Hyperinfection by Strongyloides stercoralis: Series of Cases in a Regional Hospital in Southern Spain

Abstract

Background: Strongyloidiasis is a neglected tropical disease caused by the nematode Strongyloides stercoralis. In immunosuppressed patients, it may progress to hyperinfection syndrome (HIS) and disseminated strongyloidiasis (DS), both of which are associated with high mortality rates. We reviewed cases of HIS and DS in a Spanish hospital located in an area with endemic strongyloidiasis. Methods: All of the patients who met the HIS or DIS criteria between 1999 and 2023 at the Vega Baja Hospital in Orihuela (Alicante, Spain) were included. Results: Five patients were identified, four of them autochthonous (median age 72 years, 80% male), with three cases of HIS and two cases of DS in the form of meningitis, due to E. faecalis and E. coli. The most common risk factor, observed in three patients, was corticosteroid use. Two patients died. Conclusions: This case series highlights the severity of infections in immunocompromised patients in an endemic area of Spain, emphasizing the need to establish screening protocols for patients at risk of immunosuppression, including both locals and migrants.

1. Introduction

Strongyloidiasis is a neglected tropical disease estimated to affect 614 million people. Regions in Southeast Asia, Africa, and the Western Pacific account for 76% of global infections [1].

It is caused by Strongyloides stercoralis, an intestinal nematode that penetrates intact human skin in its filariform larval stage. From the skin, it enters venous circulation, reaches the lungs, traverses the alveoli, and migrates through the bronchi to ascend the trachea to the pharynx, where it is swallowed. Within the submucosal layer of the small intestine, it develops into an adult female, depositing eggs. When the eggs hatch, rhabditiform larvae are excreted in feces or transform into filariform larvae, which can re-enter the body through the intestinal mucosa or perianal skin. This process, known as autoinfection [2], leads to chronic infection, usually asymptomatic or mildly symptomatic in immunocompetent individuals.

In immunocompromised individuals, however, autoinfection can intensify, leading to what is known as hyperinfection syndrome (HIS) [3]. This condition results in a high burden of larvae in the normal parasite lifecycle locations, causing severe respiratory and gastrointestinal symptoms. Disseminated strongyloidiasis (DS) may also occur, characterized by the presence of larvae in organs outside their usual lifecycle. Additionally, these larvae can carry microorganisms from the intestinal flora, resulting in complications such as sepsis caused by Gram-negative bacilli or bacterial meningitis [2]. Corticosteroids are the primary trigger of DS and HIS (67% of cases), although other conditions like transplantation, the use of other immunosuppressive drugs, or HTLV-I infection may also precipitate it [4,5].

Both conditions have lethality rates ranging from 44.8% to 68.5% in different studies [6], increasing to 85–100% without treatment. This is, in part, due to the low index of suspicion surrounding the infection and its complications.

In Spain, cases of autochthonous strongyloidiasis have been reported, mainly in the Mediterranean region, and are largely associated with old men who had been in contact with agriculture [7].

We aimed to collect all of the HIS and DS cases recorded at a regional hospital in Vega Baja del Segura, Alicante, Spain.

2. Material and Methods

A retrospective observational study was conducted on all of the patients diagnosed with HIS or DS at Vega Baja Hospital (Orihuela, Spain), between January 1999 and December 2023. The Orihuela health department serves a population of around 167,000.

