Immunocompromised Host Infections

Question 1

Organisms associated with early (<1 month) infection in SOT

Answer 1

Bacterial infections, donor-derived infections

Question 2

Infections in SOT in intermediate (1-6 month) period

Answer 2

CMV, EBV, PK, PCP, Cryptococcus, TB

Question 3

Infections in SOT in late (>6 months) period

Answer 3

Lower risk than intermediate period but higher than normal population; caution with rejection treatment

Question 4

Immunodeficiency associated with alemtuzumab

Answer 4

T-cell deficiency (anti-CD52)

Question 5

Infections during early post-HCT period (out to 20-30 days)

Answer 5

Pre-engraftment period (from transplantation to neutrophil recovery, around 20–30 days post-HCT) (1) Infections associated with neutropenia and/or compromised mucosal barriers (2) Bacterial and fungal infections as well as reactivation of HSV (3) OI risk associated with potency of immunosuppressive regimen

Question 6

Infections in HCT: Early post-engraftment (from engraftment to day 100)

Answer 6

(1) Defects in cell-mediated immunity (2) Susceptible to common bacterial/viral infections as well as several opportunistic pathogens (e.g., CMV, PJP, and pathogenic molds such as Aspergillus) (3) Increased risk of GVHD with matched unrelated donors, mismatched donors, and/or cord blood recipient, which augments infection risk (4) T-cell depletion delays immune reconstitution, which is associated with opportunistic viral and fungal infections. (5) Cord blood transplant recipients may have an increased infectious risk because of delayed engraftment.

Question 7

HCT infections Late post-engraftment (after day 100)

Answer 7

(1) Increased OI risk during this period in patients with chronic GVHD, CMV- seronegative donor/CMV-seropositive recipient, and receipt of high-dose/myeloabla- tive and radiation-based chemotherapy regimens (2) OI risk decreases in patients whose immunosuppression is tapered and who do not have the previous risk factors

Question 8

Risk factors for HSV reactivation in malignancy/HCT

Answer 8

highest risk of reactivation include patients with acute leukemia, patients who receive alemtuzumab, patients who undergo allogeneic HCT, and patients with GVHD requiring treat- ment with steroids.

Question 9

Most common cause of community-acquired encephalitis

Answer 9

Most common cause of community-acquired encephalitis ii. HSV accounts for 5%–10% of all encephalitis cases worldwide. iii. More than 90% caused by HSV-1

Question 10

Acyclovir-resistant HSV mechanism and cross-resistance

Answer 10

Treatment of acyclovir-resistant HSV i. Occurs in around 3%–6% of immunocompromised individuals (a) Usually caused by decreased thymidine kinase activity, which confers resistance to simi- lar antivirals such as famciclovir and ganciclovir

Question 11

Indications for primary HSV ppx in SOT

Answer 11

SOTRs: Antiviral prophylaxis should be considered for all HSV-seropositive recipients not
already receiving CMV prophylaxis (see text that follows).
(a) Acyclovir 400–800 mg orally twice daily
(b) Valacyclovir 500 mg orally twice daily
(c) Famciclovir 500 mg orally twice daily

Question 12

Indications for HSV ppx in HCT

Answer 12

Patients with hematologic malignancy and/or recipients of HCT: Primary prophylaxis during active therapy, including periods of neutropenia (a longer period of HSV prophylaxis may be considered for HCTRs with GVHD and/or previous frequent HSV reactivations)

Question 13

Greatest risk group for CMV disease in SOT

Answer 13

greatest risk of CMV infection is in CMV-seronegative recipients who receive an allograft from a CMV-seropositive donor.

High risk: D+/R-
Intermediate: any R+
Low: D-/R-

Question 14

CMV risk factors in SOT

Answer 14

CMV risk factors in SOTRs: (a) Immunosuppression (type of drug, dose, timing, and duration) (1) Use of lymphocyte-depleting agents increases risk. (2) Use of mTOR (mammalian target of rapamycin) inhibitors decreases risk. (b) Host factors (age, comorbidities, leukopenia, lymphopenia)

Question 15

spectrum of CMV disease

Answer 15

CMV disease: CMV replication and signs/symptoms (a) CMV syndrome: Malaise, cytopenias, fever (b) Tissue-invasive CMV disease: Pneumonitis, enteritis, hepatitis, encephalitis, retinitis (c) CMV retinitis is the most common manifestation of CMV disease in patients with HIV infection. (d) CMV enteritis is the most common manifestation of CMV disease in SOTRs. (e) CMV pneumonitis is the most common manifestation of CMV disease in patients with hematologic malignancy.

