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Clinical Grand Rounds
Wednesday, September 10th, 2003
History
 CC: Feeling short of breath and tired
 HPI: 39 YO AA male who has a relatively negative
PMH presented with C/O fever, fatigue, and DOE.
Noted he had slowly progressive fatigue and DOE
over recent weeks. About a week PTA, he
developed acute onset of fever. He noted he has had
multiple life stressors recently, and his life has been
"in turmoil".
History
 He denied weight loss, night sweats, or hemoptysis.
Denied any BRBPR, no melena, no N/V and no
abdominal pain. No history of blood disorders,
anemia, or any type of bleeding problem.
REVIEW OF SYSTEMS
 Negative except as in history of present
illness.
PAST MEDICAL HISTORY
 Oral cancer, status post surgery with bone graft
 Skin rash treated with antifungal
ALLERGIES
 None.
MEDICATIONS
 Griseofulvin for skin rash
 No herbal, no OTC, no ASA, no chronic
NSAIDS
SOCIAL HISTORY
 He is bisexual.
 Not Married, no children
 Has a supportive family
 Hx of smoking crack, last
use 9 mo ago
 Denies IVDA, Occasional
ETOH
 Works in a warehouse
distribution center
 Has small grand nieces and
grand nephews who he has
been exposed to fairly
recently, although they do
not live with him. O/W no
ill contacts.
FAMILY HISTORY
 His mother is alive and well at 57
 Father’s health unknown
PHYSICAL EXAMINATION
 VS: T-max 103 on the day of admission, Nl sat%,
HR 66, RR 18, BP 111/65.
 HEENT: Left jaw scarring and deformity, PERRL,
EOMI, non-icteric sclera
 Neck: Supple. No LAD
 Lungs: CTAB, no egophony
 Cardiac: RRR. Nl S1, S2, 2/6 SEM, no R/G
 Abdomen: Soft, NT/ND, no HSM
Physical Examination
 Extremities: No cyanosis, clubbing, or edema.
No petechiae. No rash.No axillary, neck, or
inguinal LAD
 Neurologic: Nonfocal, A/O x 4
Imaging and Lab
 CXR NAD
 Chem 8 WNL,TP is 8.2, alb 3.8, AP 88, AST 42,
ALT 43, LDH 844 (upper limits of normal 618), TB
0.6, direct is 0.0. WBC 9.1, Hgb 4.5, Hct 13.1,
MCV 89, platelet count 625, 70% polymorphs, 24%
lymphocytes. Nucleated RBCs present.
Reticulocyte, absolute 0.8 K/uL
 Fibrinogen 391, Ddimer >1050
 Stool heme negative
Lab
 CT abd, pelvis, and chest: Small peripheral nodule
6 mm in the midline; small hypodensity in the right
lobe of the liver reflecting possibly a hemangioma
or cyst; 1 cm left external iliac chain node, and a 1
cm left groin node; no masses, abscesses, or free
fluid was seen
 HIV ELISA reactive, HIV PCR 110,000
 Parvovirus IgM positive
 CD4: 130
Lab
 Coombs’ negative
 normal iron, folate and
B12 levels
 ferritin 3223
 Epo level 115 mU/ml
 urine histo Ag negative
 serum crypto antigen
negative
 blood cultures negative
Anemia and HIV
Impact
 Prevalence 63-95% of
HIV-infected patients
 certain populations at
higher risk





African Americans
low CD4
high viral load
low MCV
zidovudine
 Most common hem
abnormality
 most common
symptom is fatigue
 marked effect on QOL
demonstrated
JID
Anemia and HIV
survival impact
 CDC cohort study, >19,000 patients
 Median survival decreased regardless of
CD4, AIDS, age, neutropenia,
throbocytopenia, antiretroviral therapy and
PCP prophylaxis
Blood 1998, 91:301-8
Anemia and HIV
survival impact
 Reversal of anemia clearly associated with
decreased hazard of death
 increased hazard with increased CD4
(although decreased incidence)
 not causal evidence
Anemia and HIV
survival impact
 EuroSIDA
 6725 pts
 12 mortality



3.1 % if no anemia
15.9% if Hgb 8-14
40.8% if Hgb<8
 Prop. Hazards
regression model


controlled for CD4 and
viral load
still 57% increased
hazard of death per drop
in Hgb by 1g/dL (rel
hazard 1.57, P0.0001)
JID 2002:185
JID 2002:185
Anemia and HIV
Differential diagnosis
 opportunistic infection



viral (CMV, parvovirus)
mycobacterial
fungal (histoplasmosis,
cryptococcosis)
 medications (25%)
 infiltrative marrow
processes






chronic disease
nutritional deficiencies
TTP
DIC
AIHA (1/3 Coombs +)
direct HIV effect


