O936 - Complications and Sequelæ of Measles

In 1904, smallpox and diphtheria were fairly under control, so fever-causing diseases and malnutrition were the most important destroyers of human lives. This review by J. Mayer discussed measles, the complications it caused, and ways to treat it back then.

The article doesn't discuss much the frequency of each of these complications; some of them are probably quite rare. But it does demonstrate the wide variety of things that could possibly go wrong in certain (unknown) circumstances when infected with measles.

Mayer claims that measles generally is not dangerous unless complications arise, but these can arise in almost any type of tissue and can cause permanent, serious problems.

"It is hard to combat the old notion that measles is something akin to a common cold with a rash, and that there is nothing to be done but keep the patient warm. It is also difficult, as you know, to have people accept a new medical idea, which is not to be wondered at. The truth is that we, ourselves, too often encourage indifference by some such remark as 'It is only measles.'"

The most common, and thus most dangerous, is pneumonia, often caused by secondary bacterial infection. This happened in at least 5% and up to more than 20% of cases, sometimes with no clear way to prevent it from happening. Even today, in recent outbreaks in the US, 11-25% of cases needed hospitalization.

Next is laryngitis, which can also be caused by secondary bacterial infections. And otitis media, or ear infection, caused a great amount of suffering; if it led to infection, it could result in permanent hearing impairment or even death. And conjunctivitis is fairly common, sometimes leading to eye damage.

Mayer also claimed measles could cause gut problems—diarrhea, hemorrhage, colitis—but seemed like these might've been a result of mistreatment of the disease; the article wasn't clear.

These were the relatively common complications. Others were more rare but serious: meningitis, kidney problems, heart problems, etc. Skin problems such as eczema could occur.

Finally, Mayer quoted from a pamphlet distributed in Glasgow:

"Measles is a dangerous disease—one of the most dangerous with which a child under five yerars of age can be attacked. It is especially apt to be fatal to teething children. It tends to kill by producing inflammation of the lungs...It tends to maim by producing inflammations of the ears and eyes. Measles has carried off more than four times as many persons as enteric fever. It is therefore a great mistake to look upon measles as a trifling disease...It is therefore a great mistake—because as a rule children sooner or later have measles—to say, 'The sooner the better,' and to take no measures to protect them, or even deliberately to expose them to infection."

Seems like good advice.

Reference:

Mayer, J. Complications and Sequelæ of Measles. Cal State J Med 2, 221–224 (1904).

087 - Schick Immunity and Diphtheria Infection

Diphtheria is a bacterial infection that can be pretty serious and deadly, especially in children. Fortunately we can form very good immunity against it, either by infection or vaccination, with antibodies targeting only the toxin that the pathogen produces (diphtheria toxin). 

This means the vaccine is fairly simple to make, the only requirement being that it induces an immune response against this toxin. So people were trying different methods to accomplish this: injecting whole toxin (not a good idea), or toxin mixed with antitoxin (antibodies from someone/something else) to neutralize the toxin, or, the best, toxin inactivated just enough that it didn't cause problems but still induced immunity.

One thing I've noticed is that back when the diphtheria vaccine was being developed, some studies seemed to measure its effectiveness solely by something called the Schick test. This involved injecting a small amount of toxin into a patient's skin, then observing the spot for a reaction. Counterintuitively, a negative reaction (lack of inflammation) indicated immunity diphtheria, the idea being that the patient's immune system could neutralize the toxin before it caused problems. So they took "Schick-negative" to mean "immune."

But as with any test, it needs to be validated, to make sure that the results correlate well with the actual state of immunity being tested. Are Schick-negatives actually better protected from diphtheria? The studies I'm reviewing today look into that question.

087a - Schick Immunity and Diphtheria Infection

Not surprisingly, immunity against diphtheria is never perfect in everyone. E. Ashworth Underwood observed a number of subjects in Leeds to see if Schick-negatives ever caught the disease.¹

Underwood had been overseeing a vaccination program, using toxin-antitoxin mixtures, toxoid, or toxoid-antitoxin mixtures, that started in 1928. Between then and 1935, he observed 2197 Schick-negative patients. Some of these were naturally immune rather than vaccinated.

Of these, 20 came down with diphtheria. Two of them were just naturally immune, while the others were natural plus vaccinated. Except for 2, all were children between 3 and 10. In 4 cases, the disease was subclinical, but 13 needed antitoxin treatment. So there are two possibilities: either the Schick test can be negative in non-immune people sometimes, or the cases were infected with some type of pathogen that overcame their immunity.

Addressing the first possibility: at the time, C. diphtheriae strains were characterized as one of three types (or as atypical): mitis, intermediate, or gravis. This roughly seemed to correlate with how virulent they were, how serious a disease they could cause. Of the 20 cases, 19 were infected with gravis type; so it seemed possible that this type could overcome a higher level of immunity.

How does the case rate in Schick-negatives compare to the rate in Schick-positives? Underwood looked at about 85,000 Schick-positive individuals in Leeds, and saw a case rate of about 1.1%. At best with the Schick-negative cases, not counting the subclinical cases or those with a questionable Schick result, the case rate is at best half as much. So immunity could be said to be less than 50% effective. Not great.

Still, that doesn't mean the vaccine was useless. Leeds seemed to be experiencing an outbreak of a virulent strain that could overcome immunity, for one thing; the vaccine might be more helpful in other places with other strains. Also it's important to note that none of the 20 Schick-negative cases was fatal, whereas the case-fatality rate in Leeds in general was at least 8%, so the vaccine might still have had a benefit.

