Mortality review on Fulminant Varicella Infection

Mortality Review
(January 2013)

Dr Nor Hidayah Zainool Abidin
INTERNATIONAL ISLAMIC UNIVERSITY OF MALAYSIA
HOSPITAL SULTAN ABDUL HALIM

copyright to anor hidayah

14/2/2013 @ 10:06
• 29 year old gentleman
Diagnosed with DM (2 years ago) - only have history of taking traditional
medications in liquid form, not on proper follow-up
• Not taking any new medications, traditional or otherwise recently
• He started having rash on head 3 days ago along with fever and upper
abdominal pain
Rash then spread to face, trunk and bilateral upper limbs and going
downwards
Now involved bilateral lower limbs
• Also having mild URTI symptoms - cough
No diarrhea , No vomiting
• No alterations in bladder habits and bowel habits
• No past surgical history, No allergy
• Single
Doing his own business - nursery
Non smoker and non alcoholic


Examination in Yellow Zone
• alert ,pink
not tachypnoiec
hydration good
lungs: clear
abdomen: soft , non tender
• Noted vesicular rash over the skull , abdomen , upper limbs
• BP:134/78
SpO2: 100% under room air
P:86
Temp:37.4
• DXT :16.2
• ECG: normal SR


• Initially treated as GERD
• IV ranitidine 50mg STAT
Syrup MMT 30 ml STAT
IV drip 1 pint NS
Observe in ED Observation bay

WBC 9.5 Na+ 127 CK 215
HB 17.2 K+ 3.5 AST 604
PCV 50.2% Crea 77 LDH 1026
plt 175 urea 4.2
neu 77.6% Cl- 98


30 mins later in Yellow zone
• still having upper abdominal pain more on right
hypochondriac pain
• alert ,pink
not tachypnoiec
bp:147/71
pr:64
temp:37.6
dxt:12.6
• TAS done in ED : Gallbladder stone ?

Treat as Cholitihiasis

clerked 2 hours after admission to
surgical ward
• Alert , concious
not tachypneic , dehydrated
BP : 142/ 91
P : 78
T : 37
Sp02 : 100 % under RA

• Noted vesicopapular rash over the facial region, thorax and
abdomen and back
• Lungs clear, CVS DRNM
• Tender over the epigastric region

• Started on IVD 3 pint NS /day


Seen by surgical MO 3 hours later
• Normal vital signs
• Tender epigastric

• NR for hepatitis B, hepatitis C virus and RVD
pro 78
• planned for US urgent cm thus KNBM alb 42
IV pantoprazole 40mg BD glo 36
ALT 776
ALP 66
treated with IM pethidine 75mg PRN Tot Bil 19
• then given IM pethidine 100mg stat
– in the morning as pt still having abdominal pain


15/1/2013 @ 7:27 am
• alert , concious
not tachypneic
BP: 125/76
PR:71
T : 37.4
Sp02 : 98 % under RA
DXT : 10.3
abdomen : soft , pain over deep palpation over the epigastric region

• started on T metformin 500mg by HO
• was off on 17/1/2013

• US abdomen was performed on 15/1/2013:
LIVER: Slightly enlarged with increased in echogenicity and slight coarse
echotexture of parenchyma.
• Borderline hepatomegaly with fatty liver


seen by medical MO @ 6:30pm
• o/e alert, concious, not tachypnoeic
BP:152/88
HR:81
SPO2: 100 Amylase 71
T:38 Diastase 373
• Lungs: clear
CVS: DRNM
Abdomen soft, non-tender, liver palpable 2 FB
+ maculopapular rash on face trunk and back
blanches, no discharges
• Treated with IVD 4 pints normal saline over 24 hours
Cover with IV Rocephine 2 g stat and 1 g BD
• s/b medical specialist:: cont management
• Still on IM pethidine 50 mg QID, At 11pm - Cap Tramal 50mg stat

