Not your typical Strongyloides infection: a literature review and case study.

Abstract: Strongyloides hyperinfection syndrome is one of several clinical manifestations of strongyloidiasis and has a mortality rate exceeding 85%. The syndrome is characterized by a high organism burden owing to autoinfection and is most common in immunocompromised hosts. The recovery of multiple pathogens is likely due to a piggyback phenomenon that occurs when enteric pathogens are transferred to the bloodstream attached to Strongyloides larvae. Herein, we describe a case of Strongyloides hyperinfection syndrome with a novel feature in a 69-year-old Venezuelan man. To our knowledge, this is the first case of Strongyloides hyperinfection syndrome and Pneumocystis jiroveci pneumonia occurring simultaneously. Owing to its extremely high mortality rate, Strongyloides hyperinfection syndrome must be considered early in the differential diagnosis for respiratory failure when multiple pathogens are recovered in patients from endemic areas.

Key Words: hyperinfection syndrome, Pneumocystis jiroveci, pneumonia, strongyloidiasis

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Strongyloidiasis is a syndrome caused by infection with Strongyloides stercoralis, a parasite endemic to tropical and subtropical climates throughout the world, including parts of Tennessee, eastern Kentucky, and southern Appalachia. Clinical manifestations of the disease range from an asymptomatic carrier state to chronic skin, gastrointestinal, and pulmonary disease to a hyperinfection syndrome in immunocompromised hosts. This syndrome is characterized by sepsis, often with multiple enteric pathogens, and end organ dysfunction resulting from a high parasite burden. Hyperinfection syndrome has a mortality rate exceeding 85%, making prompt recognition crucial for patient survival. (1)

Case Report

A 69-year-old man from Venezuela presented for an evaluation of progressive dyspnea from an unclear cause, despite an extensive evaluation in his home country. He had a history of chronic obstructive pulmonary disease and a recently diagnosed polyclonal B-cell disorder. Three weeks before admission, and shortly after he completed a 4-week course of rituximab and cyclophosphamide, the patient had episodic fevers, rigors, loose stools, and hypoxemia with worsening pulmonary infiltrates. Despite supportive therapy, including empiric use of antibiotics and escalating doses of corticosteroids, the patient's condition worsened, and he was transferred to our institution for further evaluation.

Other past medical history was notable for multivessel coronary artery disease, hypertension, diabetes mellitus, a remote history of pulmonary embolism, and autoimmune hemolytic anemia associated with the aforementioned B-cell malignancy. Medications at presentation included methylprednisolone, clopidogrel, omeprazole, aspirin, metformin, isosorbide mononitrate, diltiazem, and a first-generation cephalosporin. He was a former 80-pack-year smoker.

At admission, the patient was hemodynamically stable, alert, and oriented and in no apparent respiratory distress (blood pressure, 138/60 mm Hg; pulse, 101 beats/min; temperature, 36.2 [degrees]C; and oxyhemoglobin saturation, 90% on room air). Notable examination findings were diffuse wheezing; a diffuse, erythematous, macular rash on his abdomen; and bilateral lower extremity edema. Laboratory test results, including a normal leukocyte count, were unremarkable. Chest x-rays showed bilateral, nonfocal interstitial markings that were more prominent than on x-rays taken elsewhere 30 days before admission (Fig. 2A and Fig. 2B).

Within 12 hours after arrival, the patient's condition deteriorated, with development of dyspnea, worsening hypoxemia, fever (39.5[degrees]C), rigors, altered mental status, and progressive interstitial infiltrates on chest x-rays (Fig. 2C and Fig. 2D). An endotracheal tube was inserted and the patient underwent bronchoscopy with bronchoalveolar lavage. He was treated empirically with IV trimethoprim-sulfamethoxazole, ciprofloxacin, and ticarcillin-clavulanate for presumed Pneumocystis jiroveci pneumonia and routine nosocomial pneumonia.

