1. Dr MC Luk Dr KB Tai CCMU, AHNH 19 Jan 2010
Bug’s Life
Dr MC Luk
Dr KB Tai
CCMU, AHNH
19 Jan 2010

2. Background 75-yr-old man NSND ADLI , lived with family
Retired civil servant (Street cleaner)

3. Past medical history Anti-GBM disease
Presented to medical team in 4/2009 with rapid progressive renal impairment
Serum Cr 420 umol/L
Proteinuria 2.2g/day & CrCl 17ml/min
Anti-GBM Ab 54.5 RU/ml (Ref <20 RU/ml)
Renal biopsy:
10/15 glom with cellular crescents, 1 completely sclerosed
Moderate degree of interstitial fibrosis & tubular atrophy
IF: diffuse global linear staining for IgG, C3, kappa, lambda
Compatible with cresenteric GN, anti-GBM disease
No pulmonary involvement

4. Eosinophilia (absolute count 1.1 x 10^9/L, 15.1%)
Urine: mild eosinophils, no malignant cells
Suspected herbs related renal toxicity initially, in view of recent herbs intake
Poison center consulted -> not related to herbs

5. Given 5 courses of plasmapharesis & prednisolone 1mg/kg/day since 7/5/09
Anti-GBM Ab normalised 18 on 25/5/09 (Ref <20 RU/ml)
Added cyclophosphamide 50mg once (on alt day) since 12/6/2009
Latest prednisolone dose 35mg daily
Cr ~380 umol/L in 6/2009
Eosinophil count 0.0

6. History of present illness
Admit to medical ward on 21/6/09
Presented with dysuria, AROU,
Acute on chronic renal failure
Cr ~ 500 umol/L (baseline ~380 umol/L)
Foley inserted, IVF & Augmentin given
Blood culture: Ecoli; Urine :no growth
Repeated vomiting -> cyclophosphamide stopped on 24/6/09

7. CXR on admission

8. Progress Generalized unwell SOB
Developed 1st episode of hemoptysis at night
Blood streaks
Desaturation with SpO2 88%
ABG: type 1 respiratory failure
Transferred to CCMU x close monitoring
Augmentin upgraded to Tazocin to cover HAP

10. Further investigation:
Anti-GBM Ab = 4
Sputum x c/st: no growth
Sputum x AFB smear x 3 –ve
Sputum x cytology: no malignant cells, but

14. Diagnosis:
Immunosuppressed,
Strongyloides hyperinfection
E coli bacteriemia
Started oral Ivermectin

15. Hemoptysis subsided
CXR: diffuse lung infiltrates decreased
O2 weaned off
Sputum & bld culture: no growth
Transferred back to general ward

16. Repeated sputum sample –ve for parasites
Repeated stool –ve for parasites
Creatinine ~ 250
Prednisolone reduced & kept at 5mg daily
Transfer to TPH on 26/7/09 for rehab

17. Strongyloidiasis (Threadworm/糞桿線蟲 )

18. Introduction Scientific Classification:
Kingdom: Animalia Phylum: Nematoda Class: Secernentea Order: Rhabditida Family: Strongyloididae Genus: Strongyloides Species:S. stercoralis

19. Strongyloidiasis
A human parasitic disease caused by the roundworm Strongyloides stercoralis
Soil-transmitted helminth
Other Strongyloides
S. fülleborni, which infects chimpanzees and baboons
produce limited infections in humans

20. Epidemiology Endemic in tropical and subtropical regions
Estimated of million people infected
Also occurs sporadically in temperate areas
More frequently found in rural areas, institutional settings, and lower socio-economic groups

21. Risk factors for acquiring Strongyloides infection
Visiting the endemic area
Bathing in contaminated rivers & beaches
Employment in agriculture & gardening
(Hx of farming in childhood)
Consuming contaminated water

22. Life cycle 2 Characteristics: Alternation between 2 cycles
free-living cycle
parasitic cycle
Potential for autoinfection and multiplication within the host

23. Free-living cycle
The rhabditiform larvae passed in the stool can either:
become infective filariform larvae (direct development)
become free living adult males and females that mate and produce eggs from which rhabditiform larvae hatch
rhabditiform larvae either develop into a new generation of free-living adults, or into infective filariform larvae
The filariform larvae penetrate the human host skin to initiate the parasitic cycle

