Diagnosis and reasoning

This elderly man has presented with intermittent upper abdominal pain for 3 weeks, in association with anorexia, nausea, and vomiting; examination reveals mild epigastric tenderness. Gastric malignancy is a very real concern here, given his age and history of dyspeptic symptoms; peptic ulcer disease, acute cholecystitis, and acute pancreatitis are other important considerations. Last but not least, the possibility of mesenteric ischemia should be kept in mind, as this is a potentially lethal condition which is surprisingly easy to overlook. His workup should start off with a complete blood count (CBC), liver profile, pancreatic enzyme assay, and ultrasound scan of the abdomen. The CBC is only significant for mild anemia and a neutrophil leukocytosis, both of which are nonspecific findings. In addition, pancreatic enzymes are within normal parameters, while the liver profile reveals only hypoproteinemia and hypoalbuminemia. However, his ultrasound scan reveals a rather peculiar finding: marked thickening of the small bowel walls. Note that this appearance is typically caused by infective and inflammatory conditions. Upper gastrointestinal endoscopy is a good next step, aiming to visualize the stomach and duodenum; this reveals erythema, whitish mottling, and erosions, along with a suspicious looking elevated lesion on the greater curvature. However, biopsies reveal a unexpected finding: multiple stages of the parasite Strongyloides stercoralis, revealing his symptoms to be due to Strongyloidiasis, a parasitic infection which is endemic in Bangladesh (and many other tropical and subtropical countries). Note also that the presence of infective filariform larvae is diagnostic of hyperinfection syndrome; this suggests that his recent medical episodes might also have been secondary to the disease. Thus, the gram negative meningitis could possibly have been due to intestinal bacterial translocation, and the 'exacerbation' of lung disease, a result of larval migration. Practice guidelines published by the World Gastroenterology Organization (WGO) recommend Ivermectin as the drug of choice in these patients. While benzimidazoles such as Albendazole and Mebendazole are considered second-line agents, Thiabendazole is no longer recommended, given the high incidence of side effects. There is no rationale in keeping him nil per oral right now; in addition, as no infective complications of strongyloidiasis (such as meningitis) are immediately present, antibacterial therapy is not indicated.

