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A 29-year-old APL patient presented with neutropenic fever

DR. SHARMIN EASMIN

PHASE-B RESIDENT

GREEN UNIT

HAEMATOLOGY DEPARTMENT

BSMMU

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Mrs. Rabeya akter, 29 years old housewife presented with the complaints of-
Fever for 10 days
Reddish and blackish spots over chest, arm and leg for same duration.
After clinical evaluation & investigations including bone marrow morphology, immunophenotyping and cytogenetic study she was diagnosed as a case of high risk Acute prolymphocytic leukemia

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Treatment:

Then she started Induction therapy
DA 3+7 from 26/05/2022 to 01/06/2022

( Inj. Daunorubicin 50mg/m² & Inj. Cytarabine 100 mg/m² )

ATRA 45 mg/m²
After induction therapy her-

CBC with PBF, Liver function, renal function & other biochemical marker were normal.

No other complications.

On 12/06/2022

Bone marrow study- morphological remission
PML/RARA Quantitative,PCR assay - negative

NCCN Guidelines Version 2.2022

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Then Consolidation therapy started on 05/07/2022-
HIDAC ( High dose Cytarabine 3 gm/m^{2 )}
ATRA continue as 2 weeks on and off

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On Day 13 of consolidation-

Headache
Blurring of vision
Double vision
Squint
On neurological examination : All cranial nerves were intact.

Fundoscopy- Papilloedema
CNS imaging- normal
Lumbar puncture & triple IT
CSF study: CNS status-1 on 06/07/2022

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On day-22 of consolidation therapy she developed :

Fever-

high grade,

continuous in nature,

highest recorded temperature 103⁰ F

associated with vomiting

not associated with chills and rigor & sweating

Cough-

Dry

Non productive

No chest pain,

No haemoptysis

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On general examination:
Severely anaemic
Dyspnoeic
Wet purpura and petechiae over neck,arm & leg
Abdominal distension
Pitting oedema – both legs
BP- 130/80 mm Hg
Pulse – 110 beat/min
SPO2 – 97-98%
Temperature- 104⁰F

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Respiratory examination:

SOB

Cough
No chest pain, haemoptysis

O/E-

RR – 32/ min
Breath sound diminished – mid & lower zone of both lung field
Bilateral basal creps on both lung field

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Gastrointestinal examination:

Tender
Shifting dullness – present
Bowel sound - present
No organomegaly

MASCC score < 21

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Haematological parameter

CBC	19/07/2022	21/07/2022	23/07/2022	25/07/2022
Hb	4.7 g/dl	6.8 g/dl	6.2 g/dl	10.4 g/dl
ESR	60 mm/1^st hour	20 mm/1st hour	50mm/1^sthour	50mm/1^sthour
T WBC	0.12 X ^9/L	0.12 X ^9/L	0.08 X ^9/L	0.14 X ^9/L
Platelet	20 x 10^9/L	5 x 10^9/L	25 X10^9/L	9 X 10^9/L
ANC	10	00	00	50

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	17/07/2022	20/07/2022	24/07/2022
Serum electrolyte	Na -130mmol/L	Na -126mmol/L	Na -130mmol/L
	K – 3.9 mmol/ L	K – 4.1 mmol/ L	K – 2.6 mmol/ L
	Cl – 110 mmol/L	Cl – 110 mmol/L	Cl – 110 mmol/L
Serum calcium		8.6 mg/dl	6.7 mg/dl
LDH			660 IU/L
Ferritin			2244 mcg/L
SGPT			24U/L
Bilirubin ( total )			0.5 mg/dl

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PT – normal
APTT – normal
CRP - > 200 mg/L ( 25/07/2022 )
Procalcitonin – 18.92 ug/L ( 25/07/2022 )
Lactate – 1.5 mmol /L
Uric acid – 2.7 mg/dl ( 25/07/2022 )
Blood,Urine,throat swab,canula site – No growth
Chest x-ray – not done

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Defination:

Sepsis:

Patients with suspected infection who have 2 or more of :

Hypotention- SBP < 100 mmHg
Altered mental status- Glasgow Coma Scale score ≤ 14
Tachypnoea – respiratory rate ≥ 22 breaths /min

Sepsis can also be diagnosed by suspected infection and increase of ≥ 2 points on the SOFA score.

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SOFA score ( Sequential Organ Failure Assessment tool )

A score of 1-4 is allocated to six organ systems ( respiratory,cardiovascular,liver,renal,coagulation & neurological ) to represent the degree of organ dysfunction, e.g. platelet count < 150 x10^9/L scores 1 point, < 25 x10^9/L scores 4 points.

Composite score out of 24

Higher scores are associated with increased mortality

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Diagnosis:

High risk APL with febrile neutropenia

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Definitions�

FN is defined as a single oral temp of ≥38.3°C (101°F) or ≥38.0°C (100.4°F) sustained over 1 hr. period.
Neutropenia <500 / mcL or <1000/mcL with predicted to be fall to <500/mcL within next 48 hour.

