Acute leukaemia

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"acute leukemia" AND treatment

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Acute Leukaemia

Definition and Overview

Acute leukaemia (AL) is a rapidly progressing clonal malignancy of haematopoietic precursor cells in which immature blast cells proliferate uncontrollably in the bone marrow, suppress normal haematopoiesis, and spill into the peripheral blood and other organs. The defining criterion is ≥20% blasts in the marrow or peripheral blood (WHO classification). Without treatment, the course is rapidly fatal within weeks to months.

The two main categories are:

Acute Myeloid Leukaemia (AML) - arising from myeloid precursors
Acute Lymphoblastic Leukaemia (ALL) - arising from lymphoid precursors (B or T cell)

Origin of lymphoid neoplasms showing the differentiation stages from which B-ALL and T-ALL emerge

Fig: Origin of lymphoid and myeloid neoplasms - stages of B- and T-cell differentiation from which specific acute leukaemias emerge (Robbins, Cotran & Kumar - Pathologic Basis of Disease)

Epidemiology

AML:

Most common acute leukaemia in adults
Median age at diagnosis: ~60 years
Incidence: ~10/100,000/year in those >60 years
Most common form of acute leukaemia in the first months of life; accounts for ~1/3 of childhood acute leukaemias

ALL:

Most common cancer of children (~2,500 new cases/year in the US)
Peak incidence of B-ALL at age ~3 years
T-ALL peaks in adolescence (adolescent males, thymic involvement)
Hispanic/Latino children have the highest ALL incidence of any ethnic group
Also occurs less commonly in adults

Risk factors for AML: prior radiation, cytotoxic chemotherapy, benzene, smoking; most cases have no identifiable cause.

Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 743

Classification

WHO Classification Approach for AML

AML classification uses a multilayered approach recognizing:

Recurrent acquired cytogenetic abnormalities
History of predisposing factors (prior cytotoxic therapy)
Association with MDS/related conditions
Morphologic stratification for the remainder

The FAB classification (French-American-British, 1976) subdivided AML into M0-M7 based on morphology and cytochemistry. This has been largely superseded by the WHO classification but the basic morphologic tenets remain.

Key AML subtypes with recurrent cytogenetics:

Cytogenetic Abnormality	Key Features	Prognosis
t(8;21); RUNX1::RUNX1T1	Granulocytic maturation, Auer rods	Favorable
inv(16) or t(16;16); CBFB::MYH11	Myelomonocytic + eosinophilia	Favorable
t(15;17); PML::RARA	APL - faggot cells, Auer rods, DIC	Favorable (with ATRA)
t(9;11); KMT2A::MLLT3	Monocytic features	Intermediate
inv(3) or t(3;3); GATA2/MECOM	Multilineage dysplasia, thrombocytosis	Adverse
Complex karyotype / monosomal	-	Adverse
-5, -7, del(5q), del(7q)	Secondary AML, older patients	Adverse

Key ALL immunophenotypic groups:

B-ALL (75%): Pro-B (CD19+, CD22+, CD10-); Common ALL (CD10/CALLA+, 50-60%); Pre-B (cytoplasmic Ig, ~10%); Mature B (surface Ig, <5%)
T-ALL (25%): Early T-precursor (CD7+, CD1a-, CD3-); Thymic (CD1a+); Mature (surface CD3+)
Goldman-Cecil Medicine, p. 1923

Pathogenesis

AML

AML cells carry an average of 10-15 mutations per cell. Key driver mutations include:

Gene	Frequency	Prognostic Significance
NPM1	~30%	Favorable (if FLT3-ITD negative)
FLT3-ITD	~25% of AML	Adverse (especially high allelic ratio)
FLT3-TKD	~10%	Intermediate/adverse
CEBPA (biallelic)	4-15%	Favorable
IDH1/IDH2	Variable	Targetable; intermediate
DNMT3A	Common	Adverse
TP53	-	Strongly adverse
RAS, RUNX1, TET2, ASXL1	-	Variable/adverse

Mutations in splicing factors (SRSF2, SF3B1, U2AF1, etc.) are almost exclusively found in secondary AML.

