Cyproheptadine Treatment of COVID-19-Induced Enteritis: Implications for Hyperinflammatory Phase Management

Abstract

A patient presented with COVID-19-induced enteritis and colitis associated with a high D-dimer. Serotonin released by activated platelets can lead to inflammation and multiorgan failure in COVID-19 infection. Cyproheptadine blocks serotonin receptors. In light of a prior report that showed that cyproheptadine successfully treated neurologic sequelae in COVID-19, we applied this treatment to this patient. Rapid clinical improvement and reduction of D-dimer occurred after 3 doses of cyproheptadine. This inexpensive, well-tolerated, oral medication may be applicable to treat hyperinflammatory sequelae of COVID-19 infection.

INTRODUCTION

Gastrointestinal involvement by coronavirus disease 2019 (COVID-19) is prevalent. Of 651 hospitalized patients, 11.4% had nausea, abdominal pain, and/or diarrhea and prognosis was worse for those with gastrointestinal symptoms.¹ Animals infected by severe acute respiratory syndrome coronavirus 2 showed enterocyte sloughing, edema, vascular dilation, and lymphocyte infiltration.² Enteritis in humans usually starts after the 10th day of infection, but rarely can present without other manifestations.³ COVID-19-induced enteritis ranges from self-limited to lethal cases.^3,4 Before COVID-19, causes of enteritis included ischemia, bacterial infections, viral infection in immune-compromised hosts, and vasculitis.⁴

Histamine receptor blockers have been used to treat and/or prevent COVID-19 complications.⁵ Cyproheptadine is a histamine receptor-1 blocker and serotonin (5-HT1A and 5-HT2A) receptor blocker.⁶ Based on the potential role of serotonin in the COVID-19 hyperinflammatory state and observations that cyproheptadine reduced cerebral inflammation in a serotonin-like syndrome induced by COVID-19, we treated an enteritis patient with this medication.^7,8

CASE REPORT

A 77-year-old White woman was admitted to the hospital with severe abdominal pain and diarrhea. Her medical history included chronic gastrointestinal, inflammatory, and allergic symptoms that were diagnosed 3 years prior to admission (PTA) as mast cell activation (MCA) syndrome. Prostaglandin D2 and leukotriene E4 levels were increased, and she had an excellent response to mast cell therapy. Home medications included famotidine, vitamins C and D, and quercetin for MCA syndrome; insulin and metformin for diabetes; quinapril and verapamil for hypertension; atorvastatin for hyperlipidemia; and levothyroxine for Graves disease.

Six months after receiving the second COVID-19 vaccine, she was exposed to a friend who was sneezing. Three days later (9 days PTA), she had nasal congestion and the nasopharyngeal swab was positive for COVID-19 RNA. Two days PTA, there was fever, sore throat, headache, cough, conjunctivitis, loss of sense of smell, and anorexia. The night PTA, she developed explosive diarrhea, severe abdominal pain, bloating, and nausea. Dehydration led to emergency department evaluation and subsequent admission. Abdominal computed tomography showed severe enteritis and colitis (Figure 1). Treatment included intravenous fluids and morphine on hospital day (HD) 1, and she was kept nil per os. From HD 1 through HD 3, intravenous ciprofloxacin and metronidazole and subcutaneous enoxaparin (5,000 units twice a day for deep vein thrombosis prophylaxis) were administered. On the morning of HD 2, pain was slightly less, but severe, diffuse abdominal tenderness remained. Diarrhea ceased while nil per os.

Figure 1.: Abdominal and pelvic computed tomography in this case study in the axial (A) and coronal (B) planes shows multiple loops of the small bowel with wall thickening and mucosal hyperenhancement (thin arrows) with associated mesenteric edema (thick arrow), surrounding fat stranding, and small-volume ascites (*). The colon (arrowhead) was also diffusely thick walled with associated inflammatory changes and was fluid filled distally suggestive of a diarrheal state. There was mild aortic atherosclerosis, but all major mesenteric arteries and the superior and inferior mesenteric veins were patent.

On HD 2 morning, she was given verbal information about the serotonin-cyproheptadine hypothesis. She consented to starting cyproheptadine 4 mg 3 times a day by the oral route. The following morning (HD 3), after 3 doses of cyproheptadine, the pain ceased. Abdominal tenderness was minimal. While she was given clear liquids, there was no diarrhea. On HD 4, there was no tenderness and she was discharged on cyproheptadine (4 mg/TID/7 days). On postdischarge day 1, the only symptoms were nonproductive cough, hoarseness, and loss of smell. The following day, the stool was partially formed.

