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The Annals of Internal Medicine Qualifies for Fail Blog.

As most readers of the blog know, I am mostly an Infectious Disease doc. I spend my day diagnosing and treating infections and infectious complications. It is, as I have said before, a simple job. Me find bug, me kill bug, me go home. Kill bug. It is the key part of what I do everyday, and if there is karmic payback for the billions of microbial lives I have erased from the earth these past 25 years, my next life is not going to be so pleasant. I will probably come back as a rabbit in a syphilis lab.

It is always fun when my hobby, writing for SBM, crosses paths with my job. This month the Annals of Internal Medicine published “Oseltamivir Compared With the Chinese Traditional Therapy Maxingshigan–Yinqiaosan in the Treatment of H1N1 Influenza. A Randomized Trial.”

I though big pharma was good at coming up with names I do not know how to pronounce. If someone could provide a pronunciation guide in the comments, it would be ever so helpful, so I will not have to embarrass myself when this entry becomes a Quackcast. Dr. Hall wrote about this article on Tuesday, and I have avoided reading her post until this one is up, so there may be overlap in what is discussed.

What is Maxingshigan–Yinqiaosan (MY)? Twelve herbs, one better than the Colonel (and speaking of pronunciation, why is it pronounced “kernel”?) but lacking the spices. It contains

zhimahuang (honey-fried Herba Ephedrae), 6 g; zhimu (Rhizoma Anemarrhenae), 10 g; qinghao (Herba Artemisiae Annuae), 15 g; shigao (Gypsum Fibrosum), 30 g; yin- hua (Flos Lonicerae Japonicae), 15 g; huangqin (Radix Scutellariae), 15 g; chaoxingren (stir-baked Semen Armeniacae Amarum), 15 g; lianqiao (Fructus Forsythiae), 15 g; bohe (Fructus Forsythiae), 6 g; zhebeimu (Bulbus Fritillariae Thunbergii), 10 g; niubangzi (Fructus Arctii Tosum), 15 g; and gancao (Radix Et Rhizoma Glycyrrhizae), 10 g.

Quite the melange of products. Could there be antiviral or immunomodulating molecules in such a hodgepodge? Certainly. There is no a priori reason that Maxingshigan–Yinqiaosan would, or would not, have efficacy against influenza or its complications.

The reasons to test MY are partly appeals to antiquity, “Traditional Chinese medicine has been used to treat seasonal influenza for thousands of years,” plus a reference that, upon searching, does not contain the word influenza. Or pneumonia. Or respiratory tract infection.

You have to wonder, when you are in the second paragraph of the introduction and looking up the primary sources and they do not match the text, just how careful the researchers and the editors of the journal are. It’s the Annals. Not very. Which is why my subscription lapsed. And, to demonstrate just how infantile I can truly be, when I discuss the journal with residents, I pronounce it as if it had one ‘n’. But do not accidentally type in the url at work with Annals spelled with one ‘n'; I discovered our firewall filter has an Anals.org weakness.

In Europe, pandemic influenza has been recognized for perhaps 500 years: “Then suddenly, in July and August 1510, a ‘gasping oppression’ with cough, fever, and a sensation of constriction of the heart and lungs began to rage, seemingly everywhere at once.” And local flu has been known for maybe 650 years. Given those numbers, “thousands of years” seems a wee bit of hyperbole, especially when the reference doesn’t support the assertion. And as best I can tell from the Googles, no influenza was reported in China until the 1800s, and given traditional diagnostic testing modalities, I doubt they were looking at patterns of disease that would be identified today as influenza.

Then they say

In a recent meta-analysis of 31 randomized clinical trials including 5514 cases of influenza, the authors concluded that TCM had significantly increased clinical efficacy compared with placebo or no intervention.

And that analysis was? A systematic review of chuanhuning for acute respiratory tract infections. Chinese Archives of Traditional Chinese Medicine. 2007;25:2200-3.

