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Persistent Clostridium difficile Colitis Mimicking A Fatal Case Of Strongyloides Hyperinfection Syndrome

Open AccessPublished:February 15, 2022DOI:https://doi.org/10.1016/j.ijid.2022.02.023

      Highlights

      • Patients from endemic areas and on chronic steroids should be screened for Strongyloides stercoralis.
      • Stool ova and parasite testing may detect Strongyloides when repeated stool samples are obtained.
      • Strongyloides antibody testing exhibits cross-reactivity with other helminths.
      • Agar-plate culture and the modified Baermann technique ideally diagnose infections caused by Strongyloides.

      ABSTRACT

      Strongyloidiasis, a disease caused by the helminth Strongyloides stercoralis, has been identified as a life-threatening parasitic infection among immunocompromised patients. In the most severe cases, which include hyperinfection syndrome and dissemination of larvae throughout multiple organ sites, there is typically a history of immunosuppression among the infected. Herein, we describe a fatal case of S. stercoralis hyperinfection in an immigrant from rural Ecuador presenting with diarrhea along with Clostridium difficile colitis after the use of a prolonged course of steroids. Despite the appropriate administration of ivermectin, living Strongyloides larvae were discovered in a tracheal lavage. The patient ultimately developed a multiorgan failure requiring life-supporting measures in the intensive care unit and later succumbed to his condition. This case of S. stercoralis hyperinfection emphasizes the importance of screening for this parasite in the appropriate clinical scenarios. The diagnosis of S. stercoralis can be made more accessible to practitioners through the use of methods such as the modified Baermann technique, agar-plate culture, and serologic antibody testing.

