Neutropenia, SOT, HSCT

Question 1

Intensity of therapeutic immunosuppression

Answer 1

Induction therapy - highest

Maintenance therapy - less, +/- GVHD Tx

Question 2

Lymphocyte-depleting agents increase risk . . .

Answer 2

cytomegalovirus (CMV),

polyoma BK virus,

Pneumocystis species,

and other fungi.

Question 3

EBV–associated posttransplant lymphoproliferative disease (PTLD)

higher risk in patients taking . . .

Answer 3

lymphocyte-depleting agents and

in those receiving sirolimus and tacrolimus

Question 4

Timeline and risk for infection SOT

Answer 4

Early Period (<1 Month ): surgical site and other nosocomial infections, IFI, and site specific related to the transplanted organ

Middle Period (1-6 Months ): viruses, opportunistic pathogens, IFI, Tb

Late Period (>6 Months )a: community accuired infections (more severe presentations) + infections associated to middle period

Question 5

Immune risks for infection BMT timeline . . .

Answer 5

– Neutropenia (early)

• Bacterial infections
• Fungal infections

– Impaired cellular and humoral immunity (late)

• Bacterial infections
• Fungal infections
• Viral infections

Question 6

Approach for the boards SOT, BMT, neutropenia

Answer 6

– Patient’s age, disease, history impact risks after BMT

– What kind of BMT did the patient have?

– Is the patient early vs. late after BMT?

Type of BMT and timeline impacts immunity, drugs and exposures

Question 7

Pulmonary Complications BMT

Answer 7

– Aspiration events with severe mucositis early after BMT

– Encapsulated sinopulmonary pathogens late after BMT

• Filamentous fungi early and late (A. fumigatus)
• Respiratory virus infection follows seasonal epidemiology

Adenovirus: reactivation and acute infection (particular issue with kids)

– HSV classically described with prior airway manipulation

Question 8

Early non‐infectious lung injury

Answer 8

• Diffuse alveolar hemorrhage: Vasculitis, drug‐induced injury, cancer‐chemotherapy / thrombocytopenia
• Idiopathic pneumonia syndrome

Question 9

Think Fusarium spp if . . .

Answer 9

Positive BCx and skin lesions (also PNA?)

Question 10

DDx of Late pulmonary syndromes

Answer 10

– CMV disease

– Respiratory virus infections

– PCP

• Non‐infectious – Bronchiolitis obliterans syndromes

Question 11

CMV Infection after BMT

– Highest risk group

Answer 11

Reactivation: Highest risk group for viral disease: D‐ / R+

Primary infection: D+ / R‐ or blood products (rare)

• Pneumonitis • Gastrointestinal disease • Encephalitis, retinitis less frequent

Question 12

CMV Tx after BMT

Answer 12

– Pre‐emptive with ganciclovir driven by PCR

• Not prophylaxis (SOT) with ganciclovir;

– Induction therapy with maintenance GCV

– Resistance to GCV is rare (as opposed to SOT)

Question 13

Pneumocystis Pneumonia Prophylaxis in BMT

Answer 13

– Bactrim

• Dapsone, atovaquone, aerosolized pentamidine

– Less effective, other infections occur**

Question 14

Pneumonia + encephalitis + fever in patient w/o BACTRIM prophylaxis, THINK . . .

Answer 14

Toxoplasmosis

Question 15

Bronchiolitis Obliterans

Answer 15

Chronic GVHD of lung; late s/p BMT

Question 16

GVHD: Acute (early after HSCT)

Answer 16

– Fever

– Rash

– GI: hepatic, colon

Question 17

GVHD: Chronic (later after HSCT)

Answer 17

– Skin changes (lichen planus, sceroderma)

– Hepatic (cholestatic)

– Ocular (keratoconjunctivitis)

– GI (oral, dysphagia)

