Mechanisms of the Symptoms of Colds and Flu

Cold and flu are common and crappy. This paper is worth reading especially when suffering from one.

Summary:
Most symptoms are due to the inflammatory response, rather than the pathogen itself. Cytokines released from damaged tissue and activated white cells diffuse locally, and circulate systemically, causing the myriad of symptoms we all know.

Symptoms can be split by timing;
early - come on and dissipate over 2-3 days: sore throat, sneeze, chills, malaise, headache
late - develop over days and last over a week; nasal congestion + discharge, malaise, cough

persisting long after infection: cough

Each symptom has its own mechanism;

Sore throat / Pharyngitis

Cytokines - especially bradykinin and prostaglandins - released locally, acting on trigeminal nerves.

Sneezing

A reflex, probably initiated by histamine acting on trigeminal nerves to trigger afferent signal to sneezing centre in brainstem. The efferent reflex is to motor and parasympathic (PS) parts of the facial nerve, and respiratory muscles.

Simultaneous lacrimation and nasal secretions occur via PS facial nerve activity, while eye closing is by somato-motor facial nerve activity. Note relation of eyes to nose, which is reversed in photic sneezing.

Runny nose / rhinorrhoea

Components: neuro-reflex glandular secretion (blocked by antimuscarinics) and capillary proteinaceous ooze due to inflammation induced endothelial junction loosening.

The colour of discharge and sputum does not relate directly to cause (bacterial vs viral) but more the intensity of inflammation, representing recruitment of white cells into the airway.

Neutrophils and monocytes contain azureophilic granules containing myeloperoxidase, giving green-yellow tinge at low concentration or murky green at higher ones.

nasal congestion

Due to venous plexus dilation at the narrow nasal valve region, caused by inflammatory mediators. Usually cycles between each nostril, under the influence of sympathetic vasconstrictor nerves.

Sinus pain

Pain is not dependent on patent ostia, but can be due to increased pressure in sinus, and distension of draining blood vessels.

Watery eyes / epiphora

Obstruction of naso-lacrimal duct as it opens in the nose, due to venous plexus engorgement.

Cough

Stimulated by vagal nerve activity, always at level of larynx or below. Hyper-reactivity of the reflex, which is normally to protect the airway, occurs due to inflammation.

Influenza damages airway epithelium > most cold viri, leading to more cough, rather than a simple head cold.

The progression from sneezing to cough can be explained by progressive inflammation spreading down the respiratory tract, stimulating trigeminal nerves, then vagus nerves.

Headache

Probably from effects of circulating cytokines on central (i.e. hypothalamic or brainstem) nervous system.

Chills

Chills occur regardless of skin temperature, due to central nervous activity, connected to shivering, changing appraisal of somatic sensation. Chills are not from peripheral vasoconstriction causes skin temperature decrease, perceived as coldness. 

Fever

Occurs more in novel exposures, i.e. pandemic viri, or in infants. Interleukins 1 and 6 are most important, circulating to the hypothalamus or to vagus nerve neurons, effecting a change in temperature set point.

Malaise and psychological effects

As well as the cumulative effects of all the above, there are separate effects on neurological activity from circulating cytokines.

Features include: psychomotor slowing, ahedonia, sleep disturbance, hyperalgesia.

Interleukins 1, 2, 6 and tumour necrosis factor are thought responsible.

Anorexia

seems to be a protective response, saving energy, starving pathogens of zinc and iron, and stimulating monocytes sand macrophages. It occurs via effects on the hypothalamic feeding centre.

Muscle aches and pains / myalgia

Probably mediated through prostaglandin E2, causing myocyte catabolism and nerve stimulation. This releases amino acids for the liver to create immune molecules like complement. the pain and breakdown can be blocked with cyclooxygenase inhibitors.

Lancet Infect Dis. 2005 Nov;5(11):718-25.
Understanding the symptoms of the common cold and influenza. 
Eccles R.

Chronotype (night owl or early bird) on MRI scans

This paper is interesting for two reasons:

1. It confirms the obvious fact that people with different sleep rhythms have different white matter properties. 
2. It fails to do much more.

Before looking critically at the paper, I will say that I agree with many of the conclusions it comes to. for instance that society's clock driven culture leaving people in chronic jet-lag states which drain them, and that flexible working hours would help those people (and the transport network).

