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
HEMOGRAM
          28/5       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    N41 L18    N71 L17   N40 L56      N68    N84 L12     N70 L24
          M4 E45     M5 E27     M2 E10    M3 E01       L27    M2 E02      M4 E02
                                                       M3 E02



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


PBF       RBC -      AEC-                 Activated
          N/N        7047/mm              lymphocyte
                                          present
Biochemistry
                  28/05        31/05      02/06   04/06     06/06    08/06   11/06

Na/k              145/         144/       139/    143/3.7   144/     143/    146/
                  4.2          3.15       3.2               3.2      3.1     3.9


Urea/creatinine   206.7/       73/        58.3/   67.1/     54.7/    28.4/   34.8/
                  9.74         2.85       1.50    0.84      0.77     0.58    0.80


SGOT/SGPT         94.8/ 85.0   410/ 200   745/    235/      166.7/   82.6/   49.0/
                                          379     294       227.6    149.8   86.7


ALP               379          679        500     591       632      567     465
TP/albumin        4.86/ 2.7    5.27/      4.16/   4.32/     4.71/    5.31/   5.53/
                               2.7        2.1     1.8       2.0      2.5     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.
Sabari krishnan final clinical meet 2 copy
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
Sabari krishnan final clinical meet 2 copy
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

 Acute tubulointerstitial nephritis- the tubules and interstitium showed
  marked interstitial edema with an intense inflammatory infiltrate of
  lymphocytes and plasmocytes.
                                             Kidney biopsy showing acute interstitial nephritis (PAS stain)


  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
Sabari krishnan final clinical meet 2 copy
Sabari krishnan final clinical meet 2 copy
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
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
Sabari krishnan final clinical meet 2 copy

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Sabari krishnan final clinical meet 2 copy

  • 1. STUDENT CLINICAL MEET Sabari krishnan 31.07.2012
  • 2. • Name : Mrs ML • Age :50/m • CR.NO:2541826 • D O A:27.05.2012 • D O D:12.06.2012 • Unit :IM2
  • 3. PRESENTING COMPLIANTS • Loose stools -15 days • Fever -15 days • Rash all over the body-14 days • Decreased urine output-10 days
  • 4. 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.
  • 5. 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.
  • 6.  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.
  • 7. 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.
  • 8. 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.
  • 9. Generalised erythematous scaly rash all over the body
  • 10. 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
  • 11. HEMOGRAM 28/5 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 N41 L18 N71 L17 N40 L56 N68 N84 L12 N70 L24 M4 E45 M5 E27 M2 E10 M3 E01 L27 M2 E02 M4 E02 M3 E02 PLATELE 1,78,000 1,50,000 85,000 64,000 96,000 1,00000 1,45,000 TS PBF RBC - AEC- Activated N/N 7047/mm lymphocyte present
  • 12. Biochemistry 28/05 31/05 02/06 04/06 06/06 08/06 11/06 Na/k 145/ 144/ 139/ 143/3.7 144/ 143/ 146/ 4.2 3.15 3.2 3.2 3.1 3.9 Urea/creatinine 206.7/ 73/ 58.3/ 67.1/ 54.7/ 28.4/ 34.8/ 9.74 2.85 1.50 0.84 0.77 0.58 0.80 SGOT/SGPT 94.8/ 85.0 410/ 200 745/ 235/ 166.7/ 82.6/ 49.0/ 379 294 227.6 149.8 86.7 ALP 379 679 500 591 632 567 465 TP/albumin 4.86/ 2.7 5.27/ 4.16/ 4.32/ 4.71/ 5.31/ 5.53/ 2.7 2.1 1.8 2.0 2.5 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
  • 13. 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.
  • 16. Units final diagnosis Drug Rash with Eosinophilia and Systemic Symptoms  Hepatitis  renal involvement -Acute interstitial nephritis -Associated renal vasculitis (?drug induced)
  • 17. Topics for discussion  DRESS syndrome • Clinical features • Pathophysiology • Treatment  Leflunomide induced vasculitis
  • 18. 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
  • 22. 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%).
  • 23.  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.)
  • 24. 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
  • 25. 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
  • 26. Renal involvement  Acute tubulointerstitial nephritis- the tubules and interstitium showed marked interstitial edema with an intense inflammatory infiltrate of lymphocytes and plasmocytes. Kidney biopsy showing acute interstitial nephritis (PAS stain)  Acute tubular necrosis - present with an infiltrate of polynuclear neutrophils and lymphocytes in the tubules
  • 27. Hematological abnormalities shiohara et al allergology international 2006;55;1-8
  • 28. 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
  • 29. • 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
  • 30. 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
  • 31. 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
  • 32. The RegiSCAR-Group Diagnosis Score for Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
  • 33. Dress syndrome most common differential diagnoses
  • 35. 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
  • 39. 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
  • 40. 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.
  • 41. 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.
  • 42. 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

Editor's Notes

  • #7: Which was
  • #9: Patient was
  • #10: This is the photograph of the patient showing ………………. which was seen…………………
  • #11: Systemic examination was within normal limits.
  • #12: He was found to have tlc, durin g the course of stay in hospital he developed
  • #13: Patient had hypokalemia during hospital st ayed corrected Deranged rft normalise dlater 10 times of baseline
  • #15: I kindly request my PATHOLOGY COLlIC TO DISCUSS THE RENAL BIOPSY SLIDE
  • #16: Underlying vasculitis
  • #18: I would like to discuss Clinical features Pathophysiology Treatment of dress syndrome and leflunomide
  • #19: Like
  • #20: Mainly aromatic anaticonvulsant being major proportion
  • #22: There is already one reported case of dress syndrome due to leflunomide from lucknow, in march 2012. in BMJ
  • #24: There are many systemic manifestation most common manoifeststion
  • #28: Other findings include
  • #29: Gp is included in pathophysiology,as ……………………..
  • #34: START WITH SJS, STEROIDS WORSENS CLINICAL COURSE
  • #35: TREATMENT INVOLVES Empirical treatment with antibiotics or NSAIDS should not be done during acute period, which may confuse or worsens the clinical picture probably due to unexplained cross reactivity.
  • #36: AFTER RESOLUTION OF RASH AND FEVR,STEROID SHOULD GRADUALLY TAPEROVER A PERIOD
  • #37: Usually patients show good clinical response to steroids, in case patient doesn’ t response to steroid, other treatment options should be considered treatment option being
  • #38: Ther is other case report