      Key Words

      Case report

      A 70-year-old male immigrant of a rural forested area of Ecuador presented with a 3-month history of dyspnea, cough, fever, malaise, anorexia, and a 70-pound weight loss. Before his presentation to our institution, he was admitted for 6 weeks to another hospital for the same complaints. During this first hospitalization, he was found to have hilar lymphadenopathy of unknown etiology, nodules of the fingers, and acute and subacute cortical strokes—all thought to be related to a case of lymphoma or lupus. Approximately 2 weeks into the hospitalization, he was initiated on 60 mg methylprednisolone once daily intravenously, given concern for both rheumatologic and oncologic processes. He underwent biopsy of his hilar nodes, serum testing for rehumatologic markers, and nasal COVID-19 PCR testing (supplementary material). All results returned unremarkable, yet suspicion remained high for a rheumatologic or malignant process. During this first hospitalization, the patient also developed profuse diarrhea, ileus, and colitis 5 days into his hospital stay. He tested negative for Trypanosoma cruzi IgG and positive for C. difficile by stool PCR. He was immediately initiated on oral vancomycin with improvement in his symptoms. He was weaned to 40 mg of oral prednisone once daily by the time of discharge from the hospital and referred to a rehabilitation facility with the instruction that it be tapered in the outpatient setting by his rheumatologist, which was never completed.
      He presented to our hospital after an 11-week rehabilitation with altered mental status and poor oral intake. A few days prior, he had been diagnosed with a urinary tract infection by an extended-spectrum beta-lactamase Escherichia coli. In our emergency department, his vital signs revealed a blood pressure of 79/42 mmHg, heart rate of 120 beats per minute, and pulse oximetry saturation of 100% on 10 liters of nasal cannula. Significant laboratory and imaging findings from this point in time are detailed in the supplementary material. Despite adequate fluid resuscitation and broad-spectrum antibiotics, the patient remained hypotensive and was thus transferred to the intensive care unit. The patient was initiated on intravenous hydrocortisone given a suspected adrenal insufficiency–related shock. His mental status improved with the above measures and so a lumbar puncture was deferred.
      A stool test returned positive for C. difficile by PCR (approximately 3 months after his last infection), and therefore, he was initiated on oral vancomycin and intravenous metronidazole. He later developed melanic stool and his hemoglobin levels dropped to 6.3 g/dL. A diagnostic upper endoscopy was thus conducted—significant for a large friable stomach ulcer and duodenal bulb biopsy specimen with adult females of S. stercoralis noted in the mucosa (Figure. 1, Row 1). Stool ova and parasite testing by sedimentation technique was unremarkable after 7 days. HIV and Human T-lymphotropic virus tests returned negative, and a new rheumatologic workup showed a persistently low C3 level of 31 mg/dL (normal 90–180) and C4 level of 16 mg/dL (normal 15–45). All other laboratory testing at that time was unremarkable. Blood cultures returned positive for E. coli 10 days into admission after having been serially negative since presentation. The patient was thus initiated on meropenem after which multiple serial blood cultures, drawn once daily, returned negative. Oral ivermectin was continued for a total of 14 days and hydrocortisone was weaned successfully. Unfortunately, the patient later developed increasing vasopressor requirements to maintain adequate mean arterial pressures and he declined in his respiratory status. A tracheal lavage specimen was provided to the cytopathology laboratory significant for Strongyloides species (Figure. 1, Row 2). In addition, serologic studies returned positive at this time for Strongyloides IgG antibody (Ab) of 1.6 (normal = <1; ARUP Laboratories). Despite all efforts, and after 5 days of intensive intervention, the patient died. With evidence of Strongyloides larvae on tracheal lavage, a hyperinfection syndrome and E. coli sepsis were thought to be the causes of the patient's demise.
      Figure 1
      Figure 1Examinations by pathology of duodenal and tracheal specimens Row 1: Histologic sections (hematoxylin and eosin [H&E] stain) showing longitudinal and cross-sectioned adult and egg forms within the intestinal mucosa (a-c) and submucosa (a) of the duodenal biopsy. The background mucosa shows active inflammation with surface erosion, inflammatory expansion of the lamina propria, and reactive epithelial changes. A longitudinal section of an adult female nematode form details the intestine and ovaries in a high-power view (c). Original magnifications: x10 (A), x20 (B), x40 (C). Row 2: A ThinPrep preparation of a sputum sample showing Strongyloides larvae (a and b, Papanicolaou stain). Septate fungal hyphae with 45-degree acute angle branching consistent with aspergillosis are also focally present (c). Original magnifications: x40 (A-C).*
      *1cc of sputum was submitted to the cytology laboratory. The specimen was processed using a liquid-based concentration technique to make the ThinPrep slide. An aliquot of specimen was also fixed in formalin and subsequently embedded in paraffin to block the cell. The Strongyloides worm was only observed on the ThinPrep slide, whereas Aspergillus hyphae was observed on both the ThinPrep slide and section from the cell block.
      Aspergillus is not a common diagnosis in our institution's cytology laboratory, and the current case was the only one that has shown fungal hyphae that are morphologically most compatible with Aspergillus in the case year. ThinPrep slides are made in our laboratory using the ThinPrep processor 5000 with most steps conducted automatically, further eliminating the chance of contamination. Thus, the possibility that the detection of Aspergillus in the sputum was contaminated can be largely excluded.
      Isolation of Aspergillus species in respiratory specimen from immunocompromised hosts often suggests an invasive infection. The organisms can also colonize immunocompetent patients without producing clinical symptoms. Airway colonization by Aspergillus species is a common feature in patients with several chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pneumothorax, interstitial pneumonia, and pneumoconiosis.
      S. stercoralis is one of the smallest parasites known to infect humans. The infectious stage of Strongyloides is a filariform larvae, which can penetrate the intact skin of a host and migrate by various pathways to the small intestine where they molt twice and become adult female worms. It is the female worms that are embedded in the submucosa of the small intestine and produce eggs. Parasitic males do not exist. Therefore, only larvae or female adults can be detected on a biopsied tissue specimen.
      In the current case, tissue specimen from a small bowel biopsy was formalin-fixed and paraffin-embedded following a standard tissue processing protocol. The parasitic worms present on H&E-stained tissue sections showed morphologic features that are most compatible with Strongyloides species. Diagnosis is made by the presence of adult females or eggs on small intestinal mucosa. In female worms, the intestine or ovaries may be prominent (C). In gravid females, an egg may be identified within the uterus. There is often granulomatous or eosinophilic inflammation in the background.