I'm writing about it because it demonstrates an example of how many MRI neuroimaging studies are flawed.
The authors relate chronotype (early bird or night owl) to brain changes, and also to use of recreational drugs (alcohol and nicotine).
Now anybody can see that people who might stay up late may be using stimulants or hedonistic substances. However in this paper they use a crude test to 'control' for this effect, by looking for a Pearson correlation coefficient between each MRI variable and each social measure (alcohol, nicotine etc). Why is this flawed?
1. Self reported consumption levels are inaccurate
2. consumption does not linearly relate to the effect on that person
3. many other substances were not included, such as chocolate, refined sugar, cannabis
4. there was no reference values for the correlation coefficient. this would probably need to be defined in a separate study, properly powered for the purpose.

This paper is the tip of the iceberg of similar studies which have the basic formula;
Take small sample of healthy males. Do MRI scans. Relate scans to some ill-defined phenomena in lay-psychology, such as 'niceness' or 'funny'. Had this study clearly defined chronotype, and dissected it out from the numerous confounding factors, it might have been of more value.
Ideally the study would have had matched pairs, or have used genuinely jet lagged people, to add relevant comparison.

“Early to bed, early to rise”: Diffusion tensor imaging identifies chronotype-specificity
Jessica Rosenberga  et al
NeuroImage 2013

Neuroscience and Genetics of PTSD

Welcome Back.

At no point was I taught about the state of the art in the pathoaetiology of stress-related disorders. I was however taught about the now defunct monoamine hypothesis. Let's assume you suffered the same fate and  talk about the neuroscience of PTSD.

The fear conditioning model of PTSD suggests that:

• Fear conditioning plasticity would have an evolutionary advantage in facilitating the rapid recognition of danger
• Malfunction in this could lead to overconditioning wherein a patient might experience too great a response to the stimulus OR develop too vague a pattern recognition system for that event
• This may be caused by elevated cortisol at the time OR elevated catecholamines

Amstadter et al discuss the three main neurobiological systems that are implicated in this model:

• The Locus Coeruleus (and noradrenargic system)
• The HPA Axis
• The Limbofrontal neurocircuitry of fear

They then discuss the genetics of PTSD - making this a really fun and varied read (as long as you just accept that there will be a lot of acronyms, because hey, this is genetics). Unsurprisingly there is a lot of difficulty in separating genetic risk factors from environmental ones but there is some solid evidence relating to serotonin receptor- and transport-related alleles, alleles relating to BDNF, Dopamine receptor modulation of traumatic memories, Corticotrophin-releasing hormone related alleles and much more.

Also they flag up lots of research that should be done. No mention of epigenetics which I positively GUARANTEE will be involved somehow, but ho hum.

Good Learning and happy new academic year.

Marblecake

Fluid resuscitation: what works best

The NEJM produced a review recently covering fluids for resuscitation. There are pretty pictures in the original paper.

The theory:
The compartment model is useful in predicting where different types of fluid go. Interstitial oedema is the primary concern with fluid loading. Cardiac overload and neuro-humoural effects can also be problematic.
The glycocalyx is an endothelial structure on the luminal side which affects oncotic pressure. Glycocalyx disruption occurs in inflammatory states (i.e. sepsis, surgery) and leads to protein leak into the interstitium.
Interstitial protein increase oncotic pressure, shifting fluid from other spaces, causing interstitial oedema. organ specific consequences of interstitial oedema include respiratory failure and intra-cranial hypertension.

One study of febrile, dehydrated children showed increased mortality with either normal saline or albumin, bringing doubt on whether fluids are beneficial in other conditions.

What to use:

There is some evidence for what fluids are best to use, but nobody knows what volumes are ideal.
Resuscitation to endpoints, like arterial or venous blood pressure, has limitations.
Albumin and normal saline are largely equivalent, except that albumin achieves similar physiological endpoints with lower volumes (ratio ~ 1 : 1.5).
Albumin can increase mortality in neuro-trauma, probably from intra-cranial hypertension.
Normal saline promotes hyper-chloraemic metabolic acidosis;
'Balanced' solutions like Haartmanns have specific side effects depending on what is used to replaced sodium chloride (lactate, acetate and calcium).  Lactate - hypotonicity; acetate - cardiotoxicity; calcium - microthrombi with citrate stabilised blood products.
Compared to balanced solutions, Normal saline was associated with more renal impairment and infections in the operative setting.
Hydroxyethyl starch (HES) is of little benefit over any other, but with greater risks.

Summary:
Fluids can be bad for patients. balanced solutions are usually > saline.


Resuscitation Fluids
John A. Myburgh, M.B., B.Ch., Ph.D., and Michael G. Mythen, M.D., M.B., B.S.
N Engl J Med 2013; 369:1243-1251September 26, 2013DOI: 10.1056/NEJMra1208627