The lavage specimens included multiple pathogens: Strongyloides stercoralis, Pneumocystis jiroveci, Pseudomonas aeruginosa, Cytomegalovirus, herpes simplex virus, and Aspergillus species (Fig. 3). Blood cultures grew Enterococcus species and Salmonella species, and the serum was positive for the cytomegalovirus pp65 antigen. The diagnosis of Strongyloides hyperinfection syndrome was made, and ivermectin, voriconazole, and ganciclovir were added to the patient's medical regimen, and corticosteroid therapy was tapered. The patient was subsequently weaned from mechanical ventilation after 11 days and discharged to a rehabilitation facility on hospital Day 27.

Strongyloides Life Cycle

Strongyloides is unusual among parasites that infect humans because it can complete an entire cycle of replication within the human host and perpetuate infection for several years. Initial infestation occurs when the infectious form, the filariform larva, enters the human host through skin that was in contact with infected fecal material or contaminated soil. After the parasite gains access to the bloodstream through lymphatic drainage, it travels to the lungs where it crosses the alveolar-capillary barrier, enters the alveoli, and ascends the bronchial tree to the larynx, where it is subsequently swallowed into the gastrointestinal tract. While in the gastrointestinal tract, the larvae mature into adult worms and fertilization occurs. Adult females penetrate the mucosa of the duodenum and proximal jejunum, where they lay eggs and can remain present for years. Adult males are expelled with feces. The eggs mature into noninfectious feeding forms called rhabditiform larvae, which, after being expelled with feces, can mature in the soil, reproduce, and infect other hosts, or the larvae can mature into filariform larvae within the human host. Filariform larvae can reenter the bloodstream of the host, by penetrating the colonic mucosa or perianal skin, and perpetuate the infectious cycle through this process of autoinfection (Fig. 1). (1-4)

Clinical Manifestations

The clinical manifestations of Strongyloides infections vary, depending on the acuity of infection and the underlying host response. The majority of patients with Strongyloides infections have uncomplicated disease, with up to 50% remaining asymptomatic. (2.5)

Acutely after infestation, most symptomatic patients present within 3 to 4 weeks with gastrointestinal, pulmonary, and skin complaints. Gastrointestinal tract manifestations predominate and most commonly include diarrhea and abdominal pain, but anorexia, nausea, vomiting, pruritus ani, bloating, and protein-losing enteropathy have also been described. (6) Pulmonary symptoms typically include nonproductive cough, wheezing, and dyspnea. Chest radiographic findings are nonspecific, and most patients present with normal findings. Migratory pulmonary infiltrates due to larval migration within the lungs may be found on x-rays.7 At the site of parasite entry (usually the feet), local skin reactions can occur, including inflammation, pruritus, edema, petechiae, and serpiginous and urticarial tracts. (2)

A similar constellation of symptoms is seen in chronic, uncomplicated infections but tends to wax and wane, sometimes for years. In contrast to the acute infection, in which gastrointestinal and pulmonary symptoms predominate, chronic infection is characterized by skin involvement. Larva currens ("running larva"), which is thought to be pathognomonic for chronic strongyloidiasis, is an urticarial serpiginous eruption at the site of parasite entry; it is usually transient, lasting several hours to days, and typically involves the buttocks, thighs, and lower extremities. (2,3,7) Forms of chronic, complicated strongyloidiasis include disseminated strongyloidiasis, sometimes referred to as overwhelming or massive strongyloidiasis, and the hyperinfection syndrome.

