Category: Inflammation

When Hype Meets Medicine: the Curious Case of Dexamethasone in COVID-19

Evidence-based medicine requires evidence. It’s not optional.”—these golden words in science- and evidence-based medicine were re-emphasized by Dr. Angie Rasmussen, virologist at Columnbia University and prolific science communicator, on Twitter recently.

For proper appreciation of the magnitude of this quote, let me elaborate on the fascinating context in which Rasmussen wrote it.

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Homeopathy: Is It Really Effective In Upper Respiratory Tract Infections With Fever In Children? Not Quite

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.

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Keep Calm and Know Your Fever (Before You Reach for That Medicine)

Growing up in the Eastern part of India, I was subject to a most peculiar cultural phenomenon known as “ThanDa lege jaabe” (ঠাণ্ডা লেগে যাবে in the vernacular, translated as: You’ll catch a cold). This odd concept, most beloved of the mothers in that region and handed down generations after generations, would teach them that any vagary of the sub-tropical weather — sun, rain, autumnal zephyrs, wet and foggy riparian winters, and everything in between — was liable to cause acute upper respiratory tract infections (uRTIs), characterized by runny nose, cough and sneeze, perhaps even progressing to pharyngitis, laryngitis or tracheobronchitis. And the most feared symptom was elevated body temperature, or fever.

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Of Serious Concern: Drug-resistant Acinetobacter baumannii in Treated Wastewater

Currently one of the most common disease-causing bacterium in the world, Acinetobacter baumannii, for sure, is a nasty bug — an emerging nosocomial (hospital-associated) pathogen, being increasingly observed in serious conditions requiring intensive care (including ventilator-associated pneumonia, sepsis, meningitis, wound infection and urinary tract infection). Unfortunately for patients, particularly immune-suppressed ones, this bug is now known to be extensively drug resistant (XDR; resistant to most antibiotics including carbapenems, with the exception of two drugs of last resort, colistin and tigecycline), with a smaller proportion resistant to even these two (known as pan-drug resistant, PDR, which are therefore virtually untreatable with the current crop of FDA-approved medications).

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Inflammation, Acupuncture, and HPA axis: Faulty Science Clouds Understanding

In the wake of my recent critique of acupuncture being touted as a remedy for allergic rhinitis, I was pointed (via a Twitter comment) towards a 2013 review in Evidence Based Complementary and Alternative Medicine, which purported to propose a mechanism for the much-claimed anti-inflammatory effects of acupuncture. There are several putative mechanisms, discussing all of which will make this post gargantuan. Therefore, I shall focus on the explanation involving the hypothalamus-pituitary-adrenal (HPA) axis.

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Occupational Health and the Law: UK vs. US; I ask a question

A UK case report on Occupational Health and Safety, published in August, came to my attention today. Two NHS Occupational Health investigators from UK, Charles Poole of the Northern General Hospital, Sheffield, and M Wong of the Dudley & Walsall NHS Trust Health Center, presented two clinical cases associated with a relatively new occupational industry in that nation: “The separation of garden waste from domestic waste, its collection and processing in industrial composting sites, so as to reduce biodegradable waste going to landfill“.

It is well known that any kind of disturbance created in a given environment, for any reason, can often potentially release harmful substances in air in form of aerosols, or minute particles capable of floating in air. We have seen that with the yeast-like fungal pathogen, Cryptococcus gattii, which was found, via environmental studies, to be present in high concentrations in the soil of Vancouver Island (British Columbia, Canada), and to spread during dry summer weather likely as airborne particles (a.k.a. “propagules”). Release and dispersal of spores of various molds during large-scale air-disturbing activities such as construction, renovation and/or demolition of buildings is a well-studied phenomenon in the fields of Infection Control and Epidemiology; for example, see Krasinski et al., 1985; Streifel et al., 1983. The waste separation, collection and processing appear to be no different. The investigators write:

The process of composting organic matter encourages the production of bacteria, fungi, spores and endotoxins, which may be released to air in bioaerosols. Levels of bacteria and fungi up to 106 colony forming units/m3 in ambient air have been reported in relation to composting…

The problem has not been studied well at all in the population of waste-composting workers, because – as the investigators indicate – reports of illness in these workers are relatively rare. As a result, no safe levels of exposure to such potentially hazardous aerosols have been defined in this context, nor have been the exact conditions conducive to exposure; we don’t know if, and/or how much of, the exposure depends on variables such as composition of the compost, weather conditions, steps and systemic controls engaged during the separation and collection process.