JID
marrow itself
cytokines
Anemia and HIV
Drug-induced
 Marrow suppression


zidovudine (AZT)
ganciclovir
 Hemolytic anemia



ribavirin
dapsone
TMP/sulfa
Anemia and HIV
Evaluation
 Initial retic count, MCV, hemolysis labs, Fe
studies
 fungal antigens
 CMV antigen
 TB/fungal blood cultures
 Parvovirus PCR
 Bone marrow biopsy
Anemia and HIV
Treatment
 Transfusion

?association with worse
outcome
 Nutritional
supplements
 Growth factors


weekly equally
effective
very safe and effective
 HAART
 androgens


stimulate RBC
production
increase epo production
and decrease excretion
Parvovirus B19




Single stranded DNA
Sample 19, panel B
Human pathogen (1981)
Replicates in late RBC
precursors (Erythrovirus
genus) and is cytotoxic
 Receptor blood group P
antigen (globoside)


Rbc precursors
Endothelial cells
 Age 15-50% have IgG
 Spring predominant
 50% attack rate in
household contacts
 Respiratory droplet
 1/3000 units contain
parvovirus DNA
 Pooled blood products
Pediatric exanthems
1.
2.
3.
4.
Scarlet fever
Rubeola
Rubella
Epidemic pseudoscarlatina (Filatov-Dukes
disease)
5. Erythema infectiosum
6. Roseola (exantham subitum, HHV6)
Parvovirus B19





Erythema infectiosum(Fifth disease)
Transient aplastic crisis (increased erythropoiesis
Polyarthopathy syndrome (adult women)
Chronic anemia (usually immunodeficient)
Hydrops fetalis/congenital anemia
Feigin: Textbook of Pediatric Infectious Diseases, 4th ed., Copyright
© 1998 W. B. Saunders Company
Parvovirus
Feigin: Textbook of Pediatric Infectious Diseases, 4th ed., Copyright © 1998 W. B. Saunders
Company
Parvovirus B19
erythema infectiosum
 Nonspecific febrile illness
 Immune-mediated phase




 PCR in tissue persists
months
2-3 weeks with IgM peak
Slapped cheek rash/lacy
reticular
Polyarthropathy syndrome
(symmetrical, distal,
nondestructive)
Papular-;urpuric gloves and
socks syndrome
Balfour HH. Erythema infectiosum (fifth disease): Clinical review and description
of 91 cases seen in an epidemic. Clin Pediatr (Phila). 1969;8:721-727
Anderson MJ, Higgins PG, Davis LR, et al. Experimental parvoviral infection in
humans. J Infect Dis. 1985;152:257-265.
Parvovirus
Child with slapped cheek syndrome (published with
father's permission)
From: Cohen: BMJ, Volume 311(7019).December
9, 1995.1549-1552
Typical ``slapped cheek'' rash is apparent in a two-year-old child with fifth disease (erythema infectiosum), caused by
parvovirus B19 infection. The common lacelike erythema of the trunk is also present but not clearly in focus. This
disease, which is usually self-limited, is one of the six classic childhood exanthems, which include measles (rubeola),
scarlet fever, German measles (rubella), Filatov-Dukes disease (not a separate exanthem but a variant of scarlet fever or
toxin-producing staphylococcus infection), and exanthema subitum, or roseola (human herpesvirus 6 infection).
From: Feder: N Engl J Med, Volume 331(16).Oct 20, 1994.1062
Parvovirus B19
Aplastic crisis
 During viremia
 Retulocyte arrest due
to virus-induced
cytotoxicity
Electron micrograph of B19 isolate showing morphology
typical of a parvovirus (final magnification x 157 000)
From: Cohen: BMJ, Volume 311(7019).December 9,
1995.1549-1552
TABLE 1 -- HEMATOLOGIC CONDITIONS PREDISPOSING PATIENTS TO PARVOVIRUS B19ASSOCIATED ACUTE APLASTIC CRISIS
Hereditary Disorders
Sickle cell anemia
Hereditary spherocytosis and elliptocytosis
Thalassemia
Glucose-6-phosphate dehydrogenase deficiency
Pyruvate kinase deficiency
Pyrimidine-5'-nucleotidase deficiency
Congenital dyserythropoietic anemia
Acquired Disorders
Iron deficiency anemia
Chronic worn antibody-mediated autoimmune hemolyticanemia
Cold antibody-mediated autoimmune hemolytic anemia
Malaria
Blood loss
Paroxysmal nocturnal hemoglobinuria
Normal host
Pediatric Clinics of North America
Volume 43 • Number 3 • June 1996
Parvovirus B19
Chronic anemia
 Immunosuppressed hosts
do not mount neutralizing
antibody
 Sera from patients with
persistent B19 infection
typically contain antibody
to VP2 but not to VP1
 Chronic persistent anemia
 Reticulocytopenia
 High B19 DNA in serum
 Scattered giant
pronormoblasts
 Vaccine in clinical
trials
 IgIG