The abstract said “There were 31 RCTs with 5514 cases were involved.” 5514 cases of acute respiratory tract infections, not 5514 cases of influenza.  Although I may be slapped down for this, as the original is in Chinese and there is nothing on the Pubmeds relating to chuanhuning.

Looking for the primary references of the systematic review as best as I could given the language issues, the Googles find “etiological diagnosis by clinical experiments and tissue civilization experiments show namely the product of inactivated influenza virus A type Ⅰ, Ⅲ type A, pneumonia, adenovirus (Adv) Ⅲ type, Ⅳ type, intestinal syncytial virus and respiratory syncytial virus (Rsv) have inactivation” and the few trials I could locate were for a hodgepodge of viral and other upper and lower respiratory infections.

Chuanhuning is not in the current regimen to be tested, and the authors of the systemic review mention “the evidence is not strong due to the general poor methodological quality.”

The argument, not supported by the references, for testing MY is: product A may work for influenza, so let’s try an entirely different product for influenza. Could the editors of the Annals be doing a worse job at reading the papers in their journals?

They then mention “Modern pharmacologic studies demonstrated that some TCM formulas had antiviral and immunomodulating effects (13, 14).” Reference 13 is Chen N, Ren L. [Modern pharmacology research and clinical use of max- ingshigan]. Academic Journal of Guang Dong College of Pharmacy. 2004;545-6. and reference 14 is Huang JM, Chen DP, Yang LP. [The immunomodulating effects of maxingshigan on asthma mice models]. Journal of Fujian Traditional Chinese Med- icine. 2003;34:38-9. At least both references have maxingshigan in the title, but whether the content matches the assertions, well, let’s say their credibility has not been demonstrated.

Of course, no study of “Eastern” medicine would be complete without the appeal to popularity:

During the early days of the 2009 H1N1 influenza A pandemic, the popular herbal formula maxingshigan–yinqiaosan was used widely by TCM practitioners to reduce symptoms.

Years ago, at conference, one of my attendings was being detailed about a new antibiotic, and the rep finished up with “and it is popular in Europe.” To which my attending replied “So was Hitler for a while.” A pre-Interweb version of Godwin’s Law.

Searching for Maxingshigan–Yinqiaosan in the Pubmeds yields little but the intriguing, yet unavailable, Two hundred and thirty-five cases of high fever caused by exopathogen treated with yinqiao maxing shigan tang.

I went through the tedium of searching each component of MY in the Pubmeds and its relationship to influenza and found nothing of note.

So the reason for the study, really, is that people were using it. Let’s see if it really works.

They randomized people with mild PCR proven influenza to

Oseltamivir, 75 mg twice daily; maxingshigan– yinqiaosan decoction (composed of 12 Chinese herbal medicines, including honey-fried Herba Ephedrae), 200 mL 4 times daily; oseltamivir plus maxingshigan–yinqiaosan; or no intervention (control). Interventions and control were given for 5 days.

Primary outcome was time to fever resolution. Secondary outcomes included symptom scores and viral shedding determined by using real-time reverse transcriptase polymerase chain reaction.

It was not blinded, only a small flaw given the endpoint, and most patients did not receive an intervention until relatively late in the disease, when the impact would be lessened

In our study, the median time from onset of illness to randomization was 34.5 hours; 23.2% of patients presented 48 to 72 hours after the onset of symptoms.

Sooner is better with the treatment of all acute infections, and given the delay in therapy, they are approaching a natural history of disease study more than a therapeutic intervention study.

They found

Significant reductions in the estimated median time to fever resolution compared with the control group (26.0 hours [95% CI, 24.0 to 33.0 hours]) were seen with oseltamivir (34% [95% CI, 20% to 46%]; P < 0.001), maxingshigan–yinqiaosan (37% [CI, 23% to 49%]; P < 0.001), and oseltamivir plus maxingshigan– yinqiaosan (47% [CI, 35% to 56%]; P < 0.001). Time to fever resolution was reduced by 19% (CI, 0.3% to 34%; P < 0.05) with oseltamivir plus maxingshigan–yinqiaosan compared with oseltamivir. The interventions and control did not differ in terms of decrease in symptom scores (P < 0.38).

