Haematology Flashcards
Causes of microcytic anaemia
Causes of macrocytic anaemia
Microcytic anaemia FAST Fe deficiency Anaemia of chronic disease Sideroblastic anaemia Thalassaemia
Macrocytic anaemia
Megalaloblastic: B12 or folate deficiency, Anti-folate drugs (phenytoin, methotrexate), Cytotoxics: Hydroxycarbamide
Non-megaloblastic Reticulocytes Alcohol Liver disease Pregnancy Hypothyroid Myelodysplasia, MPD, MM, AA
Causes of fe deficiency anaemia
Investigations and findings
Rx
Blood loss e.g. GI
Increased need: Pregnancy, Growth
Reduced intake (e.g. veg)
Decreased absorption e.g. Coeliac disease, gastrectomy. H.pylori infection. Could be Chron’s
Clinical features
Pallor, lethargy, SOB
Atrophic glossitis, Angular stomatitis, Koilonychia
Brittle hair, brittle nails
Post cricoid webs - Plummer vinson syndrome
Bloods - Haematinics
- Low iron
- low ferritin
- High TIBC
- Reduced transferrin saturation, inctreased levels
Blood film - Hypochromic cells - Anisocytosis (size) - Poikilocytosis (shape) - Pencil cells COLONOSCOPY if unexplained anaemia (upper + lower) in >60yo. TTG if young.
Rx
Ferrous sulphate 200mg TDS - continue for 3 months after normalised levels
Causes of normocytic anaemia
BM failure Blood loss (acutely) Hypothyroid Haemolytic anaemia Pregnancy Anaemia of chronic disease Renal failure
Anaemia with macrocytosis
Increased reticulocytes
Polychromasia
Haemolytic anaemia
Lab changes in haemolytic anaemia
Common
Specific to intravascular
Specific to extravascular
All:
Reticulocytes, polychromasia
Intravascular: Hyperbillibrubinaemia LDH high Absent haptoglobins Haemoglobinuria Haemosiderinuria (brown urine)
Extravascular
Types of acquired haemolytic anaemia (just name)
Immune-mediated DAT +ve
- AIHA: Warm, cold, PCH
- Drugs: Penicillin, quinine, methyldopa
- Alo-immuneL Acute transfusion retain, HDFN
PNH
Mechanical
- MAHA: DIC, HUS, TTP
- Heart valve
Infections
- Malaria
Burns
Types of hereditary haemolytic anaemia (just name)
Enzyme: G6PD and pyruvate kinase deficiency
Membrane: Hereditary spherocytosis, Hereditary Eliptocytosis
Haemoglobinopathy: SCD, Thalassaemia
Fe deficiency anaemia signs
Management
Koilonychia
Angular stomatitis/cheilosis
Post-cricoid webs
Ferrous suplhate 200mg PO TDS
SE: GI upset
Continue until 3 months symptom free
Symptoms of any anaemia
Signs
Fatigue Dyspnoea Faintness Palpitations Headache Tinnitus
Signs Pallor Hyperdynamic circulation - Tachycardia - Flow murmur: apical ESM - Cardiac enlargement Ankle swelling with HF
What is sideroblastic anaemia
Causes
Blood results
Ineffective erythropoeisis
- Increased iron absorption
- Iron loading in BM –> Ringed sideroblasts
- Haemosiderosis: ends, liver and cardiac damage
Causes Congenital Acquired - Myelodysplastic/myeloproliferative disease - Drugs: Chemo, anti-TB, Lead
Bloods
- Microcytic anaemia, not responsive to iron
- High ferritin, high serum iron, normal TIBC
Treatment
- Remove cause
- Pyridoxine may help
Complications of regular iron transfusions in beta Thalassaemia major
How are they avoided
Iron deposition – the most important (all patients):
• Heart – cardiomyopathy
• Liver – cirrhosis
• Pancreas – diabetes
• Pituitary gland – impaired growth and sexual maturation
• Skin – hyperpigmentation
Antibody formation (10% of children) • Allo-antibodies to transfused red cells in the patient make finding compatible blood very difficult
Infection – now uncommon (<10% of children)
• Hepatitis A, B, C
• HIV
• Malaria
• Prions (e.g. new variant Creutzfeldt-Jakob disease)
Venous access (common problem)
• Often traumatic in young children
• Central venous access device (e.g. Portacath) may be required; these predispose to infection
Avoided by giving SC desferrioxamine Fe chelation
Beta Thalassaemia major features
Management