Question 16

Treatment of invasive CMV disease

Answer 16

disease, high viral load, or uncertain GI absorption. ii. Treatment should be continued until resolution of clinical symptoms, virologic clearance; for at least 2 weeks iii. Consider 1–3 months of secondary prophylaxis (maintenance dosing) after completion of ini- tial induction therapy with valganciclovir 900 mg orally once daily or ganciclovir 5 mg/kg intravenously once daily.

Question 17

CMV prophylaxis

Answer 17

Duration depends on donor and recipient CMV serological profile as well as type of SOT allograft. vi. 200 days is preferred to 100 days in most CMV donor-seropositive, CMV recipient- seronegative SOTRs (according to data from kidney SOTRs), though the optimal duration of prophylaxis is unclear in lung SOTR

Question 18

CMV preemptive therapy most common population

Answer 18

x. Preemptive therapy (as follows), rather than antiviral prophylaxis, is usually used for patients with malignancy at high risk of CMV (allogeneic HCTRs and recipients of alemtuzumab).

Question 19

Treatment of EBV-PTLD

Answer 19

Treatment of EBV-PTLD i. Surgical resection/local irradiation ii. Reduce immunosuppression (if possible) iii. Anti-CD20 therapy with rituximab (375 mg/m2 once weekly) for CD20+ B-cell PTLD iv. Cytotoxic chemotherapy

Question 20

VZV natural history

Answer 20

VZV 1. Overview a. Transmitted by aerosolized droplets or direct contact b. Incubation period of about 2 weeks c. Infectivity begins 48 hours before onset of rash and ends when all skin lesions have fully crusted

Question 21

BK virus characteristics

Answer 21

BK virus 1. Overview a. Polyomavirus b. Infection occurs commonly in the first decade of life. c. Remains latent in renal epithelial cells d. Asymptomatic urinary shedding may occur in immunocompetent individuals without consequence

Question 22

BK virus disease manifestations

Answer 22

SOTRs i. Cause of polyomavirus-associated nephropathy in 1%–15% of renal SOTRs, drastically increasing the risk of allograft loss

Patients with hematologic malignancy and/or HCTRs i. Cause of hemorrhagic cystitis in allogeneic and autologous HCTRs ii. Recent cohort showed that around 13% of allogeneic HCTRs developed hemorrhagic cystitis secondary to BK virus.

Question 23

BK nephropathy management

Answer 23

Reduce immunosuppression.
(a) Reduce goal concentrations of tacrolimus, cyclosporine, and/or sirolimus.
(b) Reduce mycophenolate mofetil dose to 1000 mg/day or less.
(c) Change from tacrolimus to cyclosporine or sirolimus, or change from mycophenolate
mofetil to leflunomide or sirolimus.

Antiviral therapy may be considered if reduced immunosuppression yields inadequate response. (a) Cidofovir 0.25 – 1 mg/kg intravenously at 1–3 weekly intervals, without probenecid (b) Leflunomide as a replacement for mycophenolate mofetil at 100 mg orally once daily for 5 days, followed by 40 mg orally once daily (goal teriflunomide concentration 40–100 mcg/mL)

Question 24

BK hemorrhagic cystitis management

Answer 24

BK hemorrhagic cystitis i. Symptomatic: Analgesia, hyperhydration, diuresis, continuous bladder irrigation ii. Antiviral therapy (a) Cidofovir 5 mg/kg intravenously weekly for 2 weeks; then every other week thereafter with probenecid OR (b) Low-dose cidofovir: 1 mg/kg intravenously weekly without probenecid

Question 25

Adenovirus treatment

Answer 25

iii. Cidofovir (a) Cytosine analog that interrupts adenovirus replication (DNA polymerase substrate) (b) Associated with electrolyte abnormalities and nephrotoxicity (c) Dose: 5 mg/kg intravenously once weekly for 2 weeks, followed by 5 mg/kg intravenously every 2 weeks or 1 mg/kg intravenously three times weekly

Question 26

Treatment of Candida endocarditis

Answer 26

Endocarditis: Lipid formulation of amphotericin B (3–5 mg/kg intravenously once daily with or without flucytosine (25 mg/kg orally four times daily) or high-dose echinocandin (caspo- fungin 150 mg intravenously once daily, micafungin 150 mg intravenously once daily, or anidulafungin 200 mg intravenously once daily)

Question 27

Histo vs Blasto distribution

Answer 27

Histoplasma capsulatum: Exists worldwide, but the most endemic region is the Ohio/Mississippi river valleys e. Blastomyces dermatitidis i. Native to North America, though cases reported worldwide ii. The most endemic regions are in the midwestern United States and in the Canadian provinces that border the Great Lakes