Hyperinfection Syndrome

Although the exact mechanisms involved in the pathogenesis of the hyperinfection syndrome are unknown, it is believed that persons with impaired host immunity are at risk for hyperinfection. In an immunocompetent host, the rate of ongoing autoinfection remains controlled, resulting in a low parasite burden. However, with impaired host immunity or delayed gastrointestinal transit time, the normal balance between the larvae being expelled into the stool and the maturation of these forms within the gastrointestinal tract is altered. This results in increased rates of autoinfection, a higher parasite burden, and hyperinfection syndrome. (1-4,8)

The association between impaired host immunity and hyperinfection was reported first by Rogers and Nelson in 1966. (10) They described fatalities from overwhelming Strongyloides infection with associated Gram negative enteric sepsis in 2 patients receiving chemotherapy or high-dose corticosteroid therapy for hematologic malignancies. Similarly, several other authors have described an association between impaired host immunity and hyperinfection. (1,3,9,11) In a review of 103 cases, Igra-Siegman et al (1) noted that 89 patients had a known impairment of host immunity, mostly due to hematologic or lymphatic malignancy or to immunosuppressive medications, particularly corticosteroids. Other diseases in which host defenses are altered have also been associated with the development of hyperinfection syndrome, including chronic alcoholism, malnutrition, burns, pancytopenia, hypogammaglobulinemia, (1,2) and infection with HTLV-1 or HIV-1.

[FIGURE 1 OMITTED]

Whereas the signs and symptoms of acute and chronic uncomplicated strongyloidiasis can be predicted from the life cycle of the parasite, hyperinfection syndrome is more dramatic because of compromised immunity and multiorgan involvement. Reported presentations include the following signs and symptoms, alone and in combination (1-5,7,8,12).

* Gastrointestinal -- severe abdominal pain, nausea, vomiting, diarrhea, intestinal obstruction, paralytic ileus, malabsorption, intestinal bleeding, and diffuse peritonitis 

* Pulmonary -- cough with sputum production, hemoptysis, wheezing, respiratory insufficiency, diffuse bilateral and lobular infiltrates, focal hemorrhages, diffuse pulmonary alveolar hemorrhage, pneumonitis, lung abscess, and acute respiratory distress syndrome 

* Neurologic -- altered mental status, seizures, meningitis, and brain abscess

* Other -- granulomatous hepatitis and parasitic invasion of the heart, kidney, peritoneum, lymph nodes, pancreas, prostate, thyroid, or parathyroid 

Secondary infections frequently occur in hyperinfection syndrome. Persistent bacteremia with enteric pathogens (eg, Gram negative organisms, enterococci, group D streptococci, and Candida) can lead to meningitis, peritonitis, and endocarditis. Three mechanisms have been proposed to explain this association: 1) the integrity of the intestinal mucosa is disrupted, which allows enteric bacteria to enter the bloodstream, 2) enteric pathogens enter the bloodstream attached to Strongyloides larvae, and 3) enteric organisms enter the bloodstream as they are excreted by the parasites already in the circulation. (7-9) In the case review by Igra-Siegman et al, (1) there was no significant difference in the secondary infection rate between the immunocompromised patients and the immunocompetent patients, suggesting that secondary infections result from hyperinfection rather than from immunodeficiency.

[FIGURE 2 OMITTED]

Diagnosis and Treatment

A definitive diagnosis of Strongyloides infection can be made by the detection of Strongyloides larvae in stool or body fluids. Stool studies can be performed by several methods. Newer agar plate culture methods yield results that are more sensitive than conventional methods, such as the direct smear method or filter paper culture method. (4) However, larvae are shed in the feces only sporadically, so none of these methods are adequately sensitive. Serial stool specimens are recommended to increase the sensitivity, which is nearly 100% if 7 or more serial specimens are analyzed. (13) Concentrated stool specimens increase the sensitivity further. Direct examination of duodenal aspirates from string testing or endoscopic sampling can be performed, but reported sensitivities range from 40 to 90%. (5)

The serum eosinophil count is increased in up to 80% of immunocompetent patients with uncomplicated infections; however, in hyperinfection syndrome, eosinophilia is often absent. (14,15) When there is a high clinical suspicion of Strongyloides infection with negative stool findings, measurement of serum antibody titers for Strongyloides by enzyme-linked immunosorbent assay may be useful in diagnosing infection in symptomatic or asymptomatic patients. (16,17) A single isotype to monitor eradication has not yet been identified, however, and after anthelmintic treatment, serum immunoglobulin levels decrease at various rates. (17)

