Hookworm infections appear globally and can cause a variety of symptoms especially in travelers, including diarrhea.[1, 2] Similar to other helminth infections, high eosinophilia is a hallmark characteristic of this disease. High eosinophilia during the acute, invasive stages of infections with schistosomiasis and strongyloides has been associated with a hypereosinophilic syndrome-type reaction.[4-6] This reaction is characterized by multiple organ impairment, often including the brain. We present a case of severe acute hookworm infection leading to a hypereosinophilic syndrome-like reaction.
We describe a 55-year-old man returning from the Philippines infected with a hookworm, the novel bacterium Laribacter hongkongensis, and a Blastocystis hominis and presenting with both gastrointestinal and neurological symptoms. The high eosinophilia caused by the hookworm infection resulted in both gastrointestinal and neurological symptoms, resembling a hypereosinophilic syndrome.
A 55-year-old Dutch male was referred to the infectious diseases department because of a 5-week-long existing diarrhea. His symptoms started during a 3-week holiday in the Philippines, during which he had bathed in hot springs and had eaten from street stalls. At first his symptoms consisted of watery stools three times a day, without blood or mucus. During the next weeks the frequency of his symptoms increased to once every hour, despite the use of loperamide. Over the course of his illness he lost 10 kg in bodyweight and developed several neurological complaints (a claw-hand and difficulty coordinating movements) (Figure 1). The patient had not noticed any skin abnormalities. After visiting the emergency room, he was asked to gather fecal samples. Because of progressive symptoms and profound eosinophilia, he was admitted to the hospital 2 days later. Physical examination at admission showed a cachectic, mildly dehydrated man with a firm, round abdomen, with over the right upper abdominal quadrant tenderness to palpation. Neurological examination showed a paresis of the extensor muscles of the fourth and fifth digits of the right hand, but could not objectify coordination problems. The patient had no noteworthy medical history besides a bipolar disorder, for which he was using lithium.
Blood tests showed a leukocytosis of 27.1 × 109/L with an eosinophilia of 8.6 × 109/L and a C-reactive protein (CRP) of 35 nmol/L. Other than a mild inflammatory normocytic anemia (hemoglobin 8.2 mmol/L) there were no further abnormalities. A Ridley concentration of patient's feces showed eggs of hookworm [determined to be Ancylostoma duodenale by polymerase chain reaction (PCR) sequencing] and cysts of Blastocystis hominis. A fecal culture, using a 0.6 cellulose filter method, showed spiral curved gram-negative rods. These were determined to be Laribacter hongkongensis (LH) by 16S rRNA gene sequencing and showed a biochemical- and antibiotic resistance profile matching previous reports on LH. The sample was negative for Salmonella, Shigella, Yersinia, and Campylobacter species. Serology for Schistosoma, Strongyloides, HIV, and syphilis were all negative. No cysts for Cryptosporidium or Cyclospora were seen. PCR showed no DNA of Giardia lamblia, Dientamoeba fragilis, Cryptosporidium species, or Entamoeba species. Chest radiography and electrocardiography showed no abnormalities.
At admission the patient received fluid replacement therapy and—awaiting test results—was treated with metronidazole. This resulted in a rapid decrease of bowel movements to watery stool once a day and decreased stomach complaints. After receiving test results, treatment was switched to mebendazol (100 mg 3 times a day) for 3 days to treat the hookworm infection. This resulted in a prompt decrease of the eosinophilia to 4.1 × 109/L after 3 days and to 0.57 × 109/L several months later at the outpatients clinic. The latter was similar to eosinophilia concentrations determined in 2008 that were ascribed to the allergic state of the patient. With treatment of the hookworm, the watery stool once daily also returned to normal. The LH and B hominis infections were left untreated because of the improvement of symptoms and self-limiting character of these infections. The patient's neurological symptoms however persisted after discharge from the hospital. The ulnaropathy improved in several weeks without treatment. The patient requested neurological consultation several months after discharge for impaired motor skills. At this point, he reported impairments in his fine motor skills of both his hands while drinking coffee or rolling a cigarette. He also complained of a decreased feeling of control and strength in both his legs. This could again not be objectified in a neurological examination. Owing to claustrophobia a magnetic resonance imaging (MRI) of the brain could not be performed. Instead, a non-contrast computed tomography (CT) was executed 8 weeks after admittance to the hospital. The scan showed multiple hypodensities in the white matter of the cerebral hemispheres (centrum semi ovale), as well as at the level of the basal ganglia, suggestive of (micro-) infarction (Figure 2).
