Long COVID (Siqueiros, 1/8/25)

A recording of this presentation is available HERE.

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This week's Grand Rounds on Long COVID was a practice-changing presentation! If you are caring for patients in a primary care setting or know someone who is suffering from Long COVID, I highly recommend you watch the entire presentation by Dr. Marcos Siqueiros, of KP Santa Clara. Dr. Siqueiros covered a TON of material, including what is known about Long COVID's epidemiology, risk factors, pathophysiology, and both medication and lifestyle/behavioral recommendations for management of Long COVID. 

Here are my notes:

Unfortunately, there are a number of different definitions of Long COVID

• CDC: symptoms persist >4 weeks after COVID (live virus no longer detectable)
• WHO: symptoms present >3 months after acute COVID illness, lasting at least 2 months
• National Academies of Science: infection-associated chronic conditions after SARS-COV2 infection, present for at least 3 months as either continuous, relapsing/remitting or progressive, affecting one or more organ systems.
• PASC: Post-Acute Sequalae of COVID, lasting 4 weeks or longer

Epidemiology

17-18% of all US adults reported having long COVID at some point since 2020, ~7% having ongoing symptoms

20 million adults in US, 2 million adults in CA are experiencing Long COVID today

Long COVID numbers have declined, but rate has been consistent 6-7%

Characteristics of  those who develop Long COVID

-higher rates of comorbid/preexisting health conditions, tend to have experienced more severe COVID illness or were hospitalized

-unvaccinated, greater # of infections PRIOR to vaccination increases risk of Long COVID

-adult population slightly lower (3x rate for people in 50s compared to 80s)

-higher rates in Females, Latinx/Hispanic

-increased rates in white Americans, rural regions, lower income households

-bisexual/transgender more likely to report Long COVID sx

Economic costs of Long COVID

-2-4 million people in US out of work due to disability to due Long COVID

-$168 billion/year, revised to $3.7 trillion/year

Clinical Manifestations

Long COVID symptoms can lingers weeks, months, longer. Severity and type can vary. Most patients will experience resolution of their symptoms by 1 year. Patience is key.

>200 symptoms under the Long-COVID umbrella, extremely non-specific, hard to categorize broadly

Symptoms tend to wax and wane, can be linked to any severity of acute infection (most people now only get mild COVID)

Symptoms vary according to variant

Pathophysiology

A complete understanding of pathophysiology is not established, but basic science is working to understand mechanism/pathways that can explain symptoms. 

-Direct AND indirect mechanisms

-ACE2 receptors ubiquitous and expressed in various tissues in the body (heart, lungs, GI), involved in breaking down Angiotensin 2 to promote homeostasis, also downregulates inflammation. If left unchecked/unregulated, can get uncontrolled/chronic inflammation. When COVID infects the host, binds to ACE2 receptor sites, which makes it less available to break down Angiotensin 2>> release of cytokines and inflammatory mediators>> immune dysregulation and chronic inflammation

Clinical management 3 common conditions:

1) Chronic Fatigue is the MOST common symptom reported with Long COVID, can last weeks/months/years. Lingers the longest. This is profound and unusual persistent sense of exhaustion after simplest of activities, including ADLs. By definition, Chronic Fatigue must be present >6 months, otherwise it is called Long-COVID with prolonged post-viral fatigue. 

Post-Exertional Malaise (PEM) commonly expressed by people with Long COVID. Can be induced by either physical or cognitive activities. Sudden drop of energy and profound fatigue that leads to struggle to complete activities for the day. Can be hours to days. Creates frustration, discouragement and fear. 

A small observational 2023 study from Amsterdam found that abnormalities due to PEM are due to significant defects in skeletal muscle due to exercise-induced myopathy with infiltration of immune t cells and amyloid deposits. Also severe reduction of mitochondrial enzyme activity>> premature lactic acid buildup in skeletal muscles. This explains marked reduction in exercise capacity. 

Treatment/Management for Long-COVID associated Chronic Fatigue

Medication

Low dose naltrexone (LDN), non selective opioid antagonist, seems to help with chronic fatigue. Well tolerated, reduced CNS inflammation, upregulates endorphins.