The actual numbers: control had fever for 26 hours, oseltamivir for 20, the MY 16 and the oseltamivir plus MY was 15, in real numbers the results are almost clinically irrelevant. And the treatment groups were randomized later than the no treatment group, and temperatures measurement started at randomization. So if the treatment groups have a head start in temperature measurement, that wipes out at mostly of the therapeutic advantage doesn’t it? Most of the difference due to when they started counting.

If you measure from symptom onset to resolution of fevers, you get

Control: 56 hours
MY: 51 hours
Oseltamivir: 55 hours
MY plus oseltamivir: 47 hours

It is the duration of illness that is clinically the important feature, so even if the effects are statistically significant, the difference is not clinically significant.  And besides fever, there was no improvement in other symptoms: “No difference in any individual symptom, including cough, sore throat, headache, or fatigue, was observed after treatment.” Fever often remits before other symptoms of influenza, and given the duration of illness, from a clinical perspective, none of the interventions did much of anything.

As to viral shedding

the median viral titer in throat swabs at enrollment was similar, and a rapid decrease in virus shedding was observed in all 4 groups (P < 0.001) Changes in virus shedding from baseline to day 5 did not differ by treatment group (P < 0.69 for time-by-treatment interaction).
Both baseline swab specimens and specimens collected on days 1 to 5 for evaluation of virus shedding were available for 148 participants. Compared with the 262 patients without viral shedding measurements, these 148 patients had lower symptom scores; a lower proportion of cough, headache, and fatigue; lower leukocyte counts; and longer time from onset of illness to randomization. Therefore, the virus shedding results from these 148 patients were not representative of the entire study population

But when you look at the actual curves,

there is separation between the oseltamivir containing regimens and those without, with the MY closer to the control. It suggests that the effect of MY is anti pyretic/immunomodulatory rather than antiviral. And given that the control group started the PCR measurements earlier as well, yo would expect slighly higher viral levels. If there is an effect from MY, it is a small one, and it appears to be less antiviral and more antipyretic, although the authors state

The study could not determine whether the observed effects of maxingshigan–yinqiaosan were due to anti- pyretic or antiviral effects.

I bet the former.

Given that the patients were all healthy, had mild illness and were treated relatively late in the disease, I would expect to any intervention to have a modest effect, and theirs was modest indeed.

Non sequitur central continues in the discussion where they discuss potential mechanisms of action and note

During the outbreak of the severe acute respiratory syndrome in Hong Kong, Poon and associates (24) showed that 2 herbal formulas had immunomodulating effects. In their study of healthy volunteers, they found that the CD4 –CD8 ratio of T lymphocytes was significantly increased after participants received Chinese herbal medicine for 14 days (24).

The reference, Immunomodulatory Effects of a Traditional Chinese Medicine with Potential Antiviral Activity: A Self-Control Study, states

We investigated the immunomodulating effects of an innovative TCM regimen derived from two herbal formulas (Sang Ju Yin and Yu Ping Feng San) for treating febrile diseases.

I am limited by language, variability in TCM medications and lousy editors at the Annals, but apparently Sang Ju Yin is Mulberry & Chrysanthemum Pills and Yu Ping Feng San, or Jade Screen Teapills, and neither have any ingredients in common with MY.

Sang Ju Yin and Yu Ping Feng San has to do with the mechanism of MY how? That is the kind of discussion the Annals has for its readers: randomness. Linear, logical thought appears passé these days. The authors seem to think all TCM are the same, and there is no reason to differentiate one TCM over another for mechanism of action: “More studies are needed to clarify the mechanisms of TCM.”

Me and my reductionist Western approach, thinking that different products, with different constituents, are actually different, with perhaps different, unrelated mechanisms of action, if they have a mechanism of action at all.

There were articles, again not available in English, that demonstrate in vitro effects of shigan on influenza A. That the references indeed demonstrate what the authors purport, well, I will have to trust the researchers and the editors of the Annals. They have done a fine job to date.

