Disseminated Strongyloides stercoralis infection in the setting of Escherichia coli meningitis and bacteraemia in a patient living with HIV on high-dose corticosteroid therapy

Abstract

Strongyloidiasis, a helminth infection caused by Strongyloides stercoralis, can be complicated by hyperinfection, especially in the setting of immunosuppression; however, many patients go undiagnosed. One clue to diagnosis is unexplained gram-negative bacteraemia or meningitis in patients who are immunosuppressed. Serology can be helpful but may be negative in these patients who are immunocompromised.

We present the case of a white cisgender man from Central America in his 40s, living with HIV, with a CD4 count of 77 cells/µL. He was diagnosed with Strongyloides hyperinfection after an increase in his steroid dose. He also had Escherichia coli meningitis and bacteraemia. Strongyloidiasis was diagnosed by stool microscopy despite a negative serology test.

This case highlights the challenges in diagnosing strongyloidiasis in the setting of immunosuppression. A high index of clinical suspicion is warranted for patients living with HIV on high-dose corticosteroids. Up to three stool microscopy studies for Strongyloides should be sent in addition to serology.

BACKGROUND

Strongyloidiasis, caused by the helminth Strongyloides stercoralis, can cause hyperinfection in people with impaired cell-mediated immunity, such as patients who had transplants and patients receiving steroids or immunosuppressant therapies. In addition, Human T- cell Lymphotropic virus type 1 has been noted to be a risk factor for strongyloidiasis.^1–5 There has been some debate, however, regarding whether HIV is a risk factor for strongyloidiasis.^{5 6} Fatalities have been reported following Strongyloides hyperinfection among patients receiving immunosuppressive treatment, including corticosteroids.^{7 8} Glucocorticoids may accelerate the replication of the parasite, leading to an increased risk for severe outcomes in asymptomatic patients due to their ability to acutely suppress both eosinophil levels (thereby masking eosinophilia) and lymphocyte activation.^8–10 In immunocompetent patients, strongyloidiasis symptoms are often mild to severe diarrhoea.¹¹ When there is a heavy burden of parasites and hyperinfection, however, symptoms can include gastrointestinal (GI) distress but also urticarial rash and Loeffler’s syndrome.¹¹ To the best of our knowledge, this is the first case in the literature of a patient with HIV on chronic steroids who developed gram-negative bacteraemia and meningitis in the setting of Strongyloides hyperinfection. Given the potential for patient mortality, greater awareness should be raised about this combination of conditions.

The diagnosis of strongyloidiasis is often established by serology, but in patients who are immunocompromised, serology may be negative, delaying diagnosis and increasing the risk for hyperinfection.^{8 12 13} In this report, we discuss the diagnostic challenges for practitioners and address the need to maintain a high index of clinical suspicion in this population.

Case presentation

Our case was a white cisgender man in his 40s, originally from Central America, living with HIV who presented with fevers and altered mental status.

He reported left upper and lower limb weakness, paraesthesia, fevers and chills, and unilateral throbbing headaches that had been ongoing for 2 days. He also reported a pruritic rash on his abdomen as well as urinary incontinence.

He had been started on antiretroviral HIV therapy—bictegravir/emtricitabine/tenofovir alafenamide 3 months prior to presentation, but he was only intermittently adherent. His CD4 count at presentation was 77 cells/µL, but his HIV-1 RNA viral copies were undetectable.

A month prior to hospital admission, he had been evaluated by his ophthalmology provider for progressive vision loss and was diagnosed with bilateral uveitis. He had been treated with oral prednisone 40 mg daily and prednisolone eye drops. The following week, B-scan ultrasound of his left eye showed extensive retinal detachment with moderately dense subretinal deposits, and his prednisone dose was subsequently increased to 60 mg orally daily.

A week later, an ambulance brought him to the emergency department after a mechanical fall. On evaluation he was febrile, but haemodynamically stable with a pulse oximetry saturation of 96% on room air.

On physical examination, he was found to have anisocoria, left-sided hemiplegia, decreased sensation over the saddle and perianal regions, and a non-confluent maculopapular rash consistent with a viral exanthem.

Investigations

Laboratory tests showed a serum sodium of 130 mmol/L (reference range 137–145 mmol/L), elevated levels of C reactive protein (16.5 mg/dL), a normal peripheral blood leucocyte count and a normal eosinophil count in the first 3 days following admission.

Because sepsis was considered, broad-spectrum antibiotics were administered. MRI of the brain revealed a right posterior limb internal capsule infarct and fluid levels in both cerebral hemispheres showing restricted diffusion and scattered areas of hyperintensity (figure 1). These results were concerning for stroke, brain abscess or septic emboli due to bacteraemia. Meningitis was also considered as a possible differential diagnosis given his initial presentation of fever, headache and focal neurological deficits. MRI of the lumbar spine showed enhancement of caudal roots but no evidence of cauda equina.