NCCN Guidelines Version 2.2022

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Emperic Antimicrobial therapy in febrile neutropenic patient

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Initial evaluation

Low risk

Out patient

No associatd comorbidity

Anicipated short duration of severe neutropenia (<100 cells/mcl for 7 days )

Good performance status ( ECOG 0-1 )

No hepatic or renal insufficiency

MASCC risk index score of > 21

Home or out patient treatment

High risk

MASCC risk index score <21 or CISNE score>3b

Inpatient status at the time of development of fever

Anicipated prolonged severe neutropenia (<100 cells/mcl for >7 days )

Severe hepatic or renal insufficiency

Uncontrolled /progressive cancer

Pneumonia or other complex infections at cinical presentation

Mucositis grade 3-4

Hospital admission

MASCC

CISNE

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MASCC, Muitinational Association of supportive care in cancer�maximum theoretical score is 26

Catagory	Weight
Burden of illness:no or mild symtopms No hypotension No chronic obostructive pulmonary disease Solid tumor or no previous invasive fungal infection Out patient status Burden of disease :moderate symptoms No dehydration Age< 60 year	5 5 4 4 3 3 3 2

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Physical examination

General physical examination.
Major co-morbid illness.
Time since last chemotherapy
Emphasis on infected sites, including

Skin, Catheter sites,
Biopsy and bone marrow aspirate sites,
Teeth, Oropharynx and gingival surfaces, Sinuses,
Lungs,
Abdomen, genitals and perianal area

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Routine laboratory tests

CBC with differential- Duration of neutropenia, Severity of neutropenia
LFTs, electrolytes, serum creatinine, blood urea nitrogen, serum lactate
Urinalysis, and cultures
Chest Xray
02 sets of blood cultures, Each set should have a volume of 20 mL
Specimens should be obtained from other sites as clinically indicated- Sputum, urine, CVC exit site, CSF, skin, stool

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Serum fungal markers tests �

test for Covid-19
viral diagnosis by PCR
Aspergillus galactomannan antigen and beta-D-glucan assay in high-risk patients.

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Initial empiric therapy�

General principles of empiric therapy
Initial antibiotic selection based on

Patient's history
Allergies
Symptoms and signs
Recent antibiotic use and culture data,
Institutional nosocomial infection and susceptibility patterns.
Antibiotics should be bactericidal.
In high-risk patients, antibiotics should generally be IV in a hospital .

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Spectrum of coverage

Gram-positive bacteria are the most frequent pathogens during FN
Gram-negative organisms continue to cause the majority of infections in other sites (e.g., respiratory tract, biliary tract, GIT, UTI, and skin).
Anaerobic coverage is not necessary to include specific anaerobic antibiotic in initial regimen.
Duration of profound neutropenia increases, the risk of invasive fungal infections.

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Recommended Approach

approach for initial therapy of high-risk neutropenic patients with fever:

●Initiation of monotherapy with antipseudomonal beta-lactam agent, such as

Cefepime,
Meropenem,
Imipenem-cilastatin,
Piperacillin-tazobactam.

NCCN Guidelines Version 2.2022

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Recommended Approach

Avoid ceftazidime monotherapy because of rising resistance rates among gram-negative bacteria and its limited activity against gram-positive bacteria, such as streptococci, compared with newer.

Ceftazidime monotherapy should not be used in gram-positive infection, such as an infection caused by viridans group streptococci in patients with severe mucositis.

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Recommended approach

The dosing of these agents for patients with normal renal function using traditional dosing (IV, over 30 minutes) are:
Cefepime – 2 g IV every eight hours
Meropenem – 1 g IV every eight hours
Imipenem-cilastatin – 500 mg IV every six hours
Piperacillin-tazobactam – 4.5 g IV every six to eight hours; if there is significant concern for Pseudomonas infection (particularly in those who are severely ill or were not receiving fluoroquinolone prophylaxis at the time of onset of illness), 4.5 g IV every six hours

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Vancomycin or others target gram-positive cocci

Indication of Vancomycin :
Suspected catheter-related infection
Skin or soft tissue infection
Pneumonia
Hemodynamic instability

**Vancomycin or agents target gram-positive cocci is not recommended as a initial regimen.

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Initial regimen

Indication of anaerobic coverage-
Necrotizing mucositis, Sinusitis , Periodontal cellulitis
Perirectal cellulitis, Intra-abdominal infection (typhlitis),
Pelvic infection, or anaerobic bacteremia.

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Combination therapy

Combination antibiotic as initial empiric therapy in FN, but none has been shown to superior to others or to monotherapy
Use extended-spectrum beta-lactam (e.g. piperacillin, ceftazidime) in combination with an aminoglycoside.
Double beta-lactams or a beta-lactam and a fluoroquinolone.
Alternative empiric regimens include-

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