STUDENT CLINICAL MEET

Sabari krishnan

31.07.2012

• Name : Mrs ML

• Age :50/m

• CR.NO:2541826

• D O A:27.05.2012

• D O D:12.06.2012

• Unit :IM2

PRESENTING COMPLIANTS

• Loose stools -15 days

• Fever -15 days

• Rash all over the body-14 days

• Decreased urine output-10 days

Significant back ground history

History of knee joint pain for past 8 months

• Bilateral symmetrical

• No early morning stiffness

• History of increasing pain with squatting and walking

• Consulted private practitioner 4 weeks back, he was

prescribed Leflunomide 10 mg b.d, HCQ 200 mg hs,

considering rheumatoid arthritis, however clinical features

not s/o of any inflammatory arthritis.

History of presenting illness

• Loose stools-15 days

-7-8 episodes/day, watery, small volume stools

-not associated blood or mucus

-associated with vomiting,4-5 episodes/day, non projectile

containing food particles, associated with pain abdomen.

• Fever -15 days

- intermittent, high grade fever , documented upto 104 F

-not associated with chills and rigor, relived by antipyretics.

Rash all over the body-15 days

-pruritic, maculopapular rash

-developed after taking medication,

-sparing oral mucosa, palms and soles,

- no h/o blister formation and scarring.

Decreased urine output 10 days

-500-600ml/day, associated with dysuria, no hematuria.

past history

• No k/c/o DM,HT, TB, asthma, CAD, CVA.

• h/o cataract operation right eye 2 yrs back.

Personal history• Chronic smoker-40 yrs, bidi 30-40/day, smoking index -1200 to

1600.

• Chronic alcoholic-20yrs,1-2 times /wk, for 20 yrs.

• Bladder and bowel habits normal.

General examination

Conscious, oriented

Vitals-PR-110/min, regular, normal volume, all peripheral pulse felt,

no RR or RF delay.

BP-116/80mmHg

RR-30/min

Temp-febrile

Spo2-92% on RA

No pallor, icterus, cyanosis, clubbing, lymphadenopathy.

Generalised erythematous scaly rash all over the body

Systemic examination

• RS-BAE present, no added sounds

• CVS-S1S2 present, no murmur

• Abdomen –soft, non tender, no organomegaly, no free

fluid, bowel sounds present.

• CNS-WNL

HEMOGRAM28/5 30/5 31/5 04/6 05/6 6/06 11/06

Hb 12.6 12.7 12.9 11.3 10.2 9.8 9.7

TLC 29,600 26,000 26,500 32,600 29,200 19,300 9700

DC N35 L18 M4 E45

N41 L18M5 E27

N71 L17M2 E10

N40 L56 M3 E01

N68 L27M3 E02

N84 L12M2 E02

N70 L24M4 E02

PLATELETS

1,78,000 1,50,000 85,000 64,000 96,000 1,00000 1,45,000

PBF RBC - N/N

AEC- 7047/mm

Activated lymphocyte present

Biochemistry28/05 31/05 02/06 04/06 06/06 08/06 11/06

Na/k 145/4.2

144/3.15

139/3.2

143/3.7 144/3.2

143/3.1

146/3.9

Urea/creatinine

206.7/ 9.74

73/2.85

58.3/1.50

67.1/0.84

54.7/0.77

28.4/0.58

34.8/0.80

SGOT/SGPT 94.8/ 85.0 410/ 200 745/379

235/294

166.7/227.6

82.6/149.8

49.0/86.7

ALP 379 679 500 591 632 567 465

TP/albumin 4.86/ 2.7 5.27/2.7

4.16/2.1

4.32/1.8

4.71/2.0

5.31/2.5

5.53/2.8

bilirubin 0.5 1.30 3.2 6.1 4.9 3.3 2.2

calcium 7.62 7.9 6.19 _ _ _ 7.85

phosphorus 7.99 3.44 2.03 _ _ _ 2.74

magnesium 2.55 1.51 1.45 _ _ _ 1.82

Investigations

• AEC(absolute eosinophil count)- 7047

• Urine R/E- Sugar –nil

Albumin-+

• 24 hrs urine protein-80

urine creatinie-600

• Bence jones proteins-negative

• SERUM ELECTROPHORESIS-no M band seen, urine protein –nil.

• Urine c/s-negative

• Blood c/s-negative

• ANA and ANCA-negative

• Viral markers –negative

• USG ABDOMEN-Mild hepatomegaly with fatty liver.

- B/L early renal parenchymal disease.

Course and management

Units final diagnosis

Drug Rash with Eosinophilia and Systemic Symptoms

Hepatitis

renal involvement

-Acute interstitial nephritis

-Associated renal vasculitis (?drug induced)

Topics for discussion

DRESS syndrome

• Clinical features

• Pathophysiology

• Treatment

Leflunomide induced vasculitis

DRESS• Term DRESS introduced in 1996 by Bocquet to differentiate DIHS with

hemotological and visceral involvement from other types of drug sesnsitivity

• Dress syndrome is severe life threatening manifestation of drug reaction including

a

– severe skin eruption,

– fever,

– hematological abnormalities [eosinophilia or atypical lymphocytes] and

– internal organ involvement.

• Formerly called Hypersensitivity Syndrome (HSS), phenytoin hyper- sensitivity syndrome, drug

hypersensitivity syndrome, drug- induced hypersensitivity syndrome, and drug-induced

delayed multiorgan hypersensitivity syndrome.