400mg/kg/day for 5-10
days
Q 4 weeks
Pediatric Clinics of North America
Volume 43 • Number 3 • June 1996
Parvovirus
Chronic anemia-HIV
 B19 DNA was found in 5 (17%) of 30
transfusion-dependent HIV-seropositive
homosexuals, and when a hematocrit of less
than 20 was used as a criterion, 4 (31%) of
13 were positive. (J Infect Dis.
1997;176:269-273)

Marrow may not be suggestive of PRCA and
giant prnormoblasts may not be present
(A) Bone marrow aspirate smear showing a giant pronormoblast with a large
intranuclear inclusion. Note the size of this erythroid precursor in comparison with
accompanying erythrocytes and lymphocyte (× 1250). (B) Immunohistochemical
stain of the bone marrow biopsy, demonstrating numerous pronormoblasts
positive for parvovirus B19 (× 250).
HSU, JACK W.. CZADER, MAGDALENA. ANDERS, VIKI. VOGELSANG, GEORGIA.
BRODSKY, ROBERT A.. PARVOVIRUS B19-ASSOCIATED PURE RED CELL
APLASIA IN CHRONIC GRAFT-VERSUS-HOST DISEASE. British Journal of
Haematology. 119(1):280-282, October 2002
Immune electron microscopy showing aggregates of parvovirus B19
particles in serum, confirming viraemia during the patient's illness.
CROWLEY, BRENDAN 1. WOODCOCK, BARRIE 2. RED CELL APLASIA
DUE TO PARVOVIRUS B19 IN A PATIENT TREATED WITH
ALEMTUZUMAB. British Journal of Haematology. 119(1):279-280, October
2002.
Parvovirus B19
other manifestations



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Neutropenia
Lymphopenia
Thrombocytopenia
Hemophagocytic syndrome
Fetal infection



30% transplacental infection rate
9% second trimester loss rate
10-20% of nonimmune hydrops
Parvovirus B19
Diagnosis
 IgM antibodies in healthy individuals



3rd day of aplastic crisis
Any rash
Persist 2-3 months
 Molecular detection in serum




Direct dot-blot
PCR (>108 copies/ml)
May persist years in tissue, months in serum
Bone marrow biopsy
Erythroblasts contain viral inclusions (thin arrows) at different stages
of development. The giant proerythroblast on the left (thick arrow)
demonstrates chromatin condensation at the periphery of the nucleus
and a central viral inclusion
British Journal of Haematology. 119(1):125-127, October 2002
Typical ‘gigantoproerythroblasts’ in parvovirus B19-associated PRCA. (A) Bone marrow
histology with several gigantoproerythroblasts (marked by asterisks) that resemble Hodgkin
cells. A small regressive erythroblast (marked with an arrow) typically contains the
immunoreactive B19-antigen. (B) Bone marrow cytology of another patient with B19
infection showing two gigantoproerythroblasts (marked by asterisks).
British Journal of Haematology. 111(4-II):1010-1022,
December 2000
Figure 2. Immunohistochemical stains using monoclonal antibodies
against parvovirus highlight intranuclear inclusions (arrow) in erythroid
precursors (×250).
From: Pamidi: Transplantation, Volume 69(12).June 27, 2000.2666-2669
Parvovirus
Isolation
 Erythema infectiosum no longer viremic
 TAC requires droplet precautions for 7 days
or duration
 Pregnant HCWs should not care for patient
Case Report
Outcome
 Transfused and quickly became
asymptomatic
 Discharged on Bactrim
 Follow-up Hgb 9.2
 Cd4 178, viral load 220,00
 Began non-AZT HAART regimen
(stavudine, lamivudine and efavirenz)