Question 28

Histoplasmosis prevention in HIV

Answer 28

Histoplasmosis (a) If CD4+ cell count less than 150 cells/mm3 , avoid activities associated with increased risk of endemic fungal infection (e.g., creating dust when working with surface soil, exposure to bird/bat droppings, remodeling old buildings) (b) Prophylaxis with itraconazole 200 mg orally once daily may be considered if CD4+ cell count less than 150 cells/mm3 if high risk because of occupational exposure and/or hype- rendemic rate in community

Question 29

Duration of PCP ppx in SOT

Answer 29

SOTRs i. In general, PJP prophylaxis should be given for at least 6–12 months post-SOT, though longer durations may be considered. ii. Lifelong prophylaxis may be considered for lung and small bowel SOTRs, as well as for any SOTR with a history of PJP or chronic CMV disease.

Question 30

PCP ppx in HCT

Answer 30

Patients with malignancy and/or HCTRs i. Allogeneic HCTRs: At least 6 months of prophylaxis and while receiving immunosuppressive therapy ii. Patients with acute lymphoblastic leukemia: Prophylaxis throughout acute lymphoblastic leu- kemia therapy iii. Recipients of alemtuzumab: For at least 2 months after receipt of the drug and until the CD4+ cell count is greater than 200 cells/mm3 iv. Recipients of purine analog therapy (e.g., fludarabine, cladribine) and other T cell–depleting agents until CD4+ cell count greater than 200 cells/mm3 v. Autologous HCTRs for 3–6 months post-HCT

Question 31

M Kansas I

Answer 31

M. kansasii (a) First-line: Isoniazid 300 mg orally once daily (with pyridoxine 50 mg orally once daily), rifampin 600 mg orally once daily, ethambutol 15 mg/kg orally once daily (b) Second-line: Clarithromycin, azithromycin, amikacin, moxifloxacin, sulfamethoxazole, streptomycin

Question 32

Management of Nocardia

Answer 32

Initial therapy depends on Nocardia spp. and infection site/severity. i. Pulmonary infection (stable) (a) Primary/empiric therapy: Trimethoprim/sulfamethoxazole 15 mg/kg/day (depending on trimethoprim component) in three or four divided doses intravenously or orally (b) Alternative: Imipenem 500 mg intravenously four times daily (imipenem more active against Nocardia than other carbapenems) with amikacin 10–15 mg/kg intravenously once daily or minocycline 200 mg intravenously or orally twice daily or linezolid 600 mg intravenously or orally twice daily (c) Duration: 6–12 months Cerebral infection (a) Primary/empiric therapy: Imipenem 500 mg intravenously four times daily and amikacin 10–15 mg/kg intravenously once daily or imipenem 500 mg intravenously four times daily and trimethoprim/sulfamethoxazole 15 mg/kg/day (depending on trimethoprim compo- nent) in three or four divided doses intravenously or orally (b) Alternative: Linezolid 600 mg intravenously or orally twice daily or ceftriaxone 2 g intra- venously twice daily or cefotaxime 2 g intravenously three times daily or minocycline 200 mg intravenously orally twice daily (c) Duration: Parenteral therapy 3–6 weeks; then change to oral therapy for at least 9–12 months

Question 33

Treatment of toxoplasma CNS disease

Answer 33

Treatment a. Pyrimethamine 200 mg orally once; then 75 mg orally once daily (if weight greater than 60 kg) or 50 mg orally once daily (if weight 60 kg or less) plus sulfadiazine 1500 mg orally four times daily (if weight greater than 60 kg) or 1000 mg orally four times daily (if weight 60 kg or less) plus leu- covorin 10–25 mg orally once daily b. Duration: At least 6 weeks, depending on response to therapy

Question 34

Strongyloides treatment

Answer 34

Treatment a. Ivermectin i. For hyperinfection and disseminated disease, may need to give 200 mcg/kg orally once daily for 7–14 days ii. For chronic infection, 200 mcg/kg orally once daily for 2 days iii. For chronic infection, may consider repeat dose at 2 weeks to treat less-susceptible forms by life cycle stage b. Alternatives i. Albendazole 400 mg daily in divided doses for 3 days, with treatment repeated 1 week later

Question 35

High-risk febrile neutropenia patients are those with:

Answer 35

anticipated prolonged (.7 days duration) and profound neutropenia (ANC <100 cells/mm3 following cytotoxic chemotherapy) and/or significant medical co-morbid conditions, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes.

