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 HIVImpact

Prevalence 63-95% of HIV-infected patients

certain populations at higher risk African Americans low CD4 high viral load low MCV zidovudine

JID

Most common hem abnormality

most common symptom is fatigue

marked effect on QOL demonstrated

Anemia and HIVsurvival impact

Blood 1998, 91:301-8

CDC cohort study, >19,000 patients Median survival decreased regardless of

CD4, AIDS, age, neutropenia, throbocytopenia, antiretroviral therapy and PCP prophylaxis

Anemia and HIVsurvival impact

Reversal of anemia clearly associated with decreased hazard of death

increased hazard with increased CD4 (although decreased incidence)

not causal evidence

Anemia and HIVsurvival 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 HIVDifferential diagnosis

opportunistic infection viral (CMV,

parvovirus) mycobacterial fungal (histoplasmosis,

cryptococcosis)

medications (25%) infiltrative marrow

processesJID

chronic disease nutritional deficiencies TTP DIC AIHA (1/3 Coombs +) direct HIV effect

marrow itself cytokines

Anemia and HIVDrug-induced

Marrow suppression zidovudine (AZT) ganciclovir

Hemolytic anemia ribavirin dapsone TMP/sulfa

Anemia and HIVEvaluation

Initial retic count, MCV, hemolysis labs, Fe studies

fungal antigens CMV antigen TB/fungal blood cultures Parvovirus PCR Bone marrow biopsy

Anemia and HIVTreatment

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. Scarlet fever2. Rubeola3. Rubella4. Epidemic pseudoscarlatina (Filatov-Dukes

disease)5. Erythema infectiosum6. 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 B19erythema infectiosum

Nonspecific febrile illness Immune-mediated phase

2-3 weeks with IgM peak Slapped cheek rash/lacy

reticular Polyarthropathy syndrome

(symmetrical, distal, nondestructive)

Papular-;urpuric gloves and socks syndrome

PCR in tissue persists months

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 B19Aplastic 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 B19-ASSOCIATED 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 AmericaVolume 43 • Number 3 • June 1996

Parvovirus B19Chronic 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

TABLE 2 -- IMMUNODEFICIENCY DISORDERS THAT HAVE BEEN ASSOCIATED WITH CHRONIC PARVOVIRUS B19 INFECTION

Congenital Immunodeficiency

Nezelof's syndrome

Common variable immunodeficiency

Severe combined immunodeficiency (SCID)

Fetus

Others

Acquired Immunodeficiency

HIV infection

Malignancy

Acute lymphoblastic leukemia

Acute myeloid leukemia

Non-Hodgkin's lymphoma

Brain tumors

Wilms tumor

Rhabdomyosarcoma

Organ transplant recipients

Renal transplantation

Liver transplantation

Cardiac transplantation

Bone marrow transplant recipients

Collagen vascular diseases

Systemic lupus erythematosus

Rheumatoid arthritis

Pediatric Clinics of North AmericaVolume 43 • Number 3 • June 1996

ParvovirusChronic 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

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.

Immune electron microscopy showing aggregates of parvovirus B19

particles in serum, confirming viraemia during the patient's illness.

Parvovirus B19other manifestations

Neutropenia Lymphopenia Thrombocytopenia Hemophagocytic syndrome Fetal infection

30% transplacental infection rate 9% second trimester loss rate 10-20% of nonimmune hydrops

Parvovirus B19Diagnosis

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

British Journal of Haematology. 119(1):125-127, October 2002

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

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

ParvovirusIsolation

Erythema infectiosum no longer viremic TAC requires droplet precautions for 7 days

or duration Pregnant HCWs should not care for patient

Case ReportOutcome

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)