**6.4 Malnutrition**

380 Current Topics in Tropical Medicine

or infarction, peritonitis, and sepsis (Krishnan et al., 2006). Although unusual, brain involvement can occur in disseminated infections, with symptoms including headache, focal seizures, altered mental state, secondary bacterial meningitis and coma (Dutcher et al.,

Since 1966, studies have reported that autoinfection may result in the dissemination of worms; denoted hyperinfection syndrome, the number of worms increases significantly, and worms are detectable in extraintestinal regions, with a mortality rate above 80% (Siddiqui & Berk, 2001). High-risk factors for hyperinfection and dissemination include corticosteroid therapy, malignancies, transplantation, malnutrition, hypogammaglobulinemia, and viral infections such as HIV (Human Immunodeficiency Virus) and HTLV-1 (Human T-

In recent decades, hyperinfection syndrome has increased significantly with the use of immunosuppressive drug therapy. Corticosteroids are widely prescribed drugs with potent immunosuppressive effects and are a major risk factor for the transformation of chronic strongyloidiasis into hyperinfection, which has a higher index of mortality (Armignacco et al., 1989; Al Maslamani et al., 2009). Corticosteroids are involved in the treatment of several diseases that are considered immunological abnormalities, such as lymphoma, rheumatoid arthritis, leprosy, chronic obstructive pulmonary disease (COPD), and polymyositis, leading

However, the role of corticosteroids in susceptibility to severe *S. stercoralis* infection is poorly understood. One hypothesis is that both endogenous and exogenous corticosteroids promote immunosuppression by decreasing the number of inflammatory cells, such as eosinophils and mast cells, and suppressing the transcription of several cytokines. In addition, corticosteroids increase the apoptosis of Th2 lymphocytes (Genta, 1989). Corticosteroids may also have a direct effect on female worms by increasing the production of ecdysteroid-like molecules, hormones that control moulting in insects and possibly helminths (Genta, 1992). An increase in these molecules increases the moulting rate and transforms rhabditiform larvae into filariform larvae, increasing the worm burden and

Patients with hematologic malignancies have a high prevalence of *S. stercoralis* infection when compared with the global index. The reported cases of hematologic malignancies and *S. stercoralis* hyperinfection syndrome are associated with glucocorticoid treatment. The malignancy usually associated with *S. stercoralis* is lymphoma that is being treated with chemotherapy. Moreover, lung cancer has been associated with hyperinfection during the

Hyperinfection syndrome is associated with transplants, and the progression of chronic intestinal infection before transplantation appears to be the most common mechanism.

promoting hyperinfection and dissemination (Genta, 1992; Siddiqui et al., 2000).

administration of immunosuppressive chemotherapy (Keiser & Nutman, 2004).

1990).

**6. Hyperinfection syndrome** 

**6.1 Corticosteroids** 

Lymphotropic Virus Type 1) (Concha et al., 2005).

**6.2 Hematologic and others malignancies** 

**6.3 Transplantation** 

to fatal hyperinfection in many cases (Keiser & Nutman, 2004).

An important cause of immunodeficiency that is related to hyperinfection is malnutrition, particularly in developing countries. Malnutrition promotes disruption of the intestinal mucosa, impairing the host's ability to expel the parasite from the gut (Olsen et al., 2009).

### **6.5 Hypogammaglobulinemia**

Patients with immunodeficient conditions, such as hypogammaglobulinemia, may develop fatal hyperinfection. Case reports show that hypogammaglobulinemia is refractory to prolonged anthelmintic therapy (Brandt de Oliveira et al., 1981; Seet et al., 2005).

#### **6.6 HIV**

Although HIV infection predisposes a patient to hyperinfection due to immunosuppression, few cases of *S. stercoralis* and AIDS have been described (Marcos et al., 2008). The association between *S. stercoralis* and HIV principally occurs in endemic areas (Siddiqui & Berk, 2001). The hyperinfection syndrome can occur in patient with HIV with immune reconstruction syndromes increased after starting of highly active antiretroviral therapy (Brown et al., 2006). On the other hand, the infection with *Strongyloides* may contribute to serious nutritional deciencies in HIV-infected individuals, such as anorexia and malabsorption (Lindo et al., 1998). However, the immunobiological and immunoregulatory mechanisms involving HIV and strongyloidiasis remain unclear.