Discussion

Strongyloidiasis is an intestinal infection caused by the parasitic nematode Strongyloides stercoralis; it is most common in (but not exclusive to) tropical and subtropical regions, with an estimated 100 to 200 million people affected worldwide. To understand the pathogenesis of the condition, it is important to know that the Strongyloides worm is unique among nematodes in having two types of life cycles: a free living cycle (rhabditiform larvae) and a parasitic cycle (filariform larvae). Humans acquire the infection when the infective filariform larvae penetrate the skin or mucous membranes; the larvae then traverse the lymphatic system, migrate into the pulmonary circulation, and travel up the bronchial tree, where they are swallowed to reach the gastrointestinal tract. In the small intestine, the larvae molt twice and mature into adult females, who produce eggs via parthenogenesis. These eggs hatch within the gut, producing rhabditiform larvae, which are passed with the stools; the excreted larvae may live freely, or subsequently transform into filariform larvae. Note that premature transformation into infective filariform larvae can occur in the intestine itself; these larvae subsequently re-enter the circulation by penetrating the intestinal mucosa or perianal skin. This is termed 'autoinfection', and is the reason why strongyloidiasis is a lifelong infection unless all larvae and worms in the body are eradicated at once. While autoinfection is usually limited by the host immune response, in patients with impaired immunity, two more severe forms of strongyloidiasis may occur: hyperinfection syndrome and/or disseminated strongyloidiasis. Hyperinfection syndrome is characterized by acceleration of the normal life cycle of S. stercoralis, resulting in increased parasite burden and turnaround; note that this can occasionally occur in immunocompetent individuals as well. Disseminated strongyloidiasis results in the spread of larvae into organs which are outside the realm of the normal life cycle; this may also result in translocation of enteric bacteria, giving rise to polymicrobial bacteremia and/or meningitis due to enteric pathogens. Strongyloidiasis is often challenging to diagnose (or even suspect), as most patients are asymptomatic; where present, symptoms are extremely diverse, and depend on the host immune response. Common gastrointestinal symptoms include anorexia, nausea, vomiting, abdominal cramps, a bloating sensation, constipation, chronic diarrhea, pruritus ani, and rarely, small intestinal obstruction. Migration of larvae into the pulmonary system (pulmonary strongyloidiasis) may result in wheezing and a mild cough initially, followed by pneumonitis (resembling Loeffler syndrome), hemoptysis, pleuritic pain, dyspnea, tachypnea, and acute respiratory distress syndrome (ARDS). Key dermatological manifestations include ground itch, larva currens, and purpuric periumbilical skin lesions. Ground itch manifests as a cutaneous eruption of pruritic papulovesicular lesions; it is commonly observed in the feet, at the point the infective filariform larvae have penetrated the skin. Larva currens is considered to be pathognomonic of strongyloidiasis; it is a pruritic, urticarial rash which is linear or serpiginous, creeping up the body at a rate of ~5 to 15cm/hour, and is believed to be due to an allergic response to the migrating larvae. Purpuric periumbilical skin lesions may occur in disseminated strongyloidiasis; these are due to vascular injury during larval migration. Note also that severe disease may result in altered mentation, seizures, meningitis, brain abscess formation, granulomatous hepatitis and invasion of organs such as the heart, kidneys, pancreas, ovaries, and prostate. Strongyloidiasis can give rise to numerous complications; these most often involve the gastrointestinal (GI), pulmonary, and nervous systems. Key GI complications include hemorrhage, malabsorption, intestinal obstruction, appendicitis, peritonitis, ileus, obstructive jaundice, pneumatosis intestinalis and eosinophilic oophoritis. Pulmonary complications include asthma, exacerbation of existing chronic obstructive pulmonary disease (COPD), pneumonitis, alveolar hemorrhage, pleural effusion, granulomatous lung disease and respiratory failure. The most important neurological complications are meningitis due to enteric bacteria, and brain abscess formation. Other complications of strongyloidiasis are rare; these include bacteremia due to hyperinfection syndrome, nephrotic syndrome, and reactive arthritis. The diagnostic workup of strongyloidiasis often requires multiple investigative modalities, including hematological studies, microscopy and cultures, serology, radiology, endoscopy, and biopsy and specimen examinations. While a leukocytosis may occur in early stages of infection, the total white blood cell count is often normal in both acute and chronic strongyloidiasis; it is only elevated in severe disease, where it may be associated with other hematological abnormalities such as anemia, thrombocytopenia and a prolonged prothrombin time due to decreased levels of clotting factors. Note that a peripheral eosinophilia (>600/mL) is common during acute illness; this represents the immune response of the host to migrating larvae, and is absent in the immunocompromised. Examination of the stools aiming to detect Strongyloides larvae is diagnostic, but of limited sensitivity; larval yield can be enhaced via techniques such as the Baermann funnel test. Specialized stool cultures are also of value, but are of limited specificity as they can give false positive results in patients with hookworm disease. Immunodiagnostic assays (e.g. the filarial complement fixation test, indirect agglutination test, radioallergosorbent test, specific immunoglobulin E, western blot, gelatin particle indirect agglutination and ELISA) are of limited use, due to their variable reliability and high rates of false negativity. Chest radiographs may demonstrate patchy alveolar infiltrates in acute strongyloidiasis and diffuse interstitial infiltrates, diffuse alveolar infiltrates, and pleural effusions in severe disease. CT imaging of abdomen and pelvis may reveal nonspecific thickening of bowel wall, while pulmonary CT scans may reveal fine miliary nodules or diffuse reticular interstitial opacities. Endoscopy is of high sensitivity and specificity; inspection of the duodenum may reveal edematous or erythematous mucosa and/or white villi, while duodenal biopsy reveals the presence of larvae in 71.4% of immunocompromised patients. Perioral string testing and duodenal aspiration may help retrieve larvae from the GI tract, while sputum analysis, CSF analysis, bronchial washing and bronchoalveolar lavage may retrieve larvae from extraintestinal sites in patients with hyperinfective and disseminated strongyloidiasis. Note that skin biopsies are useful only in severe disease; the diagnostic yield is minimal in acute and chronic disease. All patients with strongyloidiasis, whether symptomatic or asymptomatic, should be treated for prevention of hyperinfection. The treatment regime should include an anthelmintic; Ivermectin is the drug of choice. While Thiabendazole was frequently used earlier, it is now avoided because of the significant side effect profile. However, other benzimidazoles such as Mebendazole, and Albendazole are still considered second line agents. Note that in patients with hyperinfection and disseminated disease, Ivermectin should be administered daily, until all symptoms have resolved, and a larvae free period of at least 2 weeks has been achieved. If complications such as meningitis are present, antibiotic therapy targeting enteric bacteria is highly advisable. Overall, acute and chronic strongyloidiasis in immunocompetent patients carries a good prognosis. However, severe strongyloidiasis has a mortality risk as high as 80%, possibly because diagnosis is often delayed and most affected patients are immunocompromised.

Take home messages

1. Strongyloidiasis is a chronic parasitic infection which is potentially life threatening in immunosuppressed individuals.
2. The condition is often underdiagnosed due to the variable clinical manifestations, and lack of sensitivity of most diagnostic investigations.
3. Strongyloidiasis is usually a lifelong infection, unless appropriate antibiotic therapy is initiated.