Friday, June 12, 2020

Ch 2. No defenders to help - Immunity to coronaviruses in context of COVID-19

Reading time: 1:39 minutes
Readability: Grade 8

In chapter 1, we discussed how coronavirus enters the lung cells. We saw how infected lung cells raise alarm and boost defenses (interferon response). The virus using its ability to block the interferon response, continues to multiply. While the virus infects and spreads, the immune system is gearing up for a confrontation. The battle lines drawn, preparations on going. The immune system must end the enemy with precise swift action, if does not, the outcome is bad. If it does attack the enemy but without precision, there is price to pay. For now, lets see what would be the outcome if we fail to check the virus.

What if there was no defense against infections or no immune system to keep us healthy?

The outcome for a virus infected cell if anti-virus defenses do not work is inevitable cell death. The virus does it with relentless repetition and efficiency. Virus uses the infected cell to make more viruses, controlling it, damaging it from within. The new viruses made, leave the cell to go and infect more cells. These actions of the virus ravage the cell to the point where the cell cannot carry out its own functions. In the end, after the virus has completely used the resources, the cell withers away. The dying cell bursts, releasing everything inside including remaining virus particles. This continues over and over, until there is overwhelming infection in the body.

Viral induced cell-death: a cycle of damage and death
In a weakened or no immune system, there is no barrier to overwhelming infection and death. Therefore, people with broken and weak immune system are at a tremendous risk of deadly infection. Who might these people be who are at increased risk?

People who are born with defective immune system, are especially at risk. These disorders called "Primary immune deficiency disorders" are inherent and inherited disorders. These rare devastating diseases can cause trivial infections to become deadly in these patients*. They are called primary because, the defect is in the immune system itself. A second group at risk, are those with secondary immune deficiency. This is due to another condition (or medication) suppressing immunity. Common causes are malnutrition, wasting diseases, medicines like cancer treatment (Chemo) or immune suppressants. Smoking, liver or kidney diseases, organ transplants also affect immune health increasing COVID-19 risk.

2 types of immune deficiencies

*a good resource is primaryimmune.org for further reading.

Next section: Ch 3. Meet your defense forces - immunity to coronaviruses in context of COVID-19
Previous section: Ch 1. A war within - Immunity to coronaviruses in context of COVID-19
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Thursday, June 11, 2020

Ch 1. A war within - Immunity to coronaviruses in context of COVID-19

Chapter 1
Reading time: 1:43 minutes
Readability: Grade 8

Novel coronavirus SARS-Cov2 has ravaged the world with the COVID-19 pandemic. The purpose of this series is to highlight the many ways the virus and the immune system engage in war games. We will uncover espionage, understand intricate diplomacy as the virus and cells interact. We will flinch at unforgiving brutality and the bizarre consequences of a struggle to prevail.

Coronavirus (like any other viruses) lives inside human cells. Initial site of infection and home for the virus are the cells lining the respiratory tract. ACE2, a protein on surface of special lung cells (type 2 cells) allows virus to bind to cell surface. This protein is important for our health, and the virus latches on, to its advantage. Once the virus makes home inside the lung cells, it starts multiplying.
Fig 1. A Trojan horse: virus uses our protein to get inside the cells
The infected cells begin to look ill, with a change in expression of proteins on surface. These 'danger patterns' signal for attention and are a cue for immune system to respond. While the flags are being put up to raise an alarm, infected cells try and limit this enemy from within. To reduce virus spread, infected cells make proteins (called interferons) to block virus functions. These interferons boost the protective defenses of other, non-infected cells. A successful interferon response should suppress viral infection at an early stage.
Fig 2. A sick cell and a plea for help, defenses engage
It turns out that coronavirus infection has 3 stages. Stage 1 is an infected person who has no symptoms. Stage 2 is an infected person with mild symptoms and stage 3 is an infected person with severe symptoms. At present 15 to 20% of total infected people progress to severe symptoms (stage 3). This number is higher in persons above age 65 years of age. Thus, stage 1 and some stage 2 infected patients could, in theory limit the infection.

