Scientists propose cause of symptoms, treatment for long COVID-19

Authors: Gary Van Beusekom | News Writer | CIDRAP News   Posted June 10, 2022

Two studies to be presented at upcoming professional society meetings suggest that some long COVID-19 symptoms may be related to the effect of SARS-CoV-2 on the vagus nerve and that the use of enhanced external counterpulsation (EECP)—which increases blood flow—can improve some of those symptoms, respectively.

Long COVID may affect up to 15% of those who survive their infections, causing symptoms such as fatigue, muscle pain, and cognitive problems that linger for months. Neither study has been peer-reviewed, and the second one comes with the added caveat that it was conducted by an EECP provider.

Long COVID, vagus nerve symptoms may overlap

At the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), slated for Apr 23 to 26 in Lisbon, Portugal, a team led by researchers in Spain will discuss the role of the vagus nerve in long COVID, according to an ECCMID news release.

The vagus nerve runs from the brain into the torso, heart, lungs, intestines, and several muscles, including those involved in swallowing. It has a role in heart rate, speech, the gag reflex, the transfer of food from the mouth to stomach, transporting food through the intestines, perspiration, and other bodily functions.

The study authors said that SARS-CoV-2 infection may lead to long COVID symptoms such as dysphonia (voice problems), dysphagia (difficulty swallowing), dizziness, tachycardia (rapid heart rate), orthostatic hypotension (low blood pressure), and diarrhea. Long COVID has been reported to last for months to more than a year.

In the observational study, the researchers evaluated the morphologic and functional aspects of the vagus nerve in 348 patients diagnosed as having long COVID at a Spanish hospital from March to June 2021. Of the 348, 228 (66%) had at least one symptom that could be attributed to vagus nerve dysfunction (VND).

The ongoing study involved the first 22 participants identified as having at least one VND symptom; 91% of them were women, and the median age was 44 years. The most common VND symptoms were diarrhea (73%), tachycardia (59%), dizziness, dysphagia and dysphonia (45% each), and orthostatic hypotension (14%).

Nineteen of 22 participants (86%) had three or more VND symptoms with a median duration of 14 months. Ultrasound examination revealed that at 6 (27%) had alterations of the vagus nerve in the neck, including thickening of the nerve and increased echogenicity, which indicates mild inflammatory changes.

Thoracic ultrasound showed flattened diaphragmatic curves, indicating abnormal breathing, in 10 participants (46%). Ten of 16 patients (63%) had lower maximum inspiration pressures, indicating weakness of the muscles involved in breathing.

Thirteen of 18 patients (72%) had impaired eating and digestive function, including self-reported dysphagia. Among 19 patients assessed for gastric and bowel function, 8 (42%) had impaired ability to move food from the esophagus to the stomach, with 2 of these 8 reporting difficulty swallowing.

Nine of 19 patients (47%) had gastroesophageal acid reflux, with 4 of these 9 again having problems moving food to the stomach and 3 with hiatal hernia (bulging of the upper stomach through the diaphragm into the chest cavity).

A Voice Handicap Index 30 test (a standard method of measuring voice function) produced abnormal results in 8 of 17 patients (47%), indicating that 7 of the 8 had dysphonia.

“Our findings so far thus point at vagus nerve dysfunction as a central pathophysiological feature of long COVID,” the researchers said in the release.

Improvement in functional scores, fatigue after EECP

In a retrospective study to be presented this week at the American College of Cardiology’s (ACC’s) virtual Cardiovascular Summit, scientists from EECP provider Flow Therapy evaluated the effect of the therapy in 50 COVID-19 survivors, according to an ACC news release. Twenty patients had coronary artery disease (CAD), while 30 did not; average age was 54 years.

EECP uses contracting and relaxing pneumatic cuffs on the calves, thighs, and lower hip area to provide oxygen-rich blood to the heart muscle, brain, and the rest of the body. Each session takes 1 hour, and patients may undergo as many as 35 sessions over 7 weeks.

All patients completed the Seattle Angina Questionnaire-7 (SAQ7), Duke Activity Status Index (DASI), PROMIS Fatigue Instrument, Rose Dyspnea Scale (RDS), and the 6-minute walk test (6MWT) before and after they completed 15 to 35 hours of EECP therapy.