In the existing clinical literature, one of the major culprits implicated in these environment-related diseases is the ubiquitous, spore-producing mold, Aspergillus, in form of its various species, mostly commonly Aspergillus fumigatus which is the etiological agent behind various diseases involving the upper (nose and upper part of the air-tube) and lower (lower part of the air-tube and the lungs) respiratory tract. Untreated or incompletely treated, these diseases can be severe and chronic. One particularly important manifestation is the Allergic Broncho-Pulmonary Aspergillosis (ABPA, in short), which is a complex or multi-component, immunologic, inflammatory response similar to allergies or hypersensitivities – which if not detected and treated early (with antifungals and steroid immune-suppressants) can lead to serious lung damage. ABPA is generally observed in people with certain debilitating conditions, such as cystic fibrosis, or immunosuppression, but rarely in otherwise healthy individuals. In ABPA, apart from classical respiratory symptoms, reduction in lung functions, and lung abnormalities observed under X-ray, certain allergy-related responses are noted in blood (more precisely, serum) – such as:

  • Type I hypersensitivity to bits and pieces of Aspergillus (all recognized as antigens by the immune system), leading to the excessive generation of allergy-associated antibody, called Immunoglobulin E (IgE). By its action, IgE causes release of highly inflammatory mediators, such as histamine, leukotriene, and prostaglandin, from immune cells, which have both immediate and long term deleterious effects.
  • Type III hypersensitivity to Aspergillus antigens, in which small complexes of these antigens with antibody run amok through the body, depositing in blood vessels, kidneys and joints – eventually leading to immune-mediated destruction of tissues at those sites.
  • Eosinophilia, in which eosinophils, a type of white blood cells, markedly increase in number in blood and/or tissues, a common occurrence in allergy and asthma, and in parasitic (worm) infections. Activated eosinophils, a member of immune defence, are capable of causing tissue damage by various mechanisms.

The UK case report describes two late-thirties, early-forties patients, both garden waste collectors by profession, and both diagnosed with ABPA at occupational health clinics; both responded to treatment and were released with the advice not to work with waste and compost. Another member of their team, who though not ill had symptoms of asthma and tested positive for high serum IgE to Aspergillus antigens (indicating exposure) was given the same advice.

The investigators go on to make some recommendations at the end of the report. They write:

Until the results of large epidemiological studies of garden waste collectors and industrial compost workers are known, the few case reports of ABPA […] would indicate that workers with asthma who are sensitized to A. fumigatus or who have cystic fibrosis, bronchiectasis or are immunosuppressed should not work with garden waste or compost, unless their exposure to airborne fungi can be controlled. Whether asthmatics who are SPT positive or specific IgE positive to A. fumigatus will go on to develop ABPA is unknown, but they should be made aware of the theoretical risk.

Annual health surveillance by way of a respiratory questionnaire and skin prick testing is also recommended for these workers. Other cases of ABPA or EAA in garden waste and compost workers should be sought and reported, until such time that the results of a national study of UK compost workers are known.

