986.

Between 1967 and 1985 research on pneumonia in Papua New Guinea (PNG) was fundamental not only to standard treatments of disease in PNG, but also to the establishment of the World Health Organization's global Program for Control of Acute Respiratory Infections. Pneumonia was the leading cause of death in both population-based and hospital studies. Research that began in 1967 revealed a pattern of disease in adults reminiscent of that seen in industrialized countries in the early 20th century. Streptococcus pneumoniae (pneumococcus) was the predominant causative organism. Pneumococci were commensals of the upper respiratory tract that invaded first the lungs and then the blood stream. Some serotypes were more invasive than others and case fatality increased with deeper levels of invasion. The pandemic of Hong Kong (H3N2) influenza spread to the Southern Highlands in 1969 resulting in 2000 deaths. The conclusion that pneumococcal pneumonia had been the principal cause of death led to the establishment of a pneumonia research unit in Tari. A field trial of pneumococcal polysaccharide vaccine showed the vaccine to be most effective in preventing invasive disease. Vaccination reduced pneumonia mortality by 44% in previously healthy adults. The epidemiological situation was more complex in children than in adults because many different species and serotypes of bacteria could be isolated from lung aspirate. Although many of these organisms would normally have been regarded as non-pathogenic, S. pneumoniae and Haemophilus influenzae, recognized pathogens, were the principal causes of severe morbidity and mortality. The same principles of carriage of and invasion by upper respiratory commensals applied as much to children as they did to adults, and the rank order of invasive serotypes of S. pneumoniae and H. influenzae was the same in different age groups. Slow maturation of a child's immune system meant, however, that children could be susceptible to invasion by particular serotypes. Infants were frequently colonized by pathogenic bacteria within days of birth. Nasal discharge, which was extremely common, was most probably a result of domestic smoke pollution and low standards of hygiene. Aspiration of infected secretions was a likely explanation for the variety of organisms isolated from lung aspirate. A trial of pneumococcal polysaccharide vaccine showed the vaccine to be effective in preventing death from pneumonia in children 6-9 months of age provided pneumonia was not associated with other causes of death; this result was shown to be consistent with the principles of infection and invasion described above. Principles of antibiotic therapy for child pneumonia were also established at this time.

Parapneumonic empyema deaths during past century, Utah.

Bacterial pneumonia with empyema is a serious complication of influenza and commonly resulted in death during the 1918 influenza pandemic. We hypothesize that deaths caused by parapneumonic empyema are increasing in Utah once again despite advances in critical care and the availability of antimicrobial drugs and new vaccines. In this study, we analyzed the historical relationship between deaths caused by empyema and influenza pandemics by using 100 years of data from Utah. Deaths caused by empyema have indeed increased from 2000-2004 when compared with the historic low death rates of 1950-1975. Vaccine strategies and antimicrobial drug stockpiling to control empyema will be important as we prepare for the next influenza pandemic.

Historical and regulatory perspectives on the treatment effect of antibacterial drugs for community-acquired pneumonia.

A noninferiority margin based on the treatment effect of antibacterial drugs is required for noninferiority studies of community-acquired pneumonia. A quantitative estimate of treatment effect is generally determined from placebo-controlled trials, but, since the mid-to-late 1930s, no studies have compared outcomes for patients who received placebo (or no specific therapy) with those for patients who received an antibacterial drug for treatment of community-acquired pneumonia. In this article, early controlled studies, as well as observational data, are reviewed, and the beneficial effect of antibacterial drugs on mortality rates among patients with pneumococcal pneumonia is demonstrated. However, because these data were obtained in the early 20th century, several important factors have changed, including patient populations, the etiological agents of pneumonia, and medical standards of care. Thus, the applicability of these studies to the determination of a noninferiority margin for contemporary trials for community-acquired pneumonia remains in question.

George E Holtzapple (1862-1946) and oxygen therapy for lobar pneumonia: the first reported case (1887) and a review of the contemporary literature to 1899.

A commemorative plaque in York Hospital in Pennsylvania, USA, records that George E Holtzapple MD is the physician 'who discovered the use of oxygen for the treatment of pneumonia on March 6, 1885'. This paper suggests that Dr Holtzapple was not the first to use oxygen for pneumonia patients but was the first to publish a case report with a reasoned physiological explanation of oxygen therapy. His publication was intended, in his own words, to benefit 'average country practitioners' who had no other means of learning about this valuable therapy.

Pneumococcal otitis media and pneumococcal vaccines, a historical perspective.

Although pneumococcal otitis media was recognized in the 19th century, the illness stimulated little interest in prophylaxis until recently. Whole cell vaccines of killed pneumococci, developed to prevent pneumonia, were replaced by vaccines of capsular polysaccharides following demonstration of their antigenicity in adults. Failure of the latter to stimulate antibodies in infants and young children and demonstration of the efficacy of capsular polysaccharide-protein conjugate vaccines in preventing infection with Hemophilus influenzae type b has led to the development of polyvalent pneumococcal polysaccharide-protein conjugate vaccines. Preliminary studies have shown them to be highly effective in preventing invasive pneumococcal disease in the first 2 years of life, and studies of their impact on otitis media are currently in progress.

Aetiology and treatment of community-acquired pneumonia in adults: an historical perspective.

Community-acquired pneumonia is common. Most disease is mild but mortality among hospitalized patients is 5-20%. The most common aetiological pathogens are Streptococcus pneumoniae, Haemophilus influenzae, and the 'atypical' organisms, Mycoplasma pneumoniae, Legionella pneumophila and Chlamydia pneumoniae. Less common pathogens account for 10-30% of cases and the aetiology cannot be determined in one-third to one-half of cases. Classification by aetiology and initiation of specific antimicrobial therapy are difficult and treatment is often initiated empirically. Ampicillin (or amoxycillin) or erythromycin are inexpensive and effective for most patients, but their use in combination, the addition of a beta-lactamase inhibitor (e.g. amoxycillin/clavulanate) or the substitution of an expanded spectrum cephalosporin (e.g. cefuroxime) should be considered for patients with more serious illnesses or pathogens likely to be drug-resistant. Fluoroquinolones such as ciprofloxacin or ofloxacin would be acceptable if adequacy for treating pneumococcal infections were likely. New macrolides, such as azithromycin and clarithromycin, and new fluoroquinolones, such as temafloxacin and sparfloxacin, have theoretical advantages over previously available drugs, but superior efficacy has not yet been demonstrated satisfactorily. Pneumococcal resistance in various parts of the world is modifying traditional treatment. Currently, there is no drug of choice for the empirical treatment of community-acquired pneumonia.

Scientific evidence versus therapeutic demand: the introduction of the sulfonamides revisited.

Because of recent changes in Federal Food and Drug Administration (FDA) regulations, new medications may now be marketed before completion of rigorous controlled testing. In order to understand the ramifications of this development, it is instructive to recall the introduction of the sulfonamides in the 1930s. The sulfonamides, the first effective antibacterial agents, were marketed in an era of relatively few regulations. Although investigators at times designed controlled trials to evaluate use of the drugs, both researchers and practitioners generally prescribed them for severe infections, despite a lack of conclusive data as to their efficacy. The clinical usefulness of sulfonamides for a given condition often became known through uncontrolled case studies and comparisons with historical control groups. Given the relaxation of FDA regulations, this method of drug evaluation may again become more commonplace.