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Strongyloides hyperinfection syndrome complications: a case report and review of the literature.

Introduction

Strongyloides stercoralis is a soil transmitted nematode, endemic in tropical and subtropical areas. Due to increasing immigration from countries endemic with strongyloides, physicians in developed countries may also encounter this condition. Infection usually results in asymptomatic chronic disease of the gut, which can go undetected for decades. Eosinophilia and larvae in stools are often the only indicatiors of infection. The disease is classified as 'acute', 'chronic' and 'severe' strongyloidiasis and commonly manifests with cutaneous, pulmonary and intestinal features. Common clinical features of acute strongyloidiasis include maculopapular rash involving the feet, epigastric discomfort, diarrhea, occasional nausea and vomiting. Other manifestations include cough, dyspnea, wheezing, low grade fever or constipation.

Strongyloides stercoralis is also capable of causing autoinfection in the host. Strongyloides Hyperinfection (SH) is a life threatening complication of chronic strongyloidiases and usually occurs in the setting of immunocompromised state (patients with malignancy, organ transplantation or concurrent human T-cell-lymphocytic virus 1 infection or those on corticosteroid therapy). Mortality is largely due to gram negative bacteremia leading to adult respiratory distress syndrome and rarely, meningitis. We present a unique case of a patient with SH complicated by simultaneous occurrence of vancomycin resistant enteroccus bacteremia and vancomycin susceptible enterococcus bacteremia and meningitis.

Case Report

A 68-year-old diabetic female with chronic lymphocytic leukemia was transferred from an outside facility with severe respiratory distress. She was admitted to the outside hospital three days prior to transfer, with complaints of fever, shortness of breath, cough with yellow sputum, wheezing, and generalized weakness. She had been on intermittent corticosteroids and multiple courses of antibiotics for the past six months for suspected COPD exacerbations. Her recent antibiotics included cephalosporins, fluoroquinolones and macrolides. Her initial white cell count was 38.0 (thou/ul) and hemglobin was 7.7 g/dl for which she received 2 units of packed red blood cells. Her chest x-ray showed bilateral infiltrates.

On presentation to our facility, her temperature was 38.4 C, pulse was 111 beats per minute, respirations were 22/min, blood pressure was 100/60 mmHg. The oxygen saturation was 88% on 2 liters nasal cannula. On physical examination, the patient appeared tired and in mild distress. She had a diffuse maculopapular rash. Heart rhythm was irregularly irregular. Lungs had bilateral crackles and wheezes. The remainder of the physical examination including head and neck, abdominal, musculoskeletal and neurologic examination was normal.

The initial work up at our institution showed a WBC count of 57.7 (thou/ul) with neutrophils 33%, lymphocytes 64% (Table 1). The ABG results showed pH 7.45, PCO2 78, PO2 50, Bicarbonate 45, Pa[O.sub.2]/Fi[O.sub.2] ratio of 114. Chest X-ray revealed increased interstitial opacities and mild bronchial wall thickening with suggestion of bronchiectasis (Figure 1). CT head showed no acute intracranial process. CT chest demonstrated bilateral areas of ground-glass opacity with reticular and nodular thickening. Interlobular septal thickening with areas of geographic sparing and traction bronchiectasis were also noted (Figure 2). A transthoracic echo showed left ventricular ejection fraction in the range of 65 % to 70 %. Features were consistent with mild diastolic dysfunction. There was very mild aortic valve stenosis with a mean gradient of 11mm Hg. Estimated peak right ventricular systolic pressure was in the range of 45 mmHg to 50 mmHg.

Due to progressive respiratory failure, the patient was intubated and transferred to our medical intensive care unit. She was started on broad spectrum antibiotics including vancomycin, ciprofloxacin, tobramycin and caspofungin. Bronchoscopy was performed the next day and bronchoalveolar lavage showed a worm which was later identified as Strongyloides stercoralis (Figure 3). The patient continued to remain unresponsive and a spinal tap was performed, that showed a pyogenic CSF picture and grew Vancomycin Sensitive Enterococci.