Seen by surgeon 16/1/2013 @ 9:15
• Having pain over the back Na+ 127  123 CK 215  1353
No vomiting
mild abdominal pain K+ 3.5  4.5 AST 604  4565

alert Creat 77 85 LDH 1026
conscious 3325
BP:151/85 urea 4.2  5.6
P:88
T:38 Cl- 98 95
SpO2:99
Abdomen: pro 78  72
soft, tender on deep palpation alb 42 39
guarding
glo 36  33
• planned for urgent CT abdomen ALT 776  2939
– TRO pancreatitis ALP 66  131
Tot Bil 19  25

seen back by surgeon @5pm
• pt having spiking temperature

CT Abdomen: Normal
LFT , ALT increasing trend

IMP: Acute hepatitis
• transferred to medical ward @ 8.30pm


CT SCAN


Seen by medical consultant at
17/1/2013 @ 8:48
• alert
tachypnoeic - laboured breathing

• BP 158/70
P 90
T 37.5
• multiple white spot in the oral mucosa
• generalised vesicular lesion with multiple erosions especially over face
- worse over head, face, abdomen, upper chest
• infected vesicular lesions which has crusted
• multiple new vesicles noted over LL
• vesicles over scrotum
• bleeding over vesicles over face, patient unable to open left eye

To treat as infected varicella zoster complicated by varicella pneumonitis with acute
fulminant hepatitis with ocular involvement
DM

Investigation trends
Ph 7.288 WBC 9.5  23.2
pCO2 20.4 HB 17.2  20.3
pO2 82.9
PCV 50.2%  59%
HCO3 9.4
plt 175  99
BE -14.6
neu 77.6%  80%
pro 78  72  64
alb 42 39  33
glo 36  33  31
PT 22.7
ALT 776  2939  4473
INR 2.04
ALP 66  131  267
Aptt 46.4
Tot Bil 19  25  46

Medical plans
• Start IV acyclovir 500mg stat and tds and
Acyclovir cream over ruptured vesicles
• Start on HFMO2 10L/min
• Start IV flagyl 500mg tds for anerobic cover
and cont IV rocephine
• Increase IVD 6 pints / day
• To consult Hepatologist


Review by OMF Review by Opthal
• Multiple ulceration: • c/o unable to open RE since fever
- right and left buccal mucosa a/w tearing and mild redness
- Upper and lower gingival vision claims same as previous
- FOM ruptured vesicles on lid
- Soft palate Lid swelling (RE>LE, RE unable to
open eye spontenously)
minimal eye discharge
conjunctiva mild injected with
chemosis temporally
cornea clear
• Treat as BE conjunctivitis

Referred to Anaest @ 9:14
• DXT - at 11am – HI  IV actrapid 10unit stat
given
IV sodium bicarbonate 100cc infusion - completed
12.15pm

Send UFEME, urine ketone stat - done & seen

Rpt DXT aftr 1hour, if still HI - to start insulin
infusion
• Repeat DXT - 18.1mmol/L


Seen by Anaesthetist @ 12:17
• pt alert, conscious
mildly tachypnoiec
on HFMO2
able to talk in full sentences
bp - 158/70
PR - 90
SpO2 - 99%
dxt high
lungs- clear
CVS DRNM
Abd soft
generalised vesiculopapular rashes
good urine output


medical MO
review before transfer to ICU@ 14:35
concious
lethargy and septic looking
clinically dry
already started on insulin infusion

• IV vitamin K 10 mg daily
• Increase IVD 8 pints


Ph 7.288  7.326 WBC 9.5  23.2  24
pCO2 20.4  27.8 HB 17.2  20.3  20.1
pO2 82.9  265 PCV 50.2%  59%  59.7
HCO3 9.4  17.1 plt 175  99 56
BE -14.6 neu 77.6%  80%
pro 78  72  64  60
PT 22.7
alb 42 39  33  28
INR 2.04
glo 36  33  31  32
Aptt 46.4
ALT 776  2939  4473  4876
ALP 66  131  267  366
Tot Bil 19  25  46  54