On HD 1, the white blood cell count (WBC) was 18.0 per microliter (nl 3.8-9.9) with 90.4% neutrophils and 6.3% lymphocytes. On HD 2, WBC was 9.0 per microliter. On HD 3, WBC was 7.1 with 60.5% neutrophils. Hemoglobin was 17.1 g/dL on HD 1 and decreased to 11.1 on HD 2 and 12.1 on HD 3. Creatinine was 0.60 mg/dL, and blood urea nitrogen was 15. Stool culture was negative for shigella, salmonella, Yersinia, and enteropathogenic Escherichia coli. Clostridium difficile toxin was negative. On HD 2, the D-dimer was 27,466 ng/mL fibrinogen equivalent units (nl < 500), ferritin 210 ng/mL (nl 15–150), lactate 1.9 mmol/L (nl 0.7–2.0), and C-reactive protein 4.1 mg/L (nl < 10.0). Chest computed tomography excluded pulmonary embolism. After 3 doses of cyproheptadine, the D-dimer decreased to 8,349. On postdischarge day 10, she was asymptomatic and the D-dimer was 2.

DISCUSSION

This patient had severe inflammation of the small and large intestines starting 10 days after acute COVID-19 infection. She had rapid clinical improvement and a decrease in the high D-dimer in response to cyproheptadine. This is the first report to our knowledge where cyproheptadine was used to treat enteritis.

Theoretically, enteritis could be caused by delayed release of serotonin from platelets during the hyperinflammatory stage of COVID-19. Immune-mediated platelet activation in COVID-19 has been associated with release of serotonin.^7,9 Highly elevated liberated serotonin in plasma or tissue can lead to serotonin-induced inflammation and multiorgan failure.¹⁰ Studies by Mauler et al¹¹ found that (i) plasma serotonin levels correlated with CD11b expression on neutrophils and myeloperoxidase plasma levels in acute coronary syndrome; (ii) selective serotonin reuptake inhibitors resulted in depletion of platelet serotonin stores in mice and these animals had reduction in neutrophil degranulation and preserved cardiac function; and (iii) patients treated with selective serotonin reuptake inhibitors presented with suppressed levels of CD11b surface expression on neutrophils and lower myeloperoxidase levels in blood. In animal studies, cyproheptadine decreased central nervous system ischemic damage from serotonin.¹²

Liberated serotonin may also have a relationship with MCA because the mast cell has a serotonin transporter and a significant number of cytokine receptors.^13,14 The hyperinflammatory state can activate T cells, which in turn may activate the mast cell because of T-cell microparticles.¹⁵ MCA may be another contributing factor to the hyperinflammatory state.^16,17 Another potential pathway toward thrombosis is by specific cytokines that lead to recruitment of neutrophils.¹⁸ Other authors tie together serotonin release from platelets that causes ischemic injury by neutrophil degranulation.¹¹ Ischemic injury to major organs can occur with spasm and by thrombosis. One example is Kounis syndrome, which may be due to MCA and/or elevated histamine levels.¹⁹ Finally, macrophage activity and hyperferritinemia can play a role in systemic inflammation.²⁰

Limitations of applying this case to serotonin hyperinflammatory theory include that cyproheptadine also has potent histamine-1 receptor blocker activity, which could have reduced MCA. Antibiotics, low-dose enoxaparin, and time might have helped, but the pain and tenderness continued until cyproheptadine commenced and was associated with an abrupt decrease in D-dimer by 70% within 24 hours.

This report presents a new approach to treating enteritis and colitis caused by COVID-19 infection. Extrapolation of this therapy to prevent damage to end organs should be investigated (Figure 2).

Figure 2.: Pathophysiology of platelet release of serotonin in coronavirus disease 2019 infection and the role for cyproheptadine treatment.

DISCLOSURES

Author contributions: LB Weinstock is the main author, article guarantor, and the patient's physician. AM Reiersen is one of the physicians who helped develop the serotonin hyperinflammatory theory and critically reviewed and contributed to the manuscript. A. Jain is the hospitalist who cared for the patient, wrote part of the manuscript, and critically reviewed the manuscript. K. Konstantinoff and W. James were responsible for reviewing the radiology, preparing the images, and writing the caption along with critically reviewing the manuscript. F. Jalali is one of the physicians who helped develop the serotonin hyperinflammatory theory and critically reviewed and contributed to the manuscript.

Financial disclosure: None to report.

Informed consent was obtained for this case report.