Blood results
From 3-6 months age: Severe anaemia Jaundice FTT Extra-medullary erythropoiesis: - Frontal bossing - Maxillary overygrowth - Hepatosplenomegaly Signs of iron deposition - Heart: Cardiomyopathy - Liver: Cirrhosis - Pituitary - Pancreas: Diabetes - Skin: Hyperpigmentation
Management
- Life long transfusions
- Desferrioxamine SC Fe chelation
- BM transplant is only curative option: Require HLA identical sibling
B0/B0, B0/B+, B+/B+
bloods
Low Hb, Low MCV, increased reticulocytes
Hb electrophoresis: Increased HbF, HbA2 variable
Film: Target cells and nucleated RBCs
Alpha Thalassaemia types
Alpha Thalassaemia major/ Hb Barts
0 alpha globin gene: –/–
Hydrops fetalis –> death in utero
HbH disease
1 alpha globin gene a-/–
Moderate anaemia; may need transfusions
Haemolysis: Hepatosplenomegaly, jaundice
Train
2 alpha globin genes: –/aa or a-/a-
Asymptomatic
Hypochromic microcytes
Normal is aa/aa - 4 alpha globin
Beta Thalassaemia trait/hetrozygosity
Genes
Features
Blood results
B/B+ or B/B0
Mild anaemia which is usually harnless
Low MCV
Increased HbA2 and increased HbF
Hypersegmented PMN
Oval macrocytes
B12/Folate deficiency
Investigations for microcytic anaemia
LFTs
TFTs
Se B12
Red cell folate: Reflects body stores over 2-3mon
BM biopsy if cause not revealed by above
- Megaloblastic erythropoiesis
- Giant metamyelocytes
Folate deficiency
Folate sources
Causes
Absorption location
Blood + blood film results
Management
Folate sorce: Green veg, nuts, liver
Stores 4months
Absorption: Proximal JEJENUM
Causes of folate deficiency
- Reduced intake: Poor diet
- Increased demand: Pregnancy, Haemolysis, Malignancy
- Malabsorption: Coeliac, Chrons
- Drugs: EtOH, Phenytoin, Methotrexate
Bloods:
As for microcytic anaemia: LFT, TFT, SeB12, Red cell folate
Film: Hypersegmented PMN, Oval macrocytes
Management
- Assess for underlying cause
- Give B12 first unless B12 known to be normal - may precipitate or worsen SACD
- Folate 5mg/d PO
B12 deficiency
Source
Stores
Absorption
Causes of b12 deficiency
Features
Investigations
Source: Meat, fish and dairy (vegans at risk)
Stores: 4y
Absorption: Terminal ileum bound to intrinsic factor (released from gastric parietal cells)
Role: DNA and myelin synthesis
Causes
1) Reduced intake: Vegan
2) Reduced intrinsic factor: Pernicious anaemia, Post-gastrectomy
3) Terminal ileum: Chron’s, ileal resection, bacterial overgrowth
Features
1) General
- Anaemia symptoms
- Lemon tinge: pallor and mild jaundice
- Glossitis: Beefy red tongue
2) Neuro
- Paraesthesia
- Peripheral neuropathy
- Optic atrophy
- SACD = subacute combined degeneration of the cause
Investigations
- IF antibodies: Specific but lower sensitivity
- Patietal cell Abs: 90% +ve in PA but reduced specificity
What is subacute combined degeneration of the cord
Cause
Pathology
Features
Cause = pernicious anaemia
= Combined symmetrical dorsal column loss and corticospinal tract loss
–> Distal sensory ataxia esp joint position + vibration
–> Ataxia with wide gait and +ve Romberg
Mixed UMN and LMN signs
- Spastic paraparesis
- Brisk knee jerks
- Absent ankle jerks
- Upgoing plantars
Pain and temperature remain intact
B12 deficiency managament
Malabsorption ==> Hydroxocobalmin parenteral
- Replenish 1mg/48h IM
- Maintain: 1mg IM every 3 months
Dietary ==> Oral B12 (Cyancobalamin)
Parenteral B12 reverses neuropathy but not SACD
CLL
Epidemiology
Aetiology
Features
Investigations
Commonest leukaemia WW
M>F: 2:1
Elderly 70s
Aetiology
- Clones of mature B cells (memory cells)
Features
- often asymptomatic incidental finding
- Symmetrical PAINLESS lymphadenopathy
- Hepatosplenomegaly
- B symptoms: Weight loss, fever, night sweats
Investigations
- Increased WCC: Lymphocytes
- Smear cells
- Decreased serum Ig - (infections)
- +ve DAT!!!