The recommendations gave rise to some germane questions in my mind. These are, of course, valid from a clinical standpoint, and made keeping the health and welfare of the patients in mind. But given that these are related to occupational health, how do these situations play out from the perspective of the employer? How are these situations different in the UK as opposed to in the United States? For example:

  • Can/should the employers (say, a waste management firm) mandate pre-employment testing for Aspergillus-specific IgE and skin prick hypersensitivity testing?
  • Can/should the employers refuse employment to a person who tests positive for IgE and hypersensitivity because of a theoretical risk? Relatedly, can/should such an employee be made aware of this theoretical risk?
  • Should such an employee choose to ignore this theoretical risk and accept the job (or continue on the job after a diagnosis) and become inflicted with ABPA, can/should the employee be able to claim occupational exposure and Worker’s Compensation?
  • Specifically in the US context, can a Health Insurance company demand the results of these surveillance tests for a person engaged in the waste management profession, and if positive, treat this as a pre-existing condition and refuse payment in the event the employee becomes ill and needs treatment?

I don’t have the answers to any of these questions. Perhaps someone conversant with labor and/or occupational health-related laws would care to illuminate me in the comments?

Poole CJ, & Wong M (2013). Allergic bronchopulmonary aspergillosis in garden waste (compost) collectors–occupational implications. Occupational medicine (Oxford, England) PMID: 23975883

Gullibility and pseudoscience, bridged by headlines

Much have been made in the media recently, of a February 2013 paper, published by a German group in the Annals of Internal Medicine, claiming that acupuncture may help relieve seasonal allergies. Always interested in examining the bold claims of efficacy by various forms of pseudoscientific, wannabe-medicine modalities (such as homeopathy, naturopathy, and so forth), I elected to go to the source; the paper was behind an annoying paywall, but thankfully, I had institutional access, and dove in.

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Glimpse of an elusive diagnostic biomarker for Chronic Fatigue Syndrome

The clinical entity of Chronic Fatigue Syndrome1 (CFS) has so long eluded explanation. Patients of CFS complain of extreme and prolonged fatigue that is disproportionate to their physical and mental activity, and is not alleviated by any amount of rest. The condition may well last for more than 6 months at a time, and may be accompanied by a variety of other symptoms, such as pain in the muscles and/or joints without swelling, memory impairment, significant lapse of concentration, headaches, painful lymph nodes in the neck or armpit, and so forth. Physicians currently employ the 1994 case definition in which persistent (>6 months) fatigue is to be present along with at least 4 of 8 known associated symptoms, for the condition to qualify as CFS; if these criteria aren’t fully met, the condition is referred to as ‘idiopathic’ (without known cause) fatigue. Management of both conditions are practically identical.

For patients of CFS, the bouts can be debilitating, perhaps made worse by the fact that scientific research has not yet identified the root cause of the condition, and can, therefore, offer no solution beyond symptomatic relief.

Many theories as to the cause of CFS abound, such as:

  • Direct effect of viral infections;
  • Specific induction of host immunity as a result of invasion by some pathogenic microbe, et cetera.
  • Non-specific activation of the patients’ immune systems, a subset of which may be expressed as allergies;
  • Direct involvement of the central nervous system, resulting in abnormal, neurally-mediated lowering of blood pressure, which may cause light-headedness and compensatory tachycardia (i.e. increase in heart rate);
  • Indirect action of the brain, via the HPA (‘Hypothalamic-Pituitary-Adrenal’) axis, which may disturb the release of various stress-associated hormones.

In addition, symptoms in CFS may resemble those seen in many physiological, neurological, as well as psychological illnesses.

This, understandably, poses a diagnostic challenge; the problem is that all these phenomena in the human body are processed through physiological pathways that are highly inter-related, a fact which underscores the difficulty in arriving at a single factor responsible for CFS. Current thinking is, therefore, that CFS may be multi-factorial, i.e. triggered by a combination of an unknown number of factors.

In part, this is also the reason why there is no diagnostic test or ‘biomarker’ (an observable phenomenon that can be specifically attributed to the condition) for CFS, and why the diagnosis must be exclusionary, via a process of elimination of other possible conditions that may explain the symptoms. What makes diagnosis even more difficult – not to mention, controversial – is that the number, types and even severity of these symptoms are highly variable amongst patients, and the condition periodically goes into remission and relapses.