ALL

~90% of ALLs have numerical or structural chromosomal changes
T-ALL: NOTCH1 mutations in 50-70% (NOTCH1 is essential for T-cell development)
B-ALL: mutations in PAX5 (30%), IKZF1 (25%), and translocations involving ETV6, RUNX1, BCR::ABL1, KMT2A, PBX1
Philadelphia chromosome t(9;22): present in ~5% of childhood ALL but ~25% of adult ALL - constitutively activates ABL1 kinase (190 kD BCR-ABL1 in ALL vs 210 kD in CML)
Hyperdiploidy (>50 chromosomes): better prognosis in B-ALL
Hypodiploidy: worse prognosis in B-ALL
Ph-like ALL: 20-25% of adult ALLs; lacks BCR-ABL1 but has kinase-activating mutations (CRLF2, JAK2) - poor prognosis
Goldman-Cecil Medicine, p. 1922; Robbins & Kumar Pathologic Basis of Disease, p. 556-557

Clinical Manifestations

Signs and symptoms develop rapidly over weeks to months, resulting from marrow replacement and organ infiltration:

From marrow failure:

Anaemia: fatigue, pallor, headache, exertional dyspnoea, angina
Thrombocytopenia: petechiae, ecchymoses, bleeding gums, epistaxis, haemorrhage (clinically evident bleeding in ~1/3 at diagnosis)
Neutropenia: infections (bacterial) - significant/life-threatening in ~1/3 of AML, slightly fewer in ALL

From organ infiltration (more prominent in ALL):

Lymphadenopathy, hepatosplenomegaly (common in ALL)
Mediastinal mass - characteristic of T-ALL
Bone pain - common in children with ALL (periosteal infiltration)
Leukemia cutis - raised, non-pruritic rash from skin infiltration
CNS involvement - headache, nausea, cranial nerve palsies (leukemic meningitis)
Gum hypertrophy - especially in monocytic AML subtypes

Metabolic complications:

Hyperuricaemia (esp. ALL)
Elevated LDH
DIC - hallmark of APL (acute promyelocytic leukaemia, AML M3)
Tumour lysis syndrome: hypocalcaemia, hyperkalaemia, hyperphosphataemia, hyperuricaemia, renal insufficiency
Goldman-Cecil Medicine, p. 1921-1922

Diagnosis

Peripheral blood:

Anaemia and thrombocytopenia are nearly universal
~25% have platelets <20,000/µL
WBC is variable: ~25% have WBC >50,000/µL (hyperleukocytosis), ~50% between 5,000-50,000, ~25% have low WBC (<5,000)
Blasts usually present in peripheral blood

Bone marrow:

Aspiration (± biopsy from posterior iliac crest) is the definitive diagnostic step
Usually hypercellular with 20-100% blasts
Diagnosis requires ≥20% blasts in marrow or blood

AML peripheral blood smear showing numerous large blasts with irregular nuclei amid red blood cells

AML blood film: large blast cells with prominent nuclei amid normal red cells

APL (AML M3) - promyelocytes with Auer rods; inset shows faggot cell (bundles of Auer rods)

APL (AML M3): abnormal promyelocytes with Auer rods; inset shows the pathognomonic "faggot cell" with multiple Auer rod bundles

Immunophenotyping (flow cytometry):

Identifies blast population (CD45 dim, low side scatter; CD34, CD117, CD133, TdT)
Assigns lineage (myeloid vs lymphoid) and subtype
Key myeloid markers: MPO, CD13, CD33, CD117, CD64
Key B-lymphoid markers: CD19, CD22, CD10 (CALLA), CD79a
Key T-lymphoid markers: CD3, CD7, CD1a, CD4, CD8
Used for minimal residual disease (MRD) monitoring post-therapy

Additional workup:

Cytogenetics (conventional karyotype)
Molecular studies: FISH, PCR, next-generation sequencing (FLT3, NPM1, CEBPA, IDH1/2, TP53, etc.)
Coagulation studies (PT, PTT, fibrinogen - screen for DIC, essential in APL)
Lumbar puncture: recommended in ALL; not routine in AML unless CNS symptoms present
LFTs, renal function, uric acid, LDH, urine electrolytes