– Pulmonary syndromes

Question 18

Chronic diarrhea mimicking GVHD

Answer 18

Norovirus

Question 19

Adenovirus Infection after BMT

Answer 19

• More common in children, high risk BMT
• Enteritis, cystitis, upper respiratory infection, pneumonia, encephalitis, hepatitis

Question 20

DDx of Hemorrhagic Cystitis

Answer 20

• Conditioning related (early) – Cyclophosphamide
• BK virus (later)
• Adenovirus (later)

Question 21

Selected DDx of Neurologic Syndromes

Answer 21

– HHV6*

– West nile virus

– JCV – PML (especially with T‐depleting Abs)

– Pulmonary + CNS lesions: • Invasive fungal infections • Nocardia • Toxoplasmosis

• carbapenems, cefepime, PRES*

Question 22

HHV‐6 after BMT

Answer 22

Meningoencephalitis

ACV‐resistant. Treat with ganciclovir, foscarnet, cidofovir

Question 23

Posterior reversible encephalopathy (PRES), associated with . . .

Answer 23

Calcineurin inhibitors: Cyclosporin*, tacrolimus

Question 24

PLAY THE ODDS

Answer 24

• Patient completing valganciclovir prophylaxis 6 weeks prior presenting with fatigue, low grade fever and leukopenia • CMV Syndrome
• Donor died from skiing accident in fresh water lake in Florida and recipient presents 3 weeks post transplant with encephalitis • ACANTHAMOEBA
• Renal transplant recipient on valganciclovir prophylaxis presents with asymptomatic renal dysfunction • BK Virus
• Lung transplant recipient planted vegetable garden 2 weeks prior while on posaconazole prophylaxis and presents with productive cough and cavitary lung lesion • NOCARDIA

Question 25

Listeria monocytogenes in SOT

Answer 25

• Bacteremia with or without meningitis

Question 26

Nocardia in SOT

Answer 26

* Most often pulmonary nodules, CNS (15-20%), skin (15%), or bone (2-5%) * Nocardia is Neurotropic; r/o asymptomatic brain abscess Branching, Gram positive rods • Partially acid-fast by modified Kinyoun stain • TMP-SMX considered drug of choice

Question 27

CMV Syndrome

Answer 27

* CMV blood PCR postive and * Fever and * One or more of the following - Malaise, leukopenia, atypical lymphocytosis, thrombocytopenia, elevated hepatic enzymes

Question 28

Greatest risk for CMV disease after SOT

Answer 28

D+/R- and ALA Therapy (R+)

Question 29

CMV prophylaxis s/p SOT

Answer 29

Bottomline: * D+/R- or ALA for rejection → **Universal** * R+ → **Universal or Preemptive**

Question 30

GI CMV disease after SOT

Answer 30

## Footnote CMV disease of GI tract may not have detectable viremia; diagnosis often requires tissue biopsy Viral load may continue to rise during first 2 wks of Rx

Question 31

EBV - PTLD risk factors

Answer 31

* Primary EBV infection • (D+ / R-) * Antilymphocytic antibody therapy * Organ transplanted • (intestine \> lung \> heart \> liver \> kidney)

Question 32

EBV - PTLD * Clinical manifestation * Diagnosis * Tx

Answer 32

_Clinical manifestation:_ * Febrile mono-like illness + lymphadenopathy * Solid tumors _Diagnosis_: biopsy _Tx_: * Reduce Immunosuppression * **Rituximab** - anti-CD20 monoclonal antibody

Question 33

BK virus nephropathy pearls

Answer 33

Cause of nephropathy post renal transplant • Up to 15% of patients Manifests as unexplained renal dysfunction (same as w/ rejection) Renal Bx - “Gold Standard” for diagnosis Blood PCR as indicator for biopsy Detection in Low PPV but High NPV Tx: Reduce immunosuppression