Na+ 127  123  125 CK 215  1353  10537
K+ 3.5  4.5  4.0 AST 604  4565  9755
Creat 77 85  128 LDH 1026 3325  15834
urea 4.2  5.6  10.1
Cl- 98 95  90

17/1/2013
• @ 11:07 in medical ward:
• Staph aureus – sensitive strain

• @ 14:44 in ICU2:
• Acenatobacter sp – sensitive strain

• Eye swab – NG
• BFMP – negative
• Hep A – in process
• Anti – mitochondrial antibody – In process


• Case transfer in from medical ward at 2.05pm accompany by staff
nurse and PPK.
• On high flow mask oxygen 10L/minute.
• General condition of patient looks weak
• conscious
bp 148/80
hr 140
spo2 100% on hfmo2
lung clear
cvs drnm
abd distended, soft

• At 3pm - ABP : 157/88mmHg Heart rate : 146/minute spo2 : 100%
respiration rate : 10/minute

• 3.10pm - ABP : 111/82mmHg heart rate : 158/minute spo2 : 100%
respiration rate : 32/minute

• Haemodinamically stable without inotrope support.


• 3pm - CVL line attempted by HO but failed then patient
suddenly put up his right hand and talking irrelevantly
and become aggressive, do not allow anyone to go
near.
• Staff nurse tried to calm down but patient become
more aggressive
• He pull out all the invasive lines and CBD. Patient
jumped out from the bed and try to broke the window
with his hand then took the cardiac table to break the
window.
• Patient try to jump from the window but was able to be
pulled down with the help of SR, PPK, Male Nurse , 2
security guards, 2 policemen.
• Then IM midazolam 3mg was given after he waas held
down on the floor. Then patient become unresponsive
and no spontaneous breathing

• Intubated by anaest team.
– IV adrenaline 1mg x 6 ampoules ( 2 ampoule given
via endotracheal and 4 ampoule via intravenous)
– iv atropine 1mg
– iv sodium bicarbonate 8.41% 100mg
– iv calcium gluconate 1gram
• CPR commenced for 40 minutes but patient
unable to revive.
• Cardiac monitoring shows asystole
• Bp and Spo2 unrecordable. Both pupil fixed
dilated and pulses not felt.


cause of death??

• Sepsis secondary to Varricella pneumonia with
acute hepatitis


28yo, man
No smoker Uncontrol DM Metabolic acidosis Electrolyte derangement

Fever VZV Hepatitis
Multiple vesicular skin
lesion
No hx of VZV infection secondary bacterial
before infection
VZV Rhabdomyolisis
Abdominal pain

Laboured breathing VZV pneumonia Abnormal ventilation
tachypnoic Metabolic acidosis Hypoxia

Hemorhagic skin Sepsis
lesion Coagulopathy
Arrythmias
Bleeding from
injection site VZV Opthalmicus
Intracranial
VZV encephalitis Bleed
Hallucination
DEATH
Aggressive Acute Fulminant Hepatitis
behaviour
Septicaemiccopyright to anor hidayah
shock

Factors contribute to the Incident
• Underhydration in ward for the past 3 days
• Delay in starting anti-viral
• Failure to control blood sugar in ward
• Inadequate fluid resuscitation in ward prior to
transferring patient to ICU


Pathophysiology Classical
Pathogen & Immune presentation
response

Immune
Complications responses Management


Chicken-pox
• Member of Herpesviridae
• Sharing structural characteristics as a lipid
envelope surrounding a nuscleocapsid with
icosahendral symmetry – total diameter 180-
200nm
• Centrally located DNA 125000 bp in length
• little genetic variation


• Reservoir – human, no animal reservoir
• Highly contageous – attack rate ~90% in
seronegative individuals
• Both sexes and all races – equivalent
• Dermo & neutrotropic
• Disease in children – well tolerated
• More severe in adult, pregnant women and
immunocompromised  often have
hemorrhagic base