      Discussion

      Herein, we present a case of a Strongyloides hyperinfection syndrome of an immigrant complicated by gastrointestinal bleeding, gram-negative bacteremia, and respiratory failure. The use of corticosteroids is well known to be associated with hyperinfection syndrome by this nematode with a mortality rate in disseminated disease of more than 80% (
      • Marcos LA
      • Terashima A
      • Canales M
      • Gotuzzo E.
      Update on strongyloidiasis in the immunocompromised host.
      ). Notably, gastrointestinal bleeding in S. stercoralis infection has been reported (
      • Costa Silva R
      • Carvalho JR
      • Crespo R
      • Martins JR
      • Zózimo N
      • Tato Marinho R
      Strongyloides stercoralis Gastric Ulcer: A Rare Cause of Upper Gastrointestinal Bleeding.
      ). The coexistent diagnosis of C. difficile colitis may have delayed the inclusion of S. stercoralis infection on the initial differential diagnosis of his diarrhea, especially given the absence of eosinophilia during his previous hospitalization. The range of his total eosinophil counts during both described hospitalizations was less than 500 cells/µL (0.12–0.15 K/µL), which was likely due to chronic steroid use. Nonetheless, a lack of eosinophilia is not an uncommon finding among immunocompromised hosts (
      • Ericsson Charles D.
      • Steffen Robert
      • Siddiqui Afzal A.
      • Berk Steven L.
      Diagnosis of Strongyloides stercoralis Infection.
      ;
      • Costa Silva R
      • Carvalho JR
      • Crespo R
      • Martins JR
      • Zózimo N
      • Tato Marinho R
      Strongyloides stercoralis Gastric Ulcer: A Rare Cause of Upper Gastrointestinal Bleeding.
      ).
      Proper awareness of S. stercoralis infection as a lifetime parasitic infection in humans from endemic areas is a necessity. In addition, prolonged use of corticosteroids should be a consideration to screen for S. stercoralis in high-risk populations. Serologic testing for S. stercoralis may identify chronic carriers of this species given that most stool examination testing performed in commercial laboratories are poorly sensitive in detecting the larvae of S. stercoralis. Current gastrointestinal rapid diagnostic panels in stools include protozoa but not S. stercoralis. In fact, there is no current antigen-based stool test for S. stercoralis available in the United States. Duodenal biopsy and the detection of larvae is by far the most sensitive diagnostic procedure for S. stercoralis, however, most physicians choose to forego it in suspected cases (
      • Ganesh S
      • Cruz Jr., RJ
      Strongyloidiasis: a multifaceted disease.
      ;
      • Nutman TB.
      Human infection with Strongyloides stercoralis and other related Strongyloides species.
      ). A single stool examination for ova and parasites has been shown to fail in detecting larvae in as much as 70% of cases, however, it can approach 100% with up to 7 repeated examinations (
      • Salvador F
      • Sulleiro E
      • Sánchez-Montalvá A
      • et al.
      Usefulness of Strongyloides stercoralis serology in the management of patients with eosinophilia.
      ). One solution to the modern-day problem surrounding the diagnosis of S. stercoralis in the areas of diagnostic sensitivity, cost, and accessibility, is the modified Baermann technique. However, this test may be difficult to implement in commercial laboratories due to its multistep methodology and expertise required by technicians (
      • Gelaye W
      • Williams NA
      • Kepha S
      • Junior AM
      • Fleitas PE
      • Marti-Soler H
      • et al.
      Stopping Transmission of Intestinal Parasites (STOP) project consortium. Performance evaluation of Baermann techniques: The quest for developing a microscopy reference standard for the diagnosis of Strongyloides stercoralis.
      ). Therefore, the agar-plate culture, with an impressive sensitivity of 96%, may be a more suitable choice (
      • Ericsson Charles D.
      • Steffen Robert
      • Siddiqui Afzal A.
      • Berk Steven L.
      Diagnosis of Strongyloides stercoralis Infection.
      ).
      In our patient, positive Strongyloides IgG Ab was noted in the serum, however, it was discovered too late in the clinical course to affect treatment outcomes. In comparison to stool analysis, obtaining serologic samples is less time-consuming and does not require fresh stool, which can be difficult to obtain in certain clinical settings. Furthermore, the enzyme-linked immunosorbent assay (ELISA) test is both highly sensitive and specific with reported values as high as 94.6% and 97%, respectively. The sensitivity of serology may significantly decrease in immunocompromised patients owing to reduced antibody production or the presence of other helminth infections (
      • Krolewiecki A
      • Nutman TB.
      Strongyloidiasis: A Neglected Tropical Disease.
      ;
      • Repetto SA
      • Durán PA
      • Lasala MB
      • González-Cappa SM.
      High rate of strongyloidosis infection, out of endemic area, in patients with eosinophilia and without risk of exogenous reinfections.
      ;
      • Salvador F
      • Sulleiro E
      • Sánchez-Montalvá A
      • et al.
      Usefulness of Strongyloides stercoralis serology in the management of patients with eosinophilia.
      ). In the United States, where Strongyloides species are not endemic, serologic antibody testing can be a challenge due to the constant supply of larvae required to obtain antigen for preparation in future ELISA testing (
      • Ericsson Charles D.
      • Steffen Robert
      • Siddiqui Afzal A.
      • Berk Steven L.
      Diagnosis of Strongyloides stercoralis Infection.
      ). Nonetheless, the ease in obtaining this serologic specimen for sampling, as well as its impressive accuracy, make it an ideal and practical test for any clinician attempting to rule out this diagnosis.
      In conclusion, this fatal case of S. stercoralis hyperinfection highlights the need for appropriate screening for this parasite in patients originating from endemic areas and in those requiring the use of chronic steroids. Preventive treatment with administration of ivermectin in high-risk populations (patients from endemic areas with iatrogenic immunosuppression) merits discussion and should be further studied.

      Conflict of interest statement

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Funding source statement

      This case report and the writing of this manuscript was not attached to any funding support.

      Ethical approval statement

      Ethical review and approval were not required for this case report.

      Appendix. Supplementary materials

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