Her blood culture drawn on the day of admission grew Vancomycin Resistant Enterococci and a few days later, she grew a strain of Vancomycin Sensitive Enterococci in her CSF. She was treated with Albendazole and Ivermectin for SH for two weeks, Linezolid for vancomycin resistant Enterococcus (VRE) bacteremia and vancomycin for vancomycin Sensitive Enterococcus (VSE) meningitis. She was also started on IVIG due to low levels of immunoglobulins.

A few days after she had completed a two week course of antiparasitic drugs, she developed peripheral blood eosinophilia but without any redemonstration of Strongyloides in respiratory secretions. However, she was still treated with one more week of Ivermectin, after which the eosinophilia resolved.

The patient started to show a clinical response and was neurologically stable with clearing of CSF (Table 2). However, she decompensated again due to respiratory failure. She was found to have reoccurence of VSE bacteremia (Table 3) and CSF analysis showed a pyogenic process that again grew VSE.

A tracheostomy was performed for her long term ventilation. A repeat bronchioalveolar lavage showed Pseudomonas infection and therefore, she was started on Imipenem. After 2 weeks of treatment with Vancomycin, her CSF continued to show pleocytosis and culture persistently grew the same enterococcus species. Because of significant neurological dysfunction, underlying hematological malignancy, poor nutritional state and persistently positive CSF cultures, we discussed the patient's grim prognosis with the family and it was decided to withdraw life support after six weeks of hospitalization.

Discussion

Strongyloides stercoralis is a soil transmitted intestinal nematode that is endemic in many tropical and subtropical areas of the world. (1) However, a large surveillance report from a US Cancer Center showed Strongyloides infection of 0.8/10000 cases. (2) The prevalence has risen due to increased immigration to North America particularly in areas considered non-endemic in the past. (3) In United States, this infection is prevalent in Appalachia, mainly rural Tennessee and Eastern Kentucky with a prevalence of 3% and 4% respectively. (4) This parasite remains quiescent in the human intestine for as long as 30 years (5) and becomes apparent in the setting of immune dysfunction.

Strongyloides stercoralis has the ability to reproduce itself in humans. A filariform larva is transmitted from the soil and penetrates into the skin. After exposure, it can migrate to the respiratory system via bloodstream. The parasite is, then, swallowed and penetrates the duodenal wall where rhabditiform larvae hatch from the eggs to be expelled in feces; and restart the asexual cycle in soil. Rhabditiform larvae mature and penetrate the skin in perianal area, leading eventually to autoinfection. (6)

In immunocompromised patients, however, the larvae change rapidly into infectious, filariform larvae and reinvade the gut, resulting in a cycle of autoinfection. During passage of this large burden of parasites through the gut wall, bacteria may be carried along, occasionally resulting in polymicrobial bacteremia.

The term hyperinfection is used to denote Strongyloides autoinfection with a multi-log increase in parasite burden. Worms are detectable in extra intestinal sites, especially the lungs. (7) Patients with impaired cell mediated immunity such as those on long-term corticosteroids, HIV and HTLV infected patients and those with hematological malignancies are at particular risk. (8) Corticosteroids are the most widely used immunosuppressants and are specifically associated with transformation of chronic strongyloidiasis to hyperinfection. (9) The diagnosis becomes even more challenging since many of these patients present with symptoms mimicking COPD. (10) Strongyloidiasis is difficult to diagnose because the parasite load is low and the larval output is irregular. Review of literature showed that WBC count is usually within the reference range in acute and chronic strongyloidiasis and elevated in severe strongyloidiasis. During acute infection eosinophilia is common, intermittent during chronic infection, and frequently absent in severe strongyloidiasis. Microscopically identifying S. stercoralis larvae in stool is a definitive diagnostic test. However, results of a single stool examination by use of conventional techniques fail to detect larvae in up to 70% of the cases due to fluctuating larval exretion and, therefore, consecutive stool examinations have been recommended to increase the yield. (9) Blood cultures in strongyloidiasis often yield growth of enteric pathogens, most commonly Escherichia coli and/or Klebsiella species. Strongyloides serology (enzyme immunoassay, indirect fluorescent antibody) has 88-95% sensitivity. Sensitivity may be lower in severely immunocompromised patients. This test however, cannot differentiate between past and present infection. (8)

