# Fatal Outcome of Disseminated Strongyloidiasis despite Detectable Plasma and Cerebrospinal Levels of Orally Administered Ivermectin

Authors: Charles E. Rose; Christopher A. Paciullo; David R. Kelly; Mark J. Dougherty; Lawrence L. Fleckenstein
Journal: Journal of Parasitology Research
 (2009)

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## Abstract

Strongyloides stercoralis affects over 100 million people worldwide. Those people most susceptible to infection are those with an immunocompromising condition, such as cancer or human immunodeficiency virus (HIV). Local disease may spread throughout the body of the host, causing a condition termed disseminated strongyloidiasis. Standard treatment for Strongyloides stercoralis infection is oral ivermectin. We describe a patient with chronic lymphocytic leukemia diagnosed with disseminated strongyloidiasis two weeks after initial presentation. After repeated dosing of oral ivermectin with no clinical response, serum and cerebral spinal fluid (CSF) concentrations of ivermectin were measured to assess absorption.  The peak serum concentration of 49.3 ng/mL correlated with a CSF concentration of 0.14 ng/mL. Despite these concentrations, the patient eventually succumbed to multi-system organ failure. We discuss the reasons for treatment failure and explore the utility of measuring ivermectin concentrations.


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## Body

## 1. Case Report

A 59-year-old
female receiving alemtuzumab for chronic lymphocytic leukemia was admitted to a
local hospital near her home in eastern Kentucky in October 2007 for altered
mental status of two weeks duration. Admission laboratory values included a white blood count of 5 900/mm3,
hemoglobin of 10.4 g/dL, platelets of 120 000/mm3, but absence of
eosinophilia. There was evidence of
hypoalbuminemia with serum albumin of 2.4 g/dL. Chest roentgenogram revealed right upper lobe infiltrate, and
computerized tomography of the head showed only maxillary and ethmoid
sinusitis. However, bloody cerebrospinal
fluid (CSF) was found with a nontraumatic lumbar puncture (LP) with 200 000
red cells/mm3, 172 white cells/mm3, and protein of 750 mg/dL. CSF studies including Herpes simplex virus (HSV) polymerase chain reaction (PCR), cryptococcal
neoformans antigen, and bacterial culture were negative. Despite broad-spectrum antibiotics, the
patient encephalopathy and pulmonary infiltrates did not improve, and she was
transferred to a tertiary hospital in Lexington, KY, USA.Neurologic findings at the time of transfer included a Glasgow coma score of five, with no localization to pain. Sputum analysis on
admission revealed 1  + white blood cells, gram-positive cocci, budding yeast ,andStrongyloides stercoralis was
identified in the filariform stage by Gram's stain. Oral ivermectin was started at 15 grams as a single daily dose (~147 mcg/kg) via nasogastric tube [15, 16]. The following day, the ivermectin dose was
increased to 30 grams per day (293 mcg/kg) for three weeks to account for the
patient large body habitus (102 kg) and questionable ileus [15].Cerebral angiography did not demonstrate aneurysm or vasospasm. LPs 6 days apart revealed 9 00 and 6688 red
cells/mm3, respectively, and xanthochromic CSF from the second
LP. Protein and white cell numbers were normal both times.CSF studies, performed as described elsewhere, forCytomegalovirus (CMV) PCR, HSV PCR, Epstein-Barr virus (EBV), JC virus (JCV) PCR,
cryptococcal antigen, fungal culture, acid-fast stain and culture, and VDRL were
all negative [17]. Stool specimens
demonstrated rhabditiform larvae, eggs, and adult S. stercoralis,
with filariform larvae in the sputum for one week
after initiation of ivermectin. The Stronglyoides antibody was
0.13 IV (index value) which was negative by laboratory reference values (<1.49
considered negative). Lack of neurologic
improvement and persistence of S.
stercoralis from the sputum led to concern for malabsorption of oral
ivermectin. Discussion with the Food and
Drug Administration (FDA) for permission to use parenteral veterinary
ivermectin led to the measurement of plasma and CSF ivermectin concentrations
in collaboration with the University of Iowa by high-performance liquid
chromatography [18]. The ivermectin
plasma and CSF concentrations were 49.3 ng/mL and 0.14 ng/mL, respectively, on
day 10 of oral ivermectin therapy. Repeat microscopy of sputum after three weeks of therapy did not reveal
organisms. Despite 22 days of oral
therapy, the patient showed no sign of neurologic recovery. After discussion and permission from the
surrogate decision maker, respiratory support was withdrawn and the patient
expired. The family refused autopsy.