- Rai or Binet staging
- Immunophenotype!!!
CLL
Complications
Treatment
Staging scale
Complications
- Autoimmune Haemolysis
- Infection
- Marrow failure/infiltration
Natural hx
- Some remain stable for yrs
- Nodes usually enlarge slowly +/- obstruction
- Death often due to infection
- RICHTER transformation: CLL –> LArge B cell lymphoma
Treatment
Indications to treat
- symptomatic
- Ig genes un-mutated (bad prognosis)
- 17p deletion (bad prognosis)
Supportive
Chemo
Radiotherapy: Relieve LN or splenomegaly
1/3 never progress
1/3 progress with time
1/3 are actively progressing
Binet
A: <3 areas of lymphadenopathy
B: 3 or more areas of lymphadenopathy
C: Hb <10 or Put <100
Massive leucocytosis 50-200
Neutrophils and myelocytes
Basophils
Hepatosplenomegaly
CML
9;22
Chronic phase –> Advanced phase –>Blast crisis
<5% blasts 10-19% 20 + blasts
Management
- Imatinib
AML vs ALL diagnosis
20% BLAST BM cells
Cytology: AML have auer rods
Cytochemistry: AML +ve staining for myeloperoxidase, sudan black, non-specific esterase
Immunophenotyping:
AML
- MPO, CD13, CD33, CD14, CD15, glycophorin
ALL
- Precursor B cell - CD19, CD20, TdT, CD10 +/-ve
- B cell - CD19, CD20, sIg
- T-cell: CD2, CD3, CD4, CD8, TdT
Both AML and ALL have CD-34, CD45, HLA-DR
AML clinical features
AML diagnosis
BM failure: Anaemia, thrombocytopenia, neutropenia
Local infiltration: Hepatosplenomagaly, gum infiltration, lymphadenopathy (much less than ALL), Skin or other sites
Blood count and film
BM morphology
Immunophenotyping - more so to follow up disease
Cytogenic analysis on BM - affects Rx and guides prognosis
Molecular studies (when needed)
AML treatment
Supportive
- Red cells (in anaemia), platelets (if <10 or bleeding), FFP (if DIC), Antibiotics, Long line, Allopurinol (prevent breakdown of blood products leading to renal failure), fluid and electrolyte balance
Chemo - damages DNA of leukaemic cells as they are continuously dividing and lack cell cycle checkpoint control
- usually combination chemo 4-5 courses ~ 6 months
Consider transplant if poor prognosis
Nb: ATRA for promyelocytic leukaemia (DIC)
TK inhibitors for rare PH +ve
ALL features
PB: anaemia, thrombocytopenia, neutropenia
BM and other organs - lymphadenopathy (v often), Hepatosplenomegaly, Tests, CNS, kidneys, Bone (pain in long bones)
Hodgkin lymphoma staging
Ann arbor staging I; one group of nodes II: >1 group nodes same side diaphragm III; nodes above and below diaphragm IV: extra-nodal spread B if fever, night sweats, unexplained weight loss
Chemo - preserves fertility. 2-6 cycles Adriamycin (se cardiomyopathy) Bleomycin (se pulmonary fibrosis) Vinblastine DTIC
+/-
Radiotherapy: field only
(risk of breast Ca after 25y, Leukaemia 3% after 10yrs, lung/skin cancer)
PET-CT after 2 cycle ABVD to assess response and guide radiotherapy need at end of chemo
Prognosis ~ 50-90% cure
Stage I or II: 80% cured
IV: Only 50% cured
Hodgkin lymphoma epidemiology
Features
Investigations
M>F: 2:1
Bimodal age incidence 20-29 and >60
NB HL only 20% of lymphoma
Features
1) Lymphadenopathy
- Painless
- Asymmetric
- Spreads CONTINUOUSLY to adjacent LNs
- May be alcohol LN induced pain
2) B symptoms
- Fever
- NIght sweats
- Weight loss (>10% over 6 monthS)
3) Other
- Itch
- Pel ebstein fever (cyclical)
- Hepato and or splenomegaly
Biopsy: reed stein berg cells!!!