The analysis showed statistically significant improvements in all areas assessed, including 25 more points for health status on the SAQ7 (range, 0 to 100), 20 more points for functional capacity on DASI (range, 0 to 58.2), 6 fewer points for fatigue on PROMIS (range, 4 to 20), 50% lower shortness of breath score on the RDS, and 178 more feet on the 6MWT.

The change from baseline among participants who had long COVID but not CAD was significant for all end points, but there was no difference between long COVID patients with or without CAD.

“Emerging data shows that long COVID is a disease that impacts the health of vessels, also known as endothelial function,” senior author Sachin Shah, PharmD, said in the release. “EECP is a disease-modifying, non-invasive therapy that has previously shown to improve endothelial function in controlled clinical trials.”

Shah said that several study participants weren’t able to work at the beginning of the study. “Remarkably, all patients at this point were able to successfully return back to work after undergoing treatment,” he said. “These patients also showed improvement in ‘brain fog,’ which is a common symptom of long COVID.”

The researchers called for larger studies with a control group receiving sham therapy to validate their findings.

Pancreatic damage in COVID‐19: Why? How?

Authors: Ferhat Bacaksız, 1 Berat Ebik, 1 Nazım Ekin, 1 and Jihat Kılıc 2

Int J Clin Pract. 2021 Aug 6 : e14692.doi: 10.1111/ijcp.14692 [Epub ahead of print] PMCID:  PMC8420122PMID: 34331821



We aimed to evaluate the elevation of amylase and lipase enzymes in coronavirus disease 2019 (COVID‐19) patients and their relationship with the severity of COVID‐19.


In this study, 1378 patients with COVID‐19 infection were included. Relation of elevated amylase and lipase levels and comorbidities with the severity of COVID‐19 was analysed. The effects of haemodynamic parameters and organ failure on pancreatic enzymes and their relations with prognosis were statistically analysed.


The 1378 patients comprised of 700 (51.8%) men and 678 (%49.2) women. Of all patients, 687 (49.9%) had mild and 691 (50.1%) patients had severe COVID‐19 infection. Amylase elevation at different levels occurred in 316 (%23) out of 1378 patients. In these patients, the amylase levels increased one to three times in 261 and three times in 55 patients. Pancreatitis was detected in only six (%1.89) of these patients according to the Atlanta criteria. According to univariate and multivariate analyses, elevated amylase levels were significantly associated with the severity of COVID‐19 (odds ratio [OR]: 4.37; P < .001). Moreover, diabetes mellitus (DM; OR: 1.82; P = .001), kidney failure (OR: 5.18; P < .001), liver damage (OR: 6.63; P < .001), hypotension (OR: 6.86; P < .001) and sepsis (OR: 6.20; P = .008) were found to be associated with mortality from COVID‐19.


Elevated pancreatic enzyme levels in COVID‐19 infections are related to the severity of COVID‐19 infection and haemodynamic instability. In a similar way to other organs, the pancreas can be affected by severe COVID‐19 infection.

What’s known

  • It has been suggested that COVID‐19 can cause pancreatic damage.
  • There are a limited number of studies related to the possibility of an increase in the level of pancreatic enzymes in COVID‐19 patients.

What’s new

  • COVID‐19 does not directly cause pancreatic damage.
  • Pancreatic enzyme elevation in patients with COVID‐19 develops in the advanced stages of the disease caused by multiple organ dysfunction and shock.


Coronavirus disease 2019 (COVID‐19) infection was initially considered to attack only the upper respiratory tract, but was later found to potentially affect almost all systems. This is caused by the angiotensin‐converting enzyme 2 (ACE2) receptors that coronavirus binds to in order to enter the cells. These receptors are also commonly available in the gastrointestinal system such as in hepatic, pancreatic and colonic cells.12

Recent studies have shown that COVID‐19 infection can cause damage to the pancreas caused by the high expression of ACE2 receptors from the pancreatic tissue.3 Additionally, it has also been reported that hyperglycaemia can occur because of pancreatic islet cell damage in patients with COVID‐19 and that severe patients with COVID‐19 should be followed up closely in terms of pancreatic damage.45

