A clinical guide to stem cell and bone marrow transplantation - part 4 docx

Table 5.3 Infectious Complications and Occurrence in BMT RecipientsFirst Month Post-Transplant Viral: genital Bacterial: Gram positive S.. Management of fever in the neutropenic BMT pati

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7 Management

a) See Table 5.1 for blood component therapy 2

b) Avoid invasive procedures that could result in additional blood loss, unlessabsolutely necessary

c) Transfuse packed red blood cells if HCT is less than 25% or Hgb is less than 8g/dL, if active bleeding occurs, or prior to general anesthesia or invasive procedureswhere blood loss is anticipated (as clinically indicated)

(1) All blood products must be irradiated to prevent GVHD

(2) Leukocyte-reduction filters are used for PRBCs and platelets to reduceexposure to HLAs and CMV

(3) Give CMV-negative products to CMV-negative patients, since the virus

is carried on granulocytes and may increase the risk of CMV infection.(4) Premedicate with acetaminophen, diphenhydramine, or hydrocortisone(alone or in combination) if the patient has a history of transfusion reaction.d) Transfuse children more than 1 year of age with 10 to 15 mL/kg/transfusion

c) Graft rejection in the allogeneic matched sibling donor recipient is thought toresult from marrow rejection by host T cells not eliminated during conditioning 9

d) T-cell depletion of donor marrow to prevent GVHD also contributes to graftrejection

e) In the autologous BMT setting, graft failure is thought to be due to infusion ofinadequate numbers of stem cells, ex vivo manipulation of marrow (purging), andcryopreservation.3

3 Risk factors

a) Recipient of HLA-incompatible marrow graftb) Recipient of matched unrelated donor marrow graftc) Recipient of umbilical cord blood transplant

d) Patients with severe aplastic anemia with history of multiple transfusionspretransplant

e) Patients with thalassemia, immunodeficiency, or Fanconi's anemiaf) Patients whose clinical condition necessitates limitation of pretransplantconditioning

g) T-cell depletion of marrow graft orh) Ex vivo marrow manipulation (purging/cryopreservation)

4 Clinical features

a) A complete absence of hematopoietic activity (rise in the WBC or platelet count)beyond the period expected There is wide variation in mean day of engraftmentbetween types of stem cell/marrow grafts; however, a sustained rise in the WBCcount is expected before 30 to 40 days post-transplant

b) A loss of hematopoiesis after an initial rise in blood countsc) Little or no hematopoiesis noted on bone marrow analysis perfumed 30 to 40 days

or greater post-transplant

c) Reinfusion of allogeneic marrow with or without further conditioning (dependent

on patient's clinical condition)d) Reinfusion of ''backup" marrow or stem cells if availablee) Attempted marrow stimulation with colony-stimulating factors: granulocyte-macrophage colony-stimulating factor (Leukine, Prokine), 250 µg/m 2 /d IV, or

granulocyte colony-stimulating factor (Neupogen): 5 to 10 µg/kg/d

II Infectious Complications

A Infection 1 2, 5, 6, 8, 10, 11, 12, 13

1 Definition

a) Most frequently occurring complication of BMT, which exists when the body orpart of the body is invaded by a pathogenic agent that mutiples (colonizes) andproduces detrimental or injurious effects to the body

b) An opportunistic infection is one that is usually the consequence of defectivefunctioning of the normal immune system Such an infection is caused bymicroorganisms that lack virulent infection-producing properties, unless a defect orgroup of defects is present in the host's immune system.3

c) The timing of post-transplant bacterial, fungal, viral, and protozoal infectionvaries (see Figure 5.1 on p 125)

disorders: Staphylococcus aureus, Pseudomonas, Escherichia coli.)

c) Immunosuppression induced by the pretransplant preparative regimen,prophylaxis, or treatment for acute or chronic GVHD and the disease process ofGVHD

virus (VZV) and CMV Infections that result from humoral defects include

pyogenic organisms and Streptococcus pneumonia.

(2) Decreased serum immunoglobulin levels

3 Incidence

a) Occurrence of infection varies because of a number of host factors, which includeunderlying disease, host endogenous flora, and pretreatment infections

b) Overall incidence rates: 11

Table 5.3 Infectious Complications and Occurrence in BMT Recipients

First Month Post-Transplant

Viral:

genital

Bacterial:

Gram positive (S epidermidis, S auerus,

Streptococci)

Skin, blood, sinopulmonary

Gram negatives (E Coli, P aeruginosa,

Klebsiella)

Gastrointestinal, blood, oral, perirectal

Fungal:

Candida species (C albican, glabratta krusei) Oral, esophageal, skin

1–4 Months Post-Transplant

Viral:

Enteric viruses (rotavirus, coxsackie,

(continued)

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Table 5.3 (continued)

Protozoa:

Greater than 12 Months Post-Transplant

Sinopulmonary and blood

Reprinted with permission from Ezzone and Camp-Sorrell, 1994.