To select cases, we reviewed the Clinical Documentation department registry and selected cases with a strongyloidiasis diagnosis (cods 127.2 of CIE.9 and B78.0, B78.9 of CIE.10I) between 1999 and 2023. We also reviewed all of the cases with a strongyloidiasis diagnosis in the Microbiology lab registry (by positive IgG antibodies to Strongyloides, fecal culture, coproparasitological examination, or a positive fecal DNA detection by real-time polymerase chain reaction (RT-PCR)) from 2016 to 2023. Serological testing was performed at the Spanish National Centre for Microbiology (Instituto Nacional de Salud Carlos III, Majadahonda, Madrid) using a non-automated IVD-ELISA detecting IgG antibodies against filariform larval raw antigens (DRG Instruments GmbH, Marburg, Germany). The optical density (OD) index was calculated by dividing the optical density of each sample by the cutoff value. OD values of over 1.1 were considered to be positive [8]. Coproparasitological examinations and fecal cultures were conducted at Vega Baja Hospital’s microbiology laboratory. The Mini Parasep SF Alcorfix system was used as fecal concentrator. Strongyloides cultures were grown on Mueller Hinton agar, incubated at 28 °C, and examined for five days for characteristic larval tracks. Molecular detection was performed to detect the presence of the parasite in a qualitative real-time PCR (qPCR) assay carried out at the National Center for Microbiology (Health Institute Carlos III, Majadahonda, Madrid, Spain). Stool samples for the RT-PCR were stored at −20 °C until processing. The DNA extraction was performed using the QiaAmp DNA stool Mini kit (Qiagen, Hilen, Germany) following the manufacturer’s instructions. For the qPCR, S. stercoralis-specific primers targeting the 18S ribosomal subunit, as described by Saugar et al. [9], were used. The amplification and detection were carried out using a Corbett Rotor-Gen 6000 RT-PCR cycler (Qiagen Corbett, Hilden, Germany) as described by Saugar et al. [9].

Once the strongyloidiasis cases were selected, two researchers reviewed the clinical records to look for cases meeting the HIS or DS definitions.

The cases were classified as autochthonous if the patients had resided in the Vega Baja region for >30 years and had no history of travel to endemic areas [1,10]; otherwise, the cases were considered as imported.

HIS was defined as a strongyloidiasis diagnosis plus severe gastrointestinal or respiratory symptoms and the detection of larvae in duodenal aspirate, sputum, a pulmonary or intestinal biopsy, or feces.

DS was defined as a strongyloidiasis diagnosis plus the detection of larvae in other fluids or tissues outside the lifecycle or the molecular identification of the helminth in those sites.

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Vega Baja Hospital (code PI-2024-032). Informed consent was waived.

3. Results

During the 1999–2023 period, three cases of HIS and two cases of DS were diagnosed (

Table 1. Clinical–epidemiological characteristics of hyperinfection syndrome (HIS) and disseminated strongyloidiasis (DS) cases at Vega Baja Hospital (Orihuela, Alicante) between 1999 and 2023.

	Case 1	Case 2	Case 3	Case 4	Case 5
Year of diagnosis	1999	2007	2015	2017	2022
Clinical presentation	HIS	HIS	HIS	DS	DS
Birthplace	Spain	Spain	Spain	Spain	Spain
Type of case	Imported (Algeria)	Autochthonous	Autochthonous	Autochthonous	Autochthonous
Gender	Male	Male	Male	Male	Female
Age (years)	70	69	72	80	78
Occupation	Unknown	Farmer	Carrier	Stock farmer	Farmer
Comorbidities and Risk Factors	Bladder cancer, asthma	Lung cancer	Severe COPD, cor pulmonale, respiratory failure	Severe COPD, atrial fibrillation, diabetes mellitus	Mantle cell lymphoma
Immunosuppression treatment	Oral corticosteroids	Chemotherapy and radiotherapy. Inhaled corticosteroids	Oral and inhaled corticosteroids	Oral and inhaled corticosteroids	Ibrutinib
Clinical symptoms	Digestive	Respiratory (hemoptysis and dyspnea)	Digestive (febrile diarrhea) and cutaneous lesions.	Digestive (diarrhea) and respiratory (COPD exacerbation)	Digestive (diarrhea and vomiting) and cutaneous (pruritus)
Method of Diagnosis (in Serology, Optical Density Index)	Larvae in duodenal biopsy; serology not requested	Larvae in sputum; serology not requested	Larvae in large intestine biopsy and fecal samples Serology +(8.88)	Larvae in fecal cultures and fresh fecal samples. Serology +(1.16)	Stool PCR+ Serology +(9.78)
Eosinophilia (cells/µL)	670	600	750	640	570
HIV Serology	Unknown	Unknown	Negative	Negative	Negative
HTLV-I serology	Unknown	Unknown	Not requested	Not requested	Negative
Treatment	Thiabendazole	None	Ivermectin → Albendazole	Ivermectin	Ivermectin
Treatment duration (days)	Unknown	Not applicable	10 (3 ivermectin and 7 albendazole)	7	9
ICU Stay	No	No	Yes (2 days)	No	Yes (35 days)
Complications	Unknown	Hemoptysis	Paralytic ileus Deterioration of the level of consciousness not studied Stenotrophomonas maltophilia pneumonia	Deterioration of the level of consciousness Meningitis due to E. faecium	Deterioration of the level of consciousness and neurological focality. Meningitis due to E. coli Bilateral right-predominant cerebral ischemia
Total Hospitalization Days	Unknown	2	14	83	120
Outcome	Lost to follow-up	Death	Death	Recovery	Recovery with sequelae

