A 50-YEAR-OLD MALE WITH GENERALISED WEAKNESS & SHORTNESS OF BREATH

DR KAZI FAZLUR RAHMAN SAJID

RESIDENT PHASE B

DEPARTMENT OF HAEMATOLOGY

BANGABANDHU SHEIKH MUJIB MEDICAL UNIVERSITY

CASE

Md Ishaque Ahmed, 50 years of age, Diabetic, Hypertensive, CKD, patient came here with complaints of

• Generalised weakness for 1 month.
• Shortness of breath, cough for 10 days.

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CONTINUE

• According to patients statement he was relatively well about 1 month back then he developed generalised weakness, usually persist all over the day & faced difficulties in doing daily activities .

• He also complained about cough for 10 days.

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1. Productive in nature .
2. Not associated with haemoptysis, chest pain.
3. Associated with shortness of breath , more in supine position .

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• With these complaints he went to the local hospital and diagnosed as a case of anaemic heart failure . In that time patient was dyspnoeic , bilateral basal crepitations, raised JVP .

• On query He stated he was diagnosed case of CML CP since 2013 on the basis of history, and investigations .

• He was on Imatinib 400 mg once mg since then. But he discontinued his treatment for 8 months due to financial reasons.
• In that time he had suffered from several episodes of fever , & H/O blood transfusion due to anaemia.

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• After that he consulted with doctor and prescribed with dasatinib 100 mg once daily .
• In that time he was suffered from 3 episodes of pleural effusions. For this reasons dasatinib has stopped after 1.5 years and again switched to imatinib 400 mg.

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• In august 2021 , he has suffered from Sub Dural haematoma with several episodes of convulsions.
• In that time during routine test he was found pancytopenia.

• Then He was started with Azathioprine and Eltrobopag from 5.9.21.
• Imatinib was stopped.

• Then he was admitted in outside hospital & diagnosed as anaemic heart failure , & treated accordingly.
• Then patient is shifted to BSMMU in 2.10.21 for better management.

• After admission , patient was ill looking ,anaemic , there was periorbital oedema ,mild bilateral basal crepitations present.
• BP : 100/80 mmHg
• Pulse : 94 bpm
• Temperature : 98.4
• Spo2 : 98%

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Other systemic examinations reveals no abnormality.

Ferritin

Present condition of patient

1. Patient is febrile for last 4 days.
2. Patient complained about some irrelevant talking .

CT SCAN OF BRAIN.

Bilateral subdural chronic haematoma.

Generalised ceebral atrophy

Left maxillary sinusitis.

• Viral screening and auto antibodies to rheumatological disease are sent.

Diagnosis

• Our diagnosis is Anaemic Heart Failure ( improved ) with CML CP with Haemophagocytic syndrome with CKD , Hypertension , diabetes , chronic subdural haematoma.

• CML in 2013

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• Start imatinib 400 & discontinue for 8 months in 2016
• Start dasatinib for 1.5 years develop complications.

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• Restart imatinib 400 mg

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• Last august attacked by SDH and diagnosed pancytopenia , BM done revealed HLH. Imatinib stopped , azathioprine & eltrombopag started.

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• Last octobor developed anaemic heart failure.

HAEMOPHAGOCYTIC SYNDROME

• Hemophagocytic lymphohistiocytosis (HLH) is a group of diseases belonging to histiocytosis syndrome .
• It manifests as
• Fever
• Pancytopenia
• Enlargement of organs such as the liver/spleen, as well as liver dysfunction.

Pathogenesis

Diagnostic criteria

Other features supporting an HLH diagnosis that are not part of the HLH-2004 criteria include

• Hyperbilirubinemia,
• Hepatomegaly,
• Elevated lactate dehydrogenase and D- dimer levels

Partial thromboplastin time, and fibrinogen are

normal.

These findings may help to discriminate HLH from septic

shock and conditions such as autoimmune hemolytic anemia,

and they are also useful in assessing response to therapy.

• Lymphoma as a hidden trigger of HLH may be difficult to detect.
• Use of positron emission tomography–guided imaging, repetitive tissue sampling, and consultation with a lymphoma reference pathologist, are recommended.

• Diagnostic tests for genetic HLH include functional assessment of lymphocyte cytotoxicity and guided genetic testing.
• They are useful for detecting potential genetic predisposition to HLH in select patients, but pending results must not delay the clinical decision to treat HLH.

HS score

Treatment

• First, immunosuppressants are administered to suppress the overactivation of the immune system, which is the main pathogenesis of HLH, to prevent various side effects caused by cytokines secreted from immune cells.

• The HLH-94 protocol consists of corticosteroids, typically dexamethasone, cyclosporine A (CSA), intrathecal therapy.

