Fever in Immunocompromised Child

Introduction

• Fever physiologyRole of pyrotoxinsRole of neutrophils in the causation of fever Role of temperature regulatory centers

• Temporal profile of fever• Compensatory mechanisms• Types of fever• Non-infectious fevers• Fever in the immunocompromised child

Primary immunodeficiency

• Combined T cell and B cell deficiencies• Predominantly antibody deficiencies• Disease of immune – regulation• Congenital defects of phagocyte number and function• Complement disorders• Auto inflammatory disorders• Well defined immunodeficiency syndromes

Acquired immunodeficiency: Causes

• Steroid therapy• Hemato-lymphoid malignancies• Solid tumors with bone marrow infiltration• Chemotherapy• Post splenectomy• Sickle cell disease• Post transplant immune suppressive therapy• Acquired immunodeficiency syndromes

Bacterial Viral Fungal ParasiticGram positiveStaphylococcus aureus Cytomegalovius Candida species P. cariniiCoag. neg. Staph Dissem. Varicella zoster AspergillusEnterococci Herpes simplex MucormycosisClostridium

Gram negativeEscherichia coliKlebsiellaProteusSalmonellaPseudomonas aeruginosaAcinetobacter

Pattern of Infections in Immunocompromised Children

Fever in children with malignanciesWhy is the immune system compromised?

1. Bone marrow infiltration causing a deficiency of phagocytic cell number

2. Deficiency of phagocytic (B&T) cell function – Effects of chemotherapy

3. Alteration in gut flora characteristics – bad vs good bacteria

Contributory factors1. Poor nutrition2. Mucosal breaches in oral, gut and perianal mucosa – Due to3. Chemotherapy, surgery, radiotherapy or invasive procedures4. Poor seroconversion after routine immunization5. Recurrent infections of and in childhood

Febrile NeutropeniaFever >38oC may be the only indication of an underlying infectionFebrile neutropenia in an immunocompetent child is relatively easy while that in

immunocompromised: A nightmare

Even this sign may be absent and patient instead may be hypothermic,

hypotensive, listless or confused.

Definition:

A single oral temperature of >38.3ºC (101ºF) OR temperature of >38.0ºC

(100.4ºF) sustained for 1 hour in ANC < 500

Infection must be considered and treated empirically if any signs of clinical

deterioration are present in a neutropenic child, regardless of the recorded

temperature.

Any child with neutropenia is prone to infections

ANC< 1500: Mild

ANC<1000: Moderate

ANC< 500: Severe

ANC<100: Critical

> 7 days: Prolonged neutropenia

Clinical features of inflammation are suppressed in a child

with immunosuppression.

•Degree of neutropenia

• Duration of neutropenia

• Chemotherapy induced vs Hematologic disorder

• Underlying co-morbid condition

• Function of the neutrophils

• Ability of the bone marrow to respond to an infectious insult

• Function of other components of the immune system

Risk of infection in neutropenia

Risk stratification

Helps guide initial empirical therapyHigh risk

– Anticipated prolonged neutropenia > 7 days– ANC <500– Significant co-morbidities– AML, Burkitt’s, Induction phase of ALL– Relapsed disease with marrow involvement– HSCT– Abnormal vitals/ Clinically unstable– Very high septic markers, Hepatic transaminases (>5 times),

abnormal KFT– Associated anemia, Thrombocytopenia

Phillips RS, Lehrnbecher T, Alexander S, Sung L. Updated systematic review and meta-analysis of the performance of risk prediction rules in children and young people with febrile neutropenia. PLoS One 2012; 7:e38300.

Low risk patients • Clinically stable and well looking • Temperature <39oC • Non-intensive phase of chemotherapy • Malignancy in remission • Lack of medical comorbidities • ANC ≥ 100/mm3 and likely to rise within the next 7 days • Absolute monocyte count > 100/mm3 • Not fulfilling any criteria for high risk category

Perron T, Emara M, Ahmed S. Time to antibiotics and outcomes in cancer patients with febrile neutropenia. BMC Health Serv Res 2014; 14:162. Fletcher M, Hodgkiss H, Zhang S, et al. Prompt administration of antibiotics is associated with improved outcomes in febrile neutropenia in children with cancer. Pediatr Blood Cancer 2013; 60:1299.