COPD—chronic obstructive pulmonary disease; DS—disseminated strongyloidiasis; HTLV-I—human T-cell lymphotropic virus type I; HIS—hyperinfection syndrome; ICU—intensive care unit; HIV—human immunodeficiency virus.

). Four were autochthonous, and one was considered to be likely imported (a local resident who had lived in Algeria). The median age was 72 years (IQR 70–78), with a male predominance (4:1).

All of the cases presented risk factors for HIS/DS as they were immunosuppressed (active neoplasms, use of systemic corticosteroids, chemo/immunotherapy, or other immunosuppressive medications). The predominant clinical manifestations were gastrointestinal (diarrhea and vomiting).

There were two cases of DS, both involving the central nervous system and complicated with bacterial meningitis. The first case was an 80-year-old COPD patient on high doses of corticosteroids (equivalent to 100 mg of prednisone daily) who presented with diarrhea, respiratory symptoms, and acute meningitis caused by Enterococcus faecium, with larval presence detected in the cerebrospinal fluid. The treatment included the discontinuation of corticosteroids, ivermectin, vancomycin, and gentamicin, resulting in a full recovery without sequelae. The second case was a 78-year-old woman undergoing maintenance therapy with ibrutinib for mantle cell lymphoma, who developed a month-long diarrhea, pruritus, and meningitis caused by Escherichia coli. She required ICU admission and suffered bilateral cerebral ischemia, predominantly on the right cerebral lobes, as a complication. The treatment involved the discontinuation of ibrutinib, ceftriaxone, and ivermectin. She was discharged with residual left-sided hemiparesis.

The two reported deaths were autochthonous cases. The first (Case 2) involved a 69-year-old male with lung carcinoma undergoing chemotherapy and inhaled corticosteroids, who developed respiratory symptoms, including dyspnea and hemoptysis, with a larval presence in his sputum. He died before receiving antiparasitic treatment. The second (Case 3) involved a 72-year-old male with COPD and recurrent exacerbations, who initially presented with diarrhea followed by paralytic ileus. A CT scan revealed the significant distension of the cecum, ascending colon, and transverse colon up to the splenic flexure, with a thickened wall suggesting a possible tumoral origin. A colonoscopy showed pancolitis with an infectious appearance. The biopsy findings revealed chronic granulomatous colitis with filariform larvae invading vessels. The treatment included corticosteroid discontinuation and ivermectin for three days, which was later switched to albendazole due to supply issues. He was admitted to the ICU for respiratory and neurological deterioration, subsequently developing pneumonia caused by Stenotrophomonas maltophilia and dying after 14 days of hospitalization.

4. Discussion

This case series highlights significant cases of HIS and DS in an endemic area of Spain, predominantly affecting old men with a history of agricultural exposure [11].

