Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2683_Библиотеки_им_академика_М_И_Перельмана.pdf
Haematological disorders
a risk of developing leukaemia. The choice of treatment
will depend on the stage of disease, histological pattern and
prognostic factors. Autologous stem cell transplantation is
used for management of resistant disease or relapse.
The international prognostic score used as a tool for
prognosis estimation in patients newly diagnosed with advanced Hodgkin lymphoma includes age 45years or more,
male sex, stage IV disease, lymphocytopenia and leucocytosis and low Hb and albumin levels. The prognosis is
generally good, and 5-year survival rates reach around 81%
nowadays.
Non-Hodgkin lymphoma
Aetiology
NHL is a highly heterogeneous group of lymphoproliferative
malignancies. Given the heterogeneity, its presentation is
variable, as is response to treatment. NHL is five times more
common than Hodgkin disease. The median age of presentation is older than 50years. Exceptions are high-grade
lymphoblastic and small noncleaved lymphomas, which are
most commonly found NHL in children and young adults.
The cause is multifactorial and includes:
• genetic predisposition
• immunosuppression (particularly HIV infection, also
transplant recipients)
• viruses (e.g. EBV, hepatitis C virus)
• autoimmune disorders (Sjögren syndrome and
Hashimoto thyroiditis)
Pathology
As mentioned, NHL is a heterogeneous malignancy showing diverse histological cell patterns and clinical course. It is
characterized by neoplastic proliferation of B lymphocytes
(usually) or T lymphocytes forming solid tumours within
the lymphoid system which do not have RS cells.
The most commonly used classification is the WHO
classification. It classifies neoplasms by the cell of origin,
and is summarized in Table36.9.
Clinical features
The clinical presentation is diverse and can differ among
different NHL types.
Low-grade lymphomas:
• Slowly progressing, painless lymphadenopathy, usually
peripheral. Sometimes associated with spontaneous
regression of enlarged lymph nodes.
• Hepatosplenomegaly and bone marrow involvement
causing cytopenia can occur.
• Systemic symptoms including fatigue, fevers, weight
loss and extranodal involvement are uncommon at
early stages but become prominent in advanced disease.
Intermediate- and high-grade lymphomas:
• Rapidly growing, bulky lymphadenopathy is the most
frequent feature at presentation.
Table36.9 Word Health Organization classification of
non-Hodgkin lymphoma
B cell T cell
Precursor B-cell neoplasm
• Precursor
B-lymphoblastic
lymphoma
Mature (peripheral) B-cell
neoplasms
• High grade
○
Diffuse large B-cell
lymphoma; 30%–58%
of all non-Hodgkin
lymphoma
○
Mediastinal large B cell
○
Primary central nervous
system lymphomas
○
Primary effusion
lymphoma
○
Burkitt lymphoma
○
Mantle cell lymphoma
• Low grade
○
Follicular lymphoma;
20%–25% of all nonHodgkin lymphoma
○
Mucosa-associated
lymphoid tissue
lymphoma
○
Waldenström
macroglobulinaemia
Precursor T-cell neoplasm
• Precursor T-lymphoblastic
lymphoma
Mature (peripheral) T-cell
neoplasms
• High grade
○
Enteropathy-type T-cell
lymphoma
○
Peripheral T-cell
lymphoma
○
Subcutaneous
panniculitis-like
○
Systemic anaplastic
○
Angioimmunoblastic
• Low grade
○
Mycosis fungoides
and cutaneous T-cell
lymphomas
• Systemic symptoms (fever, weight loss, fatigue, night
sweats) and extranodal involvement (gastrointestinal
and genitourinary tract, skin, CNS, bone marrow) are
common.
• Hepatomegaly and splenomegaly.
• Depending on the system involved, specific features
resulting from a mass effect can occur, and most
commonly involve hydronephrosis due to ureter
obstruction, testicular mass, mediastinal mass causing
superior vena cava syndrome and abdominal mass
mimicking bowel obstruction.
Diagnosis is confirmed by lymph node biopsy for histology,
immunohistochemistry and cytogenetics. Staging should
then be performed to determine the extent of disease with
use of the Ann Arbor system (see Fig.36.1). This usually
comprises CT or PET scan and bone marrow biopsy.