Question 34

SOT: Toxoplasmosis Risk factors and Tx

Answer 34

• Acquired from donor, reactivation, blood transfusion or ingestion **• D+ / R-** * HEART \> LIVER \> KIDNEY TRANSPLANT * TREATMENT: **sulfadiazine-pyrimethamine-leucovorin**

Question 35

Selected Unexpected D+ derived infections in SOT

Answer 35

* Lymphocytic choriomeningitis virus (LCMV): Hamsters and rodents * Rabies virus * Chagas’ Disease (Trypanosoma cruzi) * HIV, HCV, HBV, West Nile Virus (WNV) * Remember the “Window” prior to development of antibodies

Question 36

OTHER PEARLS FOR BOARDS… SOT

Answer 36

\>If you’re thinking PCP but its not ⇒ think TOXO \>Patient presenting atypically during first month post transplant ⇒ think donor transmitted infection \>Remember drug interactions and syndromes • TTP and PRESS (RPLS) induced by calcineurin inhibitors • Sirolimus-induced pneumonitis \>Remember Strongyloides hyperinfection syndrome \>TB- Don’t miss a case! \>BK, CMV and EBV/PTLD – know how to diagnose and manage

Question 37

Immune suppression drug associations Rituximab (anti‐CD20) ⇒ Alemtuzimab (anti‐CD52) ⇒ BCR – ABL Tyrosine – kinase inhibitors – (ex. imatinib, dasatinib, nilotinib, more)

Answer 37

* **Rituximab** (anti‐CD20) • **Hepatitis B reactivation, PML** * **Alemtuzimab** (anti-CD52): Herpes viruses (esp. **CMV**), fungal infections (**PJP**, Aspergillus) * Imatinib, dasatinib, nilotinib, etc: • (**VZV** reactivation, Hep B reactivation). * JAK/STAT inhibitors (ex. tofacitinib, ruxolitinib): VZV, CMV, PCP, M. Tb

Question 38

Neutropenic “syndromes” Viridans Streptococci

Answer 38

• **Key points:** neutropenia, mucositis, high‐dose cytosine arabinoside, fluoroquinolone * Can present with fever, flushing, chills, stomatitis, pharyngitis * **VGS shock syndrome** * Endocarditis unusual (\<10%) * **S. mitis, S. oralis**

Question 39

* Typical patient‐ neutropenic, progressive sepsis * Recognize holes in protection, specific syndromes

Answer 39

* – ARDS, rash, quinolones, mucositis ⇒ viridans Streptococci * – Sepsis with β‐lactams ⇒ Stenotrophomonas, ESBL * – Sepsis with carbepenems ⇒ KPC * – Lung and skin lesions ⇒ P. aeruginosa, Fungi * – Skin lesions, gram + ⇒ Corynebacterium jeikeium * – Mucositis (upper, lower tract) ⇒ Fusobacterium spp., Clostridium spp., Stomatococcus mucilaginosis

Question 40

Neutropenia and Skin Lesions

Answer 40

* **Candidiasis** – Small, tender papules * **Aspergillus** – ulcerative, necrotic, minimal erythema * **Other filamentous fungi** (Fusarium, P. boydii) – Multiple, erythematous, different stages * **P. aeruginosa** – Ecthyma gangrenosum

Question 41

Neutropenia and Fusarium

Answer 41

Invasive pulmonary disease with skin lesions

Question 42

Neutropenic Enterocolitis

Answer 42

• Neutropenic enterocolitis (typhlitis) – Can be accompanied by bacteremia • Hint: mixed, anaerobic (C. septicum, C. tertium, B. cereus)

Question 43

Hepatosplenic Candidiasis

Answer 43

Fungi invaded by portal vasculature • Presentation after engraftment: abdominal pain, increased LFTs (alk phosph), fever, leg / flank pain

Question 44

Alemtuzumab • Anti‐CD52 Ab (**Campath**)

Answer 44

* Reactivation of **CMV** is the most common infectious complication * Other risks: PCP, IFI (T cell)