• Etoposide, to delete activated T cells and suppress inflammatory cytokine production .
• A reduced etoposide frequency, from twice weekly to once a week, with or without a reduction in dose from 150 mg/m2 to 50-100 mg/m2, should be considered.

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• In the HLH-2004 study, CSA was administered upfront instead of after 8 weeks.
• In HLH-94, intrathecal therapy is only suggested in case of progressive neurological symptoms after 2 weeks of therapy or if an abnormal cerebrospinal fluid has not improved.

• Adults with primary HLH may need allogeneic hematopoietic SCT, which has dramatically improved outcomes in children.

MaL HLH

• Mal-HLH comes in 2 forms: “malignancy-triggered HLH” as a presenting feature of the malignancy at diagnosis or at relapse and “HLH during chemotherapy”.

Malignant triggering

• Corticosteroids are often used as first-line treatment to combat inflammation.
• In highly active HLH, or if severe organ damage is imminent, dose-adjusted etoposide (50-100 mg/m2) may be used prior to tumor-specific treatment.
• Etoposide can be added to CHOP or CHOP-like protocols (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone [CHOEP] or dose adapted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin [DA-EPOCH])

HLH during chemotherapy

• “HLH during chemotherapy” develops during or after treatment of a malignant disorder and is probably underrecognized.
• In neutropenic patients after induction chemotherapy for AML, as many as 9% may develop HLH with infections (fungal, bacterial, central-line associated) as the most frequent trigger.

• HLH has to be considered when cytopenia is unduly prolonged after chemotherapy, fever persists in spite of antibiotic treatment, and other HLH parameters are present.
• These patients benefit from anti-inflammatory treatment with corticosteroids (prednisolone 1-2 mg/kg or dexamethasone 5-10 mg/m2) and, possibly, IVIG 1.6 g/kg over 2 to 3 days.
• Etoposide should be used sparingly, because bone marrow recovery is central for immune reconstitution.

Infection-associated HLH

• Viral infections, in particular EBV, HIV, cytomegalovirus, or influenza, are common triggers of HLH.

EBV

• A more conservative approach with a short course of corticosteroids (with/without IVIG) is justified in patients with less severe disease or improving clinical manifestations.
• Monitoring of ferritin, sCD25, cell counts, and EBV DNA in affected patients aids in assessing treatment response. EBV DNA levels .103 copies per milliliter have been reported to be relevant for the development of EBV-HLH.

• Because EBV replicates in B cells, the addition of rituximab (eg, 375 mg/m2 once weekly, 2-4 times) to HLH-directed therapy may be effective in clearing the reservoir of virus in EBV-triggered HLH.

• HLH induced by intracellular infections, such as tuberculosis, leishmaniasis, or rickettsial disease, usually does not need HLH-94–like treatment but responds to specific antimicrobial treatment

Salvage treatment of relapsed and�refractory HLH

• Salvage treatment of adults with refractory/ relapsing HLH usually requires intensification using combined chemotherapy and consolidation with alloSCT.

• The anti-CD52 antibody alemtuzumab (median dose 1 mg/kg split over a median of 4 days) has been reported to be beneficial in refractory pediatric patients; a reduced dose or prolonged maintenance.
• Other salvage options include CHOP-like protocols plus etoposide and targeted inhibition of JAK signaling with ruxolitinib.
• Plasmapheresis or the use of cytokine adsorption columns may aid in rescuing critically ill patients from a deleterious cytokine storm.

• In November of 2018, the U.S. Food and Drug Administration approved emapalumab (anti– IFN-g monoclonal antibody) as a second-line therapeutic agent for primary HLH in children and adults.

Clinical management of MAS-HLH

• Treatment of MAS-HLH is different from that recommended for HLH as a result of partial pathogenetic diversity.
• HLH in patients with underlying rheumatic conditions is historically called macrophage-activation syndrome (MAS; MAS-HLH).

• Early recognition and diagnosis of MAS-HLH are essential for efficacious management.
• Conventionally, corticosteroids are the first-line treatment.
• High-dose pulse methylprednisolone (1 g/d

for 3-5 consecutive days) is 1 frequent initial approach.

• CSA (2-7 mg/kg per day) can be added in patients with an insufficient immediate response.
• IL-1–blocking therapy with anakinra a dose of 2 to 6 mg/kg up to 10 mg/kg per day subcutaneously in divided doses is suggested.
• Experience with anti–IL-6 blockade with tocilizumab is also increasing.
• Finally, in patients with severe active disease or CNS involvement, despite steroids, CSA, and/or anakinra, a reduced dose of etoposide (50-100 mg/m2 once weekly) may be very effective.

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HLH-like cytokine storm induced by�novel immunotherapies

• Novel immunotherapies may induce a cytokine storm resembling HLH that requires specific treatment.