Liam Scheff has now turned his attention from HIV to avian influenza, with predictable results. Analysis below…
Scheff’s self-stated goal is to “…review some of the bright and shiny inconsistencies that have come into view on the bird flu.” However, he’s not exactly consistent himself, ranging from minor errors to total contradictions of his own words. He starts off discussing “stray cats and Chinamen:”
In March, 2006, The Associated Press reported: “In Austria, state authorities said Monday that three cats have tested positive for the deadly strain of bird flu in the country’s first reported case of the disease spreading to an animal other than a bird.”
The report quoted the World Health Organization (WHO), which said that “bird flu poses a greater challenge to the world than any infectious disease, including AIDS…”
Really? Bigger than AIDS? Who knew? But why would it be so? Because three cats in Austria tested positive? What does that mean? How many cats, in all of Austria, did they test? What would happen if you tested every cat?
Of course, he mocks the finding and ignores the significance. Thing is, cats typically don’t get flu, and the fact that it’s able to infect such a wide range of mammals (several species of cats, dogs, stone martens, potentially foxes and hyenas, etc.) is what makes it worrying and a major finding, not just that “three cats in Austria” tested positive.
He then discusses a “2004 Nature Medicine study” that he suggests shows that “millions” of people have tested positive for “bird flu.” Too bad that’s not the case at all.
In fact, seroepidemiological studies conducted among the rural population in China suggest that millions of people have been infected with influenza viruses of the H4-to-H15 subtypes. Specifically, seroprevalence levels of 2−7% for H5 viruses alone have been reported, and the seropositivity of human sera for H7, H10 and H11 viruses was estimated to be as high as 38, 17 and 15% respectively.
As an “investigative journalist,” I’m surprised he didn’t fact-check this a bit more. These data didn’t come from the Nature Medicine paper; they came from a 1992 paper in Seminars in Respiratory Infections. Revere over at Effect Measure already commented on this paper back in December. Thing is, in this paper they only measured antibodies to the hemagglutinin, and didn’t test the neuraminidase type. (The hemagglutinin and neuraminidase are two surface proteins of the virus, and are recognized by the immune system. They give the virus its “H” and “N” type). So Scheff is simply wrong when he equates “antibodies to H5” with antibodies to H5N1. Low-pathogenicity H5 avian viruses have previously been reported, including both H5N1 and H5N2 serotypes, so even if they had typed the neuraminidase and found it to be H5N1, we still don’t know if (assuming the Chinese seroprevalence data are indeed correct) they were exposed to the strain of high-pathogenicity H5N1 that’s circulating currently. Indeed, there is evidence that humans can–and have–been infected occasionally with avian influenza viruses, but the high-pathogenicity H5N1 virus seems to be in its own category.
And that’s just the beginning.
Scheff next sarcastically addresses the 2005 NEJM report documenting H5N1 in two children from Vietnam. He suggests that, instead of H5N1, the childrens’ deaths were due to a combination of their lifestyle (poverty, poor sanitation) and the antibiotics they were given. He cites a few reports of adverse reactions to these drugs (no surprise to anyone who’s ever administered or taken antibiotics; allergies and other adverse reactions are always a concern), but he ignores even part of what he cites. Reactions to antibiotics are typically pretty quick: as even he notes, they develop “within minutes to hours of drug administration”. However, the girl died a day later, and her brother died 4 days after treatment. I also find it very difficult to accept that the doctors wouldn’t have mentioned an adverse reaction to the antibiotics in the case report.
He then makes this strange statement: “What do antibiotics do for viruses? Nothing. Nothing at all. Presuming a virus was the problem.” However, a virus wasn’t presumed–a bacterial infection was, which was why antibiotics were given. It’s right there in the paper: “The differential diagnosis was septicemia [bacteria in the blood] from a gastrointestinal source or acute encephalitis.” H5N1 wasn’t diagnosed until after death. Additionally, while Scheff claims that “no one was interested” in examining whether “toxic shock” (presumably due to antibiotic administration) played a role in the deaths of these children, he’s obviously overlooking the fact that it was the very examination of tissue samples from these kids that led to the diagnosis of H5N1. Additionally, H5N1 has been suggested in other cases (and cell culture models) to cause massive cytokine production. This is similar to the “Spanish” influenza virus of 1918, which was capable of causing a “cytokine storm” that resulted in a massive immune response, lowered blood pressure, and “shock”–which can be the cause of death, rather than the secondary bacterial infections that typically cause death during influenza virus infections. So “shock” alone wouldn’t be diagnostic of an antibiotic reaction.
