**8.2 Hyperinfection syndrome**

The histology of lungs affected by hyperinfection syndrome revealed alveolar haemorrhage with large numbers of larvae in the alveoli, septa, pleurae and blood vessels. Many larvae were present throughout the walls of the tracheobronchial tree, with an increase in number toward the upper respiratory tract. Larvae in the lungs provoked inflammatory infiltrate

Fig. 2. Histopathology of *Strongyloides stercoralis* in the lungs and intestine of a 48-year-old woman with a gastric carcinoid tumor treated with chemotherapy. A and B: Pulmonary parenchyma. Note the presence of larvae in alveolar space (arrow). C and D: Female worms in the duodena (arrows). HE stain.

384 Current Topics in Tropical Medicine

The obligate pulmonary phase of the parasite's life cycle typically occurs within hours after infection. During larval passage through the lungs, the parasite induces haemorrhage in the alveolar spaces, inflammatory infiltrate, and, occasionally, granuloma (Kinjo et al., 1998). Histopathological analyses of human intestines have shown that *S. stercoralis* eggs and adult females colonise the duodenum and upper jejunum. Studies have also demonstrated the presence of oedema, duodenal villous atrophy, and crypt hyperplasia with disrupted epithelium due to the inhibition of cell proliferation and apoptosis (Coutinho et al., 2006; Werneck-Silva et al., 2006). Surface damage, ulceration, an increase in mucus secretion and functional changes in the intestine have also been reported. In many cases, the eosinophil infiltrates are associated with the intensity of the infection (Rivasi et al., 2006; Kishimoto et

The histology of lungs affected by hyperinfection syndrome revealed alveolar haemorrhage with large numbers of larvae in the alveoli, septa, pleurae and blood vessels. Many larvae were present throughout the walls of the tracheobronchial tree, with an increase in number toward the upper respiratory tract. Larvae in the lungs provoked inflammatory infiltrate

Fig. 2. Histopathology of *Strongyloides stercoralis* in the lungs and intestine of a 48-year-old woman with a gastric carcinoid tumor treated with chemotherapy. A and B: Pulmonary parenchyma. Note the presence of larvae in alveolar space (arrow). C and D: Female worms

**8.1 Acute infection** 

al., 2008).

**8.2 Hyperinfection syndrome** 

in the duodena (arrows). HE stain.

and were occasionally walled off by granulomas. Bronchopneumonia is probably a consequence of tissue damage inflicted by the invading larvae (Zumla & James, 2002). In the human intestine, hyperinfection results in mucosal oedema, acute inflammation, mucosal haemorrhage, and focal ulceration with numerous *S. stercoralis* larvae, adult worms and ova embedded within the small bowel villi (Sathe &Madiwale, 2006; Al Maslamani et al., 2009).

Fig. 3. Histopathology of the lungs of rats in an experimental model of strongyloidiasis on day 3 post-infection: A and B: Controls; C and D: Infected with *S. venezuelensis.* Note the scarce hemorrhagic foci with larvae in the alveolar spaces (arrows); E and F: Infected with *S. venezuelensis* and treated with dexamethasone. Note the prominent hemorrhagic foci showing larvae in the alveolar spaces (arrow). HE stain.

Hyperinfection Syndrome in Strongyloidiasis 387

remodelling similar to asthma, characterised by hyperplasia of goblet cells and increased bronchiolar wall thickness caused by oedema, hypertrophy of smooth muscle cells, neovascularisation and collagen deposition, was reported. In contrast, immunosuppression with dexamethasone interferes with the pulmonary cycle of *Strongyloides venezuelensis*  infection and promotes greater haemorrhage, which is provoked by the substantial quantities of larvae that pass into the alveolar spaces, accompanied by a decrease in eosinophil and mast cell migration and impaired formation of granulomas (Tefé-Silva et al., 2008). In addition, dexamethasone treatment inhibited airway remodelling, contributing to

In the small intestine of rodents infected with *S. venezuelensis*, females and fertile eggs were observed in the wall of the gastrointestinal tract and invading the intestinal mucosa, with increased inflammatory exudate and eosinophils (Machado et al., 2005). Dexamethasone treatment promoted increased mucus production, which progressed to a massive mucosal invasion of fertile eggs and adult parasites that was accompanied by the erosion of the intestinal epithelial layer. Interestingly, the inflammatory response was relatively inconspicuous. Proliferative activity increased in the crypts and the villous fusion, resulting in an apparent reduction in the number of intestinal epithelial cells. In addition, dexamethasone enhanced parasite fertility and proliferation, with dissemination of the larvae to other visceral organs, such as the spleen, kidneys, heart, liver and brain (Machado

Mice infected with *S. venezuelensis* and treated with dexamethasone showed increased blood neutrophil numbers and a reduction in eosinophil and mononuclear cell numbers in the blood, bronchoalveolar cells, and peritoneum when compared to *S.* venezuelensis infection in the absence of dexamethasone. In addition, dexamethasone impaired the host immune response, decreasing the production of cytokines such as tumour necrosis factor (TNF), interferon (IFN), interleukin-3 (IL-3), IL-4, IL-5, IL-10, and IL-12 in the lungs and circulating antibodies such as IgG, and IgE but increasing the overall parasite burden in the intestines