Things, yet are not straightforward as it were. The coronavirus has tools to counteract the very mechanism that can help humans. In a strategic countermove, the covid-19 virus blocks the ability to make interferon. It neutralizes the 'sensor' proteins inside the cell. This handicaps the cell to detect the virus and interferes interferon production. Besides effect on interferon production, the viruses cripple the response to the rest. This allows the virus to keep infecting more cells, spreading fast causing damage. The virus copies itself into millions of viruses, setting a stage for a battle where both armies number in millions.

References:
- Li G, Fan Y, Lai Y, et al. Coronavirus infections and immune responses. J Med Virol. 2020;92(4):424‐432. doi:10.1002/jmv.25685
- Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020 Mar 1;38(1):1-9.
- Fung, To Sing, and Ding Xiang Liu. "Human Coronavirus: Host-Pathogen Interaction." Annual review of microbiology 73 (2019): 529-557.

Next section: Ch 2. No defenders to help - Immunity to coronaviruses in context of COVID-19
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Tuesday, June 9, 2020

Lifestyle recommendations in management of chronic hives

The previous section discussed the role of medications in management of chronic hives. Medications are effective, but life style changes also impact chronic urticaria.

In 2013, Omalizumab (Xolair) injection trial worked in patients failing high dose antihistamines. In the study, Omalizumab  improved hive and  itch symptoms. Similarly, the placebo group also showed significant  (30-33%) reduction in symptoms  but less than Omalizumab. So what might be the cause  of this placebo benefit?
It is my hypotheses that,

"The  patients knew their adversary and had a greater understanding of the disease process. They were ‘at peace’ with their hives. Their anxiety was less. They were also likely not attributing their hives to 'being allergic to everything'. The exhaustion and stress of hyper-vigilance (being super aware of all actions) reduced."

This brings us to lifestyle recommendations:

1. Take actions to reduce stress. Identify any personal, professional or physical stressors. Once identified, take steps to reduce them.
2. Yoga, meditation and mindfulness help. Anything that can help take your mind off the itching can help the medications help you better
3. Take control of your anxiety. Recognize the contribution of the  positive feed-forward loop where anxiety can  worsen hives.  Worse hives, lead to more anxiety. You get  the picture.


The feed forward loop between anxiety and hives

4. Try to get as much of restful sleep as possible. Sleep is an  unrecognized victim of chronic hives. People with uncontrolled hives do not sleep well for many reasons. Waking up several times a  night to scratch all over is an obvious cause. Medications necessary  to control hives (antihistamines in high  doses) can affect sleep quality.



The feed forward loop between poor sleep and hives

5. Weight can have an adverse impact. The documentary ‘fat, sick and nearly dead’, is about a person whose hives resolve with weight loss. It could be worth  trying since there is not much to lose (except weight). High dose  antihistamines stimulate appetite contributing to weight gain. Corticosteroids (e.g. prednisone) can also cause weight gain. This weight - hives relation could be the third positive feed forward loop.


The feed forward loop between weight gain and hives

6. Take your medications of time!

The steps above should be complementary to the medication regimen as prescribed by your physician.

To jump directly to other sections on this topic
  1. Why do I get hives all the time with seemingly no cause?
  2. What if my hives bruise, blister, scar or heal with marks on skin?
  3. What is happening in skin that leads to chronic hives? 
  4. How to effectively manage hives and why do antihistamines work in most cases?