Figure 1.

MRI of the brain revealed a right posterior limb internal capsule infarct, fluid levels in both cerebral hemispheres with restricted diffusion and scattered areas of hyperintensity, concerning for stroke. 1. Right posterior limb internal capsule infarct; 2. Fluid levels in both cerebral hemispheres.

Due to the patient’s altered consciousness, a lumbar puncture was ordered. Cerebrospinal fluid (CSF) analysis showed a total leucocyte count of 98 cells/10⁹/L with 35% neutrophils, a protein concentration of 297 mg/dL (reference range 15–45 mg/dL) and glucose level of <20 mg/dL (reference range 40–70 mg/dL), with a serum glucose level of 128 mg/dL. CSF gram stain showed gram-negative rods while CSF bacterial cultures grew Escherichia coli. Blood cultures were also positive for E. coli. Other tests for meningitis were negative. Agar plate culture of the CSF for S. stercoralis, a concentrated smear of CSF for Strongyloides larvae and Strongyloides serologies were all negative.

As part of his workup, the patient had a skin biopsy of his maculopapular rash, demonstrating superficial perivascular lymphocytic infiltrate with few eosinophils but no histological evidence of Strongyloides. Stool cultures, faecal PCR tests for Shigella, Salmonella, Campylobacter and Clostridium difficile and faecal culture for other bacterial pathogens were all negative. The first sample sent for the faecal microscopy ova and parasites test including Strongyloides was positive for a larvae and faecal helminth. Subsequent stool tests done days after therapy was initiated were negative.

The patient remained persistently febrile despite broad-spectrum antimicrobials. Based on the patient’s clinical picture, including gram-negative bacteraemia, meningitis, stool microscopy findings, immunocompromised state and steroid use, there was a high degree of suspicion for disseminated Strongyloides infection.

Treatment

Two hundred micrograms per kilogram of oral ivermectin daily was started after the diagnosis of Strongyloides hyperinfection was suspected as well as broad-spectrum antibiotics for E.coli bacteraemia and meningitis and continued for a total of 2 weeks. There was an unfortunate delay in therapy as the ivermectin was started only after the first faecal microscopy ova and parasite test came back positive.

Outcome and follow-up

Within 48 hours, the patient became afebrile, and his mental status also improved. Repeat blood cultures showed no growth. Repeat stool examination 2 days later was negative for Strongyloides. Repeat CSF analysis 6 days after the initial test showed the total leucocyte count had decreased to 28 cells/mm³ with 7% neutrophils. The patient had a good overall response and was discharged home in a stable condition.

Discussion

Strongyloides is a parasite, more specifically a nematode, that is prevalent in the tropical and subtropical regions of the world.^{1 2 5} One of its unique features is its ability to cause autoinfection, reinfect its host and persist in the hosts’ bodies for their entire life. Chronic infection can be asymptomatic; however, once hosts’ defences become compromised, the normal life cycle of the organism may be accelerated and cause a hyperinfection syndrome. The parasite then migrates to any organ other than its preferred reproductive route (skin, GI or lungs), resulting in a disseminated disease in the liver, brain (as in our case), heart or urinary tract. Although these processes can occur in any person, patients who are immunocompromised are usually the most susceptible.^2–4

Hyperinfection syndrome (HS) and disseminated strongyloidiasis (DS) can be fatal, and often occur in patients with impaired cell-mediated immunity, such as those with organ transplants and especially those on corticosteroid therapy.^{3 4 7} Steroids represent one of the main triggers predisposing patients to HS and DS by immediately increasing their risk of infection, which is sometimes directly dependent on the dose.^{9 14 15} Some authors have suggested that by suppressing eosinophilia and inducing apoptosis of lymphocytes, glucocorticoids can induce the parasite transformation from rhabditiform larvae to filariform larvae (the infective form within the host) leading to HS.^{7 8} In our case, there was evidence of immunosuppression, given his HIV/AIDS diagnosis, low CD4 count and prolonged exposure to high-dose steroids (>40 mg/day), the latter of which increased his likelihood of developing an HS. The role of HIV, however, in the development of HS and DS is a matter of controversy. HIV has been shown in several studies to increase the risk of strongyloidiasis infection, but this has not been definitely associated with HS or DS.⁶ DS is also no longer considered an AIDS-defining illness due to the discordance between HIV prevalence and HS/DS. More published data and studies are needed, however, to better understand the risk of DS and HS in people with HIV. More information is needed especially related to immune interaction between HIV and S. stercoralis and the role of IgE antibodies, eosinophils and Th2-mediated activity in this context.⁶ Since steroid-associated risk is well proven, it is reasonable to screen for strongyloidiasis in high-risk patients before commencing prolonged high-dose corticosteroids to minimise the risk of HS.⁷

Occasionally, strongyloidiasis is associated with gut translocation of bacteria and subsequent bacteraemia. The migrating ability of the parasite across several organs/tissue promotes the distant dissemination of enteric pathogens and accompanying gram-negative bacteraemia, meningitis and sepsis.2 7 9 16 The most common organisms include E. coli and Streptococcus gallolyticus (previously bovis),¹⁶ but other enteric pathogens may also be involved. Thus, the unexplained presence of enteric pathogens in the blood or other sterile body fluids should trigger a search for concomitant strongyloidiasis, as in our case where E. coli was found in both the CSF and blood.