4 Risk factors/etiology

a) Hematologic/lymphoid malignancyb) Hematologic/lymphoid malignancy in relapsec) Excessive previous treatment

d) Prolonged neutropenia and immune deficiencye) Allogeneic transplant recipient

5 Clinical features/signs and symptoms (Table 5.4)

6 Management of fever in the neutropenic BMT patient

a) Thorough physical exam twice daily to identify potential sites of infection; culturepotential sites if possible

b) With onset of fever (> 38°C), panculture: Obtain blood cultures from all CVLsite, peripheral blood culture (optional), throat, urine, and stool cultures for bacteriaand fungus, and CMV buffy coat (optional)

c) Obtain chest x-ray with onset of fever

d) Initiate broad-spectrum gram negative and gram positive antibiotic coveragebased on transplant center's experience and pathogen history (2–3 drug combinationusually indicated)

e) Modify antibacterials based on culture sensitivities

f) Daily blood cultures with fever (rotate lumen cultured, or culture most frequentlymanipulated lumen from central venous line)

g) If defervescence results from broad-spectrum antibacterials, panculture with newfever spikes

h) If fever continues despite broad-spectrum antibacterials, fungal infection should

be presumed and systemic antifungal therapy initiated in the form of amphotericin B(minimum of 0.5 mg/kg/d)

Table 5.4 Clinical Features and Common Signs and Symptoms of Infection in BMT Patients

Fever, chills, malaise, night sweats Mycobacterium avium complex (MAC),

hepatitis, CMV, tuberculosis (TB)

fissures/fistulas (pseudomonas, Klebsiella)

chest tightness, rales

Pneumocystis carinii pneumonia, bacterial

infection, CMV, toxoplasmosis,

cryptococcosis Aspergillus, TB, MAC,

respiratory syncytial virus, adenovirus, parainfluenza

scaling, eruptions, necrotic ulceration

Varicella-zoster virus (VZV), HSV, fungus,

Genitourinary Rashes, lesions, ulcers, dysuria,

hematuria

HSV, adenovirus, bacteria, BK virus (human polyoma)

motor/sensory deficits

Cryptococcosis, toxoplasmosis, HSV, VZV,

Aspergillus

dysphagia, pharyngitis, esophagitis

Candidiasis, HSV, CMV, gram-negative bacteria

i) If fever continues despite broad-spectrum antibacterial and antifungal coverage, adiligent search for possible fever source is warranted (viral cultures, stool forelectron microscopy, frequent chest x-ray, culture and/or biopsy suspected lesions,meticulous evaluation of pain)

is undercooked, or is poorly stored

3 Clinical features

a) Early symptoms include vomiting and fever

b) Diffuse liquid diarrhea, which may be bloodyc) Painful abdominal cramps

a) Stool culture (should always send for ova and parasites and C difficile toxin with

any diarrheal illness)

b) Fecal leukocytes: Presence of white cells suggests bacterial infection, althoughneutropenic BMT patients are unable to mount white cell response

c) Stool from viral culture and electron microscopy to rule out viral infectiond) Serum electrolytes at least daily with high gastrointestinal losses, more frequently

if losses are excessive

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e) Stool electrolyte and osmotic gap:

Stool osmotic gap formula

= 290 - 2 X ([Na] X [K])

Secretory diarrheas tend to have elevated stool [Na] and a resultant lower osmotic gap (< 100mOsm/L) In viral illness and conditioning-related toxicity, the stool tends to have decreased [Na]and increased stool osmotic gap (> 100 mOsm/L) 8

f) Gastrointestinal endoscopy with culture and biopsy (rule out GVHD, and furtherevaluate infection)

6 Management

a) Treat dehydration with IV/PO fluids and correct electrolyte abnormalities

b) Bowel rest for 24 to 48 hours, then BRAT (bananas, rice, applesauce, toast) diet iftolerated

c) Continue total parenteral nutrition if already established

d) For culture positive bacterial enterocolitis, administer co-trimoxazole (8 mg/kg

divided qid for 21 days) or ciprofloxacin:

(1) Children: 20 to 30 mg/kg/24 h divided q12h for 10 to 14 days(2) Adults: 250 to 500 mg PO q12h for 10 to 14 days