Monday, June 8, 2020

Why the management of hives and itching in chronic hives (urticaria) may require a higher dose of medications

Disclaimer: Following is not medical advice, please discuss with your physician before making any medical decisions. In the preceding section, we discussed the chemicals released by immune cells that cause effects leading to wheals and itching. Management of hives thus depends on systematically blocking these chemicals released so that they cannot do what they are designed to do. So, 


Due to the predominant role of locally produced histamine, it is clear why antihistamines play such a central role in management of hives. In fact, experts treating chronic hives often recommend daily antihistamines such as cetirizine (e.g. Zyrtec or its generic equivalents), Fexofenadine (e.g. Allegra or its generic equivalents), or Loratidine (e.g. Claritin or its generic equivalent) sometimes in double, triple or even quadruple doses! What would the reason be for this? It comes down to the fact that to cause its mayhem, histamine has to bind to its receptor on cells. Histamine binds to its receptor in a reversible manner, so when an antihistamine comes along, it kicks off the histamine from the receptor and occupies the same place on the receptor site, thus preventing histamine from doing its thing.

Why antihistamines in high doses are often suggested in management of hives

If high dose histamine-1 receptor blockers are not enough, then physicians will often recommend a Histamine-2 receptor blocker. Once the histamine receptor -1 is bound and out of commission, and a person is still having problems with hives, then the next target is to block the histamine 2 receptor. This property belongs to a class of medications, whose most famous role is to suppress acid in stomach. Yep, Ranitidine (Zantac etc, withdrawn from market in 2020) and Famotidine (Pepcid etc) are sold over the counter as acid reflux medications for heart burn. Interestingly, they achieve this by blocking the histamine-2 receptor on stomach lining which reduced acid being produced.

If a person is still breaking out in hives in spite of being on high dose H1 blocking medications, then the next step is to target the Leukotrienes that are also thought to be involved in some patients. This is achieved by a prescription medication called Singulair or Montelukast. This drug blocks the leukotrienes from binding to its receptors and thus blocking their action.

A representation of the ways in which these drugs can help control itching and hiving is given in figure below.

Why the management of hives involves medications such as anti-histamines, acid-reducing medications and Montelukast

Thus you can appreciate that the key to managing the terrible symptoms of chronic hives are sequential and systematic blockade of the pathways involved in the genesis of hives. In fact, the options do not end with the above drug, depending how severe the hives are the options can extend further down the list as noted in the figure below with the last choices being some harsh medications with fair amount of side effects such as immuno-modulators and immuno-suppressants. The last two are almost like 'weak chemo' type medications that are needed to regulate or suppress the immune system, so as to not keep producing those inflammatory chemicals we spoke about earlier.

The inverted triangle of medication choices for hives: More patient can be controlled with the earlier steps and fewer and fewer patient require the progression steps
Hopefully, this article has made clear why the medications in chronic hives are the to be tried the way they are.

To jump directly to other sections in this topic
  1. Why do I get hives all the time with seemingly no cause?
  2. What if my hives bruise, blister, scar or heal with marks on skin?
  3. What is happening in skin that leads to chronic hives? 
  4. What are lifestyle recommendations in management of chronic hives?

Sunday, June 7, 2020

What is happening in skin that leads to chronic hives?

 
A useful pathway gone awry

It all begins right at the interface of blood vessel and the tissue.  Blood vessels are present in all tissues. These pipes (vessels) lined by a special layer  of cells called ‘endothelial cells’ carry components of blood. Endothelial cells fit into each other like ‘paver stone’. Under normal situations, cells fit tight to keep the ‘pipe’ from leaking. Blood flows through and very little fluid (plasma) leaks out into the tissue. The hives occur due to leakage of fluid into tissue more than normal. This leads to expansion of tissue spaces with fluid. Under the skin this looks like a hive (wheal) and in deeper tissue can present as angioedema. Thus, angioedema is the same process but in a different location.

A simple version of events is in the diagram that follows,



A process diagram showing why hives cause swelling and itch

A bit more detailed explanation is in the remainder of the article if you still are interested.