Scheff also makes much of the issue that lumbar punctures (“spinal taps”) were performed on the children–after he chides the officials for their faulty diagnosis and lack of allergy testing, and then calls the children “poorly cared for” (partly because of the test they did perform!) Diagnostic tests often are invasive; it’s the nature of the game, unfortunately. I’ve had a spinal tap, and I agree they’re definitely unpleasant, but they’re needed to rule out (or confirm) bacteria in the cerebral spinal fluid. Scheff makes much of the description in the article of the boy’s LP as a “slightly traumatic lumbar puncture:”
What does this mean, exactly? That the child squirmed, the flesh was torn wider than was intended, it bled a great deal, he was frightened, they did the procedure poorly and went into a nerve or jammed the needle in too far? Who knows? They don’t say, only that it was “traumatic”.
I’m no doctor either, so I didn’t know exactly what a “traumatic” LP was, but it would surprise the hell outta me if the NEJM published an article discussing a patient’s emotional reaction to a procedure in that type of language. So, I checked it out. It took me all of a minute on Google to find out that it’s apparently referring to the appearance of the specimen (“first specimen bloody, rest clear”), resulting, I assume, from the introduction of red blood cells into the fluid during the puncture. It’s not referring to child’s mental state.
Scheff also makes an issue of the fact that the researchers even reported the atypical presentation of H5N1 in the Vietnamese children. The authors of the case report noted that the children had no respiratory symptoms and instead presented with diarrhea and encephalitis, leading them to conclude that physicians should consider H5N1 for a wider range of symptoms than seen typically with influenza. Again, that’s one thing that makes this report so important: they’re not typical cases, suggesting that the case definition for suspect H5N1 infection needs to be broadened so that we’re not missing cases. Scheff seems to want doctors to consider every possibility, except the ones he disfavors. And of course, he suggests that this “look beyond the norm” message is really some kind of conspiracy: “If I didn’t know better, I’d say that it sounded like somebody was trying to make it a lot easier to diagnose people with bird flu.” Docs just can’t win with Mr. Scheff–if you consider more than the typical pathogens, you lose; if you make a narrow assumption that turns out to be wrong, you also lose. Nothing like stacking the deck. Perhaps Scheff doesn’t realize that in birds, influenza is an intestinal illness. Just because we’ve not seen it present that way previously in humans doesn’t mean it’s not possible.
He goes on to suggest that physicians are even attributing just “fever and diarrhea” to infection with H5N1, regardless of viral presence: “Fever and diarrhea in Vietnam used to be ‘fever and diarrhea’…But now we don’t have to think about that. Because now, it’s ‘deadly H5N1′”. Of course, sarcasm aside, this is patently false–if even a minority of cases of “fever and diarrhea” in Vietnam or elsewhere were considered to be H5N1, we’d have a helluva lot more than 224 cases by now. Additionally, it’s even noted in the article that “culture and parasitologic examination of stool specimens did not reveal enteric pathogens.” Checks for normal diarrheal pathogens were done–and were negative. Out-of-the-box thinking was necessary–sometimes, hoofbeats do mean zebras instead of horses.
Sheff also misstates how the case of H5N1 was diagnosed. He claims:
It should be noted that only one child’s death was attributed to the flu – the younger brother, who died in five days. Why? Because only his sample remained when the WHO came to town, nine months later, scavenging for potential flu cases. The children died in February, 2004; the WHO made the bird-flu diagnosis in November.