• Transmission
– direct contact with the rash
– Airborne respiratory droplets
– vertical transmission mother to baby during pregnancy

Localize replication
Seeding to
at undefined site Ultimately develop
reticuloendothelial
(presumably the viremia
system
nasopharynx)


Signs and symptoms
• In healthy children
– the disease is generally mild
• The illness usually 14–16 days after exposure
– Incubation period 10-21 days
• Prodromal symptoms : particularly in older children
– Low-grade fever preceding skin manifestations by 1-2 D
– 24-48 hr before rash
• Mild abdominal pain
• Mild cough and runny nose
– Mild headache
– malaise or irritability

Signs and symptoms

• red, itchy rash appear first on the scalp, face, trunk
• Diffuse and scattered nature
• quickly turn into clear fluid-filled vesicles
• 24-48 hr later, vesicular fluid become cloudy – recruitment of
PNM leucocytes and presence of degenerated cells and debris.
• Ultimately vesicle may rupture and release fluid (infectious
virus) or reabsorbed
• Umbilication of lesion
• oropharyngeal, vagina involvement : common
• cornial involvement and serious ocular disease : rare
• Itching may range from mild to intense


• Vesicle involve cornium and dermis
• Degenerative changes balloning, presence of
multinucleated giant cells and eosinophilic
intranuclear inclusion
• Infection at localize blood vessels of the skin
resulting in necrosis an epidermal hemorrhage


Immune response

• Natural infection induces lifelong immunity
• Newborn babies of immune mothers are protected by
passively acquired antibodies during their first months of life


HSV
• Mechanism of reactivation VZV resulting in
Herpes zoster is unknown
• Presumedly virus infect dorsal roots ganglia
during chicken pox, remain latent until activated
• Histopathologic examination  Hemorrhage,
edema and lymphocytic infiltration


High-risk groups
• High risks of complications
– Newborns and infants whose
mothers never had chickenpox
or the vaccine
– Teenagers & Adults
– Pregnant women
– People whose immune systems are impaired by
another disease or condition
– People who are taking steroid medications for another
disease or condition, such as asthma
– People with the skin inflammation eczema


COMPLICATIONS

• herpes zoster shingles • Endocarditis, myocarditis
• secondary bacterial skin and • toxic shock-like syndrome
soft tissue infections • hepatitis
– severe invasive group A • thrombocytopenia
streptococcal infection
increases the risk - fold* hemorrhegic varicella
• bacteremia • cerebellar ataxia
• pneumonitis • encephalitis
• osteomyelitis
• septic arthritis
• Coagulopathy, DIVC


VZV CNS infection
• Aseptic meningitis and encephalitis
• In many cases of aseptic meningitis
– no etiology is identified
– VZV has been identified as the 3rd most common
cause after herpes virus and enterovirus.


Classic meningeal signs Classical Encephalitis signs

• Headache • Altered level of conciousness
• Confusion
• neck stiffness • Behavioural abnormalities
• Hallucination
• Photophobia • Agitation
• present with or without • Personality changes
a preceding rash. • Frank psychotic state

• typically have pleocytosis
• elevated protein on CSF analysis
• Prompt treatment with high-dose intravenous acyclovir
on an empiric basis is typically the standard of care.

Varicella pneumonia
• The most common and serious complication
• Reported incidence in healthy adults that is
25-fold greater than in children
• Varicella pneumonia is so uncommon
– large-scale studies are difficult to conduct
– most published studies represent either
collections of small case series or retrospective
analyses over many years.


• Varicella pneumonia usually presents 1–6 days after
the onset of the rash
– Tachypnoea
– chest tightness
– Cough
– Dyspnoea,
– Fever
– Occasionally with pleuretic chest pain
– haemoptysis.
• Physical findings are often minimal and chest
radiographs typically reveal nodular or interstitial
pneumonitis
• With the exception of hypoxia, physical signs are a poor
guide of severity


• There is a strong correlation between
pneumonia and the development of new
respiratory symptoms.
• increased risk in smoker
• Increased number of skin spots (>100
spots), i.e. severity of rash, was a factor that
increased the risk of developing pneumonia,
may be a reflection of enhanced viraemia.