Strongyloidiasis is diagnosed on the basis of suspicion in patients with clinical signs and symptoms of the disease; however, in approximately 50% of cases, the infection is asymptomatic, complicating diagnosis. In some cases, diagnosis is difficult despite a low

The classic triad of urticaria, abdominal pain and diarrhoea is suggestive of a diagnosis of strongyloidiasis. Parasites are usually found in the faeces; they are sometimes also seen in other body fluids or in tissue samples (Basile et al., 2010). The parasitological diagnosis is usually made after an examination of the faeces, and several diagnostic methods can be used to detect *S. stercoralis*, including stool examination, a modified Baermann technique, and stool culture on a blood agar plate. Enzyme-linked immunosorbent assays (ELISA) are used for serological diagnosis and have proven valuable in detecting both symptomatic and asymptomatic strongyloidiasis infection, with a high specificity for detecting IgG antibodies

In patients with a disseminated infection, the diagnosis is relatively straightforward, given the high numbers of larvae that exist in the stool and, usually, in the sputum. White blood

intestinal worm load and larval excretion in the faeces (Rajapurkar et al., 2007).

the dissemination of the parasite (Tefé-Silva et al., 2012).

et al., 2011).

**9. Diagnosis** 

and faeces (Machado et al., 2011).

to *S. stercoralis* (Basile et al., 2010).

#### **8.3 Hyperinfection syndrome in experimental models**

Animal models are important for understanding the mechanism of hyperinfection. Studies in experimental models of *S. venezuelensis* infection have reported that filariform larvae were surrounded by inflammation mediated by eosinophils and mast cells in the lungs. The infection also promoted an important granulomatous response, sometimes entrapping the larvae, which is probably an attempt by the host to contain the parasite. In addition, airway

Fig. 4. Histopathology of the duodena of rats in an experimental model of strongyloidiasis on day 14 post-infection: A and B: Controls; C and D: Infected with *S. venezuelensis.* E and F: Infected with *S. venezuelensis* and treated with dexamethasone on day 14 post-infection. Note the massive mucosal invasion of fertile eggs and adult parasites, accompanied by erosion of the intestinal epithelial layer. HE stain.

Animal models are important for understanding the mechanism of hyperinfection. Studies in experimental models of *S. venezuelensis* infection have reported that filariform larvae were surrounded by inflammation mediated by eosinophils and mast cells in the lungs. The infection also promoted an important granulomatous response, sometimes entrapping the larvae, which is probably an attempt by the host to contain the parasite. In addition, airway

Fig. 4. Histopathology of the duodena of rats in an experimental model of strongyloidiasis on day 14 post-infection: A and B: Controls; C and D: Infected with *S. venezuelensis.* E and F: Infected with *S. venezuelensis* and treated with dexamethasone on day 14 post-infection. Note the massive mucosal invasion of fertile eggs and adult parasites, accompanied by

erosion of the intestinal epithelial layer. HE stain.

**8.3 Hyperinfection syndrome in experimental models** 

remodelling similar to asthma, characterised by hyperplasia of goblet cells and increased bronchiolar wall thickness caused by oedema, hypertrophy of smooth muscle cells, neovascularisation and collagen deposition, was reported. In contrast, immunosuppression with dexamethasone interferes with the pulmonary cycle of *Strongyloides venezuelensis*  infection and promotes greater haemorrhage, which is provoked by the substantial quantities of larvae that pass into the alveolar spaces, accompanied by a decrease in eosinophil and mast cell migration and impaired formation of granulomas (Tefé-Silva et al., 2008). In addition, dexamethasone treatment inhibited airway remodelling, contributing to the dissemination of the parasite (Tefé-Silva et al., 2012).

In the small intestine of rodents infected with *S. venezuelensis*, females and fertile eggs were observed in the wall of the gastrointestinal tract and invading the intestinal mucosa, with increased inflammatory exudate and eosinophils (Machado et al., 2005). Dexamethasone treatment promoted increased mucus production, which progressed to a massive mucosal invasion of fertile eggs and adult parasites that was accompanied by the erosion of the intestinal epithelial layer. Interestingly, the inflammatory response was relatively inconspicuous. Proliferative activity increased in the crypts and the villous fusion, resulting in an apparent reduction in the number of intestinal epithelial cells. In addition, dexamethasone enhanced parasite fertility and proliferation, with dissemination of the larvae to other visceral organs, such as the spleen, kidneys, heart, liver and brain (Machado et al., 2011).

Mice infected with *S. venezuelensis* and treated with dexamethasone showed increased blood neutrophil numbers and a reduction in eosinophil and mononuclear cell numbers in the blood, bronchoalveolar cells, and peritoneum when compared to *S.* venezuelensis infection in the absence of dexamethasone. In addition, dexamethasone impaired the host immune response, decreasing the production of cytokines such as tumour necrosis factor (TNF), interferon (IFN), interleukin-3 (IL-3), IL-4, IL-5, IL-10, and IL-12 in the lungs and circulating antibodies such as IgG, and IgE but increasing the overall parasite burden in the intestines and faeces (Machado et al., 2011).