Differential diagnosis:

Aplastic anaemia (hypocellular marrow, no blasts)
Myelodysplastic syndrome (<20% blasts)
Leukemoid reaction (blasts rarely reach 20%)
Infectious mononucleosis (mimics ALL)
Marrow infiltration by other small round cell tumours
Goldman-Cecil Medicine, p. 1922-1923; Henry's Clinical Diagnosis and Management, p. 786-787

Treatment

Acute Myeloid Leukaemia

Induction chemotherapy ("7+3"):

Standard: cytarabine (continuous infusion x7 days) + anthracycline (daunorubicin or idarubicin x3 days)
Goal: achieve complete remission (CR) - defined as <5% blasts in marrow, recovery of normal blood counts

APL - special treatment:

All-trans retinoic acid (ATRA) + arsenic trioxide (ATO) is now standard first-line therapy
This has transformed APL from the most lethal to the most curable subtype
Beware of differentiation syndrome (dyspnoea, fever, pulmonary infiltrates) during treatment
DIC must be managed aggressively with FFP, cryoprecipitate, platelet transfusions

Targeted therapy (mutation-specific):

FLT3 inhibitors: midostaurin (added to induction for FLT3-mutated AML), gilteritinib (relapsed/refractory)
IDH1 inhibitors: ivosidenib
IDH2 inhibitors: enasidenib
BCL-2 inhibitor: venetoclax (combined with hypomethylating agents - azacitidine/decitabine) - particularly for older/unfit patients

Post-remission/consolidation:

Favorable-risk AML (t(8;21), inv(16), NPM1 mutated without FLT3-ITD): high-dose cytarabine consolidation
Intermediate/adverse-risk AML: allogeneic haematopoietic cell transplantation (allo-HCT) in first CR
Allo-HCT in first CR achieves disease-free survival of ~55-60%; meta-analyses confirm survival advantage over chemotherapy for adverse/intermediate-risk AML

Acute Lymphoblastic Leukaemia

Treatment phases in ALL:

Induction (4-6 weeks): vincristine, glucocorticoids, asparaginase ± anthracycline; for Ph+ ALL, add tyrosine kinase inhibitor (imatinib/dasatinib/ponatinib)
CNS prophylaxis: intrathecal methotrexate (±cytarabine); cranial radiation now largely replaced by intrathecal chemotherapy to reduce neurotoxicity
Consolidation/intensification
Maintenance: mercaptopurine, methotrexate for 2-3 years (critical in ALL to prevent relapse)

Key targeted agents in ALL:

Imatinib/dasatinib/ponatinib for Ph+ ALL (BCR-ABL1)
Blinatumomab (bispecific T-cell engager, CD19/CD3): used to achieve MRD-negative state before transplant
Inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate): relapsed/refractory B-ALL
CAR-T cell therapy (tisagenlecleucel): relapsed/refractory B-ALL in children and young adults

Allo-HCT in ALL:

Adults in first CR: ~65% cure rate with transplant
Transplant in second CR: 40-50% cure rate
MRD negativity before transplant improves outcomes
Blinatumomab recommended to achieve MRD-negative state before transplantation
Harrison's Principles of Internal Medicine 22E (2025), p. 1522-1524; Goldman-Cecil Medicine, p. 1923-1925

Prognosis

AML prognostic risk groups (ELN 2022 framework):

Risk	Features	5-year OS
Favorable	t(8;21), inv(16)/t(16;16), NPM1 mut (FLT3-ITD-neg), biallelic CEBPA	~50-60%
Intermediate	NPM1 mut + FLT3-ITD, t(9;11), normal karyotype without mutations	~30-40%
Adverse	t(6;9), inv(3), TP53 mut, complex karyotype, monosomal karyotype, secondary AML	<20%

ALL prognostic factors:

Age (older = worse), WBC at presentation (high = worse)
Ph+ ALL and Ph-like ALL: adverse (now partially overcome by TKI therapy)
t(12;21) ETV6::RUNX1: favorable (25% of childhood B-ALL)
Hyperdiploidy: favorable in B-ALL
CNS involvement at diagnosis: adverse
MRD status after induction: the most powerful prognostic factor

Overall: With modern therapy, ~40-50% of younger AML patients and ~50-70% of children with ALL achieve long-term remission/cure. Older patients (>60-70 years) with AML have substantially worse outcomes due to both disease biology and treatment intolerance.