25. Parasitic cycle Filariform larvae penetrate the human skin
transported to the lungs where they penetrate the alveolar spaces
carried through to the pharynx
swallowed and then reach the small intestine
become adult female worms in the intestine, produce eggs, which yield rhabditiform larvae
rhabditiform larvae can either be passed in the stool (enter free-living cycle), or can cause autoinfection

27. Autoinfection
The rhabditiform larvae become infective filariform larvae, which can penetrate either the intestinal mucosa (internal autoinfection) or the skin of the perianal area (external autoinfection)
Clinical significance of autoinfection:
may permit the organism to persist for decades and cause clinical manifestations long after the initial infection
may give rise to potentially fatal hyperinfection with disseminated disease in patient with depressed cell-mediated immunity

28. Clinical presentation
Acute strongyloidiasis
Chronic strongyloidiasis
Disseminated disease/Hyperinfection syndrome 

29. Acute strongyloidiasis
Based on experimental human infections with many hundreds of larvae
Most likely overestimate the severity and perhaps the tempo of naturally acquired infections

30. Skin manifestation
local reaction at the site of larval entry can occur almost immediately
Cutaneous reactions include inflammation, edema, petechiae, urticarial tracts, and severe pruritus

31. Cutaneous larva migrans
larvae migrates through the skin and produces a raised, red, twisting (serpiginous) pattern on the skin.

32. larva currens ("running" larva)
a red line that appears, moves rapidly (>5 cm/day) and then quickly disappears.
more common on the buttocks,
pathognomonic of strongyloidiasis

33. Pulmonary manifestations
occur as larvae migrate through the lungs several days later
dry cough, throat irritation, dyspnoea, wheezing, and hemoptysis
repeated episodes of fever and mimicking bronchitis

34. GI symptoms
begin about 2 weeks after infection, with larvae detectable in the stool after 3 to 4 weeks.
Epigastric pain
Aggrevated by PPI (which reduces the HCl content of the stomach and allows the strongyloides to thrive)
diarrhea, anorexia, nausea, and vomiting

35. Chronic strongyloidiasis
Frequently asymptomatic, only present with eosinophilia
Chronic gastrointestinal manifestations
intermittent vomiting, diarrhea, constipation, and borborygmus,
GIB, intestinal obstruction
Dermatologic manifestations
Pruritus ani, urticaria and larva currens rashes
Recurrent asthma
Nephrotic syndrome

36. Hyperinfection syndrome
High mortality rate ~ 15% to 87%
Immunocompromised status
Repeated cycles of autoinfection increase the parasite burden
nondisseminated hyperinfection
Larvae are increased in numbers but confined to the organs normally involved in the pulmonary autoinfective cycle (i.e., GIT, peritoneum, lungs),
disseminated hyperinfection
migration of larvae to organs beyond the range of the pulmonary autoinfective cycle
e.g. heart, CNS, Kidney, and endocrine glands

37. Mechanism of organ damage:
1)Tissue inflammation as a direct consequences of organ invasion by the filariform larvae
2) Associated gram-negative bacteremia
enteric bacteria can be carried by the filariform larvae or gain systemic access through intestinal ulcers

38. Increased risk with impaired cell-mediated immunity:
Immunosuppressive therapy (e.g. steroid, Vincristine or anti-TNF alpha therapy)
HTLV-1 carriers
Alcoholics, diabetics, malnutrition
Hypogammaglobinemia
AIDS (but not common)
Hematological malignancies (esp. lymphoma)

39. The risk of corticosteroid in hyperinfection syndrome
Most frequent risk factor for hyperinfection
~2x to 3x increase in risk of transforming chronic strongyloidiasis to hyperinfection
Pathogenesis:
Reduce circulating eosinophils by inhibiting their proliferation & increasing apotosis
Induce cell death in immature lymphocytes
May directly affect the female worms, increasing the output of infective larvae

40. Hyperinfection syndrome
Clinical Manifestations :
Varies; depends on affected organs
Unlike chronic infection, eosinophilia is often absent
Fever and chills should prompt a search for an associated bacterial infection
Hyperinfections are often complicated by infections caused by gut flora
Blood cultures from patients with hyperinfection have grown E coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas, Enterococcus faecalis, Streptococcus bovis, Candida species