The patient was infected with three microorganisms associated with gastrointestinal symptoms. However, his persistent diarrhea and neurological symptoms did not fit any of the typical presentations of these three pathogens. The symptoms combined with the high eosinophilia do however resemble the clinical course seen with a hypereosinophilic syndrome. This syndrome is associated with multiple organ impairment and eosinophilia of more than 1.5 × 109/L. Similar eosinophilic toxicity has also been described in high eosinophilia during the acute, invasive stages of other helminth infections, such as with strongyloides and schistosomiasis.[4, 6] This type of reaction is more often seen during infections primarily related to the digestive tract, such as Schistosoma mansoni, less frequent with Schistosoma haematobium.
The multiple cerebral microinfarctions around the basal ganglia, as seen on the patient's CT scan, could explain the coordination difficulties and would fit the diagnosis of hypereosinophilic encephalopathy. The ulnaropathy could also be explained by an eosinophilic vascular mononeuropathy multiplex, but after electromyographic analysis, is more likely to be a pressure neuropathy due to the marked weight loss.
Symptoms of a chronic hookworm infection are usually caused by the characteristic iron-deficient anemia and hypoproteinemia, due to a sustained intestinal blood loss. Infection occurs when naked skin is put into contact with warm, wet soil contaminated with larvae. This can cause a local dermatitis, which the patient had not noticed. The larvae penetrate the skin and are hematogenously transported to the lungs, where they travel through the airways into the digestive tract. The larvae mature in the small intestines, where they start to produce eggs. Acute infection among travelers can cause gastrointestinal symptoms with nausea, vomiting, abdominal pain, and sometimes diarrhea. High eosinophilia (>1.5 × 109/L) is a hallmark characteristic of this infection, typically surfacing 5 to 9 weeks after infection. The latter is consistent with the increase in diarrhea 5 to 7 weeks after the infection in the Philippines.
The patient's stool also tested positive for LH. In 2001, LH was first isolated from blood and pus of empyema of a 54-year-old man admitted to a Hong Kong hospital with liver cirrhosis complicated by sepsis. The seagull-shaped (lat. Larus), gram-negative rods were classified via 16S rRNA gene sequencing as being both a new species and new genus. Eating raw infected fish will cause infection in humans. Most frequent symptoms are watery or bloody diarrhea (resp. 80%/20%), abdominal pain (75%), and vomiting (35%). The disease is self-limiting with a median duration of symptoms of 4 days. A large multicenter case-control trial in Hong Kong did not find LH in its control group (n = 1,894), suggesting causal relationship between gastroenteritis and LH. However, studies fulfilling Koch's postulates for causality have not been performed, making this bacterium of questionable significance in the patient's history.
Cysts of the protozoa B hominis are often found in stool samples, especially in returning travelers (up to 30%). There is considerable controversy about its role as a pathogenic organism. If decided to treat, first choice would be metronidazole.
After making the hypothesis of a reactive hypereosinophilic syndrome-like reaction, it should be noted that one cannot exclude the direct pathogenic role of any of the microorganisms found in the patient's feces. Especially the role of LH is uncertain, because little is known about the pathogenic nature of this bacterium. It could very well have had a significant or additive role in the gastrointestinal symptoms of the patient for a prolonged period of time. Furthermore, the empirical metronidazol treatment resulted in a rapid decrease of the diarrhea. Metronidazol is not known to be effective against Ancylostoma nor did LH show in vitro sensitivity. This suggests either a pathogenic role of B hominis, sensitive to this agent, or the possibility of an occult Gardiasis (despite a negative PCR). Finally, when recognizing the reactive hypereosinophilic syndrome at an early stage, immunosuppressant therapy could be considered to prevent further organ damage.
We treated a 55-year-old man with complicated traveler's diarrhea and eosinophilia, who was infected with three pathogens, including A duodenale and LH. We hypothesize that the high eosinophilia caused by the acute hookworm infection resulted in both neurological and gastrointestinal symptoms, resembling a hypereosinophilic syndrome.
Declaration of Interests
The authors state they have no conflicts of interest to declare.