CT/MRI CAP
G6PD
Pathophysiology
Features
Diagnosis
Causes
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the commonest red blood cell enzyme defect. It is more common in people from the Mediterranean and Africa and is inherited in an X-linked recessive fashion. Many drugs can precipitate a crisis as well as infections and broad (fava) beans
Pathophysiology
↓ G6PD → ↓ glutathione → increased red cell susceptibility to oxidative stress
Features neonatal jaundice is often seen intravascular haemolysis gallstones are common splenomegaly may be present Heinz bodies on blood films. Bite and blister cells may also be seen
Diagnosis is made by using a G6PD enzyme assay
Some drugs causing haemolysis
anti-malarials: primaquine
ciprofloxacin
sulph- group drugs: sulphonamides, sulphasalazine, sulfonylureas
Some drugs thought to be safe penicillins cephalosporins macrolides tetracyclines trimethoprim
Platelet transfusion indications
Pre-procedure
ffer platelet transfusions to patients with a platelet count of <30 x 10 9 with clinically significant bleeding (World Health organisation bleeding grade 2- e.g. haematemesis, melaena, prolonged epistaxis)
Platelet thresholds for transfusion are higher (maximum < 100 x 10 9) for patients with severe bleeding (World Health organisation bleeding grades 3&4), or bleeding at critical sites, such as the CNS.
It should be noted that platelet transfusions have the highest risk of bacterial contamination compared to other types of blood product.
Pre-invasive procedure (prophylactic)
Platelet transfusion for thrombocytopenia before surgery/ an invasive procedure. Aim for plt levels of:
> 50×109/L for most patients
50-75×109/L if high risk of bleeding
>100×109/L if surgery at critical site
If no active bleeding or planned invasive procedure
A threshold of 10 x 109 except where platelet transfusion is contradindicated or there are alternative treatments for their condition
For example, do not perform platelet transfusion for any of the following conditions: Chronic bone marrow failure Autoimmune thrombocytopenia Heparin-induced thrombocytopenia, or Thrombotic thrombocytopenic purpura.
DIC features
Causes
Treatment
low platelets, low fibrinogen
prolonged prothrombin time, APTT and bleeding time
Schistiocytes
Causes
- Sepsis
- Malignancy (esp APML)
- Trauma
- Obs
Treatment
- FFP
- Platelets
- Heparin
Tumour lysis syndrome criteria
Positive laboratory TLS requires 2 or more of the below within 7 days of chemotherapy or 3 days before: uric acid > 475umol/l or 25% increase potassium > 6 mmol/l or 25% increase phosphate > 1.125mmol/l or 25% increase calcium < 1.75mmol/l or 25% decrease
Positive clinical TLS requires any one of:
increased serum creatinine (1.5 times upper limit of normal)
cardiac arrhythmia or sudden death
seizure
Causes of thrombocytopenia
Causes of severe thrombocytopenia ITP DIC TTP haematological malignancy
Causes of moderate thrombocytopenia heparin induced thrombocytopenia (HIT) drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides) alcohol liver disease hypersplenism viral infection (EBV, HIV, hepatitis) pregnancy SLE/antiphospholipid syndrome vitamin B12 deficiency
Myeloma cause
The most likely underlying diagnosis is myeloma. Myeloma typically presents with the CRAB features: Elevated calcium Renal failure Anaemia Bone pain
The stem states this lady is in the early stages of disease. Therefore it is unlikely there are any bony metastases. In the early stages of disease the most likely biochemical pattern to see in myeloma as:
Raised calcium
Normal or high phosphate
Normal alkaline phosphate