Supportive Care

Hyperuricaemia prophylaxis: allopurinol or rasburicase (especially before initiating treatment)
Tumour lysis syndrome monitoring and management
Broad-spectrum antibiotics for febrile neutropenia (empiric antipseudomonal coverage)
Antifungal prophylaxis during prolonged neutropenia
Platelet transfusions (threshold typically <10,000/µL or <20,000/µL with bleeding)
Red cell transfusions for symptomatic anaemia
G-CSF may shorten duration of neutropenia post-chemotherapy

Sources:

Goldman-Cecil Medicine International Edition, Chapters 168/169
Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 13
Henry's Clinical Diagnosis and Management by Laboratory Methods, Chapter 34/35
Harrison's Principles of Internal Medicine 22E (2025)
Recent systematic review: Comparative efficacy in low-intensity AML treatment (Li et al., 2025, PMID 40229815)

Differentiate between all and aml

From the detailed information already gathered in our previous session, here is a comprehensive differentiation between ALL and AML:

ALL vs AML - Complete Differentiation

1. Basic Identity

Feature	ALL (Acute Lymphoblastic Leukaemia)	AML (Acute Myeloid Leukaemia)
Cell of origin	Lymphoid precursor (B or T lymphoblast)	Myeloid precursor (myeloblast, monoblast, erythroblast, megakaryoblast)
Alternate name	Acute lymphocytic leukaemia	Acute myelogenous leukaemia
Blast type	Lymphoblasts	Myeloblasts (± Auer rods)

2. Epidemiology

Feature	ALL	AML
Primary age group	Children (peak at age 3 years)	Adults (median age ~60 years)
Most common cancer in	Children (<15 years)	Older adults
Gender	Slightly more common in boys	No strong gender predominance
Ethnic predisposition	Hispanic/Latino children - highest incidence	None well-defined
In infancy	Less common than AML in first months	Most common AL in first few months of life

3. Morphology

Feature	ALL	AML
Blast morphology	Small-medium lymphoblasts, scant cytoplasm, condensed chromatin, inconspicuous nucleoli	Large myeloblasts, abundant cytoplasm, fine chromatin, prominent nucleoli (3-5), cytoplasmic granules
Auer rods	Absent	Present (pathognomonic when seen)
Special variant	-	APL (M3): faggot cells (multiple Auer rod bundles)
Cytochemistry - MPO	Negative	Positive (key distinguishing stain)
Sudan Black B (SBB)	Negative	Positive
PAS stain	Positive (chunky block positivity)	Negative or diffuse weak positivity
Non-specific esterase (NSE)	Negative	Positive in monocytic subtypes

4. Immunophenotype

Marker	ALL	AML
TdT (terminal deoxynucleotidyl transferase)	Positive (hallmark)	Negative (except some AML-M0)
CD34	Often positive	Often positive
CD10 (CALLA)	Positive in common B-ALL	Negative
CD19, CD22, CD79a	Positive (B-ALL)	Negative
CD3, CD7	Positive (T-ALL)	Negative
CD13, CD33, CD117	Negative	Positive
MPO (cytoplasmic)	Negative	Positive
CD64	Negative	Positive (mature myeloid)
CD41, CD61	Negative	Positive in megakaryoblastic AML