According to a recent meta-analysis, the most common infectious complication of DS is bacterial sepsis, followed by bacterial meningitis [6]. In our series, we identified two cases of DS with acute meningitis; both were autochthonous. No bacterial sepsis was observed, although it cannot be ruled out in Case 2.

The eosinophilia prevalence in our cases was higher than that in previous studies, where only 22.5% [3] to 29.4% [6] showed eosinophilia. This could be related to the type of immunosuppression present in our patients.

All of the patients had risk factors for HIS/DS, which were mainly corticosteroid use or other immunosuppressive therapies (chemotherapy or immunotherapy). Corticosteroids are, according to other reviews, the main risk factor for developing severe strongyloidiasis. In the study by Rojas et al. [6], among 338 cases, 134 were using corticosteroids, 64 had neoplasms (solid or hematological), and 53 were on other immunosuppressants. The conditions most associated with corticosteroid use in patients developing HIS or DS are COPD and hematological neoplasms [4], which are consistent with our case series. It is important to note that low doses of corticosteroids have also been implicated in HIS. In our series, one patient was on a chronic dose of 5 mg/day of prednisone, although a month earlier, he had been treated with prednisone doses exceeding 20 mg/day due to a COPD exacerbation.

In Spain, routine screening for Strongyloides stercoralis is not conducted in the autochthonous population. However, according to the latest ECDC recommendations, screening should be offered to all of the immigrants from high-endemic countries in Asia, Africa, the Middle East, Oceania, and Latin America [12]. Furthermore, for individuals about to undergo immunosuppressive treatment, especially with corticosteroids, solid organ or hematopoietic stem cell transplantation, or those infected with HTLV-1 or HIV [13], screening should be extended to include intermediate-risk patients such as short-term travelers to high-endemic areas or elderly individuals living in regions with past transmission, such as Northern Italy or the Valencian Community [11,14] where our hospital is located.

In a recent study conducted in Gran Canaria, the prevalence of antibodies against S. stercoralis was estimated at 1.1% in the general Canarian population, 2.38% in individuals awaiting organ transplantation, and 4.8% in those about to start biological treatments; most of whom were autochthonous patients [15]. Additionally, neither the country of origin nor the presence of eosinophilia helped predict who would present with the disease, raising the question of whether the screening of at-risk patients should also be extended to other regions of Spain.

In 2019, a systematic review of 1083 autochthonous cases of strongyloidiasis identified 23 cases of hyperinfection, 1 in the Canary Islands and 22 in the Valencian Community (Valencia and Orihuela, including 4 cases presented here) [7].

A more comprehensive study including serological surveys of the native Spanish population in different areas of the country could help in better understanding the role of strongyloidiasis and its endemicity in our country.

The best tool for screening is serology. However, in immunosuppressed patients, it is recommended to combine serological and parasitological techniques due to the lower sensitivity of serology [13]. In our series, serology was available in three cases and was positive in all of them, though in one case, the titer was very low (positive optical density index > 1.1). If the serological and parasitological test results are delayed, empiric preventive treatment with ivermectin should be considered, a strategy shown to be the most cost-effective [16].

The treatment should include the discontinuation of immunosuppressants, if possible, and daily ivermectin until a clinical response is achieved, for at least one week. Some authors recommend combining ivermectin with albendazole. In our series, the two deceased patients received suboptimal treatment, one due to drug unavailability, highlighting the importance of ensuring the availability of ivermectin in hospitals, even in those outside the highly endemic areas.

This series emphasizes the predominance of autochthonous cases over imported ones. The lower index of suspicion in autochthonous cases may have led to a higher number of severe presentations in this population [11].

As a limitation of our series, it is worth noting that systematic case identification only began in 2009 with the introduction of electronic medical records and that, as with any retrospective study, it is subject to information biases.

5. Conclusions

We present a series of five cases of HIS/DS in our department, most of which were autochthonous. We believe that the care of immunosuppressed people should be improved and Strongyloides stercoralis infection should be screened in all patients, including both migrants from endemic areas and autochthonous populations, before initiating immunosuppressive treatment.