A recently published paper, with the outcomes of a collaborative European Randomized Controlled Trial (RCT) undertaken in Germany and Ukraine, is making waves amongst jubilant homeopaths as yet another evidence supporting their long-held belief in the clinical effectiveness of homeopathy. Naturally, this 2016 paper in the Journal Global Pediatric Health by van Haselen et al. piqued my curiosity and I dove in to see what the hullabaloo was all about.
Spoiler: Nothing much, actually. Yet another homeopathy study of poor methodological quality… with a twist at the end that made me go “Hmmm…” But I digress; let me unpack the paper’s content.
The Condition Treated: URTI
URTI, or upper respiratory tract infections, is a catch-all term for what is known as the common cold, an acute, usually mild and self-limiting viral infection of the upper respiratory tract, with symptoms ranging from sneezing and sniffling, nasal congestion and discharge (“rhinorrhea” or runny nose); to sore throat, cough, sometimes low-grade fever; to even headache and malaise. Various types of viruses may cause the symptoms of common cold; most commonly, Rhinoviruses, and also the viruses responsible for influenza and parainfluenza, adenoviruses, Respiratory Syncytial virus (RSV), various enteroviruses, coronaviruses, and human metapneumovirus. Except for the influenza virus, none of the other viruses associated with common cold have specific antiviral treatment options.
Common cold can affect adults and children differently. In the US, uncomplicated URTIs annually send approximately 25 million individuals to seek medical care, including nearly 2 million to the Emergency Departments (ED); in a third of these visits, unnecessary antibacterial agents are prescribed due to inaccurate patient perception that bacteria causes colds. This inappropriate antibiotic-seeking trend lead to increased utilization of health services and direct associated costs for both adults and children. In addition, since young children get colds at a higher frequency and for a longer duration that do adults, this ubiquitous affliction accounts for serious productivity loss, in terms of approximately 22 million missed days of school and 20 million absences from work, including time taken by caregiving parents tending to ill children.
image credit: Memo Angeles/Shutterstock
To be sure, common cold is decidedly a societal burden in terms of human suffering and economic losses; in addition, inappropriate use of antibacterial agents is known to contribute to the growing phenomenon of antibiotic resistance. These are some genuine concerns that are exploited by alternative medicine practitioners to peddle ineffective modalities such as homeopathy and acupuncture, without ever emphasizing the self-limiting nature of these symptoms.
I have now mentioned self-limiting nature of common colds twice – why? Because this is a central concept, along with ‘regression to the mean’, which are important to understand in order to assess the claims of homeopathy and other alternative medicine modalities.
Self-limiting nature of URTIs
Systematic studies of the natural history of cough and cold in children of various ages have yielded an interesting observation; the symptoms, most commonly nasal congestion, runny nose and coughs, usually peak on day 2 to 3 of illness and then gradually improve, finally resolving spontaneously by a couple of weeks. Post-nasal drip (nasal discharge running backward into the throat) may cause the cough to linger in some children for a little while longer, up to 3-4 weeks. Symptoms in older children and adolescents resolve within a week in absence of any other comorbidities. Interestingly, even when the etiology was found upon testing to be bacterial (such as Streptococcus pneumoniae or Hemophilus influenzae) in about a third of the children, the types, severities and durations of their symptoms were no different than those from viral etiologies found in the majority.
To clarify, in a minority of children, sometimes common colds may lead to secondary complications, some of which may be due to acute bacterial superinfections and need to be treated with appropriate antibiotics. The symptoms of these complications are rather well-studied, and the treating physicians are able to use their clinical judgement to resolve those. But for the overwhelming majority of cases, symptomatic colds resolve on their own.
Now, back to the study…
The second paragraph of the introduction —where Homeopathy is extolled— the authors mention ‘popularity’ in Germany, reports of positive user experience, and common use in German children especially for flu or cold related problems, and introduce the brand name of the preparation ‘influcid’ they used in this study. The only two articles cited about influcid’s efficacy (nothing about general homeopathy’s efficacy claims in these condition) are in German (from 1992) and Russian (from 2010).