In this study, we evaluated the amylase and lipase elevations in patients with COVID‐19 in order to investigate the relationship between pancreatic enzyme elevations and the severity of COVID‐19 infection and to identify the underlying conditions.Go to:


The study included 1378 patients with COVID‐19 infection who presented to our hospital between March and December 2020. Clinical characteristics including temperature, blood pressure, laboratory parameters, treatments and comorbidities were monitored throughout hospitalisation. In addition to other laboratory parameters, amylase and lipase levels were also studied in order to determine the ratio of patients with elevated pancreatic enzymes. Values above 105 U/L for amylase and 65 IU/L for lipase were considered high.6 Patients with pancreatitis were identified according to the Atlanta criteria.7

Additionally, pancreatic enzyme elevation in COVID‐19 infection was investigated with regard to the severity of disease. Patients were divided into two groups based on the severity of their COVID‐19 symptoms: mild (n = 687) and severe (n = 691). Patients with fever, headache, loss of taste and smell and generalised myalgia without tachypnoea (oxygen saturation >92%) were considered to have a mild infection, whereas patients on invasive or non‐invasive respiratory support or with deteriorated haemodynamic conditions were considered to have severe COVID‐19 infection.8

The causes of pancreatic enzyme elevation were compared between patients with mild and severe COVID‐19 infection and between surviving and non‐surviving patients. Relation between elevated pancreatic enzymes and metabolic parameters, haemodynamic findings, single and multiple organ failures was also examined.910

Hypotension was evaluated based on mean arterial pressure (MAP). A MAP value of 60‐110 mmHg was accepted as normal, <60 mmHg as hypotensive and >110 mmHg as hypertensive.11

Liver damage was determined according to the 2019 European Association for the Study of the Liver (EASL) guidelines, based on the upper limits of normal (ULN) serum alanine aminotransferase activity (ALT) and serum alkaline phosphatase activity (ALP), as follows: ALT ≥5 × ULN or ALP ≥2 ULN [in the absence of known bone pathology] or ALT ≥3 ULN with simultaneous increase of total bilirubin concentration ≥2 ULN.12 Kidney injury was determined according to the RIFLE (Risk, Injury, Failure, Loss of kidney function and End‐stage kidney disease) criteria.13

The study was conducted in accordance with the Helsinki Declaration and the study protocol was approved by the local ethics committee (No: 611, Date: 16 October 2020).

2.1. Statistical analysis

Data were analysed using SPSS 26.0 for Windows (Armonk, NY: IBM Corp.). Normal distribution of data was assessed using Kolmogorov‐Smirnov, Shapiro‐Wilk test, coefficient of variation, skewness and kurtosis. Continuous variables were expressed as mean and standard deviation (SD), and categorical variables were expressed as percentages (%). Student t test and Mann‐Whitney U‐test were used in paired groups to compare pancreatic enzymes and disorders of other organs between patients with severe and mild COVID‐19 infection. ANOVA test was used for parameters homogeneously distributed in triple groups. Bonferroni correction was used to determine the significant results in groups. Welch’s ANOVA and Kruskal‐Wallis tests were performed for non‐homogeneous parameters. Pearson and Spearman correlation coefficients were used to analyse the relationship between pancreatic enzyme elevation and other parameters. Univariate and multivariate analyses were performed to determine the factors associated with pancreatic enzyme elevation. All tests were bilateral and a P‐value of <.05 was considered significant.Go to:


The 1378 patients comprised of 700 (51.8%) men and 678 (%49.2) women. The prevalence of kidney failure, DM, ischaemic hepatitis and sepsis was significantly higher in patients with severe COVID‐19 compared with patients with mild disease. Moreover, amylase and lipase levels were also higher in patients with severe COVID‐19 (Table 1).


