Osteopathic Manipulative Therapy Effects on Post-Acute Sequelae of COVID-19 (PASC) or Long COVID

II. Description of the protocol and hypothesis with pilot data:

To date, individuals suffering from Long-COVID still do not have a specific proven treatment for this disease as a whole; however, an OMT sequence that was generated for prolonged post-COVID olfactory dysfunction was shown to generate significant increase in smell intensity after one treatment. Below is the abstract for a pilot trial:

Osteopathic Manipulative Therapy Effects on Prolonged Post-COVID Olfactory Dysfunction In 2019, the emergence of SARS-CoV2 created countless threats to public health that were unique to the pathogen. One of the first cardinal symptoms of infection is a sudden loss of smell and taste. Most people who survive their infection regain their sense of smell; however, a small amount of the population have prolonged decrease, complete absence, or abnormalities of smell long after the infection has resolved. This study represents a single-blinded pilot trial conducted during 2021 to examine the effects of a single treatment with OMT in individuals who have self-identified prolonged post-COVID anosmia, hyposmia or parosmia (n=20). This study was conducted at 2 locations within Ohio University.

Patients were randomly assigned to either the OMT group or a placebo/light touch/sham group by a flip of the coin and subsequently underwent pre-treatment smell testing of 4 items (Orange, Red Onion, Bourbon, and Perfume) they were then treated based on group selection, and subsequently underwent post-treatment smell testing to determine change in olfactory function. It was hypothesized that the OMT group would have a greater improvement in olfactory function when compared to the placebo group. A Mann-Whitney test indicated that the post and pre-treatment differences in the correct smell intensity scores of red onions were significantly higher for participants who received OMT treatment (Mdn = 2.00) compared to participants who received a non-osteopathic treatment (Mdn=1.00), U=20, p=0.019, r=5. There was a correlation of an increase in smell intensity in 2 out of the 3 remaining smell items, the mean difference between pre-smell treatment and post-smell treatment in the OMT group was higher than the placebo group. This therapy is a potential treatment for individuals suffering from this PASC related symptom and should be investigated further to determine the magnitude of OMT's effects on prolonged post-COVID olfactory dysfunction.

Side effects from the treatment group in the above study were minor but included light-headedness, drowsiness. After one treatment, there was significant improvement in olfactory dysfunction in participants in the treatment group as outlined by the study above. A poster presentation for the above study was accepted at 3 national conferences (American Academy of Osteopathy, American Academy of Physical Medicine and Rehabilitation, and American College of Physicians in San Diego) this past year.

The OMT sequence generated for the above trial is reproducible and safe. The OMT protocol designed for the above trial was as follows:

1. Rib Raising: A patient sits on edge of a treatment table, the physician faces the patient and places hands on the posterior aspect of the thorax (focus of palpation being on the vertebral-chondral junction), following patient inspiration and expiration the physician elevated and depresses the rib cage in tandem. This is classically hypothesized to engage the Sympathetic chain and cause an initial stimulation followed by a decrease in sympathetic tone via decreasing restriction of the anatomical space. 2. Suboccipital Release: The patient lies supine. The physician places the pads of their phalanges slightly inferior to the occiput and then applies a slight therapeutic force to the area to stimulate CN-X. The physician stops applying pressure when a "release" of the fascial plane is appreciated by the physician. This is classically hypothesized to engage the parasympathetic nervous system and stabilize parasympathetic tone via decreasing restriction of the anatomical space. 3. Thoracic Inlet Release: The patient lies supine. The physician places each hand on the ipsilateral aspect of the thoracic inlet and then engages the anatomical space in three different planes of motions (Flexion/extension, Lateralization(Rt)/Lateralization (Lt), and Rotation(Clockwise/counterclockwise)). Once the physician engages all planes, they then place the thoracic aperture into restriction in relations to the above planes of motion and hold the position until there is a "release" or an increase in pulse of the carotids which implies a fascial plane changing to a state of decrease tone. This is classically hypothesized to decrease restriction to flow in which it relates to the thoracic inlet for lymphatic drainage. 4. Miller Pump: The patient lies supine. The physician places each hand on the ipsilateral ribs 2-4 on the anterior aspect of the thorax. The patient is instructed to inhale and exhale through their mouth. On exhalation the physician places a force into the thorax to slightly compress the thorax. During the inhalation phase of the respiratory cycle the physician maintains pressure to prevent the rib cage from expanding. On the following exhalation phase, the physician applies force to the thorax to "take up slack" that the thorax would physiologically generate on the following inhalation motion. The physician then repeats 2-3 more times pending on the patient's compliance of the physician introduced force/thorax restriction. On the following inhalation, the physician releases the force and the thorax rebounds to physiological range of motion. This is classically hypothesized to generate a negative pressure gradient that generates a rebound thoracic expansion that correlates to an influx of lymphatic drainage within the thoracic cavity via the thoracic inlet. 5. Pedal Pump: The patient lies supine. The physician places each hand on the dorsum of the patient's feet and moves the feet into dorsi-flexion followed by plantar flexion 3 times. This is classically hypothesized to assist with venous pooling in the lower extremity and "pump" venous flow as well as lymphatic flow into the greater circulation. 6. Suboccipital Release: This is repeated as this was part of the initial protocol. It is unethical to not include this step as individuals who benefitted from the initial protocol underwent this repeat maneuver and received symptomatic relief from prolonged post-COVID olfactory dysfunction. This stage is also hypothesized to continually stimulate the parasympathetic nervous symptom through re-engagement of the vagus nerve as listed above. 7. Cranial Sequence of Sinus Effleurage followed by indirect force within vault hold: This is the final aspect and hypothetically the most important aspect of the sequence. The description of this protocol will be divided in two parts (the actions required to complete and the experimental hypothesis that differentiates the classical hypothesis)