#### **6.7 HTLV-1**

HTLV-1 is a virus that infects T cells and induces lymphocyte proliferation with the production of a Th1-type immune response in humans. The genome of the HTLV-1virus is diploid and, following interaction with the immune system, HTLV-1 enables the transcription of the viral DNA by integrating into the host genome effectively evading immune surveillance without killing the host (Iriemenan et al., 2010). Strongyloidiasis is strongly associated with HTLV-1, which predisposes patients to severe infections by depressing cell-mediated immunity or IgE responses (Grove, 1996; Carvalho & Da Fonseca Porto, 2004). *Strongyloides* and HTLV-1 may promote the Th1-type response in patients, increasing interferon levels and decreasing Th2-type responses, such as interleukin 4 (IL-4), IL-5, IL-13, and IgE, important host defences against helminths, and a decrease in this response allows not only an increasing in autoinfection but also decreased parasite killing.

Hyperinfection Syndrome in Strongyloidiasis 383

IL-4 has multiple immunoregulatory functions, including T-cell growth factor activity, B-cell regulation, serum IgE level enhancement, and stimulation of the growth and/or differentiation of macrophages, hematopoietic cells, and mast cells (Urban et al., 1991; Negrão-Correa et al., 2006; Wilkes et al., 2007). IL-4 decreases the fecundity and survival of adult worms and increases intestinal smooth muscle contraction, facilitating the expulsion

IL-5 regulates the production of eosinophil myelocyte precursors in bone marrow, the development of mature eosinophils after helminth infection and, in most instances, the production of a number of other cytokines, including IL-4 and IL-13, and chemokines such

IL-13 also participates in the defence mechanisms against helminths, promoting an increase in the intestinal fluid content and increased smooth muscle contractility, a phenomenon that may contribute to worm expulsion (Porto et al., 2001; Shea-Donohue & Urban, 2004; Patel et

The humoral immune response complements defence mechanisms against strongyloidiasis with the production of immunoglobulins by plasma cells. Several immunoglobulins, such as IgE, IgG and IgM, are essential for the elimination of the parasite (Ligas et al., 2003;

IgE antibodies can mediate the activation of accessory cells and the recognition of parasite antigens, promoting goblet cell mucus secretion and the degranulation of mast cells that release mediators affecting parasite survival (Machado et al., 2009). IgG and IgM can transfer immunity against the human parasite in the presence of the complement system

Laboratory models have suggested that both T and B cells mediate the immune response through an increase in immunoglobulins, eosinophils and mast cells and hyperplasia of goblet cells, which require interleukins and chemokines for their development and activation. In strongyloidiasis, dexamethasone seems to primarily suppress cytokines such as IL-1β, IL-4, VEGF, TNF-α, IFN-γ, IL-3, IL-4, IL-5, IL-10 and IL-12 and decreases the production of IgG and IgE antibodies during *S. venezuelensis* infection (Machado et al., 2011;

The complement system activates both classical and alternative pathways with chemoattraction and binding of granulocytes in association with effector cells, which are essential against *S. stercoralis* (Vadlamudi et al., 2006). Studies have reported that complement component C3 is required during *S. stercoralis* infection and facilitates eosinophil degranulation and larval death during the innate immune response (Kerepesi et al., 2006). *Strongyloides* infection induces the production of leukotrienes, which are required to invoke the protective expulsion of parasites. Leukotrienes play an important role in controlling parasite burdens, as well as in altering the parasite reproductive cycle and eliminating the *S.* 

and neutrophils (Abraham et al., 1995; Vadlamudi et al., 2006)

as RANTES and eotaxin (Herbert et al., 2000; Klion & Nutman, 2004; Mir et al., 2006).

of the parasite (Concha et al., 2005).

**7.3 Humoral immune response** 

Machado et al., 2005).

Tefé-Silva et al., 2012).

**7.4 Other responses** 

**8. Pathology** 

*venezuelensis* parasite (Machado et al., 2005).

The pathology of strongyloidiasis differs in different stages of infection.

al., 2009).

In addition, this association reduces the efficacy of anthelmintic drugs, increasing the prevalence of infection (Montes et al., 2009; Iriemenam et al., 2010). Stool examinations should be performed with special attention to detect *S. stercoralis* larvae in all patients infected by HTLV-1 (Carvalho & Da Fonseca Porto, 2004).