C Bacterial pneumonia

1 Causative organisms

a) First month post-BMT: gram-positive organisms (Staphylococcus epidermidis, Streptococcus), gram-negative organisms (Pseudomonas aeruginosa, Klebsiella), and atypical organisms (Legionella, Chlamydia, Mycobacterium, Mycoplasma)

b) One to four months post-BMT: gram-positive organisms

c) Four to 12 months post-BMT: gram-positive organisms (S pneumoniae

[pneumococcal pneumonia], Haemophilus influenzae)

2 Risk factors

a) Debilitation

b) Chronic GVHD (pneumococcal pneumonia)

c) Increased age at time of transplant

a) Arterial blood gas to evaluate degree of hypoxemia

b) Isolation of causative organism through culture of sputum (low yield)

c) Bronchoalveolar lavage, transbronchial biopsy, computed tomography

(CT)—guided needle or open lung biopsy samples for culture and pathology

6 Management of bacterial pneumonia 5

a) Drug choices are based on causative organism and sensitivities

b) Empiric treatment includes broad-spectrum gram-positive and gram-negativecoverage (third-generation cephalosporin/aminoglycoside [see chapter 7])

(1) Children: ceftriaxone or cefotaxime plus gentamicin or tobramycin

(2) Adults (Mycoplasma, S pneumoniae, Legionella, and H influenzae):

azithromycin, clarithromycin, erythromycin, or doxycycline (rifampin may

be added for documented Legionella) (3) Adults (Klebsiella pneumoniae, Enterobacter, Chlamydia, S aureus):

erythromycin plus imipenem or ceftriaxone or cefotaxime

(4) Aspiration suspected, with severe mucositis (S pneumoniae, Bacteriodes,

or other oral flora): clindamycin or metronidazole(5) Pneumococcal pneumonia: penicillin G or third-generation cephalosporin

b) One to four months post-BMT: gram positive organisms

c) Four to 12 months post-BMT: gram-positive organisms (Streptococcus, H.

influenzae)

2 Clinical features

a) Gram-negative bacteremia causes massive vasodilation, resulting in deficientcirculating blood volume, cardiac output, and tissue perfusion Cellular hypoxia andacidosis result

b) Complications may include vascular collapse, adult respiratory distress syndrome(ARDS), renal failure, congestive heart failure, arrhythmias, DIC, and viral andfungal infections

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c) Signs and symptoms include

(1) Warm shock: fever; widening pulse pressure; change in level ofconsciousness and behavior; flushing; warm, dry skin; tachycardia;

tachypnea; decreased PO 2; urine output normal to slightly increased(2) Cool shock: cool skin, peripheral edema, tachycardia, hypotension,tachypnea, pulmonary congestion, progressive hypoxemia, oliguria, thirst(3) Cold shock: cold, clammy skin; tachycardia; thready pulse; severehypotension; high central venous pressure; high pulmonary wedge pressure;respiratory failure; profound hypoxemia; metabolic acidosis; severe oliguria

f) Chest x-ray: Rule out capillary leak or ARDS

4 Management

a) With above symptomatology, initiate empiric antibiotic therapy immediately aftercultures are obtained (empiric choice is broad-spectrum coverage for gram-negativeand gram-positive organisms and should be based on transplant center's pathogenhistory)

b) Modify antibacterials based on culture sensitivities

c) Ensure hemodynamic stability: crystalloid/colloid to maintain blood pressure andperfusion of vital organs.

d) Swan-Ganz thermodilutional catheter as needed to monitor and manage fluidstatus

e) Vasopressors to maintain blood pressure if crystalloid/colloid ineffectivef) Treat hypoxemia: oxygen support/mechanical ventilation if needed

E Clostridium difficile 5, 8, 14

1 Definition: C difficile causes a pseudomembranous enterocolitis infection secondary to

broad-spectrum antimicrobial use or chemotherapy, which alters the normal balance of gutflora

2 Risk factors

a) Prior history of C difficile colitis

b) Recent chemotherapyc) Prolonged use of antibiotic therapy

3 Clinical features

a) Feverb) Explosive, liquid diarrhea (may be bloody)c) Foul-smelling stool or flatulence

d) Crampy abdominal pain

4 Differential diagnosis

a) Viral enteritis (e.g., CMV, rotavirus, adenovirus)

b) Salmonella/Shigella enteritis

c) Giardiasisd) Chemotherapy/radiation (total body irradiation)-induced diarrheae) Gut GVHD