5. Genetics and Molecular Biology

Feature	ALL	AML
Most common translocation in children	t(12;21) ETV6::RUNX1 - 25%, favorable	t(8;21) RUNX1::RUNX1T1 - favorable
Philadelphia chromosome t(9;22)	Present in ~5% children, ~25% adults - ADVERSE	Present in rare de novo AML (<1%), very adverse
Most common adult ALL mutation	t(9;22) BCR-ABL1 (190 kD protein)	FLT3-ITD (~25-30%), NPM1 (~30%)
NPM1 mutations	Rare	~30% - favorable (without FLT3-ITD)
FLT3 mutations	Rare	~30-35% - adverse (especially high allelic ratio)
NOTCH1 mutations	T-ALL: 50-70%	Absent
PAX5/IKZF1	B-ALL: 30% and 25% respectively	Absent
APL-specific	Absent	t(15;17) PML::RARA - unique to APL
KMT2A (MLL) rearrangements	Infant ALL (very adverse)	t(9;11) - intermediate
Hyperdiploidy (>50 chr)	B-ALL - favorable	Not applicable
Hypodiploidy	B-ALL - adverse	Not applicable
Ph-like ALL	20-25% of adult ALL - adverse	Not applicable

6. Clinical Features

Feature	ALL	AML
Lymphadenopathy	Prominent (common at diagnosis)	Mild or absent
Hepatosplenomegaly	Common and prominent	Less pronounced
Mediastinal mass	T-ALL - frequent (thymic involvement)	Rare
Bone pain	Common, especially in children (periosteal infiltration)	Less common
CNS involvement	More frequent (headache, cranial nerve palsies)	Less common
Gum hypertrophy	Absent	Monocytic AML subtypes
Skin infiltration (leukemia cutis)	Less common	Monocytic AML
DIC	Uncommon	APL (AML M3) - hallmark
Infections at presentation	Common (~1/3), slightly fewer than AML	~1/3, more pronounced
Hyperuricaemia	More common (rapid cell turnover)	Present but less striking

7. Laboratory Findings

Finding	ALL	AML
Anaemia	Universal	Universal
Thrombocytopenia	Universal	Universal
WBC	Variable; can be very high	Variable
LDH	Markedly elevated	Elevated
Uric acid	Often very high	Elevated
Coagulation (DIC)	Usually normal	Abnormal in APL (low fibrinogen, prolonged PT/PTT)
Serum lysozyme	Normal	Elevated in monocytic AML
CSF involvement at diagnosis	More frequent	Less frequent

8. Treatment

Treatment Aspect	ALL	AML
Induction backbone	Vincristine + steroids + asparaginase ± anthracycline	"7+3": cytarabine x7d + anthracycline x3d
Phases of therapy	Induction → Consolidation → Maintenance (2-3 years)	Induction → Consolidation (no prolonged maintenance)
Maintenance therapy	Essential (mercaptopurine + methotrexate)	Not standard (except APL)
CNS prophylaxis	Mandatory (intrathecal MTX ± cytarabine)	Only if CNS symptoms (not routine)
APL treatment	Not applicable	ATRA + arsenic trioxide (highly specific)
Targeted therapy	TKIs (imatinib/dasatinib) for Ph+ ALL; blinatumomab; inotuzumab; CAR-T	FLT3 inhibitors (midostaurin, gilteritinib); IDH1/2 inhibitors; venetoclax
Lumbar puncture at diagnosis	Recommended in all patients	Only if CNS symptoms
Allo-HCT in first CR	High-risk and Ph+ ALL	Intermediate/adverse-risk AML

9. Prognosis

Feature	ALL	AML
Children	Excellent: ~90% cure rate in standard-risk	~60-70% with intensive therapy
Adults	~40-50% (worse than children)	~30-40% in younger adults; <20% in elderly
Best prognostic subtype	Childhood B-ALL with t(12;21) or hyperdiploidy	APL with t(15;17) - >90% cure rate with ATRA+ATO
Worst prognostic subtype	Ph+ ALL (partially overcome with TKIs); infant KMT2A-rearranged	Complex karyotype, monosomal karyotype, TP53 mutation
MRD monitoring	Critical - MRD negativity predicts sustained remission	Important - used to guide transplant decisions

10. Key "One-Line" Distinguishing Points

Feature	Favors ALL	Favors AML
Child under 15	✓
Adult over 60		✓
TdT positive	✓
MPO positive / Auer rods		✓
Mediastinal mass	✓ (T-ALL)
DIC at presentation		✓ (APL)
t(9;22) in adult	✓ (more common in ALL)	Less common
Prominent lymphadenopathy	✓
Gum hypertrophy		✓ (monocytic)
2-3 year maintenance therapy needed	✓
ATRA responsive		✓ (APL only)

