COVID-19-associated diarrhea

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ifrah Fatima, M.B.B.S[2]

Synonyms and keywords:

Overview

SARS-CoV-2 mainly causes severe acute respiratory syndrome but may also present with gastrointestinal symptoms like diarrhea. It invades through the Angiotensin-converting enzyme 2 (ACE2) and the serine protease TMPRSS2 receptors present abundantly not only in the lungs but also in the enterocytes of the small intestine. A greater percentage of occurrence of diarrhea was noted in patients with severe COVID-19 when compared to non-severe disease. Likewise, patients with gastrointestinal symptoms were more likely to have a severe respiratory disease with ARDS requiring ventilatory support. The presence of the virus in the stool raises suspicion for fecal-oral transmission of SARS-CoV-2. Appropriate personal protective equipment (PPE) must be used while handling sources of contamination like feces.

Historical Perspective

• The etiological agent is SARS-CoV-2, named for the similarity of its symptoms to those induced by the severe acute respiratory syndrome, causing coronavirus disease 2019 (COVID-19), is a virus identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China.
• The growing number of patients however, suggest that human-to-human transmission is actively occurring.
• The outbreak was declared a Public Health Emergency of International Concern on 30 January 2020.
• On March 12, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic.

Classification

There is no established system for the classification of diarrhea in COVID-19.

Pathophysiology

• SARS-CoV-2 uses the Angiotensin-converting enzyme 2 (ACE2) and the serine protease TMPRSS2 receptors for cell entry.
• These receptors are presently abundantly not only in the lungs but also in the enterocytes of the small intestine.
• Other sites of expression of the receptors in the gastrointestinal tract are-the upper esophagus, liver, and colon.
• Entry of the virus causes disruption of the enterocytes and may lead to inflammation and alteration of intestinal permeability.
• COVID- 19 is being treated by a trial of many different antivirals and antibiotics.
• Diarrhea could also be a result of an alteration of the gut microbiota due to any of these.

Causes

Diarrhea in a patient hospitalized due to COVID-19 may be due to:

• COVID-19 associated diarrhea
• Secondary bacterial infections
• Clostridium difficile diarrhea and recent use of antibiotics
• Other infectious causes

Differentiating COVID-19 associated diarrhea from other Diseases

COVID-19 diarrhea must be differentiated from other diseases that cause diarrhea, such as:

• Secondary bacterial infections
• Clostridium difficile associated diarrhea
• Viral causes
• Parasitic causes

• Crohn's disease
• Ulcerative Colitis
• Autoimmune hepatitis

'To review the differential diagnosis of diarrhea, click here.