Demographic data and biochemical parameters of patients with mild and severe COVID‐19

Mild COVID‐19±SDSevere COVID‐19±SDP
N687 (49.9%)691 (50.1%)
Age60.2 (29‐84)65 (51‐86)<.001
Gender F/M356/331322/369.053
Amylase (U/L)82.6 ± 50.4264.7 ± 292.0<.001
Lipase (IU/L)59.7 ± 51.279.0 ± 24.2.045
ALT (IU/L)70.4 ± 60.282.7 ± 56.4<.001
AST (IU/L)61.6 ± 40.7180 ± 135.5<.001
ALP (IU/L)84.1 ± 35.4133.2 ± 107.2.295
GGT (IU/L)54.2 ± 51.579.4 ± 58.9.099
T.Bil (mg/dL)0.67 ± 0.331.95 ± 1.53<.001
LDH (IU/L)411.9 ± 2101137 ± 248.7<.001
Urea (mg/dL)45.7 ± 26.9187.0 ± 92.8<.001
Creatinine (mg/dL)0.89 ± 0.493.74 ± 1.96<.001
Glucose (mg/dL)138 ± 85.0290 ± 135<.001
WBC (cell/µL)9840 ± 448518 422 ± 6039<.001
Lymphocyte (cell/µL)1993 ± 6651655 ± 946<.001
CRP (mg/L)107.8 ± 67.2217.9 ± 69.1<.001
Procalcitonin (ng/mL)1.04 ± 4.658.03 ± 19.7<.001

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Abbreviations: ALP, alkaline phosphatase, GGT, gamma glutamyl transpeptidase WBC, white blood cell, CRP, C reactive protein; ALT, alanine transaminase; AST, aspartate transaminase; LDH, lactate dehydrogenase; SD, standard deviation.

Amylase elevation at different levels occurred in 316 (%23) out of 1378 patients. In these patients, the amylase levels increased one to three times in 261 and three times in 55 patients. Pancreatitis was detected in only six (%1.89) of these patients according to the Atlanta criteria. Amylase and lipase elevation was found to be related to the severity of COVID‐19 infection in the remaining patients. The development of DM, kidney failure, hypotension and ischaemic hepatitis was found to be related to mortality from COVID‐19 infection. However, there was no relationship between lymphopenia and elevated amylase levels (Table 2). On the other hand, patients older than 65 years were more likely to have (1.89 times) elevated increased enzyme levels.


Relationship between amylase level in COVID‐19 patients and gender, comorbid status, severity and consequence of COVID‐19, haemodynamic status, other organ failures and laboratory parameters