Question 36

MASCC score cutoff for high/low risk neutropenia

Answer 36

. High-risk patients have a MASCC score ,21 (B-I). All patients at high risk by MASCC or by clinical criteria should be initially admitted to the hospital for empirical antibiotic therapy if they are not already inpatients (B-I). ii. Low-risk patients have a MASCC score >21 (B-I). Carefully selected low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy (B-I).

Question 37

Indications for empiric Gram-positive coverage in febrile neutropenia

Answer 37

``` Severe sepsis Pneumonia Suspected CRBSI SSTI History of colonization Severe mucositis through FQ ppx if cephalosporins used ```

Question 38

Mean time to defervescence in FN with empiric abx

Answer 38

With empirical antibiotics, the median time to defervescence in patients with hematologic malignancies, including HSCT, is 5 days [63, 129–130], whereas for patients at lower risk with solid tumor, de- fervescence occurs at a median of 2 days

Question 39

Recommendations for unexplained persistent F on empiric abx for clinically stable patients with febrile neutropenia

Answer 39

Unexplained persistent fever in a patient whose condition is otherwise stable rarely requires an empirical change to the initial antibiotic regimen. If an infection is identified, antibiotics should be adjusted accordingly (A-I). In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recovery; the traditional endpoint is an increasing ANC that exceeds 500 cells/mm3 An im- portant exception, as noted above, is for low-risk outpatients who are being treated with empirical oral or IV therapy. If they have not responded with improvements in fever and clinical symptoms within 48 h, they should be re-admitted to the hos- pital and re-evaluated, and an IV broad-spectrum antibacterial regimen should be initiated.

Question 40

Causes of false-positive B-D-toucan

Answer 40

hemodialysis, hemolysis, serum turbidity, hyperlipidemia, visible bilirubin, use of blood products including immuno- globulin and albumin, bacteremia, and the specimen’s exposure to gauze may confound interpretation of the test.

Question 41

Benefit of FQ ppx in high-risk neutropenia

Answer 41

A meta-analysis of 17 placebo-controlled or no treatment– controlled trials of fluoroquinolone prophylaxis demonstrated a relative risk reduction of 48% and 62% in all-cause mortality and infection-related mortality, respectively, among fluo- roquinolone recipients [161], especially among recipients of ciprofloxacin (RR, 0.32; 95% CI, 0.13–0.82)

Question 42

Use of CSFs in febrile neutropenia

Answer 42

Myeloid CSFs are not recommended as adjuncts to antibiotics for treating established fever and neutropenia. Although days of neutropenia, duration of fever, and length of hospital stay have been minimally (but statistically significantly) decreased in some randomized studies, the actual clinical benefit of these reduc- tions is not convincing

Question 43

Acyclovir ppx in neutropenia

Answer 43

HSV-seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive acyclovir antiviral prophylaxis (A-I). Prophylaxis should be given until recovery of the white blood cell count or resolution of mucositis, whichever occurs later. Duration of prophylaxis can be extended for persons with frequent recurrent HSV infections or those with GVHD or can be continued as VZV prophylaxis for up to 1 year [273].

Question 44

Prophylaxis vs preemptive tx in SOT D+/R-

Answer 44

Liver/kidney: either (ppx x3-6 months) Heart/pancreas: ppx x3-6 months Lung: ppx x6-12 months

Question 45

CMV prevention in SOT R+

Answer 45

Kidney/liver: either (ppx x3 months) Heart: either (ppx x3 months) Lung: ppx x6 months

Question 46

Impact of thymo on CMV prevention

Answer 46

We recommend that treatment of rejection with anti- lymphocyte antibodies in at-risk recipients should result in reinitiation of prophylaxis or preemptive therapy for 1 to 3 months (weak, moderate)266-268; a similar strategy may be considered during treatment of rejection with high dose ste- roids or plasmapharesis (weak, very low).

Question 47

Duration of treatment of CMV disease

Answer 47

treatment doses of (val)ganciclovir are recommended until eradication of CMV DNAemia below a specific threshold and resolution of all clinical signs of CMV disease. Eradica- tion of CMV DNAemia is defined as below LLOQ on 1 highly sensitive assay (LLOQ < 200 IU/mL; see Diagnostic section), or lack of detection on 2 consecutive less sensitive assays. Secondary prophylaxis, de- fined as continuing prophylactic doses after discontinuing treatment dosing, is not associated with fewer relapses after suppression of CMV DNA.60

Question 48

Suspicion for drug resistance in CMV in SOT

Answer 48

• Drug resistance should be suspected in patients with a prior cumulative (val)ganciclovir exposure that exceeds 6 weeks and clinical treatment failure despite at least 2 weeks of antivi- ral treatment or development of CMV DNAemia during pro- phylaxis (see Resistance section)(strong, moderate)