If this tissue swelling process is a problem, why do we even have it in the first place? Under specific situations, this process is useful and serves a purpose.  For example, when we are bit by a mosquito, or stub a toe, there is tissue damage.  Injury causes local inflammation and the blood vessels to be leaky, to begin repair. Therefore, mosquito bites wheal and a stubbed toe swells. This leaked fluid, rich in plasma proteins and healing factors starts tissue repair.

The main chemical that is known to cause this is histamine, released by the immune cells in the tissue. So in the discussion of triggers of acute hives, Histamine released from immune cells in allergic reaction or infection triggers hives. Thus, hives can either be local response to injury, or generalized immune activation.

The problem becomes chronic when tissue immune cells release histamine without provocation. This happens over and over again, without an obvious trigger, or specific purpose.
Thus chronic hives are due to,
  • Inappropriate release of histamine from skin immune cells (such as the mast cell)
  • Histamine causes endothelial lining to leak. This in turn causes fluid to move into the tissue from circulation.
  • This leaked fluid with expanded tissue spaces, manifests as hive (under skin). Swelling in deep tissue becomes angioedema.
  • Histamine will also stimulate the itch nerve fibers stimulating a profound itch. Angioedema (deep tissue swelling) does not itch but the area can feel numb. Pain and pressure fibers send signals to brain so a swollen lip feels as if a dentist anesthetized it.
In chronic secondary urticaria, another disease, triggers immune cells to release histamine. Appearance of chronic hives is then a symptom of that underlying condition



A simplified flow diagram showing the cascade of events leading to hives (click for higher resolution image)


Histamine is not the only chemical released by the skin/tissue immune cells. It is but, the most famous and primary culprit. The immune cells produce other inflammatory chemicals leukotrienes (LTs) , prostaglandins (PGs), chemokines, cytokines.  These are all potent molecules like histamine. There are also other immune factors we may not even have discovered, all involved in the process outlined above.

Histamine  (acting through its receptor(s) is the primary chemical playing a role in hives, though some other can also participate. (Click for higher resolution)

It is easy to recognize the complexity of the pathways in perpetuation of chronic hives. To jump directly to other sections in this topic
  1. Why do I get hives all the time with seemingly no cause?
  2. What if my hives bruise, blister, scar or heal with marks on skin?
  3. How to effectively manage hives and why do antihistamines work in most cases?
  4. What are lifestyle recommendations in management of chronic hives?

What if my hives bruise, blister, scar or heal with marks on skin?

There are some clinical features that can help a physician to distinguish whether the chronic hives may be the idiopathic kind or the secondary kind. A clue could lie in the answer to a very important question: What if my hives bruise, blister, scar or heal with marks on skin? or leave with no trace leaving a normal looking skin?

Not all chronic hives are the same, look for red-flag symptoms

Most people which chronic hives will have the chronic idiopathic variety as it is the vastly more common of the two. There are some features that can distinguish the more benign chronic idiopathic hives from chronic secondary hives but these are not hard and fast rules. Hives in chronic idiopathic urticaria are usually transient, fleeting (appear and disappear in less than couple hours, at most 1 day only to reappear in another location – thus they tend to ‘move’ around), they go away leaving a normal looking skin, and never blister, scar or heal with discolored bruises. All these properties (lasting longer than a day, don't move around and have some of the other skin changes) are often seen in chronic secondary urticaria, since main driver of hives in this case (and the skin changes) is a ‘bad’ type of inflammation.

The major types of chronic urticaria


Chronic idiopathic urticaria, can be further divided into chronic spontaneous urticaria (hives that come on their own without any provocation or trigger) or chronic inducible urticaria (hives that be induced by physical triggers like pressure, scratching the skin, hives from sunlight, heat etc). There is a large degree of overlap between these two clinically, and it is rare to find a pure inducible urticaria patient as most will have some component of spontaneous hiving.