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1. The patient lies supine. The physician places the pads of their phalanges overtop of the lambdoid suture. The physician then applies a slight therapeutic force on the suture until a "release" of the fascial plane is appreciated by the physician. A "release" is sometimes felt as an increase in pulsatile activity. The physician then places the pads of their phalanges just lateral to the posterior-aspect of the sagittal suture until a "release" of the fascial plane is appreciated by the physician. The physician then places the pads of their contralateral thumbs just lateral to the posterior-aspect of the sagittal suture and spreads the fascia abutting the suture laterally until a "release" of the fascial plane is appreciated by the physician. The physician then places the pads of their phalanges just lateral to the midline of the frontal bone to apply a slight therapeutic spreading force until a "release" of the fascial plane is appreciated by the physician. The physician then engages the skull in the "vault hold" in which the 5th digit of each hand is overlying the ipsilateral squamous aspect of the occiput, the 4th digit is overlying the mastoid process of the temporal bones, the 3rd digit is overlying the zygomatic process of the temporal bones, the 2nd digit is overlying the greater wings of the sphenoid and the 1st digit is overlying the cranium. The physician then holds this position lightly until the cranial respiratory motion (the phenomenon of paired skull bones motion along suture lines) is appreciated. This allows the physician to determine how the sphenoid is moving relative to the occiput and parietal bones, depending on the motion that is appreciated, the physician moves the structures to the least amount of restriction and moves the bones back to their physiological baseline of which a "release" is appreciated. 2. The vault hold is classically hypothesized to be sensing the "pulse" of CSF movement as it moves through the CNS. This is where the hypothesis that is used in this study differentiates from the classical hypothesis.

* The classical hypothesis seems incorrect. CSF is produced and consumed in "steady state". The choroid plexus generates CSF as a continuous function and arachnoid granulations absorb CSF in a continuous function. There is no "pump" as there is with the heart to generate forward blood flow. The real question is, what is generating the paired skull bones movement along suture lines, and why did this maneuver help improve olfactory function? * This research team is hypothesizing that this pulse appreciated on paired cranial bones on suture lines could be a pulse of the sympathetic nervous system. This is not proven, nor is it described in classical Osteopathic or Allopathic literature. This hypothesis is supported more in-depth below.

The original pilot study was designed to engage the olfactory region and correlated lymphatic and vascular drainage. Below is a brief discussion of the hypothesis for the pilot study:

The pathology of SARS-CoV-2 viral particles has been studied extensively; however, there are still speculations regarding how the virus causes a prolonged olfactory dysfunction. There is significant evidence that the SARS-CoV-2 viral particle has a spike protein (S2) that gains entrance to the human host via attaching Angiotensin-Converting-Enzyme 2 (ACE-2) receptor and is endocytosed into the cell in respiratory epithelium. It has also been determined that the Transmembrane Serine Protease Gene 2 (TMPRSS2) gene is also responsible for viral entry into the host \[1\]. The ACE-2 receptor and TMPRSS2 are distributed in high concentration throughout the nasal respiratory tract \[1\],\[2\].

In general, there are 4 main hypothesized mechanisms surrounding SARS-CoV-2 olfactory dysfunction:

1. general nasal obstruction due to rhinorrhea 2. olfactory neuron destruction 3. viral CNS infiltration affecting olfactory neurons 4. injury to support cells within the nasal epithelium \[3\].

A significant number of individuals who were infected with SARS-CoV-2 and have olfactory dysfunction do not report rhinorrhea or nasal congestion \[4\]. The timeline of recovery from anosmia does not align with the timeline for regeneration of olfactory neurons and support cells, causing this hypothesis to be less likely \[3\]. In addition, the CNS infiltration via entrance through olfactory neurons has limited evidence based on the lack of brain tissue alteration observed via magnetic resonance imaging \[3\].

Injury to the support cells has increasing evidence as the most likely mechanism of action in SARS-CoV-2 causing olfactory dysfunction. These support cells have significant TMPRSS2 and ACE-2 receptor expression as discussed above. It has been shown that the infection of the golden Syrian hamster with SARS-CoV-2 has shown significant damage to olfactory epithelium (OE). Bryche, et al. determined that the damages to the OE were due to sign

• Blood Pressure(BP) [Срок оценки: Each in-person treatment event, total of 1 BP at arrival after being enrolled for baseline and then a repeat 10 minutes after treatment (regardless of which treatment arm); repeat sequence at the 2nd in-person visit for a total of 4 BP readings]
• Heart Rate (HR) [Срок оценки: Each in-person treatment event, total of 1 HR at arrival after being enrolled for baseline and then a repeat 10 minutes after treatment (regardless of which treatment arm); repeat sequence at the 2nd in-person visit for a total of 4 HR readings]