Treatment of Strongyloides infections can be challenging. Historically, the anthelmintic pyrvinium pamoate was considered the treatment of choice, but it had an eradication rate of only 30 to 85% and has not been manufactured since 1989. Benzimidazoles (thiabendazole, mebendazole, and albendazole) were the next generation of anthelmintic agents. These drugs have a broad spectrum of activity against helminths, disrupting energy production in the parasites. The final common pathway of the benzimidazole is thought to be inhibition of [beta]-tubulin polymerase, causing disruption of cytoplasmic microtubule formation. These anthelmintics not only kill adult gut-dwelling stages of the parasite but also sterilize the larvae and eggs. (18) Thiabendazole, approved for human use in 1962, has been the most commonly used agent in this group. It has an extremely high rate of eradication, nearly 100% in some series. However, it has largely fallen out of favor as a first-line agent because the incidence of adverse reactions, including liver dysfunction, fatigue, dizziness, nausea, and anorexia, is greater than 30%. (4)

Ivermectin, an antibiotic used initially in veterinary medicine to treat nematode infections, became available for human use in the late 1980s. It inhibits neurotransmission in nematodes and arthropods by stimulating the release of [gamma]-aminobutyric acid from presynaptic nerve terminals and inhibiting [gamma]-aminobutyric acid-dependent neurotransmission. Eradication rates two years after treatment with ivermectin are as high as 97%. (4) Its reported adverse effects are similar to those reported for the benzimidazoles, but they generally occur with less frequency and severity. The World Health Organization lists ivermectin as the drug of choice for the treatment of hyperinfection syndrome and disseminated S stercoralis. (13)

[FIGURE 3 OMITTED]

Complete eradication of the parasite burden in uncomplicated infections before initiating immunosuppressive therapy is essential to ensure that hyperinfection syndrome will not develop during immunosuppressive therapy. Cure rates in asymptomatic chronic carriers are nearly 100%. Complications of untreated infection in immunocompetent patients most commonly include paralytic ileus, a malabsorptive syndrome, nephrotic syndrome, and low birth weight. (4,15,19,20) Immunosuppressed patients, in addition to being at a higher risk for these complications, are also at an increased risk for the development of pneumonia, sepsis, meningitis, abscess formation, disseminated S stercoralis disease, or Strongyloides hyperinfection syndrome. (4) Death, usually due to sepsis from Gram negative and Gram positive enteric bacteria, such as Escherichia coli, Klebsiella pneumoniae, and Enterococcus species, occurs in greater than 80% of immunosuppressed patients with hyperinfection syndrome. (13,21) Before immunosuppressive therapy is initiated, screening for Strongyloides infection should be considered in asymptomatic patients at risk, such as those with unexplained eosinophilia, those with a history of serpiginous or cutaneous lesions, or those with a history of exposure to contaminated soil or human feces in endemic areas.

In critically ill patients from endemic areas who present with a diffuse constellation of symptoms not responsive to conventional therapy, a high clinical suspicion of Strongyloides hyperinfection syndrome is crucial for accurate, timely diagnosis and treatment. The present case highlights a patient who presented with an overwhelming infectious burden from multiple sources. To our knowledge, this is the only reported case of Strongyloides hyperinfection syndrome and Pneumocystis jiroveci pneumonia occurring in the same host simultaneously.

References

1. Igra-Siegman Y, Kapila R, Sen P, et al. Syndrome of hyperinfection with Strongyloides stercoralis. Rev Infect Dis 1981;3:397-407.

2. Longworth DL, Weller PF. Hyperinfection syndrome with strongyloidiasis. Curr Clin Top Infect Dis 1986;7:1-26.

3. Scowden EB, Schaffner W, Stone WJ. Overwhelming strongyloidiasis: an unappreciated opportunistic infection. Medicine (Baltimore) 1978;57:527-44.