FeatureAmylase (normal)Amylase (1‐3 times)Amylase (more than 3 times)P‐values
N/%1062 (77.0%)261 (19.0%)55 (4.0%)
Female (678%‐49.2%)565 (83.3%)100 (14.8%)13 (1.9%)<.001
Male (700%‐50.8%)497 (71.0%)161 (23.0%)42 (6.0%)
COVID‐19 severity
Mild COVID‐19 (687%‐49.9%)612 (89.1%)71 (10.3%)4 (0.6%)<.001
Severe COVID‐19 (691%‐50.1%)450 (65.1%)190 (27.5%)51 (7.4%)
Healing (909%‐66.0%)793 (87.2%)109 (12.0%)7 (0.8%)<.001
Death (469%‐34.0%)269 (57.4%)152 (32.4%)48 (10.2%)
Absent (866%‐62.8%)703 (81.2%)143 (16.5%)20 (2.3%)<.001
Available (512%‐32.6%)359 (70.1%)118 (23.0%)35 (6.9%)
Kidney failure
Absent (934%‐67.8%)808 (86.5%)114 (12.2%)12 (1.3%)<.001
AKI (316%‐22.9%)186 (58.8%)101 (32.0%)29 (9.2%)
CRF (128%‐9.3%)68 (53.1%)46 (36.0%)14 (10.9%)
Blood pressure
Normal (810%‐58.8%)727 (89.7%)76 (9.4%)7 (0.9%)<.001
Hypotension (466%‐33.8%)260 (55.8%)161 (34.5%)45 (9.7%)
Hypertension (102%‐7.4%)75 (73.6%)24 (23.5%)3 (2.9%)
Normal (562%‐40.8%)488 (86.8%)65 (11.6%)9 (1.6%)<.001
1‐3 times (488%‐35.4%)389 (79.7%)86 (17.6%)13 (2.7%)
3‐5 times (135%‐9.8%)89 (65.9%)37 (27.4%)9 (6.7%)
5‐10 times (65%‐4.7%)36 (55.4%)20 (30.8%)9 (13.8%)
>10 times (61%‐4.4%)32 (52.5%)26 (42.6%)3 (4.9%)
>1000 (IU/L) (67%‐4.9%)28 (41.8%)27 (40.3%)12 (17.9%)
Normal (468%‐34.0%)428 (91.4%)36 (7.7%)4 (0.9%)<.001
1‐3 times (564%‐40.9%)454 (80.5%)98 (17.4%)12 (2.1%)
3‐5 times (121%‐8.8%)76 (62.8%)38 (31.4%)7 (5.8%)
5‐10 times (71%‐5.1%)35 (49.3%)27 (38.0%)9 (12.7%)
More than 10 times (45%‐3.3%)22 (48.9%)16 (35.6%)7 (15.5%)
>1000 (IU/L) (109%‐7.9%)47 (43.1%)46 (42.2%)16 (14.7%)
Normal (966%‐70.1%)737 (76.3%)191 (19.8%)38 (3.9%).092
1‐2 times (234%‐17.0%)176 (75.2%)45 (19.2%)13 (5.6%)
More than 2 times(178%‐12.9%)149 (83.7%)25 (14.0%)4 (2.3%)
Normal (909%‐66%)722 (79.4%)158 (7.4%)29 (3.2%).072
1‐2 times (254%‐18.4%)173 (68.1%)62 (24.4%)19 (7.5%)
More than 2 times (215%‐15.6%)167 (77.7%)41 (19.1%)7 (3.2%)
Total Bilirubin
Normal (1059%‐76.9%)860 (81.2%)171 (16.2%)28 (2.6%)<.001
1‐2 times (257%‐18.6%)172 (66.9%)68 (26.4%)17 (6.7%)
More than 2 times (62%‐4.5%)30 (48.4%)22 (35.5%)10 (16.1%)
Normal (<225 IU/L) (161%‐11.7%)157 (97.5%)4 (2.5%)0 (0.0%)<.001
Normal‐1000 (IU/L) (969%‐70.3%)788 (81.3%)158 (16.3%)23 (2.4%)
1000‐2250 (IU/L) (148%‐10.7%)79 (53.4%)55 (37.2%)14 (9.4%)
>2250 (IU/L)(100%‐7.3%)38 (38.0%)44 (44.0%)18 (18.0%)
Lymphocyte levels
Normal (724%‐52.5%)581 (80.3%)119 (16.4%)24 (3.3%).120
Mild lymphopenia (489%‐35.5%)360 (73.6%)111 (22.7%)18 (3.7%)
Severe lymphopenia (165%‐12.0%)121 (73.3%)31 (18.8%)13 (7.9%)

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Abbreviations: AKI, Acute kidney injury; ALP, alkaline phosphatase, GGT, gamma glutamyl transpeptidase; ALT, alanine transaminase; AST, aspartate transaminase; CRF, Chronic renal failure; LDH, lactate dehydrogenase.

The prevalence of elevated amylase was 2.04 times higher in men than that in women. Hypotension (odds ratio [OR]: 6.63), sepsis (OR: 6.20), ischaemia‐related liver damage (OR: 6.63) and renal failure (OR: 5.18) were found to be significantly associated with pancreatic enzyme levels (Table 3).


Analysis of factors affecting enzyme elevation in COVID‐19 patients with elevated amylase and lipase

OR95% ClP valueOR95% ClP value
COVID‐19 Severity4.373.28‐5.81<.0013.762.90‐4.88<.001
Death from COVID‐195.083.89‐6.64<.0014.233.33‐5.36<.001
Kidney failure5.183.95‐6.79<.0013.783.00‐4.75<.001
Liver damage6.634.56‐9.64<.0013.092.43‐3.94<.001

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A very strong positive correlation was found between amylase and lipase levels in all patients (r: .828, P < .001), which implicates that the increased amylase in COVID‐19 patients is caused by the pancreas. A weak correlation was found between amylase level and age or gender. Likewise, a weak but statistically significant correlation was found between amylase level and DM. A strong correlation was detected between the amylase level and the severity of COVID‐19. Additionally, the presence of liver damage, renal failure, hypotension and multiple organ dysfunction syndrome (MODS) in these patients was moderately correlated with amylase level (Figure 1).FIGURE 1

Correlation between amylase level and risk factors in COVID‐19 patients with hyperamylasaemiaGo to:


We found that 23% of patients with COVID‐19 infection had pancreatic enzyme elevations, and we also detected a relationship between pancreatic enzyme elevation and the severity of COVID‐19 infection, haemodynamic instability and MODS.

