Strongyloides hyperinfection and its association with COVID-19 treatment
Corticosteroids are an important treatment modality for a multitude of indications. Currently, dexamethasone is one of the only proven treatment options for patients suffering from COVID-19.
When using corticosteroids, clinicians must maintain awareness of a multitude of potential side effects. One potential complication that may not immediately come to mind is the induction of Strongyloides hyperinfection syndrome.
Strongyloidiasis is a syndrome caused by the parasitic nematode Strongyloides stercoralis. Strongyloides are found throughout the world in most tropical and temperate climate zones. Although the true incidence is not known, Strongyloides is thought to be responsible for up to 100 million infections worldwide. A meta-analysis of strongyloidiasis prevalence among migrants born in endemic countries found a pooled seroprevalence of 12.2%, with those from East Asia and the Pacific (17.3%), sub-Saharan Africa (14.6%) and Latin America and the Caribbean (11.4%) having the highest seroprevalence. Strongyloidiasis is considered to be uncommon in the United States, although there are rural areas of the Southeastern U.S. and Puerto Rico with rates that approach 4%.
S. stercoralis has a unique life cycle that can persist in a host for a lifetime due to its autoinfection life cycle. Initial infection occurs when infectious larvae are encountered in the environment and burrow through the skin of a host. The larvae then enter the vascular system and travel into the lungs, where they continue to mature. Eventually the host coughs them up and swallows them. In the intestinal tract, females lay eggs, which hatch and develop into infectious filariform larvae. The larvae then are excreted into the environment or burrow into the vascular system, restarting the cycle.
In hyperinfection syndrome or disseminated strongyloidiasis, impaired host immunity leads to an accelerated autoinfection cycle resulting in numerous migrating larvae that penetrate the gut and invade other organs. Hyperinfection syndrome has been associated with use of a number of immunosuppressive drugs but is most often associated with corticosteroid use in patients with an asymptomatic infection. Hyperinfection syndrome is not dependent upon the dose, duration or route of administration of corticosteroid. Even short courses of treatment in immunocompetent individuals have resulted in hyperinfection syndrome and death. If not recognized and treated promptly, mortality rates can approach 90%.
The first case reports of fatal strongyloidiasis in patients receiving corticosteroids were published in 1966. The paper described the disease in five patients who presented with a severe clinical picture characterized by upper abdominal pain, nausea, vomiting, diarrhea and severe hypoproteinemia. At present, there are two publications reporting manifestation of Strongyloides infection during corticosteroid treatment for COVID-19.
The first case was reported in a 59-year-old woman admitted to a hospital in Italy for COVID-19. Upon hospitalization, she was initiated on treatment including dexamethasone. Because of her worsening clinical status, two doses of tocilizumab were also administered. Although her clinical status continued to improve, she was found to have increased eosinophil counts, abdominal pain and itching. Stool examination revealed the presence of S. stercoralis larvae, as well as a positive serology titer. She was successfully treated with ivermectin and was discharged from the hospital.
The second case reported was a 68-year-old man who moved to the U.S. from Ecuador 20 years before. He was hospitalized with COVID-19 and developed hypoxemic respiratory failure requiring intubation. He was treated with one dose of tocilizumab, as well as three courses of methylprednisolone. On day 12 of hospitalization, sputum cultures were obtained with Gram’s and iodine stains, revealing larvae consistent with Strongyloides species. Ivermectin treatment was initiated, but his clinical status continued to worsen, so albendazole was added for adjunctive therapy. Initial and repeated stool ova and parasites and Strongyloides serum antibody were negative. He endured a prolonged illness that required antibiotics for pneumonia and presumed meningitis, vasopressors, as well as a 2-week course of ivermectin and albendazole. On day 38 of his illness, a repeat Strongyloides serology test was positive. This case highlights challenges in diagnosing Strongyloides in patients who have received immunosuppressive treatment with multiple courses of corticosteroids.
Ivermectin is the drug of choice for all Strongyloides infections at a dose of 200 µg/kg per day orally. The duration depends on the severity of infection. Asymptomatic or uncomplicated infections require 1 to 2 days of treatment. Notably, a recent study showed no difference in efficacy using a single dose vs. multiple doses for uncomplicated infections. Patients with immunosuppression or hyperinfection syndrome require daily dosing given for at least 2 weeks after stools are negative for larvae to ensure eradication due to the autoinfection cycle. Ivermectin is preferred because of its low incidence of side effects and proven safety profile. Alternative treatment options include albendazole or thiabendazole. However, ivermectin has been shown to be more effective than albendazole, which has cure rates ranging from 38% to 87%. Ivermectin is also substantially less costly than albendazole in the U.S. Both ivermectin and albendazole are better tolerated and more widely available than thiabendazole, which is not available in the U.S. If patients are unable to take ivermectin orally or though nasogastric tube, rectal or parenteral formulations have been used. However, these come from veterinary formulations and would require compassionate use approval. There is little evidence for combination therapy, but it has been successfully used in case reports.
Notably, ivermectin is being used by some clinicians for COVID-19 treatment. Although the published evidence to date is mixed for clinical efficacy for COVID-19, this approach could potentially benefit patients who have asymptomatic Strongyloides infections.
A proposed strategy for reducing the risk for Strongyloides hyperinfection during COVID-19 pandemic has been suggested for patients who have a moderate to high risk for Strongyloides infection. The strategy includes that:
- Outpatients with asymptomatic or mild COVID-19 who are not currently candidates for dexamethasone should undergo screening test and be treated with ivermectin if positive.
- For hospitalized patients who are being considered for dexamethasone use, presumptive treatment with ivermectin should be considered. This is especially important if Strongyloides serologic test results are delayed or unavailable.
- For hospitalized patients with unexplained invasive gram-negative rod infection after receiving dexamethasone or other immunosuppressive agent, diagnostic testing for Strongyloides is recommended along with initiation of ivermectin while awaiting test results.
Being aware of the potentially lethal Strongyloides hyperinfection syndrome in these patients is necessary to help mitigate risk through early diagnosis of Strongyloides infection. Implementing a screening and treatment policy for patients in to help prevent hyperinfection syndrome is warranted.
- Asundi, A, et al. Lancet Glob Health. 2019:doi:10.1016/S2214-109X(18)30490-X.
- Buonfrate D, et al. Lancet Infect Dis. 2019:doi:10.1016/S1473-3099(19)30289-0.
- Croker C, et al. Am J Trop Med Hyg. 2010:doi:10.4269/ajtmh.2010.09-0750.
- Cruz T, et al. N Engl J Med. 1966:doi:10.2056/NEJM196611172752003.
- Krolewiecki A, Nutman TB. Infect Dis Clin N Am. 2019:doi:10.1016/j.idc.2018.10.006.
- Lier AJ, et al. Am J Trop Med Hyg. 2020:doi:10.4269/ajtmh.20-0699.
- Marchese V, et al. Infection. 2020:doi:10.1007/s15010-020-01522-4.
- Stauffer WM, et al. JAMA. 2020:doi:10.1001/jama.2020.13170.
- For more information:
- Jeff Brock, PharmD, MBA, BCPS-AQ ID, is an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at firstname.lastname@example.org.