4. Zaha O, Hirata T, Kinjo F, et al. Strongyloidiasis: progress in diagnosis and treatment. Intern Med 2000;39:695-700.

5. Nagaraj P, Czachor JS, Hawley B. Strongyloides hyperinfection with pulmonary hemorrhage and ARDS. Infect Med 2000;17:208-12.

6. Boyd WP, Jr. Campbell FW, Trudeau WL. Strongyloides stercoralis--hyperinfection. Am J Trop Med Hyg 1978;27(Pt 1):39-41.

7. Wehner JH, Kirsch CM. Pulmonary manifestations of strongyloidiasis. Semin Respir Infect 1997;12:122-129.

8. Upadhyay D, Corbridge T, Jain M, et al. Pulmonary hyperinfection syndrome with Strongyloides stercoralis. Am J Med 2001;111:167-169.

9. Rivera E, Maldonado N, Velez-Garcia E, et al. Hyperinfection syndrome with Strongyloides stercoralis. Ann Intern Med 1970;72:199-204.

10. Rogers WA, Jr. Nelson B. Strongyloidiasis and malignant lymphoma: "Opportunistic infection" by a nematode. JAMA 1966;195:685-687.

11. Cruz T, Reboucas G, Rocha H. Fatal strongyloidiasis in patients receiving corticosteroids. N Engl J Med 1966;275:1093-1096.

12. Cook GA, Rodriguez H, Silva H, et al. Adult respiratory distress secondary to strongyloidiasis. Chest 1987;92:1115-1116.

13. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis 20011;33:1040-1047.

14. Sanchez PR, Guzman AP, Guillen SM, et al. Endemic strongyloidiasis on the Spanish Mediterranean coast. QJM 2001;94:357-363.

15. Nonaka D, Takaki K, Tanaka M, et al. Paralytic ileus due to strongyloidiasis: case report and review of the literature. Am J Trop Med Hyg 1998;59:535-538.

16. Loutfy MR, Wilson M, Keystone JS, et al. Serology and eosinophil count in the diagnosis and management of strongyloidiasis in a non-endemic area. Am J Trop Med Hyg 2002;66:749-752.

17. Lindo JF, Atkins NS, Lee MG, et al. Short report: long-term serum antibody isotype responses to Strongyloides stercoralis filariform antigens in eight patients treated with ivermectin. Am J Trop Med Hyg 1996;55:474-476.

18. Horton J. Albendazole: a review of anthelmintic efficacy and safety in humans. Parasitology. 2000; 121 (Suppl):S113-S132.

19. Wong TY, Szeto CC, Lai FF, et al. Nephrotic syndrome in strongyloidiasis: remission after eradication with anthelmintic agents. Nephron 1998;79:333-336.

20. Dreyfuss ML, Msamanga GI, Spiegelman D, et al. Determinants of low birth weight among HIV-infected pregnant women in Tanzania. Am J Clin Nutr 2001;74:814-826.

21. Adedayo AO, Grell GA, Bellot P. Case study: fatal strongyloidiasis associated with human T-cell lymphotropic virus type 1 infection. Am J Trop Med Hyg 2001;65:650-651.

To accomplish great things, we must dream as well as act.
--Anatole France

Elizabeth B. Foreman, MD, Philip J. Abraham, MD, and Jeffrey L. Garland, MD

From the Division of Community Internal Medicine, the Division of Pulmonary Medicine, and the Department of Critical Care Medicine, Mayo Clinic, Jacksonville, FL.

Reprint requests to Jeffrey L. Garland, MD, Department of Critical Care Medicine, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. Email: [e-mail].

Accepted November 23, 2005.

RELATED ARTICLE: Key Points

* Strongyloides stercoralis is endemic to several regions of the United States as well as tropical and subtropical climates worldwide.

* Strongyloidiasis should be considered when patients' respiratory symptoms worsen after the start of therapy with corticosteroids or other immunosuppressants.

* Strongyloides hyperinfection syndrome has a mortality rate exceeding 85%.