## 2. Discussion

This report describes an immunocompromised patient with disseminatedStrongyloides presenting to a community
hospital with two weeks of altered mental status. On transfer to a tertiary
hospital, repeat LP confirmed evidence of hemorrhagic CSF with persistent
elevation in CSF red blood cells and xanthrochromia. S. stercoralis organisms were observed
on sputum Gram stain, which was subsequently confirmed in stool and additional
sputum samples. Despite immediate
institution of ivermectin after transfer to the tertiary care center, the
patient did not improve neurologically and expired after being transitioned to
comfort care.The patient may have died
from subarachnoid hemorrhage and advanced encephalitis secondary to
disseminated strongyloidiasis. A
previous report ofS. stercoralis showed an erythrocytic CSF
predominance [14]. The hemorrhagic CSF and
xanthochromia were likely secondary to capillary rupture or local inflammation
from the host immune response. Previous  neuropathology has demonstrated the
presence of the Strongyloides larvae within capillaries,
meninges, and brain tissue in a case of disseminated strongyloidiasis
after administration of corticosteroids [19].As in this patient, amajor
difficulty in disseminated strongyloidiasis is overcoming the delay in
diagnosis both because of delayed presentation for medical evaluation and the
vague symptoms that accompany disseminated disease. However, pulmonary and
gastrointestinal abnormalities with an infiltrate and ileus in an
immunocompromised host should
warrant consideration of the diagnosis [20]. Eosinophilia may be mild and nonspecific and because of low parasite
load and irregular larval output. Microscopy of a single stool specimen not surprisingly fails to detect
larvae up to 70% of the time [5].
Strongyloides antibody may show
cross-reactivity with other helminth infections including filariasis, Ascaris lumbricoides, and acute
schistosomiasis [21, 22]. While serology
has a negative predictive value of 95%, our patient had a negative antibody
test for Strongyloides despite
microscopic evidence of pulmonary and gastrointestinal diseases [23]. It is possible that false-negative serology
in our patient was related to immunosuppression from either her hematologic
malignancy or chemotherapy.While delay in
diagnosis may have contributed to the poor
outcome, inadequate central nervous system penetration of ivermectin or
ivermectin neurotoxicity may have played a role. Bowel obstruction and ileus are
commonly described in hyperinfection syndrome, and intestinal inflammation, and
bowel edema from penetration ofStrongyloides may
impair absorption. In this situation the
absorption of oral medications is unclear, and determination of ivermectin
concentrations appears useful to assess adequacy of oral treatment.
Hypoalbuminemia may also affect the
pharmacokinetics and distribution of ivermectin. Ivermectin is highly bound to
serum albumin, and lower levels of albumin can increase clearance of unbound drug
as well as additional effects of contribution to tissue edema which can slow
absorption and increase the volume of distribution [14]. Increased clearance or volume of distribution may interfere with
achievement of effective levels in the central nervous system.We were able to
achieve a relatively high ivermectin plasma level in our patient, with a daily
dose of 293μg/kg. The plasma
concentrations in our patient were similar to those observed in healthy
volunteers following multiple oral doses of 60 mg given on days 1, 4, and 7 [24]. Because the concentrations were similar to those observed in healthy
volunteers after multiple oral doses, we concluded that there was adequate intestinal
absorption and we did not further pursue use of parenteral ivermectin [24].Despite the higher
oral ivermectin dose and achievement of plasma concentrations that were higher
than circulating ivermectin plasma levels in previous patients, our patient did
poorly [14, 25]. Unfortunately, the
effective therapeutic plasma concentration in humans is not known. Therefore, establishing CNS penetration by
measuring adequate CSF concentrations may be important in the prediction of
outcome. At steadystate, the CSF
concentration in our patient suggested less than 1% CSF penetration of orally
administered ivermectin. Moreover, in
the previous study by Turner et al. after five daily subcutaneous ivermectin
doses of 200 μg/kg, there were no detectable levels in the CSF using the same
assay methodology used in this study [25]. The
plasma levels measured after the initial dose and the seventh daily dose were
5.8 ng/mL and 12.1 ng/mL, respectively, and at 14 days steady-state plasma
concentrations
were 11.4–17.4 ng/mL [25].Lastly,
it seems unlikely that neurotoxic side-effects of ivermectin contributed to the
poor outcome of the patient. Adverse
neurologic effects include mydriasis, ataxia, tremors, emesis, lethargy, and
coma [13, 24–26]. However, our patient was comatose prior to and after three
weeks of therapy. Moreover, healthy volunteers have tolerated single doses of
2 000 μg/kg, and doses up to 1 091 μg/kg given three times at 72-hour intervals
without evidence of toxicity [24].When orally
administered ivermectin therapy fails to produce a clinical response, alternate
methods of therapy should be considered. Subcutaneous ivermectin has been used
in numerous cases to overcome poor oral absorption [9, 14, 25, 27, 28]. While no
parenteral antihelminthic medications are FDA approved for use in humans, permission may be obtained on
an individual basis to administer these agents by alternative routes with
evidence of problems of enteral absorption.


## 3. Conclusion

The mortality in disseminated
strongyloidiasis is high, likely from progression of disease prior to
diagnosis. Ivermectin remains the drug
of choice and is typically given orally at a dose of 200μg/kg per day for two
weeks or until resolution of symptoms. Because of possible impaired absorption, hypoalbuminemia, or extensive
central nervous system disease, serum concentrations may help discriminate when
either higher oral doses or parenteral ivermectin is necessary. Two case reports as well as ours showed
microscopic evidence of Strongyloides eradication with serum concentrations ranging from 11.4 to 49.6 (ng/dL). We were able to measure a CSF ivermectin
concentration of 0.14 ng/dL, which suggests a less than 1% central nervous
system penetrance. Because of extensive mortality,
early diagnosis and treatment are paramount in disseminated strongyloidiasis.



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*Source: 818296-2009-03-23.xml*