41. Diagnosis
Detection of larvae
Serology

42. Detection of larvae Serology Stool examination
In chronic strongyloidiasis, excretion of larvae is usually sporadic and in small numbers. A single stool examination may not be able to detect larvae.
Aspiration of duodenojejunal fluid may be required to detect Strongyloides in such patients
In disseminated strongyloidiasis, filariform larvae can be found in stool, sputum, bronchoalveolar lavage fluid, pleural fluid, peritoneal fluid
Serology

43. Detection of larvae Serology
ELISA serology is useful for detection of both symptomatic and asymptomatic strongyloidiasis
Highly sensitive but not specific
However, ELISA can be falsely negative in immunocompromised hosts
False +ve in patient with Ascaris spp, Filariae
The anti-strongyloides antibody can persist for years after treatment

44. Treatment
Azole drugs
act by selectively inhibiting the microtubular function of the helminth
Thiabendazole
Albendazole
Mebendazole

45. extended to 7 to 14 days in complicated infections
Thiabendazole
was first introduced in 1963 and for many years was the treatment of choice for S. stercoralis infection.
At a dose of 25 mg/kg twice a day for 3 days, its efficacy at clearing stool and improving symptoms in patients with chronic strongyloidiasis has ranged from 67% to 81%
extended to 7 to 14 days in complicated infections
Side effects occur in up to 95% of patients
nausea
foul-smelling urine,
neuropsychiatric effects,
malaise, or dizziness

46. Albendazole
400 mg orally twice a day for 3 days has been shown to clear stool of S. stercoralis larvae in 38% to 45% of patently infected individuals and to normalize serologies in 75% of chronically infected individuals in whom larvae were not detectable
few side effects reported

47. Mebendazole
has been used successfully to treat a number of patients with S. stercoralis hyperinfection
It is poorly absorbed, and therefore decreased accessibility to migrating larvae, leading to treatment failure

48. Ivermectin Semisynthetic agent from avermectins
paralyses worms by opening chloride channels and increasing chloride conductance
given on 1 or 2 days cleared larvae from the stool at a rate comparable to that of thiabendazole
much better tolerated
Compared with albendazole, it has shown better rates of larval clearance from stool with a similarly favorable side effect profile

49. Possible side effects:
skin rash,
dizziness,
myalgia,
Mazzotti reaction

50. Mazzotti reaction
seen in patients after undergoing treatment of onchocerciasis with the medication diethylcarbamazine (DEC)
due to death of the larvae, there is abrupt release of parasite-specific antigens and induces a pro-inflammatory response leading to eosinophil migration and degranulation in the skin
symptom complex
fever,
urticaria,
swollen and tender lymph nodes,
tachycardia, hypotension,
arthralgias,
oedema,
abdominal pain

51. Treatment Uncomplicated infection
Disseminated disease/hyperinfection syndrome

52. Uncomplicated infection
Ivermectin (per oral) - 1st line
200 mcg/kg as a single dose
200 mcg/kg/day for 2 consecutive days
Some advocate two single 200mcg/kg/day, administered two weeks apart
Albendazole (per oral) - 2nd line
400 mg PO twice daily for two to three days
Less effective

53. Disseminated disease/hyperinfection syndrome
Anthelminthic drugs
May need prolong or repeat therapy
five to seven days of ivermectin
or combine ivermectin with albendazole until the patient responds
If not able to receive oral therapy due to ileus or obtundation, alternative regimens (not FDA approved) include subcutaneous ivermectin, PR ivermectin administration, and a parenteral veterinary formulation

54. Disseminated disease/hyperinfection syndrome
Associated Gram-negative bacteremia
Broad-spectrum antibiotics
Common bacteria (cultured from blood and/or spinal fluid): Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Bacteroides fragilis, Pseudomonas aeruginosa and Alcaligenes faecalis

55. Monitoring of treatment response
Treatment failure may occur even Ivermectin
Complete blood counts with eosinophils
Follow-up stool or upper small bowel fluid (~ 2 wks after treatment initiation)
Titre of strongyloides antibodies (~ 3 months after treatment

56. ~ The End ~ Strongyloidiasis Hyperinfection Patient at risk
Secondary bacterial infection
Treatment
Ivermectin
Albendazole
~ The End ~