Patrice et al The American Journal of Medicine (2011)124,588-597

Drugs causing DRESS

continued

Clinical features of DRESS

Delayed onset, usually 2-6 wks, after initiation

of drug therapy.

Persistence or aggravation of symptoms

despite the discontinuation of the culprit drug.

Typically presents with rash and fever (87%).

severe systemic manifestations

lymphadenopathy (75%),

hepatitis (51%),

hematologic abnormalities (30%).

interstitial nephritis (11%),

arthralgia's,

Other symptoms: pruritus, oliguria, hepato-renal syndrome, and asthenia.

Can affect any organ system (lungs, CNS, GI, etc.)

SKIN MANIFESTATION OF DRESS

Classically generalised erythematous maculopapular rash.

Periorbital, facial or neck edema with pinhead-sized

characterised feature at early stage. Rash often generalised

into severe exfoliative dermatitia.

shiohara et al allergology international 2006;55;1-8

Augusto J et al. Nephrol. Dial. Transplant. 2009;24:2940-2942

Hepatic involvement

Mild transaminitis to fulminant hepatic failure.

Increase in transaminases due to necrosis

Usually anicteric, if icteric its poor prognosis

Pathogenesis is due to eosinophilic infiltration

driven by interleukin 5.

shiohara et al allergology international 2006;55;1-8

Renal involvement

Kidney biopsy showing acute interstitial nephritis (PAS stain)

Acute tubulointerstitial nephritis- the tubules and interstitium showed marked interstitial edema with an intense inflammatory infiltrate of lymphocytes and plasmocytes.

Acute tubular necrosis - present with an infiltrate of polynuclear neutrophils and lymphocytes in the tubules

Hematological abnormalities

shiohara et al allergology international 2006;55;1-8

PATHOPHYSIOLOGY

Causative drug induces hypersensitivity as a result of

abnormalities in the production and detoxification of its

active metabolites.

Genetic predisposition, as the risk is increased in patients

with a positive family history for DRESS syndrome, in slow

acetylators, and in blacks .

• Accepted hypothesis for sulfonamides and anticonvulsants..

Joint Bone Spine 72 (2005) 82–85

• DRESS syndrome induced by anticonvulsants

may be related to epoxide–hydrolase

deficiency, which leads to accumulation of

toxic metabolites known as arene oxides. The

toxic effects of these metabolites on cells may

trigger an immunological response

HHV 6

• HHV 6-recently incriminated as a cofactor in development of

DRESS.

• Acts as a trigger in patient with predisposing immunological

and genetic susceptibility

• It interfere with drug metabolism, by altering the enzymes

involved in drug detoxification

Tohyama M, et al. Arch Dermatology 2002;138:268-9

1. Maculopapular rash developing > 3 weeks after starting suspect drug

2. Prolonged clinical symptoms 2 weeks after discontinuation of the suspected drug

3. Fever > 38° C

4. Liver abnormalities (ALT > 100 U/L) or other organ involvement

5. Lymphadenopathy

6. Human herpesvirus 6 reactivation

7. Leucocyte abnormality

Leukocytosis ( > 11 x 109/L)

Atypical lymphocytosis (>5%)

esinophilia .1.5 x 109/L

The RegiSCAR-Group Diagnosis Score for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Dress syndrome most common differential diagnoses

Treatment

Role of steroids

• The main stay of treatment is systemic corticosteroids.

• Rapid resolution of rashes and fever occur within days after starting

systemic steroids, usual dose is prednisolone 40-60mg/day

• Systemic steroids can reduce symptoms of delayed hypersensitivity

reactions.

• Systemic steroids needs to be tapered over 6-8 wks to prevent the relapse

of various symptoms of this syndrome.

shiohara et al allergology international 2006;55;1-

8

Other treatment modalities

The patient in this case developed a systemic

illness characterized by fever, skin rash, diffuse

lymphadenopathy, profound peripheral

eosinophilia, mild transaminitis, altered mental

status, and acute kidney injury following

reexposure to intravenous vancomycin. As seen

here, renal biopsy revealed a granulomatous

acute interstitial nephritis (AIN) (lower left)

with a cellular infiltrate consisting of numerous

eosinophils, lymphocytes, neutrophils, plasma

cells, and macrophages (lower right).

Lymph node biopsy was consistent with a reactive lympadenitis. Vancomycin was discontinued, and the patient received intravenous methylprednisolone for 3 days followed by oral prednisone tapered over 4 weeks, with complete resolution of the systemic illness and recovery of kidney function back to baseline. This presentation is consistent with DRESS.

TAKE HOME MESSAGE

Early recognition of symptoms is vital to

minimize morbidity and mortality,

Discontinuation of causative drug-immediate and

life long.

All granulomatous vasculitis with eosinophilia,

are not chrug-strauss, it could be due to DRESS

also.

Further course of the patient

• Seen in nephrology OPD after 14 days of discharge, Cough

with expectoration, high grade fever, upper abdominal pain -2

days, admitted in ward.

• CT CHEST AND ABDOMEN -patchy consolidation with

ground glassing in lingula and b/l lower lobe, splenic infarct.

• UGIE- 2 deep ulcer 1 anterior and 1 posterior duodenal wall,

next day developed perforation peritonitis, modified graham’s

patch repair done.

• Patient died due to VAP, sepsis and MODS.

Overall diagnosis

DRESS- Leflunomide induced

– Hepatitis

– Renal involvement

Nephritis

Associated vasculitis ?drug induced

Duodenal ulcers with perforation peritonitis

– ?steroid related / exacerbated

– ?vasculitis associated with leflunamide

– Sepsis, MOD Death