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Strongyloides stercoralis is a unique parasite that can cause fatal disease years after the exposure, often in the setting of SH, with mortality as high as 87%. (6) Lam et al. carried out a retrospective study and evaluated the characteristic features of seven patients. All the patients left the endemic area more than 20 years ago. (11) Mortality is mainly due to gram negative, often polymicrobial bacteremia and meningitis because of leakage of gut flora from the ulcerated bowel mucosa or bacteria carried on the surface of the larvae as they migrate to extra intestinal sites. A review published in 1999 identified 38 case reports of bacterial sepsis complicating strongyloidiasis, 68% of those patients had bacteremia out of which 12% were polymicrobial. (12)

Gram negative bacterial meningitis has been reported in Strongyloides hyperinfection especially in association with immunosuppression. (13) Our patient had active chronic lymphocytic leukemia with hypogammaglobulinemia and was on intermittent steroids for six months, which explains her predisposition to SH. In addition, she received multiple courses of antibiotics to treat COPD exacerbation including cephalosporins, flouroquinolones and macrolides, which predisposed her to VRE bacteremia. Vancomycin resistance is found to be an independent predictor of mortality in severe enterococcal bacteremia. (14) Furthermore, patients infected with Enterococcal faecium have a worse prognosis than those with E. faecalis. (15) Our case is unique for its rarity. Although association of Enterococcus faecium meningitis with SH has been reported, (16) to our knowledge there are no reported cases of concomitant VSE and VRE bacteremia in a patient with SH in literature.

A concern arising from this discussion may relate to the use of Linezolid, a static drug, for VRE bacteremia in this time and era of Daptomycin availability. A recent retrospective study was published in Journal of antimicrobial chemotherapy, which showed that Linezolid was as effective as Daptomycin in the treatment of VRE bacteremia. (17) However, it has been found that appropriate therapy against VRE bacteremia results in no improvement in long term survival in patients with this infection since these patients are extremely sick at onset of bacteremia. (18)

We report a rare case of SH in order to highlight the clinical suspicion and awareness needed by clinicians, to detect and treat this potentially fatal condition in a timely manner.

Conclusion

Patients with underlying risk factors should be suspected of having strongyloidiasis as the outcome can be fatal. Immunosuppressed patients who experience any unusual gastrointestinal or pulmonary symptoms or suffer from unexplained Gram-negative sepsis should be suspected of having strongyloidiasis. Early identification by enzyme-linked immunosorbent assay serology, stool testing or duodenal aspiration may prevent the fatal complications of SH. Early treatment of strongyloidiasis in these patients would improve morbidity and mortality.

References

(1.) Boulware DR, Stauffer WM, Hendel-Paterson BR, Rocha JL, Seet RC, Summer AP, Nield LS, Supparatpinyo K, Chaiwarith R, Walker PF. Maltreatment of Strongyloides infection: case series and worldwide physicians-in-training survey. Am J Med. 2007 Jun;120(6):545.e1-8.

(2.) Safdar A, Malathum K, Rodriguez SJ, Husni R, Rolston KV. Strongyloidiasis in patients at a comprehensive cancer center in the United States. Cancer. 2004 Apr 1;100(7):1531-6.

(3.) Lim S, Katz K, Krajden S, Fuksa M, Keystone JS, Kain KC. Complicated and fatal Strongyloides infection in Canadians: risk factors, diagnosis and management. CMAJ. 2004 Aug 31; 171(5):479-84.

(4.) Concha R, Harrington W Jr, Rogers AI. Intestinal strongyloidiasis: recognition, management, and determinants of outcome. J Clin Gastroenterol. 2005 Mar; 39(3):203-11.

(5.) DeVault GA Jr, King JW, Rohr MS, Landreneau MD, Brown ST 3rd, McDonald JC. Opportunistic infections with Strongyloides stercoralis in renal transplantation. Rev Infect Dis. 1990 Jul-Aug; 12(4):653-71.