To justify the promulgation of this study, the authors write: “… there is no approved specific therapy for URTI and because conventional medicines sometimes lead to side-effects and inappropriate use of antibiotics…” This statement, while true in the strictest sense, omits the most important clarifications – that this applies only uncomplicated URTIs, and that “no approved specific therapy” doesn’t mean that there are no guidelines for treating young and older patients for the symptoms of common cold.
Strangely, this paper appears to be a substudy in a pediatric cohort for a study done in adult and pediatric patients with URTI and fever, for which the results have been published in an English-language German altmed journal in 2015. I don’t know what the publication policies of Global Pediatric Health are, but republishing of the same results seems a rather odd move for a journal. I am surprised that the peer reviewers for this journal would allow this.
Study qua study it is not remarkable. Children aged 1-11 years were recruited in Ukraine and Germany, both nations where homeopathy is highly popular, if they displayed clinical symptoms of URTI with fever. Subjects were randomized to receive:
- Either what was termed (with no reference given) as a ‘standard’ treatment (with paracetamol, a.k.a. acetaminophen in the US – an over-the-counter medicine with pain-killing, fever-reducing and mild anti-inflammatory effects; ambroxol, a mucolytic agent with mild pain-relieving action; and oxymetazoline nasal spray, a decongestant which acts by constricting nasal blood vessels to reduce the flow of fluids into the mucosa)
- Or this ‘standard’ treatment supplemented with the homeopathic preparation marketed as Influcid.
What is Influcid, anyway?
It is a combination preparation containing “6 homeopathic single substances (Aconitum D3, Bryonia D2, Eupatorium perfoliatum D1, Gelsemium D3, Ipecacuanha D3, and Phosphorus D5)”; the manufacturer’s website (which I shall not link to from here) lists these ingredients in greater details with descriptions and claims of clinical benefit of each (with no reference adduced for any). Interestingly, the website doesn’t indicate the doses of the individual substances included in the combination; the paper does, and it is important to understand these doses. ‘D’ refers to decimal (same as the ‘X’ designation in other countries) dilutions; a D2 means a 1:100 dilution, D3 a 1:1000, and D5 a 1:100,000. Which brings us to two crucial dilemmas.
It depends upon the starting dose of course – but these relatively lower dilutions increase the likelihood of the molecules of the actual substances derived from these plant and salt-based ingredients being present in the final preparation. Therefore,
- It begs the question whether these preparations can technically be considered “homeopathic”. In various Aphorisms of his homeopathic treatise Organon Hahnemann talked about 8-12 succussions (the shaking and serial dilution process), but throughout his life, he has practised centesimal (dilution steps by 1:100) and even LM (1:50,000) dilutions. In comparison, to such infinitely diluted material (no molecule of the original substance likely remains at a dilution beyond D24/24X or 12C), the D1-D5 doses are positively choc-a-bloc full of the starting material, which ought not to jive well with classical Hahnemannian homeopathy.
- That raises an additional, and more concerning, issue. The substances in this preparation are derived from:
- Aconite/Monkshood plant – most species are extremely poisonous; the toxic principle causes cardiovascular and sensorimotor collapse.
- White Bryony/English Mandrake vine roots – all plant parts carry a toxic glycoside which induces severe vomiting which can be fatal.
- Eupatorium/Boneset/Feverwort plant – used in Native American traditional herbal medicine, this plant has shown moderate anti-inflammatory activities in vitro and in animal studies, making it a good target for ethnopharmacological studies; however, there is no evidence of its clinical efficacy.
- Gelsemium/Yellow Jasmine rhizome and roots – known poisonous plant, with one toxic alkaloid that cause extreme relaxation of involuntary muscles by inhibiting certain nerves (which can lead to nausea, diarrhea, spasms, blindness and even death) and another which causes DNA damage.
- Ipecac rhizome and roots – toxic alkaloids from Ipecac irritate the gastric mucosa and stimulate certain brain parts to induce vomiting.
- White phosphorus – molecular phosphorus that is flammable and highly toxic, causing severe liver damage and necrosis of the jaw.
Clearly, not substances one bandies about willy-nilly, with no regulation. However, the claims of safety appear justified from the clinical data presented by the study under discussion and its parent study; therefore, I imagine that the undisclosed starting concentrations of these substances are low enough so that even at 1:100 dilutions, they are rendered non-toxic. Interestingly, at the manufacturer’s website, the section on “Clinical Evidence” speaks of “years of positive experience and studies” but actually refers to the study under discussion as evidence, like a self-fulfilling prophecy.