Organism			Age predilection	Travel History	Incubation Size (cell)	Incubation Time	History and Symptoms			Diarrhea type∞				Food source	Specific consideration
							Fever	N/V	Cramping Abd Pain	Small Bowel	Large Bowel	Inflammatory	Non-inflammatory
Viral	Rotavirus		<2 y	-	<102	<48 h	+	+	-	+			+	-	Mostly in day cares, most common in winter.
	Norovirus		Any age	-	10 -103	24-48 h	+	+	+	+			+	-	Most common cause of gastroenteritis, abdominal tenderness,
	Adenovirus		<2 y	-	105 -106	8-10 d	+	+	+	+			+	-	No seasonality
	Astrovirus		<5 y	-		72-96 h	+	+	+	+			+	Seafood	Mostly during winter
Bacterial	Escherichia coli	ETEC	Any age	+	108 -1010	24 h	-	+	+	+			+	-	Causes travelers diarrhea, contains heat-labile toxins (LT) and heat-stable toxins (ST)
		EPEC	<1 y	-	10†	6-12 h	-	+	+	+			+	Raw beef and chicken	-
		EIEC	Any ages	-	10†	24 h	+	+	+		+		+	Hamburger meat and unpasteurized milk	Similar to shigellosis, can cause bloody diarrhea
		EHEC	Any ages	-	10	3-4 d	-	+	+		+	+		Undercooked or raw hamburger (ground beef)	Known as E. coli O157:H7, can cause HUS/TTP.
		EAEC	Any ages	+	1010	8-18 h	-	-	+		+		+	-	May cause prolonged or persistent diarrhea in children
	Salmonella sp.		Any ages	+	1	6 to 72 h	+	+	+		+	+		Meats, poultry, eggs, milk and dairy products, fish, shrimp, spices, yeast, coconut, sauces, freshly prepared salad.	Can cause salmonellosis or typhoid fever.
	Shigella sp.		Any ages	-	10 - 200	8-48 h	+	+	+		+	+		Raw foods, for example, lettuce, salads (potato, tuna, shrimp, macaroni, and chicken)	Some strains produce enterotoxin and Shiga toxin similar to those produced by E. coli O157:H7
	Campylobacter sp.		<5 y, 15-29 y	-	104	2-5 d	+	+	+		+	+		Undercooked poultry products, unpasteurized milk and cheeses made from unpasteurized milk, vegetables, seafood and contaminated water.	May cause bacteremia, Guillain-Barré syndrome (GBS), hemolytic uremic syndrome (HUS) and recurrent colitis
	Yersinia enterocolitica		<10 y	-	104 -106	1-11 d	+	+	+		+	+		Meats (pork, beef, lamb, etc.), oysters, fish, crabs, and raw milk.	May cause reactive arthritis; glomerulonephritis; endocarditis; erythema nodosum. can mimic appendicitis and mesenteric lymphadenitis.
	Clostridium perfringens		Any ages		> 106	16 h	-	-	+		+		+	Meats (especially beef and poultry), meat-containing products (e.g., gravies and stews), and Mexican foods.	Can survive high heat,
	Vibrio cholerae		Any ages	-	106-1010	24-48 h	-	+	+	+			+	Seafoods, including molluscan shellfish (oysters, mussels, and clams), crab, lobster, shrimp, squid, and finfish.	Hypotension, tachycardia, decreased skin turgor. Rice-water stools
Parasites	Protozoa	Giardia lamblia	2-5 y	+	1 cyst	1-2 we	-	-	+	+			+	Contaminated water	May cause malabsorption syndrome and severe weight loss
		Entamoeba histolytica	4-11 y	+	<10 cysts	2-4 we	-	+	+		+	+		Contaminated water and raw foods	May cause intestinal amebiasis and amebic liver abscess
		Cryptosporidium parvum	Any ages	-	10-100 oocysts	7-10 d	+	+	+	+			+	Juices and milk	May cause copious diarrhea and dehydration in patients with AIDS especially with 180 > CD4
		Cyclospora cayetanensis	Any ages	+	10-100 oocysts	7-10 d	-	+	+	+			+	Fresh produce, such as raspberries, basil, and several varieties of lettuce.	More common in rainy areas
	Helminths	Trichinella spp	Any ages	-	Two viable larvae (male and female)	1-4 we	-	+	+		+		+	Undercooked meats	More common in hunters or people who eat traditionally uncooked meats
		Taenia spp	Any ages	-	1 larva or egg	2-4 m	-	+	+	+			+	Undercooked beef and pork	Neurocysticercosis: Cysts located in the brain may be asymptomatic or seizures, increased intracranial pressure, headache.
		Diphyllobothrium latum	Any ages	-	1 larva	15 d	-	-	-	+			+	Raw or undercooked fish.	May cause vitamin B12 deficiency

∞Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field

Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field

† It could be as high as 1000 based on patient's immunity system.

Epidemiology and Demographics

• Diarrhea is an uncommon gastrointestinal symptom (anorexia, nausea, and vomiting are more common) in patients with COVID-19 but may be the presenting symptom in a few patients.
• The frequency of occurrence of diarrhea varies between 1%-35%.
• It varies widely between different studies probably due to the different criteria used to define diarrhea.
• Greater percentage of occurrence of diarrhea was noted in patients with severe COVID-19 when compared to non-severe disease.
• Likewise, patients with gastrointenstinal symptoms were more likely to have severe respiratory disease with ARDS requiring ventilatory support.

• There is no data on predilection based on age, gender, geographical location, or race.

Risk Factors

Common risk factors in the development of gastrointestinal symptoms in patients with COVID-19 infection include:

• Inflammatory bowel disease patients- due to use to glucocorticoids, but not TNF-alpha inhibitors
• Increasing age
• Other comorbidities such as HTN, DM
• Use of glucocorticoids

Screening

• There is insufficient evidence to recommend routine screening in detecting covid associated diarrhea.

Natural History, Complications, and Prognosis

• Presence of diarrheal symptoms in covid-19 infection is associated with severe form of disease.
• Severe or poor prognostic form of disease can be described as ARDS requiring ventilatory support.

Diagnosis

Diagnostic Study of Choice

• COVID-19 diarrhea can be diagnosed based on the history of diarrhea and a positive stool test for SARS-CoV-2
• There are no established criteria for the diagnosis of diarrhea in COVID-19.