Types of Hodgkin lymphoma
Type Frequency Prognosis Notes 1) Nodular sclerosing Most common (around 70%) Good prognosis More common in women. Associated with lacunar cells
2) Mixed cellularity
Around 20%
Good prognosis
Associated with a large number of Reed-Sternberg cells
3) Lymphocyte predominant
A*round 5%
Best prognosis
3) Lymphocyte depleted
Rare
Worst prognosis
Aplastic anaemia
Characteristics
Causes
Characterised by pancytopenia and a hypoplastic bone marrow
Peak incidence of acquired = 30 years old
Features
normochromic, normocytic anaemia
leukopenia, with lymphocytes relatively spared
thrombocytopenia
may be the presenting feature acute lymphoblastic or myeloid leukaemia
a minority of patients later develop paroxysmal nocturnal haemoglobinuria or myelodysplasia
Causes
idiopathic
congenital: Fanconi anaemia, dyskeratosis congenita
drugs: cytotoxics, chloramphenicol, sulphonamides, phenytoin, gold
toxins: benzene
infections: parvovirus, hepatitis
radiation
vWD
Types
Investigation
Management
Most common inherited bleeding disorder. The majority of cases are inherited in an AUTOSOMAL DOMINANT and characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are common whilst haemoarthroses and muscle haematomas are rare
Role of von Willebrand factor
large glycoprotein which forms massive multimers up to 1,000,000 Da in size
- promotes platelet adhesion to damaged endothelium (via gp1b)
- carrier molecule for factor 8
Types
type 1: partial reduction in vWF (80% of patients)
type 2*: abnormal form of vWF
type 3**: total lack of vWF (autosomal recessive)
Investigation
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristocetin
Management
- Transexamic acid for mild bleeding
- Desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
- Factor VIII concentrate
What is thrombophilia
Investigations
Coagulopathy predisposing to a thrombosis, usually venous
Inherited
- Factor V Leiden/APC resistance
- Prothrombin Gene Mutation
- Protein C and S deficiency
Acquired
- Progesterones in OCP
- Anti-phospholipid syndrome
Investigations
- FBC, Clotting, Fibrinogen conc
- Factor V Leiden/APC resistance
- Lupus anticoagulant and ant–cardiolipin Abs
- Assays for AT, Protein C and S deficiencies
- PCR for prothrombin gene mutation
Factor V Leiden other name
Pathophysiology
APC resistance
Protein C normally deactivates F5 and F8
Immediate blood transfusion reactions
1) Haemolytic (mins)
- Agitation, fever, abdo/chest pain,
- Hypotension –> shock
- DIC –> haemorrhage
- Renal failure
Mechanism = ABO incompatibility –> IV Haemolysis
Rx: Stop transfusion. Tell lab, FLUID RESUS, Treat DIC
2) Non haemolytic febrile reaction
- Fever, rigors, chills
Mechanism: Due to WBC HLA antibodies (of recipient)
Rx: Slow transfusion. Paracetamol 1g
3) Allergic reaction (immediate)
- Urticaria, itch - but ranges in severity:
- Angiodema
- Anaphylaxis
Mechanism: Recipient IgA deficiency, Anti-IgA IgE
Rx: Discontinue and give antihistamine e.g. chlorephenamine 10mg/IV/IM. Can restart transfusion after symptoms settle. If more severe - discontinue and treat urgently
4) TRALI A rare but potentially fatal complication of blood transfusion. - Development of hypoxaemia / acute respiratory distress syndrome within 6 hours of transfusion. Features include: - hypoxia - pulmonary infiltrates on chest x-ray - fever - hypotension Mechanism: Anti-WBC Abs in donor plasma
Rx: Stop transfusion, Rx ARDS
5) TACO
A relatively common reaction due to fluid overload resulting in pulmonary oedema. As well as features of pulmonary oedema the patient may also be HYPERTENSIVE a key difference from patients with TRALI.