ManagementURGENCY: Suspect, diagnose and manage are the KEYWORDS

• High risk patients are to be hospitalized and administered broad spectrum IV antibiotics

• Knowledge of locally prevailing bacteriological profile and antimicrobial susceptibility data

• Administer first dose of antibiotic without any delay preferably within 60 minutes

• Delay: Increases the morbidity and mortality

Clinical evaluation in febrile neutropeniaHistory:• Duration of fever• Presence of rigors• Symptoms to suggest focus of fever• Respiratory: Cough, chest pain, rapid respiration/

breathlessness • GIT: Abdominal pain, vomiting, loose stools, melena,

hematochezia • Other focus: Mouth ulcers, skin infections, perianal painSuthar R, Bansal D, Marwaha RK. Febrile neutropenia: outline of management. Indian J Pediat.2013;80:138

Clinical evaluation in febrile neutropeniaClinical examination•Vital signs and general condition – Important to rapidly recognize hemodynamic

compromise due to septic shock – needs urgent therapy

• Review of foci of infection/complications of neutropenia

– Oral cavity for mucositis/candida/patch on the tonsils or pharynx/dental infections

– Skin: Pyoderma, petechiae, thrombophlebitis, central venous line/port site infections

– Chest: Signs of lower respiratory infection (especially assess for signs of hypoxia with minimal chest findings suggestive of PCP or viral neumonias)

– Abdomen: Distension, mass, free fluid, tenderness (suggestive of neutropenic enterocolitis); perianal exam for anal fissures/abscess

Other factors determining the plan of therapy• Type of cancer: Hematolymphoid malignancy versus solid tumor• Disease status: Active disease versus in remission• Phase of treatment: On intensive chemotherapy versus maintenance

Band neutrophils

Diagnostic evaluation• CBC• Peripheral smear• CRP – caution in immunocompromised children• Blood culture• Urine culture• CSF culture• Imaging – chest• US Scan – for fungal collections in the liver,

spleenand lungs or deep seated abscess in the abdomen or KUB

• Echo – to rule out valvular vegetationsShridhar KA , Rau ATK, Ravanamma PV, Rau A. Significance of C reactive protein during febrile neutropenia in pediatric malignancies Ind. Pediatrics. 2009; 46(9): 797-799.

Evaluation protocol for febrile neutropenia

Confirm ANC and fever criteria ↓ confirmed febrile neutropenia

Detailed clinical examination and evaluation↓

Cultures / X-ray chest↓

Asses and assign risk↓

Start therapy

• Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52:e56.

• National Institute for Health and Care Excellence. Neutropenic sepsis: prevention and management of neutropenic sepsis in cancer patients. 2012. http://publications.nice.org.uk/neutropenic-sepsis-prevention-and-management-of-neutropenic-sepsis-in-cancer-patients-cg151 (Accessed on June 19, 2013).• Lehrnbecher T, Robinson P, Fisher B, et al. Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update. J

Clin Oncol 2017; 35:2082.

Choice of empiric coverageBroad Spectrum coverageMonotherapy OR combinationsMonotherapy: (Anti-pseudomonal Beta lactams)

Piperacillin-tazobactum4th generation cephalosporin: cefoperazone-sulbactum or CefepimeCarbapenems: meropenem Carbapenems can be reserved as second line antibiotics to prevent the emergence of drug resistant organisms. Colistin is reserved as third line drug.

Combination: Meropenam plus aminoglycoside, Vancomycin (esp. if settings of Gram positive)Metronidazole for anerobes esp. abdominal sepsis

Specific gram positive cover is added only if patient has evidence of any of the following

• Hemodynamic instability • Severe sepsis • Radiographically confirmed pneumonia• Clinically suspected catheter related infection • Skin or soft tissue infection • Known colonization with MRSA, Vancomycin resistant enterococcus

(VRE), Penicillin resistant streptococcus • Severe mucositis

Further management is based on continuous clinical assessment and culture reports

Antifungal therapyIndications during febrile neutropenia •Non responsiveness to first line antibiotic therapy after a week •Evidence of fungal infection on imaging •Recurrence of fever after apparent recovery from FN •Fever after prolonged antibiotic therapy •Options available:

Ucanazole Voriconazole Amphotericin Caspofungin Others

Empirical antibiotic therapy in low risk patients

• Stable clinical condition• No co – Morbidities• No mucosal breach• Recovering ANC• At the end of the chemotherapy cycle

Low risk situation

Options availableOral quinolonesOral macrolides – if atypical organisms are suspectedIV ceftazidime for a short duration – 5to 7 days till afebrile

Duration of antibiotic therapy in FN• Gram positive organism grown – 7 to 10 days of therapy with recovery

of ANC

• Gram negative organism grown – 14 days of therapy with recovery of ANC

• Deep seated S. aureus (culture positive) infection – 6 to 8 weeks

• Fungal infection (stomatitis, superficial skin ) – 7 to 10 days

• Deep seated Aspergillosis / Mucormycosis – Gold standard Amphotericin B x 8 – 12 weeks

• Resistant fungal infections – Voriconazole /Caspofungin - 6 to 8 weeks

Biochemical markers of infection

• Monocytosis – First sign of marrow recovery

• ESR – Poor sensitivity and specificity

• CRP – delayed acute phase reactant – unreliable in severely neutropenic situations and in liver disease/involvement

• Procalcitonin – Better than CRP; useful to decide on cessation of therapy

• Serum Ferritin – Trend of values better than single value

Role of antibiotic and fungal prophylaxisPneumocystis carinii prophylaxis –

Cotrimoxazole 4-5 mg/kg on 3 days of the week Pentamidine 4mg/kg /dose IM/IV every 2 – 3 weeks

Candida prophylaxis– Fluconazole 4-5 mg/kg/day – especially during induction in acute myeloid leukemia

Antiviral therapy• IV Acyclovir – To be started as early as possible in case of suspected

/ frank varicella infection

• Varicella zoster Immunoglobulin / IVIG in case of severe associated existing / predicted neutropenia

• Strict barrier nursing

• Constant search for target organ damage as a consequence of disseminated varicella infection

• Active immunization with varicella vaccine after induction and during remission phase of disease

• Therapy for other associated viral infections – H1N1 or Dengue

Supportive care during febrile neutropenia

• Component therapy

• Packed RBC – Leucocyte depleted platelet concentrates

• FFP

• Granulocytes

• Reverse barrier nursing nutritional support psychological support financial support

Reverse barrier nursing and general instructions

• Hand washing• Reverse barrier nursing – Separate room for mother and

child• Eating freshly cooked food• Drinking boiled water• Eating only fruits with peels which should be removed

before consumption• Avoiding contact with obviously infected patients• Avoid all live and pulse polio oral vaccines during therapy

Colony stimulating factors

• Granulocyte Colony Stimulating Factor (G-CSF)

• Rationale – reduces the duration of neutropenia reduces the severity of neutropenia does not reduce the mortality due to febrile neutropenia

•Dose 5 to 10 µg /dose/day Route – subcutaneous

•Duration of therapy – Till the ANC ˃ 1500/mm3 Better if started early in the neutropenic cycle

•Generally avoided during the induction phase of chemotherapy

Therapy algorithm

Case scenarios

Case -1A 3 year old boy, a case of acute lymphoblastic leukemia who is on maintenance chemotherapy, was brought with fever. O/E vitals were stable and examination showed no focus.

Hb 7.8 g%, TLC 1800/cu.mm, Platelets 58000/cu.mm

ANC 550/cu.mm

Blood culture was sent and child was started on Inj Cefoperazone + sulbactam

Chemotherapy medicines were stopped.

No improvement in 48 hrs, repeat cultures, Meropenem+Amikacin

Deteriorated over 5 days, hepato-spleenomegaly

Repeat workup, fungus, CECT, echo, USG, bone marrow, malaria, leptospirosis, TB, Ricketsia, dengue: Non contributory, pancytopenia worsened ?? Viral reactivation suspectedCMV PCR in blood: high viral load, Improved with IV Gancyclovir, Recovered

Case -1Fever not responding to anti-bacterials in a child with cancer

Resistant bacterial infection

Tuberculosis

Fungal infection

Viral / reactivation of latent viral infections

Disease relapse

Hidden focus of infection – abscess, infective endocarditis, etc.

