Episode 41- “The Perfect Storm:” Part 2: Hyperinfection syndrome and ivermectin

Hello and welcome to Episode 41 of ER-Rx. Last week in part one of our Strongyloides “mini grand rounds” series, we discussed the use of dexamethasone for patients with COVID and the diagnosis and clinical manifestations of strongyloidiasis. We left off by saying that immunosuppressed patients, including those taking corticosteroids, who are chronically infected with strongyloides can develop what’s known as “strongyloides hyperinfection syndrome.”

Unique to strongyloides, eggs can hatch in the intestines and cause autoinfection without an environmental stage. This can lead to chronic infection lasting decades in patients who are immunocompetent or it can develop into hyperinfection syndrome in those who are immunocompromised. In this scenario, impaired immunity leads to accelerated autoinfection and massive proliferation and dissemination of larvae to almost any organ. Patients at risk include alcoholics, the malnourished, those with HIV or HTLV-1, or those taking corticosteroids.

In chronic strongyloidiasis and in hyperinfection syndrome, the larvae are limited to the GI tract and the lungs, usually, but in disseminated strongyloidiasis the larvae can invade almost any organ- with a mortality rate of up to 90% if left untreated. Signs and symptoms include the GI and cutaneous manifestations discussed in the last episode, along with pulmonary symptoms such as pneumonitis, respiratory failure, and ARDS. We can also see neurologic and systemic symptoms including septic shock and recurrent gram-negative bacteremia that occurs when larvae carrying bacteria penetrate mucosal walls and enter the blood stream.

So how do we treat strongyloides? For intestinal infections or for prophylaxis, the most recommended agent is ivermectin, dosed at 200 mcg/kg of actual body weight (no max dosing) for 1-2 days. In the setting of hyperinfection syndrome or disseminated strongyloidiasis, ivermectin is typically continued until stool and sputum exams are negative for 2 weeks, but there are no standardized guidelines for treatment and duration is variable. I should take a second here to mention that ivermectin was actually considered for treatment of COVID itself, since it has shown some activity against the virus. Nevertheless, at this time the CDC recommends against its use for this indication, so I won’t go into that- but I know many of my listeners may routinely use this agent for COVID as it is listed in some international COVID treatment guidelines.

Please note that ivermectin has a relative contraindication in pregnant/lactating women, patients weighing < 15 kg, and patients with confirmed or suspected Loa loa co-infection. This is very important to remember. Loa loa, or “the eye worm,” is typically found in West and Central Africa (think countries like Equatorial Guinea, Gabon, Cameroon, Central African Republic, Chad, Congo, and Nigeria). In patients with a high Loa loa load, treatment with ivermectin has been associated with fatal encephalopathy. The mechanism behind this is complex and not fully understood, but it’s thought that rapid killing of the larvae causes inflammation and hemorrhage. Patients from these countries have a contraindication to ivermectin and ID should be contacted to determine an alternative plan.

So, how do we prevent hyperinfection syndrome in patients with COVID who we want to treat with corticosteroids? An opinion letter published in JAMA in July of 2020 by Dr. William Stauffer from the University of Minnesota, and an ID physician at my site, Dr. Jonathan Alpern, proposes a potential strategy. Their basic premise is that: knowing most patients with chronic strongyloides are asymptomatic and that diagnosis is neither timely nor accurate, we have to presume chronic underlying infection based on country of origin. This means that prior to starting dexamethasone, we should give a cheap, effective drug-up front. And that drug is ivermectin.

Specifically, in the outpatient setting, they recommend screening and treatment for all patients at risk of strongyloides, even if they are COVID negative or are positive with mild symptoms and are not candidates for dexamethasone. In the inpatient setting, they recommend presumptively treating all COVID positive patients who may be candidates for dexamethasone. In patients in the hospital who have unexplained gram-negative infections after receiving immunosuppressants like dexamethasone, they recommend diagnostic testing for strongyloides along with ivermectin therapy. At my site, we’ve developed a COVID treatment orderset that includes these recommendations. Feel free to reach out to me on errxpodcast.com or the errxpodcast Instagram page for more info.

Lastly, before I wrap up, I wanted to address a question that we routinely get from providers and nurses, both in the ER and in the ICUs, and that is, “how come this wasn’t a thing before?” We’ve given high-dose hydrocortisone (200 mg hydrocortisone = 6.7 mg dexamethasone) to millions of people with septic shock without giving them ivermectin first. How come our cancer patients aren’t being given ivermectin prior to their high-dose corticosteroid treatments? And what about all of those prednisone prescriptions for COPD and asthma? Those are all valid questions. The answer is that hyperinfection syndrome is thought to be one of the most neglected conditions in tropical and in general medicine. Although we don’t have incidence or prevalence estimates of hyperinfection, there are hundreds of case reports—a few of which I’ve added to my Read by QxMD collection that you can access on the Show Notes and on the website. Overall, this condition is likely underreported due to diagnostic challenges and a lack of clinical awareness of the syndrome. Long story short, this may be something that we have missed in the past, and this will continue to be more of a thing in the future- especially if you practice in an area that has refugees from at-risk countries.

In conclusion, with more than 44 million first-generation immigrants in the US, the perfect storm of chronic strongyloides, COVID, and corticosteroid use is something to look out for. In patients born outside of North America, Australia, or Europe, consider ordering ivermectin 200 mcg/kg for 2 days prior to the first dexamethasone dose, and contact ID if there is any question about previous travel history, birthplace, or risk of Loa loa co-infection.

As always, thank you so much for your time. If you can, please remember to leave a review of the show on Apple Podcasts—I’ll post a direct link to Apple Podcasts in the Show Notes.