The clinical presentation of HS can differ among patients but may include nausea, vomiting, diarrhoea, weight loss, abdominal pain, GI haemorrhage, cough, fever or dyspnoea.² In our case, the patient did not present with any GI symptoms on admission. His main complaints were headache, high fevers and a possible episode of syncope a few hours prior, which led us to the workup for meningitis. As confirmed in our case, due to increased parasite turnaround and dissemination, some patients with HS may only present with catastrophic clinical manifestations of shock or meningitis.^{7 9 16} It is therefore imperative that at-risk patients are appropriately screened for Strongyloides. According to evidence-based guidelines for screening and management of strongyloidiasis, immunocompetent individuals coming from endemic areas (Africa, Latin America, Asia and Oceania) should be screened routinely via serology.¹⁷ In addition, patients who are immunocompromised or at risk for immunocompromise who are high or intermediate risk for exposure to S. stercoralis should also be screened.¹⁷ Furthermore, in patients who are immunocompromised, the serology alone may not be sufficient and stool examinations should be performed. Dissemination of Strongyloides is associated with high mortality,¹⁸ and increased screening awareness among providers in non-endemic settings is warranted. Empiric therapy with ivermectin has been advocated for patients at risk to avoid dissemination.¹⁸

The presence of eosinophilia in patients who have lived or travelled to endemic areas should generate a high suspicion for strongyloidiasis,^{19 20} but eosinophilia is not always present.⁹ In this population, eosinophilia is not a strong predictor of strongyloidiasis.¹⁷ We suggest that any patient coming from an endemic region, with or without eosinophilia, should be considered for strongyloidiasis, as some patients may present with normal level of eosinophils in the beginning. This was demonstrated in our case, where the eosinophil was normal until day 4 of admission, when it increased from 3% to 10% (reference range 0%–5%).

Diagnosis of HS can be very difficult to establish, and most studies focus on finding the parasite via stool examination, but the yield is not more than 46% even after three stool samples, due to the low sensitivity of the stool microscopy test.^{2 8 9} The agar plate culture is reported to be a more sensitive technique than stool microscopy.^{8 19} In our case, only the first stool examination was positive for the larvae; once ivermectin was started, additional samples were negative. Both serum serology and agar plate culture of the CSF were negative. Thus, both serology and multiple faecal microscopies may sometimes be necessary to establish the presence of the helminth, especially in cases of unexplained gram-negative bacteraemia or meningitis in patients who are immunosuppressed and have epidemiological risk factors. The diagnostic yield of strongyloidiasis in this cohort is improved by the combination of stool microscopy studies and serology. At the same time, serological examination may yield false-negative results as in our case. Clinical suspicion remains an important component in the early diagnosis of disseminated Strongyloides to prevent poor outcomes, especially in patients who are immunocompromised.

This case had some limitations. The patient’s country of origin, gram-negative bacteraemia and meningitis test results should have prompted a more urgent initiation of ivermectin. The patient was also on high-dose steroids, which is another risk factor. It is unclear whether or not the patient’s HIV status also played a role in his strongyloidiasis infection; however, we suspect it likely played a role. Lastly, we did not check agar plate cultures of the stool which may have been helpful. Overall and fortunately, the patient was able to improve from his infection.

Patient’s perspective.

I had no idea I was harbouring dangerous worms in my body. I have been through a lot with my HIV, my vision going bad but the experience with these life-threatening infections all related to these Strongyloides worms has been truly scary. I am grateful to my treatment team for all their dedication and care.

Learning points.

• It is imperative that individuals coming from endemic areas should be screened routinely for strongyloidiasis.

• Strongyloides hyperinfection syndrome and disseminated disease can occur in patients who are immunocompromised, including those who are also taking immunosuppressants, such as high-dose steroids.

• Gram-negative bacteraemia and meningitis in this setting, with or without gastrointestinal symptoms or eosinophilia, should always prompt workup for strongyloidiasis.

• Strongyloides hyperinfection is a life-threatening condition that warrants early detection and management.

• Empiric therapy for high-risk patients with ivermectin is important to prevent mortality.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).