From reading that, you’d think the boy’s sample was just sitting around, waiting for the WHO. But by reading the paper, you find he’s leaving a heckuva lot of intervening information out. From the NEJM article:
Patient 2 (the “younger brother”) was included in an ongoing study of the causes of acute encephalitis, and hence throat and rectal swabs and cerebrospinal fluid and serum specimens were stored at -80°C.
After his death, patient 2’s samples were then tested for a variety of viruses as a part of this study, including dengue, Japanese encephalitis virus, herpes viruses, enteroviruses, and varicella-zoster. These tests all took time (and all came back negative), and then they note that “further efforts at identification were delayed until late October.” For anyone who does these types of retrospective diagnostic studies, you probably know that this is just how it goes–at times, if things aren’t critical, they get pushed to the back burner. When they resumed the investigation, they inoculated the samples onto two different cell lines, and cytopathic effects (CPE) were seen. It was only then that they began to suspect influenza. Even if this was because “the WHO came into town, scavenging for cases” as Scheff contends (unreferenced, I might add), so what? It’s known that influenza can cause encephalitis, though it’s not a common manifestation, so it’s not as if it’s unreasonable to test a patient who died of encephalitis of unknown cause for viruses that are known to cause it! It’s rather common-sensical, as a matter of fact. What was unique about this case, however, was that it wasn’t caused by your run-of-the-mill influenza virus: it was caused by H5N1, which was then subsequently isolated from the patient’s stored throat and rectal swabs as well. It’s not some vast conspiracy; it’s just how diagnosis of rare infections happen.
Sheff also seriously contradicts himself. He again quotes the NEJM article, which says regarding bird exposure: “We cannot rule out the possibility of mild or subclinical infection in persons exposed to either ill poultry or ill persons,” and jeers:
“Mild bird flu” can’t be ruled out? I’ve never heard that on the evening news. So what would make a case “mild or subclinical” versus “fatal”?
Yeah, some jaws are probably dropping, since Scheff’s opening salvo was all about the claim that millions in China had been infected–obviously either mildly or subclinically–with H5 serotypes of influenza! And he may not have “heard that on the evening news,” but even he admits he read it in the New York Times. Clearly, the main difference between “mild or subclinical” versus “fatal” is that those with a mild infection survived–and those with a fatal infection, obviously, died. We have much evidence for the latter–127 deaths and another 97 cases severe enough to require hospitalization–but thus far, there hasn’t been much evidence that the high-pathogenicity strains of H5N1 are causing much mild or subclinical infection. This is something I’ve written about previously, and I still would be somewhat surprised if there were no subclinical (or mild-but-unrecognized) cases that we’re missing, but thus far, there simply isn’t much evidence for them. Hopefully that will change soon as studies looking for such cases get underway, but from the evidence we have now, we simply can’t say that they’re out there. I wonder if Scheff will criticize these surveillance studies as “scavenging for potential flu cases,” as he does regarding the Vietnamese cases.
Finally, Scheff makes an odd argument about culling of birds:
Of all the birds that have died worldwide, how many actually died of illnesss? No one seems to be bothered by the question…
And indeed, no one denies that millions of birds have been purposely culled to prevent the spread of the virus. But it’s not only to prevent human disease; it’s also to prevent its spread through the domestic poultry (though Scheff claims that it’s “because it could be infectious in humans”, which is only a part of the reason). Additionally, it’s not that it “could be” infectious in humans–it is infectious in humans. It simply isn’t highly contagious in humans yet (difference is explained here)–which Scheff spends more time emphasizing (as if that point hadn’t been hammered home enough by other journalists and researchers? Doesn’t almost every article on the topic discuss how the real trouble starts when/if it becomes human-to-human transmissible?).
However much you stretch things in biology, there is simply no place for viruses as the causative agents of diseases.
Maybe that’s coming in Part 2.
de Jong et al. 2005. Fatal Avian Influenza A (H5N1) in a Child Presenting with Diarrhea Followed by Coma. NEJM. 352:686-691.
Palese, P. 2004. Influenza: old and new threats. Nature Medicine 10:S82 – S87.