087b - The Schick Test and Active Immunisation in Relation to Epidemic Diphtheria

In this similar study, Parish and Joyce Wright observed diphtheria cases in London.² Usually immunized people didn't get it, or if they did, it was almost too mild to recognize. They did notice a ward with 27 Schick-negative children, 11 of whom seemed to be carrying gravis diphtheria without symptoms.

In a school near London, there were 248 children and 33 staff. All of these got immunized if they were Schick-positive. An outbreak occurred in 1934, started by newcomers (when vaccination was interrupted by measles, chickenpox, and scarlet fever outbreaks), resulting in 4 cases in Schick-positives and 8 in Schick-negatives (one naturally immune). Half the positives were moderate severity, and 5 of the negatives were called "mild or moderate." They also seemed to be carrying the organism for a while, even two months later.

Again, it seemed like gravis strains were the cause of the outbreak. Unfortunately, it wasn't clear how high an antibody might protect against it.

087c - Alteration in the Incidence of the Gravis, Mitis, and Intermediate Types of C. diphtheriæ in Manchester: And Their Clinical Correlation in a Further Series of 940 Cases
According to Robinson and Marshall in this study, it's difficult to distinguish the three types of diphtheria clinically.³ Though they do cause more or less severe cases on average, and have other distinguishing characteristics, such as in lab cultures. The case-fatality rates were about 15% for gravis, 7.7% for intermediate, and 0.5% for mitis, though other researchers had different results.

They report 13 cases in Schick-negative people (12 of them naturally immune, one immunized). None had a mitis strain by itself, though one had a triple-type co-infection. Three had intermediate, the rest gravis. Two of the gravis cases were fatal, but most were mild.

In people Schick-negative due to toxoid-antitoxin vaccination, 11 got diphtheria. All but 2 cases were gravis, and 5 were severe. One died. So overall, it's not possible to conclude that Schick-negatives will only have mild cases, if any. The authors recommend periodic boosters, though nothing specific.

087d - Review of the Observations which have Accumulated with regard to the Significance of Diphtheria Types in the Last Four Years (1931-1935)⁴
In this paper, K.E. Cooper and colleagues talk about the types of diphtheria again: how types can be distinguished, the severity of disease they cause, etc. Apparently virulence doesn't always correlate with toxin production, they claim.

In Cork, more than 70 people died of diphtheria for every 100,000 in the 1920s, higher than anywhere else. The problem declined after many were immunized. After that, there were 81 cases in 2 years, and 18% of them died in the general population. (22% of non-immunized cases died, while no vaccinated child died.)

In other places, there was a lot of deadly gravis, some more than in others, where other strains predominated. In Leeds, they broke down cases by age, and found that in children under 5, case-fatality was 9-13%; it was 3-11% in ages 5-10 (the high end being gravis epidemics), and 1-4% in ages 10-15. So it's pretty dangerous in young children, unfortunately.

In Cork, Leeds, Manchester, and Stafford together, 5% of all gravis cases were vaccinated, 2.5% of intermediate cases, and 1% of mitis. I'm not sure if this takes into account the proportions of each population (as in, if 95% of the population is vaccinated but only make up 5% of the cases, that's different from if 5% of the population is vaccinated but makes up 5% of the cases). But not all of the cases in vaccinated people were mild; 3 gravis cases were fatal. The conclusion was vaccination is generally helpful though.

087e - Diphtheria in Liverpool with special reference to type incidence and severity⁵
H.R. Shone and colleagues looked at the different diphtheria types again. They found that of all cases for all types, the highest rates were in ages 5-9 (about 50% of cases), another 30% in ages 0-4, 14% in 10-14, and the rest in over 14. There was maybe slightly more mitis in ages 0-4 and more gravis in 5-9 and over 14, if the numbers were accurate.

In contrast to others, they found that intermediate infections were most severe, but the difference wasn't really significant between intermediate and gravis. This was reflected in case-fatality rates: 2.4% for mitis, 10.7% for intermediate, and 6.6% for gravis. And in terms of cause of death, it seemed like mitis caused more laryngeal complications while the others were just super-toxic.

Case-fatality rates went down as age increased, so the youngest children had the highest proportion of deaths, unfortunately.

108 vaccinated patients got diphtheria, though their Schick status wasn't tested (so they might not have been Schick-negative). 50% of the cases were gravis, 34.3% intermediate. Two of the intermediate cases died, two sisters 6 and 9 years old. Another 21 were severe.

Conclusions
None of these studies really made a rigorous investigation of the connection of Schick status and immunity, so I'm not sure what can be said, except that Schick-negative status is not always indicative of total immunity. It's important to note that it didn't seem to matter whether the immunity came from a vaccine or from previous infection, especially in the face of gravis.

I don't think Schick tests are done today, though I'm not yet sure why, so maybe it was decided they weren't that useful. We'll see, hopefully.

References:

1. Underwood, E. A. Schick Immunity and Diphtheria Infection. The Lancet 225, 364–369 (1935). 

2. Parish, H. J. & Wright, J. The Schick Test and Active Immunisation in Relation to Epidemic Diphtheria. The Lancet 225, 600–604 (1935). 

3. Robinson, D. T. & Marshall, F. N. Alteration in the Incidence of the Gravis, Mitis, and Intermediate Types of C. diphtheriæ in Manchester: And Their Clinical Correlation in a Further Series of 940 Cases. The Lancet 226, 441–445 (1935). 

4. Cooper, K. E., Happold, F. C., McLeod, J. W. & Woodcock, H. E. de C. Review of the Observations which have Accumulated with regard to the Significance of Diphtheria Types in the Last Four Years (1931-1935). Proc R Soc Med 29, 1029–1054 (1936). 

5. Shone, H. R., Tucker, J. R., Glass, V. & Wright, H. D. Diphtheria in Liverpool with special reference to type incidence and severity. J. Pathol. 48, 139–154 (1939).