(6.) Kazuto K, Akira H, Tetsuo H, Yasushi I, Manabu N, Nagisa K, Fukunori K, Jiro F. Endoscopic and histopathological study on the duodenum of Strongyloides stercoralis hyperinfection. World J Gastroenterol. 2008;14(11):1768-1773.)

(7.) Siddiqui AAA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis. 2001 Oct 1;33(7):1040-7. Epub 2001 Sep 5.

(8.) Keiser PB, Nutman TB. Strongyloides stercoralis in the Immunocompromised Population. Clin Microbiol Rev. 2004 Jan; 17(1):208-17.

(9.) Asdamongkol N, Pornsuriyasak P, Sungkanuparph S. Risk factors for strongyloidiasis hyperinfection and clinical outcomes. Southeast Asian J Trop Med Public Health. 2006 Sep; 37(5):875-84.

(10.) Liu HC, Hsu JY, Chang KM. Strongyloides stercoralis hyperinfection presenting with symptoms mimicking acute exacerbation of chronic obstructive pulmonary disease. J Chin Med Assoc. 2009 Aug; 72(8):442-5.

(11.) Lam CS, Tong MK, Chan KM, Siu YP. Disseminated strongyloidiasis: a retrospective study of clinical course and outcome. Eur J Clin Microbiol Infect Dis. 2006;25(1):14-8. doi: 10.1007/s10096-005-0070-2.

(12.) Link K, Orenstein R. Bacterial complications of strongyloidiasis: Streptococcus bovis meningitis. South Med J. 1999 Jul; 92(7):728-31.

(13.) Newberry AM, Williams DN, Stauffer WM, Boulware DR, Hendel-Paterson BR, Walker PF. Strongyloides hyperinfection presenting as acute respiratory failure and gram-negative sepsis. Chest. 2005 Nov;128(5):3681-4.

(14.) DiazGranados CA, Zimmer SM, Klein M, Jernigan JA. Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis. Clin Infect Dis. 2005 Aug 1;41(3):327-33. Epub 2005 Jun 28.

(15.) Chou YY, Lin TY, Lin JC, Wang NC, Peng MY, Chang FY. Vancomycin-resistant enterococcal bacteremia: comparison of clinical features and outcome between Enterococcus faecium and Enterococcus faecalis. J Microbiol Immunol Infect. 2008 Apr;41(2):124-9.

(16.) Zeana C, Kubin CJ, Della-Latta P, Hammer SM. Vancomycin-resistant Enterococcus faecium meningitis successfully managed with linezolid: case report and review of the literature. Clin Infect Dis. 2001 Aug 15;33(4):477-82. Epub 2001 Jul 11.

(17.) Mave V, Garcia-Diaz J, Islam T, Hasbun R Vancomycin-resistant enterococcal bacteraemia: is daptomycin as effective as linezolid. J Antimicrob Chemother. 2009 Jul;64(1):175-80. Epub 2009 May 7.

(18.) Han SH, Chin BS, Lee HS, Jeong SJ, Choi HK, Kim CO, Yong D, Choi JY, Song YG, Lee K, Kim JM Vancomycin-resistant enterococci bacteremia: risk factors for mortality and influence of antimicrobial therapy on clinical outcome. J Infect. 2009 Mar;58(3):182-90. Epub 2009 Feb 23.

Asif Najmuddin, MD

PGY II, Internal Medicine, WVU Hospitals, Morgantown

Sarah Hadique, MD

Fellow, Pulmonary and Critical Care Medicine, WVU Hospitals, Morgantown

John Parker, MD

Professor and Section Chief, Pulmonary and Critical Care Medicine, WVU Hospitals, Morgantown
Table 1: Laboratory data on admission

Variable                            Value (Reference values)