Sources:

Goldman-Cecil Medicine International Edition, Chapters 168/169
Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter 13
Henry's Clinical Diagnosis and Management by Laboratory Methods, Chapters 34/35
Harrison's Principles of Internal Medicine 22E (2025)

Types of fever

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I now have rich textbook material to compile a comprehensive answer. Here is the full breakdown:

Types of Fever

Fever is classified based on its temperature pattern over time (duration, height, fluctuation, and periodicity). Understanding the pattern is diagnostically important as each pattern is characteristically associated with specific diseases.

Normal Body Temperature (Reference)

Site	Normal Range
Oral	36.4 - 37.4°C (97.5 - 99.3°F)
Axillary	~1°F (0.6°C) lower than oral
Rectal	~1°F higher than oral
Core (rectal/tympanic)	Up to 37.8°C (100°F) accepted as upper limit of normal

Fever = core body temperature >38°C (100.4°F)

Classification by Pattern

1. Continuous (Sustained) Fever

Temperature remains above normal and does not fluctuate more than 1°C (2°F) in 24 hours
Temperature never returns to normal
Sustained high plateau

Causes:

Typhoid fever (classic: stepladder rise in week 1 → continuous plateau in week 2)
Lobar pneumonia
Urinary tract infection
Rickettsial infections (typhus)
Meningitis

"When the fever does not fluctuate for more than 1°C during 24 hours, but at no time touches the normal, it is described as continued."

S. Das Manual on Clinical Surgery, p. 11

2. Remittent Fever

Temperature daily fluctuations exceed 2°C but never touches normal between fluctuations
Temperature remains elevated throughout
Most common fever pattern seen in clinical practice

Causes:

Infective endocarditis
Brucellosis ("undulant fever" - classic remittent/undulating character)
Typhoid (early stages)
Viral infections
Most bacterial infections
Pel-Ebstein fever (a special remittent pattern - see below)

3. Intermittent Fever

Temperature rises then falls back to normal or below normal each day
There is a clear afebrile period between spikes
The spike pattern gives diagnostic clues:

Sub-type	Spike frequency	Plasmodium species
Quotidian	Daily (every 24 hours)	P. falciparum (early), P. knowlesi
Tertian	Every 48 hours (alternate days)	P. vivax, P. ovale (Benign tertian); P. falciparum (Malignant tertian)
Quartan	Every 72 hours (every 3rd day)	P. malariae
Double tertian	Twice daily	Mixed P. vivax infection

Other causes of intermittent fever:

Pyogenic abscesses
Kala-azar (visceral leishmaniasis)
Lymphoma
Filariasis (periodic fever, often correlating with full/new moon)

"These regular fever patterns (quotidian, daily; tertian, every 2 days; quartan, every 3 days) are seldom seen today as patients receive prompt and effective antimalarial treatment."

Harrison's Principles of Internal Medicine 22E (2025)

4. Hectic (Septic) Fever

Also called "swinging fever" or "picket fence fever"
Very wide daily swings in temperature (often >2°C), alternating between very high spikes and near/below normal
Associated with rigors (chills, shivering) during temperature rise and drenching sweats during defervescence
Essentially a severe form of remittent/intermittent fever

Causes:

Pyaemia and septicaemia
Deep-seated abscess (liver abscess, subphrenic abscess, renal abscess)
Lateral sinus thrombosis (classic "picket fence" pattern - diurnal temperature spikes >39.4°C)
Miliary tuberculosis
Infective endocarditis
P. falciparum malaria (in early phase before synchronization)

"The classic initial symptoms of lateral sinus thrombosis include a picket fence fever pattern (diurnal temperature spikes that exceed 103°F/39.4°C)."