It would appear from one abstract, that 31.25 mg/ml of maxing shigan had multiple effects on viral replication in the test tube and that 31.25 mg/ml was the optimal concentration of the product.

In the study patients received 200 mL of MY orally 4 times daily. So for fun, assume 100% bioavailabilty. Lets assume 31.25 mg/ml in the preparation the patients received. Who knows. 200 x 31.25 is 6250 mg. A human volume is about 70,000 mls.  Assuming a uniform volume of distribution, that gives the concentration of MY at 0.089 mg/ml. Seems a wee bit below the needed MIC. Of course, a lot of assumptions in the calculation, mostly around the concentration of the medication, its absorption and the volume of distribution. The first and third were guesses, the second was probably a large overestimation (medications are rarely 100% absorbed). The real concentrations of MY are probably much less that 0.089 mg /ml.

50% alcohol will also inactivate influenza in vitro. Outside of a frat party, those levels are not achievable in vivo. Always the issue of going from in vitro to in vivo studies

The authors finish up with

In conclusion, in previously healthy young adults and adolescents who presented with uncomplicated 2009 H1N1 influenza A virus infection, therapy with oseltamivir and maxingshigan–yinqiaosan (alone and in combination) was associated with faster resolution of fever. Maxingshigan– yinqiaosan can be used as an alternative treatment of H1N1 influenza A virus infection when oseltamivir is not available.

and the abstract, which is all most people will read, ends with

These data suggest that maxingshigan– yinqiaosan may be used as an alternative treatment of H1N1 influenza virus infection

So here is where I am going to get picky.

My take, looking at the PCR data, is that MY does not treat influenza. There is no real change in the PCR viral concentrations. When you treat an infection, you kill it, or at least prevent it from reproducing. They did not treat influenza, they treated an epiphenomena of influenza, the fever. Treating fever is not the same as treating infection. And of course, it looks like the effect is an artifact of when they started counting, and given the lack of response of other symptoms, this is a mostly a natural history of influenza study.

And should you treat fever? Well, no. There is an interesting literature, with many a methodological issue, that suggests treating a fever is not a good idea.

In animal models and human studies, treating a fever is associated with prolonged illness and, depending on the study, increased mortality. There is no definitive study, but an hour of perusing the literature will show an interesting pattern. Fevers are usually good. Treating fevers is usually bad.

Fevers are an important and ancient response to infection. Most parts of the immune system function better at higher temperatures. Sometimes the patient lacks the physiologic reserve to cope with the metabolic demands of fever (poor cardiac or lung function) and strokes and heart attacks may be larger if the patient has a fever. So sometimes you need to treat fevers. But for most acute infectious diseases that have been evaluated, patients  and animals that have their fever suppressed are have a more prolonged illness, more complications, or increased mortality.

I never treat my kids fevers. They make less noise when they are 102 and will probably resolve their infection faster if I let the fever go, and that will get them to school and me to work that much sooner. Of course, when my wife takes over, she gives them Tylenol. No man is a hero to his valet. Not that my wife is my valet. It is a saying.

I could find no specific data regarding outcomes in treating influenza associated fevers, but I expect like most other infections, it would be a bad idea. And there is always that point in the inflammatory response where the beneficial effects are overwhelmed by the adverse effects of too brisk a response: SIRS, sepsis, TSS and the ever popular cytokine storm, although the fever per se is not issue in those processes.

What annoys, and concerns me at the end, is the confusion between treating influenza and treating the symptoms of influenza. The first was not demonstrated, the second perhaps was and is usually a bad idea.

Conclusion

The effects of MY on fever are probably not real, and if real are mostly clinically irrelevant and probably counterproductive for the treatment of influenza.

As to the mechanics of the paper (proper use of references, critical thinking), if it were from a college student, I would give it a ‘C’.  If it were from a resident on service? Flunk.

And the Annals? In my professional lifetime they have gone from a first tier journal to second tier to now? Now, I shed a tear. Almost as funny as Fail Blog.

Posted in: Basic Science, Clinical Trials, Herbs & Supplements, Science and Medicine

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