Dosed at bedtime 0.5mg-4.5mg (start low go slow, increase q2-3 weeks)

Side effects: vivid dreams, insomnia, GI upset (mild). If sleep disturbances, can give earlier in day

Anecdotally, about 1/2 of people that try LDN report some improvement in fatigue and brain fog

Lifestyle 

Stress relief, sleep, nutrition 

People able to reduce sugar and caffeine intake demonstrate less fatigue

Avoiding dehydration is key

Review meds and others substances that can worsen fatigue

Control comorbid chronic conditions that also exacerbate fatigue (DM, OSA)

Pacing is a mindset of learning to conserve energy balancing time spent on activity vs. time spent on rest with goal to increase participation in activities. Deliberate self-management strategy. Has evidence in Long COVID to improve energy and endurance

2) Brain fog is an umbrella term used to describe cognitive dysfunction associated with Long COVID. It is vague. No way to distinguish. Areas of cognition impacted: memory (working memory), attention (conversation details, following complex stories, multi-tasking), fluency (word finding), executive function (step by step actions, organizing or performing cognitive tasks). 

Possible mechanisms of brain fog: 

Direct: COVID enters CNS by retrograde transport along olfactory nerves, virus can cause direct toxic injury

Indirect: disrupted blood brain barrier, more permeable and porous. Disruption of BBB allows entry of inflammatory mediators to enter the CNS, disrupting cognitive function (2023 study in Nature Neuroscience found elevated biomarkers in people with long COVID and brain fog similar to TBI patients). Further study needed.

Off label Medications

• Guanfacine (old drug used for hypertension, selective alpha 2 receptor agonist, thought to improve working memory, improved attention. Used in TBI, ADD). Can drop BP. Protocol out of Yale combine guanfacine with NAC. (see below)
• Also SSRI/SNRI, stimulants (care w/habituation, tolerance, should be used rarely), amantadine (influenza anti-viral) increases dopamine release and prevents reuptake (used in TBI and CFS, 100mg BID)
• LDN (see above)

Lifestyle 

Stress reduction, screening for and management of anxiety/depression

Reduce neuroinflammation with healthier eating (low in carbs, simple sugar, low in caffeine)

Avoid neurotoxic substances: ETOH, cannabis, other drugs

Limit screen time (neuro-stressor), too much screen time can overtax brain and worsen brain fog

Quantity/quality of sleep: sleep hygiene rests nervous system, reduces neuroinflammation (turn off electronic devices)

3) Orthostatic Intolerance (OI) and Postural orthostatic tachycardia syndrome (POTS)

OI: uncomfortable symptoms that arise when moving to an upright position (faint, dizzy, palpitations, chest pain, SOB, blurry vision, coat-hanger headache). Often patients with OI need to lay down or sit to make symptoms to stop.

POTS: Same symptoms of OI, accompanied by HR increases >30 bpm within 10 minutes of standing

OI and POTS are both due to dysregulation of Sympathetic and Parasympathetic balance, probably involves Vagus nerve. Need to r/o underlying cardiac conditions! 

NASA lean test can distinguish OI vs. POTS

Three pillars of management of OI/POTS:

1. Hydration: ultra hydration, drink at least 2L of fluid/day, wake up and hydrate first thing int he AM, hydrate every 2-3 hours
2. Salt Loading: increase sodium intake to at least 3000mg/day, can go as high as 10,000mg/day (very high), add salt or sodium tablets
3. Compression: compression garments in lower limbs, torso

                    mid-thigh/waste-high compression stocking (20-30mmHg compression)

                    belly/abdominal binders

                   commercial body shapewear (e.g. Spanx)

Also, discourage people from laying around in bed for prolonged time, can worsen symptoms in the long run. If rest needed, avoid resting flat (HOB up by 6-10 inches) to minimize orthostasis. Get up slowly, give CNS chance to accommodate posture

Avoid anything that worsens dehydration: alcohol, caffeine, hot temperature (stream baths, hot day)

Medications (see image below)

Non-selective BB, e.g. propranolol

Flourinef (BP)

Midodrine

Ivabradine

IV saline boluses

Additional Notes:

-Paxlovid not shown to treat or prevent Long COVID

-Vaccines do prevent Long COVID, if shots tolerated, they are probably beneficial (large multi-national studies). The more boosters you get prior to getting COVID, less likely you are to get Long-COVID. For some people, vaccination improved Long COVID symptoms. However, vaccination (and reinfection) can also aggravate long COVID symptoms. Shared decision-making needed. Reasonable to pursue vaccination even in setting of long COVID. 

Be holistic, flexible, tailor to patient's individual needs.