There is a special type of chronic idiopathic urticaria, a third variety that has a mix of idiopathic as well as secondary urticaria features. This is called chronic autoimmune urticaria (confusing nomenclature but that's how it is widely known). This urticaria overall behaves like the idiopathic chronic hives clinically (skin changes similar to idiopathic kind) but is associated with presence of autoimmune antibodies to thyroid (TPO or thyroid peroxidase antibodies) . These auto-antibodies give rise to the ‘autoimmune’ in the name but are thought to have no role in the causation of hives. Some experts seem to think that presence of these TPO antibodies is a marker that these hives could last longer or be more difficult to control, but they themselves have no role in the development of actual hives.

Why do I get hives all the time with seemingly no cause?

If you suffer from hives for months without many other symptoms, you may be suffering from a condition called 'Chronic Urticaria'. Chronic (urticaria) hives are hives that last 6 weeks or more. This 6 week cut-off is important as hives that last for longer than 6 weeks are rarely caused by an external cause (trigger). The culprit for most hives cannot be identified in majority of cases.

Six-week cut-off is important

Acute hives, i.e. hives that last for a few days or few weeks (but less than six weeks) may be on occasion be tracked back to an external ‘trigger’. These triggers can be an allergy (a new medication, new food, new thing that you may come in contact with or environmental allergen breathed in etc). More commonly, acute hives can be part of a recent or ongoing infection (common viral or bacterial infections) can manifest with hives as ‘by-product’ of the immune activation necessary to treat the infection.

Acute hives can have triggers

Chronic hives, they are another story..When hives last as long as what people with chronic hives suffer from (often several months, years or even decades), this is not an a ‘reaction’ to an external trigger (as in case of acute hives) but a reflection of an ‘internal issue manifesting on surface’. This manifestation is in form of chronic hives, and thus they are a symptom of an internal disorder. Now, this internal disorder can be as a result of subtle or significant disturbances. And this can be found by doing common laboratory testing, such as complete blood count, liver, kidney, thyroid function or a urine analysis and occasionally markers of inflammation (either ESR – erythrocyte sedimentation rate, also called ‘sed rate’) or CRP (C-reactive protein).

If the common tests are normal, and a person has chronic hives, it is presumed that this internal issue is subtle and the disease is called Chronic Idiopathic Urticaria (CIU). If there is obvious abnormality in any of the common tests, then the test can possibly point towards a potential cause of hives and is called Chronic Secondary Urticaria ("secondary", since it is as a result of, or secondary to this other condition, that is driving the hives). Thus there are 2 main categories of chronic hives, chronic idiopathic (spontaneous) urticaria OR Chronic secondary urticaria.
Classification of hives based on how long you've had them

Chronic idiopathic urticaria is more like a nuisance - a ‘tendency’ to hive. There is no ‘smoking gun’ pointing to the cause and a person just hives as part of who they are. Sometimes, people suffering from chronic hives drive themselves crazy thinking they are allergic to this or that. They may question whether they are now allergic to banana, since they broke out in to a hive-rash after having a banana an hour ago, but they’ve had bananas all their life! Or it was something around the house, a new perfume, a new soap and the list goes on and on...many patients of chronic hives may mistakenly attribute all of their hive flares to an ‘allergy’ and have an exceptionally long list of things they are allergic to. In reality, the hives are just how they are, ‘it just is’, a nuisance, a manifestation of a subtle internal issue, no more.

Chronic secondary urticaria is a symptom on another problem, one that is lurking just underneath the surface and chooses to declare itself in form of bothersome hives. Often conditions that can present with chronic secondary urticaria are inflammatory, autoimmune conditions, blood disorders, cancers, chronic infections etc. Fortunately, these very conditions can be detected by routine tests and which is why it is important to obtain routine testing in chronic urticaria.

To jump to other sections in this topic
  1. What if my hives bruise, blister, scar or heal with marks on skin?
  2. What is happening in skin that leads to chronic hives? 
  3. How to effectively manage hives and why do antihistamines work in most cases?
  4. What are lifestyle recommendations in management of chronic hives?

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