White blood cell count (thou/ul)    57.7 (3.5-11.0 THOU/UL)
Hemoblobin (g/dl)                   10.0 (11.2-15.2 g/dL)
Hematocrit (%)                      31.4 (33.5-45.2 %)
Platelets (thou/ul)                 180 (140-450 THO/UL)
  Neutrophils (%)                   33 (40-75 %)
  Lymphocytes (%)                   64 (20-45 %)
  Eosinophils (%)                   0 (1-6 %)
  Metamyelocytes (%)                1 (0)
  Monocytes (%)                     2 (4-13 %)
  Basophils (%)                     0 (0-1%)
PT (sec)                            20.5 (9.1-11.2 Sec)
INR                                 2.2 (0.8-1.2)
PTT (sec)                           23.2 (22.5-32.0 Sec)
Sodium (mmol/l)                     132 (136-145 mmol/L)
Potassium (mmol/l)                  3.9 (3.5-5.1 mmol/L)
Chloride (mmol/l)                   74 (96-111 mmol/L)
Bicarbonate (mmol/l)                44 (22-32 mmol/L)
Urea nitrogen (mg/dl)               22 (6-20 mg/dL)
Creatinine (mg/dl)                  0.86 (0.49-1.10 mg/dL)
AST (U/liter)                       33 (5-30 U/L)
ALT (U/liter)                       74 (6-35 U/L)
Amylase (u/l)                       122 (<128 U/L)
Lipase (u/l)                        17 (6-51 U/L)
CK (u/l)                            10 (24-170 U/L)
Troponin (ng/ml)                    .048 (<0.050 ng/mL)
Digoxin (ng/ml)                     0.9 (0.8-2.0 ng/mL)
Lactic acid (mmol/l)                2.8 (0.5-2.2 mmol/L)
IgA (mg/dl)                         26 (69-309 mg/dL)
IgG (mg/dl)                         185 (613-1295 mg/dL)
IgM (mg/dl)                         9 (53-334 mg/dL)
Cortisol (ug/dl) 7:55 AM            8.1 {7.0-25.0 ug/dL (AM Sample)
Uric acid (mg/dl)                   6.6 (2.5-6.6 mg/dL)
BNP (pg/ml)                         421 (<100 pg/mL)
Albumin (g/dl)                      3.5 (3.2-4.4 g/dL)
Calcium (mg/dl)                     8.9 (8.5-10.4 mg/dL)
Magnesium (mg/dl)                   1.9 (1.7-2.5 mg/dL)
Phosphorus (mg/dl)                  3.1 (2.4-4.7 mg/dL)
Triglyceride (mg/dl)                177 (<150 mg/dL)
TSH cascade (uIU/ml)                0.6 (0.300-5.900 uIU/mL)

Table 2: Summary of CSF Analysis

       WBC    Neutrophils   Lymphocytes
Day   count       (%)           (%)       Protein   Glucose

4     1950         9             4          143       13

6      214        74            13          79        37

11     12          0            70          38        75

27     385        41            32          84        55

34     26          6            87          108       45

38    3750        77            14          97        16

42     25          9            68          98        73

Day   Culture                 Event in History

4     Vancomycin              Initiation of
      Susceptible             Vancomycin
      Enterococcus Faecium
      Group D

6     Vancomycin              Response to
      Susceptible             Vancomycin
      Enterococcus Faecium
      Group D

11    Culture Negative        Documented
                              Clearance of
                              Organism

27    Vancomycin              Recurrence of
      Susceptible             Enterococcus
      Enterococcus Faecium    -Vancomycin
      Group D                 Restarted

34    Negative                Documented
                              Clearance of
                              Organism

38    Vancomycin              Recurrence of
      Susceptible             Enterococcus
      Enterococcus Faecium
      Group D

42    Gram positive cocci     Failure to clear the
      in pairs-no growth on   organism
      culture

Table 3: Summary of Blood Cultures

Day   Blood culture result

1     Vancomycin resistence Enterococcus Faecium Group D
3     No growth
5     No growth
7     Vancomycin Susceptible Enterococcus Faecium Group D
10    No growth
21    No growth
27    No growth
35    No growth
40    No growth
42    No growth
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Title Annotation:Scientific Article
Author:Najmuddin, Asif; Hadique, Sarah; Parker, John
Publication:West Virginia Medical Journal
Article Type:Clinical report
Geographic Code:1USA
Date:Jan 1, 2012
Words:2880
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