Multidisciplinary approach is key, including PT/OT/SLT, nutrition, health education, mental health services

Advocate for patients. Validation and support are important. Bring patients in office for in person exam (no later than 3 months after symptoms started, rule out other chronic conditions)

There are no biomarkers to identify Long COVID, it's a clinical diagnosis

Look for red flag conditions (e.g. heart disease, metabolic/endocrine, etc) and optimize underlying chronic conditions.

Patience is key.

Calm in the Chaos: An Approach to Rapid Responses (Bamidele, 7/28/2021)

Kudos to Dr. Stephanie Bamidele, who delivered our very first R3 Grand Rounds of the Academic year. Her topic? Calm in the Chaos: An Approach to Rapid Responses.

A recording of her excellent presentation is available HERE for your viewing. 

And here are my notes:

Anyone who has worked in a hospital knows that rapid responses occur frequently in the hospital. But it hasn't always been that way! The concept of Rapid Response Teams emerged in the 1990s, modelled after Code Teams (which originated in the 1960s), as a standardized group of people expected to respond to a call for help before a patient requires a Code Team's assistance. The RRT goal is to intervene and respond to prevent major adverse events. And then make systems changes that allow for the next response to be even more effective. 

Anyone can activate an RRT.

RRT may be activated for a number of reasons: vital sign abnormalities, nurse or family detection of clinical deterioration, a change in mental status, and more.

Specific clinical criteria may be used to designate a RR present minutes to hours before a serious adverse event:

• HR <40 or >130
• SBP <90
• Respiratory Rate <8 or >28
• Oxygen saturation <90%
• Change in level of consciousness
• Change in urine output (<100ml/4 hours)

Like a Code, any Rapid Response starts with the basics: A (airway), B (breathing), C (circulation) and goes from there. See these images for a very clear description of events that should occur in the first five minutes of a RR: 

A	AIRWAY Assistance (call for help) Activate RRT Annunciate when providing key information Acquire Data Attend to patient until RRT arrives Access (IV) Assist as directed by team leader
B	BREATHING Bed (away from wall) Backboard if pulseless for CPR Blood glucose if altered mental status

 

C	CIRCULATION: check pulse and BP CPR Crash Cart Connect IVF Clear the Room Communicate to RRT
D	Defibrillate if Vfib or pVT Document vitals at time RRT was called
E	Explain (S-BAR) to team leader. Situation, Background, Assessment/Action, Recommendation/Report

As in all parts of life, communication is everything! 

Dr. Bamidele reminded us that a standard way of communicating (in this case, following the hospital ISBAR model) is the best way to go. Doing so, ensures that all people present at a RR, have a clear understanding of what is happening and what is being recommended.

 

Okay, doctors, so, you are the leaders of the RRT, right? What do you actually do then to be an effective leader? Here are key steps, as outlined by Dr. Bamidele:

1. Identify team members and roles: who is the leader? what are the roles? Does everyone need to be here. Start with a simple, "I am Dr. ____, and I am leading this RR"
2. Crowd control: limit to 8-9 people max, including the leader (doctor), ICU charge RN, bedside/flor RN, respiratory therapist, and any necessary techs (lab, xray, etc). Send everyone else back to work.
3. Set a calm and assertive and inclusive tone. Be respectful, willing to ask for help.
4. Promote a flattened hierarchy: think aloud, step back, voice specific findings (e.g. glucose, x ray findings, response to narcan_, ask for suggestions and/or feedback
5. Gather info via parallel processing (this is hard!): visual assessment, forming a plan, proposing an intervention
6. Have situational awareness: don't miss the forest through the trees, integrate evolving information in real time, reinforce plan, gather suggestions
7. Use closed loop communication: call out--> check back--> verification

Dr. Bamidele also gave us specific advice about the role of the Family Liaison during a rapid response or a Code event. There is mixed data on the harm/benefit of a family's presence at the bedside during these acute events, and so it is generally recommended that staff give the family the option of being present or leaving (without judgement). If the family is present, a designated staff person (RN, junior resident, etc) should be designated as the Family Liaison. That person should introduce themself, explain what is going on, stay by the family member's side (regardless of whether they stay or go), and provide that person an opportunity to ask questions. 

The aftermath

Once the Rapid response is done, it is super important to debrief, says Dr. Bamidele-- for two main reasons: first, because a Rapid Response often occurs in intense situations that may have a lasting impact on the team and that may require emotional processing and reflection. Second, reflecting on the process will hopefully allow you to do a better job next time. 

To address possible moral distress occurring in this context, consider the model of the 4As from the American Association of Critical Care Nurses (in graphic below)