Take home message for case 1

Febrile neutropenia is not always caused by bacterial and fungal infections

Reactivation of viral infections should be considered in children on prolonged chemotherapy with febrile neutropenia refractory to antibacterial and antifungal agents and without any focus.

Case -2

A 5 year old girl, a case of acute lymphoblastic leukemia on chemotherapy, was brought with fever and fast breathing. O/E child had fast breathing, hypoxia and minimal crepitations and wheeze in bilateral lung fields

Hb 9.6 g%, TLC 700/cu.mm, Platelets 32000/cu.mmANC 50/cu.mm.

Blood culture was sent and child was started on oxygen, Inj Cefoperazone + sulbactam, Amikacin and Vancomycin.Chemotherapy medicines were stopped.

Deteriorating condition and CXRCECT: cystic consolidationBAL: P cariniiTreatment with Co-trimoxazole, Recovered

Take home message for case 2

Thorough investigations should be performed to isolate the organism in febrile neutropenia, especially in sick children.

Initiation of specific therapy is life saving.

Case -3A 2 years old boy, a case of acute lymphoblastic leukemia who is on maintenance chemotherapy, was brought with fever and loose stools. O/E child had moderate dehydration. Systemic examination was normal.

Hb 8.5 g%, TLC 1200/cu.mm, Platelets 82000/cu.mm

ANC 300/cu.mm.

Child was admitted. Dehydration was corrected with IV fluids. After sending blood C/S, stool for ova, cyst, culture, IV antibiotics were started.

Protracted diarrhea

Stool for Kinyoun staining showed cysts of Cryptosporidium.

Child was started of Nitazoxanide and Azithromycin.

Take home message for case 3

Opportunistic infections should be looked for in children in immunosuppressive therapy.

Food and water hygiene is an essential component for children receiving chemotherapy.

Case -410 years old boy, a case of acute lymphoblastic leukemia who is on induction chemotherapy, was brought with abrupt onset left focal seizures with secondary generalization. O/E child was febrile (102F), drowsy (post-ictal state), PR 110/min, BP 140/90, no cranial nerve or focal neurological deficit.Hb 9.5 g%, TLC 3500/cu.mm, Platelets 20000/cu.mmANC 400/cu.mm Child was admitted in PICU. Started on oxygen, antiepileptics, broad spectrum antibiotics.

Case -4Common causes of fever with focal seizures in a child with ALLInfectionsBacterial – Gram positive / negative infections, abscessesFungal – Aspergillus, Mucor, CandidaViral – Herpes, enterovirusesTuberculosisCNS leukemiaIntracranial bleed (due to thrombocytopenia)Cerebral venous thrombosis (due to drugs like L-Asparginase)Hypertensive encephalopathy (due to steroids)Posterior reversible encephalopathy syndrome – PRES (due to chemotherapy drugs, fluctuating blood pressure due to drugs)

MRI showed B/L occipital lobe changes s/o PRES

CSF was done after stabilizationChild was managed with antihypertensives, antiepileptics and supportive care.Infective workup was negativeThere was no fever spikes after admissionSeizures did not recur.

Child was discharged on antiepiletpics and antihypertensives.Further chemotherapy were continued uneventfully.

Take home message for case 4

Non-infective causes also should be considered for fever in children on chemotherapy.

Febrile neutropenia

Thorough history and clinical examination

CBC/DLC, blood cultures and other tests as indicated

Start anti-pseudomonal β lactam; Add vancomycin and aminoglycoside if indicated

Reassess after 48 hours

Afebrile > 24 hoursANC improving trendCultures negative

Discharge on oral antibiotics

Organism isolated in culture

Change antibiotics according to sensitivity

Persistent fever, otherwise stable

Do not change antibiotics, continue evaluation

Persistent fever, worsening clinical condition, cultures negative

Upgrade antibacterial cover

Fever persists for 4 – 7 days

Add empirical antifungal , do CECT chest + PNS, galactomannan levels

Take home message• Prevention is always better than cure

• Recognize and treat febrile neutropenia speedily

• Initiate empirical therapy before receipt of culture reports

• Do not hesitate to add / change antimicrobial agents if clinically indicated

• Use of colony stimulating factor has improved prognosis and must be used early

• Supportive care is as important as therapy

• Counseling of parents during this stressful period is immensely helpful