When symptoms arise, management – in absence of a cure – focuses on treating primarily those symptoms that disrupt life and activities most, such as pain, lack of sleep, memory problems, depression, anxiety, et cetera. Long term care involves specially-developed activity programs, behavioral therapy and other interventions that aim to mitigate the physiological and psychological effects of this chronic illness.

Given that many CFS symptoms mimic those of certain immune dysfunctions involving unregulated inflammation, a lot of research has focused on understanding the inflammatory pathophysiology of CFS patients. One recent study from the Stanford University medical school, published in the Journal of Translational Medicine2, investigated the role of cytokines in this condition. Cytokines are a group of small protein molecules produced and released by various types of cells in the body, including cells which comprise the immune system. Cytokines take part in cell-to-cell signaling; released by one type of cells, cytokines affect other cells, either in their immediate environment or elsewhere in the body, by binding to receptor molecules present on the surface of these cells. These receptors recognize specific cytokines, and the binding at the cell surface initiates cascades of sub-cellular (inside the cell) biochemical reactions which lead to a specific effect. For example, some cytokines are active in regulation of developmental processes3 during the implantation of the embryo and maintenance of pregnancy. Again, ‘pro-inflammatory’ cytokines, released by certain leukocytes of the innate immune system, can recruit other leukocytes and bring them to the site of infection or injury, in order to mediate various effects4.

The Stanford group, led by Elizabeth Stringer, hypothesized that the daily variability of the levels of various cytokines in the serum may correlate with the observed variations in the severity of CFS symptoms. In a pilot study they had monitored the daily levels of 51 different cytokines in 3 women with fibromyalgia (another chronic painful condition) and CFS, and discovered that one adipokine (cytokine released by fat cells, ‘adipocytes’), called Leptin, stood out. Leptin, which regulates appetite, metabolism and behavior5, and has profound inflammatory effects, as well as a protective role in mucosal immunity6, was found to correlate significantly with the self-reported fatigue severity.

In the current study, participants (CFS patients and healthy controls, all female) were chosen carefully to account for or exclude other existing conditions that may confound (i.e. not allow proper interpretation of) the observations. Twice a day, 20 participants answered questions about the severity of fatigue, muscle/joint pain and sleep quality that they experienced during the study period, which included blood draws for 25 consecutive days. In the CFS patients, serum Leptin levels correlated strongly with daily levels of fatigue; although Leptin levels were associated with a plethora of pro-inflammatory cytokines, no other direct correlation was found, indicating that Leptin may be the central player in the CFS-associated inflammatory process mediated by a network of cytokines. None of these associations were observed in healthy controls. Leptin levels were predictive of daily fatigue levels in women with CFS, and using cytokine predictors, the authors were able to distinguish between high fatigue and low fatigue days with 78% accuracy.

Leptin Fatigue Correlation
Illustrative image composite made from parts of Fig. 2 & 3 of Stringer et al. (Ref. 2)

Interestingly, absolute Leptin levels, as well as the range of daily fluctuations, were not abnormal in CFS patients, which suggests that Leptin alone may not be responsible for causing the inflammation in CFS. As the authors indicate, larger and more detailed studies are necessary to explore a causal role of Leptin and/or its cytokine network in driving CFS severity, and uncover hitherto elusive diagnostic biomarker(s) and therapeutic targets.

Further reading:

  1. CDC information website on Chronic Fatigue Syndrome.
  2. Stringer, EA, et al. Journal of Translational Medicine 2013, 11:93; doi:10.1186/1479-5876-11-93.
  3. Saito, S. Journal of Reproductive Immunology 2001, 52:15-33; PMID: 11600175
  4. Whitney, NP, et al. Journal of Neurochemistry 2009, 108:1343-59; PMCID: 2707502.
  5. Gautron L, Elmquist JK. Journal of Clinical Investigation 2011, 121:2087-93; PMCID: 3104762.
  6. Mackey-Lawrence NM, Petri WA Jr. Mucosal Immunology 2012, 5:472-9; PMCID: 3425733.