History and Symptoms

• Diarrhea can be defined as passing of >3 loose stools per day.
• Diarrhea was the primary symptom at the onset of covid-19 infection at onset and the symptoms lasted for approximately 4 days.
• The duration of diarrhea ranged from 2-4 days with 3-8 bowel movements per day, according to various studies.
• There is not enough data from other studies on the number of evacuations, consistency of stool, and duration of symptoms.

Physical Examination

• Patients with diarrhea due to COVID-19 usually appear very sick, since diarrhea is seen in a greater percentage of patients with severe respiratory disease than non-severe disease.

• Physical examination due to diarrhea may be remarkable for:
  • Weak, low volume pulse
  • Hypotension
  • Sunken eyes
  • Decreased skin turgor

Laboratory Findings

Laboratory findings consistent with the diagnosis of covid-19 associated diarrhea include complete blood count, glucose levels, white blood cells (WBC) detection, urine analysis, calcium levels, Thyroid stimulating hormone (TSH) levels, complete metabolic panel and stool examination.

• Stool examination includes the following:
  • Stool culture
  • Stool electrolytes
  • Stool osmolality
  • Ova and parasites
  • Fecal lactoferrin
  • Fecal leukocytes

Electrocardiogram

• An ECG may be helpful in the diagnosis of covd-19 associated diarrhea. Findings on an ECG suggestive of diarrhea include sinus tachycardia.

X-ray

• The chest x ray findings in a suspected case of coronavirus infection can mimic the findings in pneumonia, which can include:

• Consolidation
• Interstitial infiltration

Echocardiography or Ultrasound

• There are no echocardiography/ultrasound findings associated with diarrhea in COVID-19.

CT scan

• Abdominal CT scan may be helpful in the diagnosis of covid-19 associated diarrhea.
• Findings on CT scan suggestive of diarrhea associated with covid-19 infection include peri-intestinal inflammatory reaction.

MRI

• There are no MRI findings associated with diarrhea in COVID-19

Other Imaging Findings

• There are no other imaging findings associated with diarrhea in COVID-19.

Other Diagnostic Studies

Other diagnostic studies for covid-19 associated diarrhea include:

• Infectious virions released from the GI tract can be monitored by real-time reverse transcriptase polymerase chain reaction (rRT-PCR)
• A study by Xiao et al assessed the clinical significance of measuring SARS-CoV-2 RNA in the feces.
• The fecal test remained positive until 12 days after the disease onset in patients with diarrhea.
• Notably, stool test for viral RNA remained positive despite negative respiratory tests. This suggests the possibility of gastrointestinal transmission via the fecal-oral route despite clearance from the respiratory tract.
• It was recommended transmission-based precautions for hospitalized COVID-19 patients should be continued till the rRT-PCR for SARS-CoV-2 turns negative.

Treatment

Medical Therapy

• Supportive management is the mainstay of treatment.
• Rehydration, fluid repletion, and potassium monitoring are essential.
• Use of probiotics may have a role if the diarrhea is being caused by alteration of the gut microbiome. This could also be potentially useful in preventing secondary bacterial infections by restoring the gut microbiota.

Primary Prevention

• Effective measures for the primary prevention of COVID-19 include::
  • Frequent handwashing with soap and water for at least 20 seconds or using a alcohol based hand sanitizer with at least 60% alcohol
  • Staying at least 6 feet (about 2 arms’ length) from other people who do not live with you
  • Covering your mouth and nose with a cloth face cover when around others and covering sneezes and coughs
  • Cleaning and disinfecting
• There have been rigorous efforts in order to develop a vaccine for novel coronavirus and several vaccines are in the later phases of trials.

Prevention of transmission through gastrointenstinal tract

• Presence of the virus in the stool raises suspicion for fecal-oral transmission of SARS-CoV-2.
• Appropriate personal protective equipment(PPE) must be used while handling sources of contamination like feces.
• Elective appointments and endoscopies should be rescheduled and extreme care must be taken by health care professionals of the endoscopy units to avoid spreading the virus from one patient to another.
• Patients listed for fecal microbiota transplantation and donors should be screened for the SARS-CoV-2.

Secondary prevention

• Effective measures for the secondary prevention of COVID-19 include:
  • Use of personal protective equipment (PPE) by the personnel handling the fecal matter.
  • Screening of fecal microbiota transplant donors for COVID-19 is also recommended.
  • Contact tracing helps reduce the spread of the disease.

References

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