• The pulmonary lesions
– endothelial damage in small blood vessels
– with focal haemorrhagic necrosis
– mononuclear infiltration of alveolar walls
– fibrinous exudates with macrophages in the alveoli
which contain eosinophilic intranuclear inclusions.
• Seems to occur through the bloodstream
rather than local extension through the
respiratory tree


• Acyclovir reduces mortality and should be
used early in the course of illness in patients
with suspected or proven chickenpox
pneumonia.
• Healing with multiple nodular shadow that
may be calcified


VZV ARDS
• The early start of antiviral agent has been
reported in a significant improvement of
oxygenations as well as fever and tachypnea
• Very rare
• Potentially life threatening


Varicella Hepatitis
• VZV hepatitis with acute liver failure
– Uncommon
– frequently fatal condition
– The few patients who survived received early
acyclovir and Liver transplant
– Most of the patients described were
immunocompromised


• presenting symptoms
– cutaneous varicella lesions
– acute abdominal or back pain
– fever
• The typical papulovesicular rash may precede ,
be concomitant with or appear delayed
relative to the abdominal complaints.

Patients with disseminated Varicella
appear to remain moderately ill for some
days and then go on to develop full-scale
liver failure with coagulation disturbances
and shock.

• The mechanisms  remains unclear
• Most likely related more to the impaired
immune function than to the virulence of the
VZV strain.
• Infection usually appears to be primary
infection
• Histopathologic examination of the liver
contributes to the diagnosis


VZV Rhabdomyolysis
• Elevated CK and myoglobin
• Muscle damage was likely to account for some
part of the elevations of AST and LDH
• Very rare
• Carries good prognosis
• Aggressive fluid therapy to protect against
renal failure


Treatment
• Treatment approaches
– supportive measures eg Hydration
– antiviral therapy
– varicella zoster immune globulin (VZIG) ( 5g/day x
5days)
– management of secondary bacterial infection.
– Recognize underlying co-morbid eg: DKA
• Early recognition of secondary bacterial
infections. Failure to recognize occult infection
may result in serious illness and even death.


Acyclovir therapy
• Oral 800mg 4 times /day for 5-7days
• Recommended for adolecents and adults < 24
hrs of infection
• More effective in HZV infection – accelerated
healing of lesions, resolution of Zoster
associated pain
• In Severe Chickenpox infection, should be
treated at the onset  reduce occurrence of
visceral complications

• Penetration into CSF  Excellent ~ 50% of
serum level
• Complications:
– Increase urea and increase creatinine ~5%
– Thrombocytopenia ~ 6%
– Gastrointestinal ~ 7%
– Neurotoxicity ~ 1%


Varicella Vaccine
• Live attenuated vaccine (Oka)
• Recommended in all children > 1 yr age and
seronegative adult


Varicella Immunoglobulin
• special consideration in Adults
– not received the vaccine
– not already had chickenpox
– higher risk for exposure/transmission

Temporary protection of non-immune individuals can be
obtained by injection of varicella-zoster immune globulin
within 3 days of exposure
The immunity acquired in the course of varicella prevents
neither the establishment of a latent VZV infection, nor the
possibility of subsequent reactivation as zoster


References
• Harrison Principles of Internal Medicine, Volume
1, 17th Edition, 2008
• Davidson’s Principles & Practice of Medicine, 20th
Edition, 2006
• Fulminant varicella Infection complicated with
ARDS and DIVC in Immunocompetent Young
Adult, Soshoku et al, 2004
• Varicella pneumonia in adults, A.H. Mohsen*, M.
McKendrick, Eur Respir J 2003; 21: 886–891
• Varicella-Zoster Virus Infection Associated with
Acute Liver Failure, Hilde et al, 1998

Mortality review on Fulminant Varicella Infection

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