The assessment of clinical conditions was done via a diary completed by parents and a questionnaire survey, in addition to baseline and follow-up visits and calls. But more on this later.
The first issue that struck me was the claim of earlier (by 2 days) symptom resolution in the Influcid group compared to the standard treatment (ST) group. To me, the absence of any adjustment or weighting in this assessment with respect to initial presentations makes this claim suspect, because per their Table 1, following the randomization of the subjects, the ST group had at baseline perceptibly higher numbers of children with impairment of ability to perform daily activities and cough, two of their main URTI symptoms considered. Even in case of the children without fever (figure 3), the ST group seemed to have more children with fever at the baseline – again with no correction applied for that important variable. I’d also have liked to see the statistical analysis applied, but it is only mentioned – not shown.
The other outcome measures (including Quality of life outcomes) presented in Table 3 seem impressive at first with overall less symptomatic drug use and for less duration in the Influcid group. Immediately thereafter, one becomes aware of the single major lacuna in this study that casts a doubt on ALL the outcome measures, especially the subjective ones: the facts that
- There was no blinding in the randomization and treatment allocation, and
- There was no placebo control for Influcid!
Subjectivity and bias in observations
Consider this for a moment: the study subjects were recruited from areas which are already primed to hold a good deal of belief in the efficacy of homeopathic medications. One of the mainstays of the clinical evaluation, especially measuring the metrics like “Quality of Life”, was dependent upon parent-completed diaries and a questionnaire survey. And these parents were privy to the information on which medication they were being given, and the fact that the ST group did not get anything resembling the Influcid pill. How can we — more importantly, why did the peer reviewers — not see the immense chance of subjectivity and bias in the recording of these results? How does one trust the outcomes of such a study?
In the popular perception, the illusion carefully created by altmed practitioners projects a softer, gentler, “patient-centric” (as the current buzzword goes) practice of medicine, vis-à-vis conventional, science-based, empiricism-focused medicine which asks hard questions, emphasizes on pesky little annoyances like evidence and facts, and is, therefore, portrayed by the same altmed practitioners as a harsh, uncaring, dysempathic system – aptly circumscribed in the name they love to use, “allopathy” (the opposite treatment) coined by Hahnemann. It has been empirically shown that the perception of empathy from the treating physician significantly reduces the duration and severity of common cold symptoms in patients. And quelle surprise! The between group difference in this study (extra-empathy/attention vs. regular) was also roughly the same ~2 days between symptom abatement in these groups. How and why did the authors, writing up a study on common cold and related symptoms, choose to ignore this crucial bit of evidence?
Finally, another important aspect. Both online and off-line, aficionados of alternative medicine modalities of various stripes often like to shake their fists at what they call the “Big Pharma”, the conglomerate of ultimate evil, pushing pills onto unsuspecting consumers and raking in profits. Realistically speaking, pharmaceutical companies invest a lot of money into new drug discovery, as well as old drug repurposing, research; they have to operate under certain rules, and though their end-goal is naturally good business, their efforts over the years have led to significant progress in humankind’s ever-emergent battle against metabolic and infectious diseases. So, unlike many others, I don’t see pharmaceutical sponsorship of research to be necessarily biased and beholden to corporate interests; I expect the scientists undertaking the research to be data-driven and able to objectively assess their experimental outcomes.
What gets my goat, therefore, is the hypocrisy shown by the aficionados and peddlers of pseudoscience. This Influcid study was commissioned and funded by Deutsche Homöopathie-Union, the German manufacturer of Influcid. Each of the study authors, located across four nations, in Germany, Ukraine, the Netherlands and the UK, has financial ties or interests related to Deutsche Homöopathie-Union. To me, it is ordinarily fine, but I have not heard a pip about this Big Homeo business in connection with the mentions of this study. Had this been a properly designed, conducted and analysed study, I’d have been happy with the outcome; after all, science progresses through constant self-corrections. But given the poor quality of the study, I have to wonder about not only the rationale behind it, but the whole associated publication/peer review process as well.