5 Diagnostic studies

a) Stool sample for C difficile toxin (also send bacterial, fungal, and viral studies to

rule out) Should be read at 24 and 48 hours If negative and diarrhea persists, repeatdue to possible sampling error (false-negative result)

b) Repeat C difficile stool sample after 10 to 14 days of therapy to ensure toxin has

e) Weight lossf) Enlarged lymph nodes may or may not be present

3 Differential diagnosis

a) GVHDb) Epstein-Barr virus (EBV) lymphomac) Hepatosplenic candidiasis

4 Diagnostic studies

a) M avium-intracellulare culture (requires special medium), including blood, stool,

and bone marrowb) Lymph node and liver biopsy (if highly suspect)

5 Management: Treat if culture is positive for acid-fast bacteria

a) Clarithromycin, 500 mg to 1 g bid, plus clofazimine, 50 to 100 mg qdb) If no improvement, add one to two additional drugs:

(1) Amikacin, 15 mg/kg/d IV bid(2) Ethambutol, 25 mg/kg/d qd for first 2 months(3) Rifampin, 10 to 15 mg/kg/d qd

c) These drugs have considerable side effects, and toxicities should be monitored

d) Blood cultures for M avium intracellulare should be negative if treatment is

c) Allogeneic transplant recipient

d) Chronic GVHD

3 Clinical features

a) Productive, prolonged cough

b) Fever, chills, night sweats

c) Loss of appetite, weight loss

b) Other bacterial, fungal, or viral infection/pneumonitis

c) Relapsed Hodgkin's or non-Hodgkin's lymphoma

5 Diagnostic studies

a) Pretransplant: purified protein derivative (PPD) tuberculin skin test with control

(Candida, mumps, tetanus toxoid) due to possible anergy: positive if TB skin test is

greater than 5-mm area of reaction

b) Chest x-ray: area of lobar consolidation

c) Sputum smear and culture

d) Bronchoalveolar lavage, transbronchial biopsy, CT-guided needle or open lungbiopsy samples for acid-fast bacteria, culture, immunofluorescent antibody andpathology

e) Lumbar puncture with samples for acid-fast bacteria and culture to rule out

c) Table 5.5 outlines current prophylaxis and treatment of TB 8, 14

Table 5.5 Prophylaxis and Treatment of TB

least 3 mo pre-BMT if possible.

Positive bronchoalveolar lavage

with pulmonary infiltrate and hilar

lymphadenopathy

Standard—6 mo isoniazid, rifampin & pyrazinamide for 2 mo, then isoniazid & rifampin for 4 mo

If drug resistance possible, add streptomycin or ethambutol to initial therapy until susceptibility is known.

Extrapulmonary other than

meningitis, disseminated (miliary),

or bone/joint

Isoniazid, rifampin, &

pyrazinamide qd for 2 mo, then isoniazid & rifampin 2 times/wk for 4 mo

For hilar LAD: 6 mo of isoniazid

& rifampin has been shown to be sufficient if drug resistance unlikely.

Alternative—9 mo (low incidence

of drug resistance) Isoniazid and rifampin daily for 9 mo

or

Isoniazid & rifampin daily for 1

mo, then isoniazid and rifampin 2 times/wk for 8 mo

Meningitis, disseminated (miliary),

or bone/joint

Isoniazid, rifampin, pyrazinamide,

& streptomycin qd for 2 mo, then isoniazid & rifampin qd for 10 mo

Give streptomycin in initial therapy until drug susceptibility known If resistance to

streptomycin possible, may use capreomycin or kanamycin instead

of streptomycin.

or

Isoniazid, rifampin, pyrazinamide,

& streptomycin qd for 2 mo, then isoniazid & rifampin 2 times/wk for 10 mo

* Capreomycin, kanamycin, ethionamide, para-aminosalicyclic, and cycloserine are difficult to manage and

should only be prescribed and monitored by a health-care provider experienced in their use.

Data from Johnson, 1993; Red Book, 1991.

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d) Table 5.6 outlines dosages and side effects of TB therapies

Table 5.6 Dosages and Side Effects of Current TB Theraphies

Vial: 1 g

mg

10–20 mg/kg/d PO/IV

secretion & urine, nausea, vomiting, hepatitis, febrile reaction, purpura (rare)

* Capreomycin, kanamycin, ethionamide, para-aminosalicyclic, and cycloserine are difficult to manage and

should only be prescribed and monitored by a health-care provider experienced in their use.

Data from Johnson, 1993: Red Book, 1991.

e) Cases of TB are reportable to the state Boards of Health

f) Consult the Infectious Disease service when managing a patient with TB

g) Isolation: Patients highly suspect for TB should be in a private, negative-pressureroom Health care providers should wear high-efficiency masks