Cummings Otolaryngology Head and Neck Surgery

5. Relapsing (Recurrent) Fever

Episodes of fever lasting several days, followed by an afebrile period of several days, then recurrence
Pattern repeats multiple times

Causes:

Relapsing fever (Borrelia recurrentis - louse-borne; Borrelia spp. - tick-borne)
Malaria (recrudescence)
Brucellosis (relapsing pattern)
Rat-bite fever
Hodgkin's lymphoma (Pel-Ebstein fever - see below)

6. Pel-Ebstein Fever

A special relapsing pattern described in Hodgkin's disease
Weeks of high fever alternating with weeks of normal/low temperature
The cycle repeats regularly
Classically described as "intermittent bouts of remittent fever"

Causes:

Hodgkin's lymphoma (pathognomonic when present)
Also reported in other lymphomas

"In Hodgkin's disease, intermittent bouts of remittent fever (Pel-Ebstein fever) is quite peculiar to this disease."

S. Das Manual on Clinical Surgery, p. 114

7. Biphasic (Saddle-back) Fever

Two distinct fever peaks separated by a brief afebrile period ("saddle" shape on chart)
First spike: viraemia phase
Afebrile dip: brief remission
Second spike: immune/end-organ phase

Causes:

Dengue fever (classic biphasic or "saddle back" pattern)
Yellow fever
Poliomyelitis (minor illness → afebrile → major paralytic illness)
Leptospirosis (two phases)
Colorado tick fever

8. Inverse (Typhoid) Fever

Temperature is higher in the morning than in the evening
This is the reverse of normal diurnal variation (normally temperature peaks in the evening)

Causes:

Tuberculosis (especially miliary TB)
Typhoid (occasionally)
Typhus

9. Step-ladder (Typhoid) Fever

Temperature rises in a step-wise pattern over several days, each peak higher than the last
Classic in the first week of typhoid fever

Cause:

Typhoid fever (Salmonella Typhi)

Summary Table

Fever Type	Pattern	Key Causes
Continuous	Always elevated; <1°C fluctuation	Typhoid (plateau), lobar pneumonia, typhus
Remittent	Always elevated; >2°C fluctuation, never normal	Most bacterial infections, brucellosis, endocarditis
Intermittent	Spikes to normal between episodes	Malaria, abscess, kala-azar
- Quotidian	Daily spike	P. falciparum, P. knowlesi
- Tertian	Every 48 hrs	P. vivax (benign), P. falciparum (malignant)
- Quartan	Every 72 hrs	P. malariae
Hectic/Septic	Wild swings, rigors + sweats	Septicaemia, pyaemia, deep abscesses
Relapsing	Days of fever → afebrile → recurrence	Borrelia (relapsing fever), malaria recrudescence
Pel-Ebstein	Weeks of fever → weeks afebrile	Hodgkin's lymphoma
Biphasic/Saddle-back	Two peaks with dip in between	Dengue, leptospirosis, yellow fever
Step-ladder	Stepwise rise each day	Typhoid (week 1)
Inverse	Higher in morning	TB, typhoid

Special Named Fevers by Disease

Disease	Characteristic Fever Pattern
Typhoid	Stepladder rise (week 1) → Continuous plateau (week 2) → Gradual lysis (week 4)
Malaria (P. vivax)	Tertian (48-hr) intermittent with cold → hot → wet stages
Malaria (P. falciparum)	Initially quotidian, then tertian (malignant tertian), hectic if unsynchronised
Malaria (P. malariae)	Quartan (72-hr) intermittent
Brucellosis	Undulant (remittent/relapsing) with evening rise
Hodgkin's lymphoma	Pel-Ebstein (weeks of fever, weeks afebrile)
Dengue	Saddle-back biphasic
Infective endocarditis	Remittent or hectic
Septicaemia/pyaemia	Hectic with rigors and sweats
Tuberculosis	Evening rise; inverse diurnal pattern in miliary TB
Filariasis	Periodic (often related to lunar cycle)

Sources:

S. Das - A Manual on Clinical Surgery, 13th Edition, pp. 11, 114
Harrison's Principles of Internal Medicine 22E (2025)
Medical Microbiology 9e
Sleisenger and Fordtran's Gastrointestinal and Liver Disease
Cummings Otolaryngology Head and Neck Surgery

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