Warfarin patients with High INR managemet
Major bleeding
- Stop warfarin
- Give intravenous vitamin K 5mg
- Prothrombin complex concentrate - if not available then FFP*
INR > 8.0 with Minor bleeding
- Stop warfarin
- Give IV vitamin K 1-3mg
- Repeat dose of vitamin K if INR still too high after 24 hours
- Restart warfarin when INR < 5.0
INR > 8.0 No bleeding
- Stop warfarin
- Give vitamin K 1-5mg by mouth, using the intravenous preparation orally
- Repeat dose of vitamin K if INR still too high after 24 hours
- Restart when INR < 5.0
INR 5.0-8.0 Minor bleeding
- Stop warfarin
- Give IV vitamin K 1-3mg
- Restart when INR < 5.0
INR 5.0-8.0 No bleeding
- Withhold 1 or 2 doses of warfarin
- Reduce subsequent maintenance dose
What is FFP used for
Universal donor
‘Clinically significant’ but without ‘major haemorrhage’ in patients with a prothrombin time (PT) ratio or activated partial thromboplastin time (APTT) ratio > 1.5
typically 150-220 mL
Can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding
In contrast to red cells, the universal donor of FFP is AB blood because it lacks any anti-A or anti-B antibodies
What does cryoprecipitate contain
Uses
Contains concentrated Factor VIII:C, von Willebrand factor, fibrinogen, Factor XIII and fibronectin, produced by further processing of Fresh Frozen Plasma (FFP).
Clinically it is most commonly used to replace fibrinogen
much smaller volume than FFP, typically 15-20mL
most suited for patients for ‘clinically significant’ but without ‘major haemorrhage’ who have a fibrinogen concentration < 1.5 g/L
Example use cases include
- DIC
- Liver failure
- Hypofibrinogenaemia secondary to massive transfusion.
It may also be used in an emergency situation for haemophiliacs (when specific factors not available) and in von Willebrand disease
Can be used prophylactically in patients undergoing invasive surgery where there is a risk of significant bleeding where the fibrinogen concentration < 1.0 g/L
What is haemophilia
Types
Features
Blood tests
Managements
Haemophilia is a X-linked recessive disorder of coagulation. Up to 30% of patients have no family history of the condition.
Haemophilia A is due to a deficiency of factor VIII whilst in Haemophilia B (Christmas disease) there is a lack of factor IX
Features
haemoarthroses, haematomas
prolonged bleeding after surgery or trauma
Blood tests
Prolonged APTT - only abnormal
bleeding time, thrombin time, prothrombin time normal
Up to 10-15% of patients with haemophilia A develop antibodies to factor VIII treatment.
Management
- Avoid NSAIDs and Im injections
- Minor bleeds: Desmopressin + transexamic acid
- Major bleeds: rhF8 (if A)
Schistiocyte causes
MAHA
Mechanical valve
Treatment of DVT/PE
1) LMWH (tinzaparin 175) + warfarin
- stop LMWH once INR >2 for 2 days
- Continue for 3-6 months
2) Start DOAC and continue for 3-6 months
If cancer pt, continue LMWH not warfarin
Target cells causes
Hyposplenism
Thalassaemia
Liver disease
RBC with a purple spot in it
Name
Conditions that cause it
Howell-Jolly bodies
- nuclear remnants
1) Post splenectomy
2) Hyposplenism
(E.g. sickle cell disease, coeliac, IBD, myeloproliferative, amyloid)
3) Megaloblastic anaemia
Platelets >600 x 10^9
Thrombosis/bleeding, headaches
Diagnosis
Mutations
Management
ET
Mutations in JAK2, calreticulin and MPL
Rx: Aspirin
Hydroxycarbamide
Anagrelide (not commonly)
Non-hodgkin lymphoma
Features
80% of lymphoma
1) Lymphadenopathy
- PAINLESS
- SYMMETRIC
- Spreads DISCONTINUOUSLY
- Multiple sites
2) Extranodal
- Skin esp T cell lymphomas
- CNS
- Oropharynx + GIT
- Splenomegaly
3) B Symptoms
- Fever
- Night sweats
- Weight loss (>10% in 6 months)
4) Blood
- Pancytopenia
- Hyperviscosity
Non-hodkin lymphoma investigations
FBC, U&Es, LFT, LDH - LDH high = worse prognosis Film - Normal or circulating lymphoma cells - +/- pancytopenia
Classification: LN and BM biopsy Staging: CT/MRI CAP - Ann Arbor staging I; one group of nodes II: >1 group nodes same side diaphragm III; nodes above and below diaphragm IV: extra-nodal spread B if fever, night sweats, unexplained weight loss
