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Children aren’t supposed to die.  That so many of us accept this statement without a blink is remarkable and wonderful, but it is also a very recent development in human history.  Modern sanitation, adequate nutrition, and vaccination have largely banished most of the leading killers of children to the history books.  Just look at the current leading causes of childhood death in developing countries to see how far these relatively simple interventions have taken us.

As we have systematically removed the leading infectious killers of children from prominence, other organisms have naturally risen to the top of the list.  This has lead some to the fatalistic (and mistaken) conclusion that we are simply opening up niches to be inevitably filled by other virulent organisms.  This assumes that there is some mandated quota of say, meningitis, that children must suffer every year, and if one organism doesn’t meet this quota then another will fill it.  Were this the case, after vaccination we’d expect to see a shift in the causes of meningitis, but at best a transient drop in the total number of cases per year as other bugs step in to pick up the slack of their fallen, virulent, meningitis-inducing brethren.  Such is not the case.

Though new organisms are now the leading causes of invasive bacterial infections in children, and we have indeed seen some increases in non-vaccine targeted strains, as I’ll discuss below, the total number of such infections has dropped precipitously.  It’s fair to say that the vaccination program has done a remarkable job improving a child’s chance of surviving to adulthood in good health.  However, no one in their right mind would argue that the current state of affairs, as good as it is, is good enough, and so we have shifted our sights to the current leading cause of invasive bacterial infections in children, Streptococcus pneumoniae (S. pneumo, or pneumococcus).

The Need for a Pneumococcal Vaccine

S. pneumo is a challenging bug to prevent and treat.  Its 90 different serotypes together cause a variety of infections, from the relatively mild such as otitis media (ear infection) and sinusitis, to the far more serious including pneumonia, sepsis, meningitis, and osteomyelitis. Much of this versatility and the primary factor determining each strain’s virulence comes from the polysaccharide capsule surrounding S. pneumo.  This gel-like substance hides many of its antigens from exposure, and is itself a poor target for the immune system.

Increasing antibiotic resistance in some strains of S. pneumo certainly doesn’t help the matter, but neither is it the primary cause of S. pneumo’s current position of infamy.  The majority of strains are susceptible to good old penicillin, and even resistant strains are susceptible to other classes of drugs.  The problem is that in a small minority of cases the infection spreads so aggressively that children die or suffer complications in spite of rapid medical care and appropriate antibiotics.

This is why in children prior to 2000, and in spite of modern medical care, S. pneumo caused around 13,000 cases of bacteremia, 2500 cases of pneumonia, 700 cases of meningitis, and 200 deaths (not to mention 5,000,000 cases of otitis media).  As always, prevention would be better than treatment, and in 2000 the first vaccine against S. pneumo for children under the age of 2 was licensed in the US (an earlier vaccine, PCV-23, existed for adults but was incapable of generating a good response in children).  PCV-7 (Prevnar) targeted only 7 of the more than 80 known serotypes, but the seven were well selected, accounting for 80-85% of the cases of invasive disease and a majority of penicillin resistant strains.

Coverage Gaps and Moving Targets

The subsequent 10 years have been almost exactly what you would hope for from the vaccine.  Invasive pneumococcal disease in children has dropped by 76% (including non-targeted serotypes), and disease from targeted serotypes, which recall made up 80% of all invasive disease before the vaccine, dropped 99%.   We’ve even seen a modest but significant decrease in the incidence of S. pneumo disease in the elderly, which is most consistent with the effect of herd immunity.  This is an outstanding success.

Though PCV-7 is effective, it’s also far from perfect.  Predictably, the strains not targeted by PCV-7 have persisted in the population and become more common.  Some of these strains are less pathogenic, but a few have shown themselves capable of virulence, and so in the last decade we’ve seen a shift in the behavior of infections caused by S. pneumo.  One such example of this may be seen in the increased rate of empyema.

Occasionally during a pneumonia bacteria can also infect the space between the lung and the wall of the chest, causing an accumulation of pus that is difficult to treat with antibiotics alone, and usually requires some form of drainage. Typically this is done with a tube inserted between the ribs or thorascopic surgery, and usually includes a prolonged hospital stay.  Needless to say, an empyema is undesirable, and the rate of this complication from pneumonia seems to be increasing.

This concerning trend has been most recently demonstrated by an article appearing in Pediatrics.  Between 1997 (3 years pre-PCV-7 licensure) 2006, the authors found an approximate 50% drop in invasive pneumococcal disease in general, pneumonia, meningitis, and bacteremia, consistent with the existing literature confirming the general efficacy of PCV-7.  However, they also were able to demonstrate a subtle increase in the rates if empyema during the same amount of time.  This means that with a near halving in the total number of pneumonias, but an increase in a complication of pneumonia, the risk of developing an empyema during a pneumococcal pneumonia has roughly doubled in the last decade.

Now comes the hard part: Why?  Well, frankly, we don’t yet know.  This study doesn’t establish the causative mechanism behind the increased incidence of empyema; it simply establishes that it has increased in spite of pneumococcal vaccination. The increase could be part of a previously occurring trend, after all, the incidence of empyema was already increasing before the vaccination was implemented.  It could be from a shift toward serotypes that are more prone to cause empyema, but aren’t targeted by the vaccine.  Unfortunately this particular study isn’t designed to look at involved serotypes, and the other literature to support this hypothesis is currently mixed.  I find it compelling to note that this very study also demonstrates a nearly identical increase in the rate of empyema associated with Staphylococcal pneumonia, suggesting an unidentified common factor between the two.

We Can Do Better

We know that PCV-7 is effective at controlling most infections from targeted serotypes, that non-targeted serotypes are beginning to thrive, and the increased rate of empyema has not been curtailed by the current vaccine.  The next logical step is to broaden our coverage to include the non-targeted pathologic strains within the vaccine.

This is precisely what has been done.  Several vaccines with a broader scope have been in development, and on February 24th the FDA licensed the first of this next generation of pneumococcal vaccines. PCV-13 targets all seven prior serotypes and includes an additional six that together comprise the most common and pathological serotypes currently in circulation (serotypes 1, 3, 4, 5, 6A and B, 7F, 9V, 14, 18C, 19A, 19F, and 23F).  It is slated to replace the current PCV-7, will follow the same 4-shot 2, 4, 6, and 12-15 month schedule, and can be used to complete a series of PCV-7 vaccinations.

This vaccine, like every other one, has undergone extensive testing for both safety and efficacy.  It is built on the identical technology as PCV-7 that has a decade’s worth of excellent safety, and will, as with all other vaccines, undergo even more rigorous post-release surveillance.

Based on PCV-7’s success, we have every reason to expect an even greater reduction in the burden of serious infections suffered by our children. If we’re lucky, we’ll soon have to declare a new bug the leading cause of invasive bacterial infections in children, not because of its success, but because of S. pneumo’s fall.

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Posted by Joseph Albietz