Although 10.9% of patients with mild COVID‐19 infection had elevated amylase levels, this rate was 34.9% in patients with severe COVID‐19 infection. It was also revealed that the causes of pancreatic enzyme elevation were hypotension and ischaemia in patients with severe COVID‐19 infection. Elevated amylase levels were detected in 10.3% and 44.2% of patients with a normal MAP and low MAP (<60 mmHg), respectively. Out of 316 patients with a high amylase level, 36.7% of the patients recovered and 63.3% of them died. Moreover, 53% of patients with ischaemic hepatitis had both amylase and lipase elevations. We consider that after the development of shock in the body, pancreatic damage occurs in addition to hepatic and intestinal injury as a result of the decrease in blood flow to the gastrointestinal system.

A study investigating the relationship between COVID‐19 infection and pancreas reported pancreatic damage in 1%‐2% and 17% of patients with mild and severe infection, respectively. The authors suggested that pancreatic damage can be exacerbated by systemic inflammation.14151617 Amylase and lipase elevation suggestive of pancreatic damage has been reported in 8.5%‐17.3% of patients with COVID‐19. Moreover, higher enzyme levels have been reported in severe COVID‐19 patients.14151617 Likewise, in two previous autopsy studies, five of 11 (45.5%) and two of eight (25%) cases were detected with focal pancreatitis with haemorrhagic and necrotic changes in the pancreas. These changes had no clinical manifestations and were attributed to ischaemia and end‐organ damage.1819 In the light of our data, we consider that pancreatic damage is the most important cause of amylase and lipase elevations. The exact pathophysiology of pancreatic damage remains unclear, while the most widely accepted hypothesis points to pancreatic ischaemia.202122 If septicaemia progresses towards septic shock, not only in COVID‐19 but also in other infections, the resulting hypotension and vasodilation reduce blood flow to organs. To protect blood flow to vital organs such as the brain and heart, blood flow to the celiac, superior and inferior mesenteric arteries are reduced as a part of the protective mechanism. Afterwards, this is followed by renal and iliac arteries. This is the neurohormonal mechanism protecting vital organs. Gastrointestinal system is the target organ of shock and hypotension. As a result, the blood flow to the liver, pancreas and the entire gastrointestinal system is reduced, thereby causing symptoms such as nausea, vomiting, distension, ileus, or diseases such as ischaemic hepatitis.

Pancreas is supplied well by pancreatic arteries that stem from the splenic, gastroduodenal and superior mesenteric arteries. Amylase, lipase, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) are released into the bloodstream caused by the ischaemia resulting from decreased blood flow to the pancreas.23 This damage is mainly caused by haemodynamic deterioration, not by the virus itself. Similarly, in our study, elevated amylase and lipase levels were found to be associated with haemodynamic parameters and hypotension.

Although increased amylase and lipase levels might have clinical importance, it seems highly unlikely to use these parameters as prognostic indicators in clinical practice, mainly because enzyme elevation occurs during the intensive care period when the disease is severe and requires mechanical ventilation. At this stage, most patients have single or multiple organ failure and require vasopressor support.

In conclusion, although ACE2 receptors are expressed highly in pancreatic tissue, pancreatic enzyme elevations occurring in COVID‐19 infection might be associated with the severity of disease and haemodynamic instability. If the opposite was the case, we would have seen too many cases of pancreatitis, mainly because the pancreas has ACE2 receptors. As a matter of fact, despite the huge number of COVID‐19 cases, which has exceeded 100 million, pancreatitis has remained only at the level of case reports.2425Go to:


Bacaksız F, Ebik B, Ekin N, Kılıc J. Pancreatic damage in COVID‐19: Why? How? Int J Clin Pract. 2021;00:e14692. 10.1111/ijcp.14692 [PMC free article] [PubMed] [CrossRef] [Google Scholar]


Data may be made available upon request to the corresponding author.


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