Treatment and prognosis
Treatment options differ because of high heterogeneity.
disease, local or extended radiotherapy and single-agent
or multiagent chemotherapy. All patients should have
polyvalent pneumococcal and influenza vaccinations.
Haemophilus influenzae type b and meningococcal vaccination are also recommended. In patients with neutropenia,
antibiotic prophylaxis is needed.
368
Myeloproliferative disease
3636
Low-grade NHL has a good prognosis, generally with
median survival of around 10 years. Advanced disease is
incurable however. Intermediate- and high-grade lymphomas are more aggressive but are also more responsive to
treatment.
Poor prognostic factors include lymphoma with features
of both high- and low-grade disease.
MYELODYSPLASTIC SYNDROMES
Myelodysplastic syndromes (MDSs) are a group of malignant haemopoietic diseases characterized by ineffective
haemopoiesis and dysplastic changes of one or more lineages of cells. There is also a high risk of transformation
into AML.
Bone marrow shows hypocellularity or hypercellularity
with disordered maturation of abnormal cells. This causes
blood cytopenia because of ineffective haemopoiesis. It can
affect myeloid (WBCs), erythroid (RBCs) and megakaryocyte (platelet) cell lines.
About 10% of MDSs are secondary to an initial insult
(secondary MDSs); for example chemotherapy or occupational exposure to radiation. Secondary MDSs have been
shown to have poorer prognosis than primary cases.
MDSs are mainly diseases of the elderly, with 86% of
cases occurring in those aged 60 years or older. They are
more common in men and in smokers.
Classification
MDS classification is constantly evolving because of continual improvements in our understanding of the disease.
Currently, the most up-to-date classification is set by the
WHO, and includes the International Prognostic Scoring
System. It assesses cell lines affected and the proportion of
cytogenic marrow abnormality (Table36.10).
Clinical features
The symptoms are nonspecific and reflect the underlying cell deficiency. Patients may present with symptoms
due to one or a combination of anaemia, leucopenia and
thrombocytopenia.
The examination can show signs of a thrombocytopenic
rash, like petechiae or ecchymoses. Symptoms of anaemia
can be evident on conjunctiva or in the mouth. Systemically,
tachycardia, palpitations or a headache can be a feature.
Splenomegaly and lymphadenopathy are usually not seen.
Diagnosis is made by elimination of non-MDS causes
of cytopenia with abnormal cell morphology and increased
bone marrow blasts.
On investigation, the FBC can show various abnormalities ranging from anaemia to monocytosis, neutropenia,
neutrophilia, thrombocytosis or thrombocytopenia.
Blood film classically shows RBCs with anisocytosis
(unequal size) and poikilocytes (abnormally shaped RBCs),
Pappenheimer bodies, basophilic stippling and irregular,
large platelets.
Management
New approaches to management with novel agents are
continuously being developed. In cases of indolent, lowrisk MDS, supportive treatment may be necessary only.
Although chemotherapy can be used with curable results
in a small number of patients, the gold standard curative
treatment is currently allogeneic haemopoietic stem cell
transplantation.
In low-risk patients, survival is longer and transmission
rates to AML are lower when compared with high-risk
MDS patients. The main goals of treatment here are symptomatic control of cytopenia, mainly anaemia that eventually requires transfusion.
Table36.10 Word Health Organization classification of
myelodysplastic syndrome
RA (<5% blasts)
Refractory cytopenia with multilineage dysplasia
MDS with isolated deletion (5q)
MDS – unclassified
RA with ringed sideroblasts (<5% blasts)
Refractory cytopenia with multilineage dysplasia and
ringed sideroblasts
RAEB 1 (5%–9% blasts)
RAEB 2 (10%–19% blasts)
AML (>20% blasts)
AML, Acute myeloid leukaemia; MDS, myelodysplastic syndrome;
RA, refractory anaemia; RAEB, refractory anaemia with excess
blasts.
MYELOPROLIFERATIVE DISEASE
Myeloproliferative neoplasms are a group of rare cancers
of bone marrow. They are caused by malignant proliferation of abnormal myeloid cells in bone marrow. The conditions are closely related to MDS. They can develop in any
MDS and AML but usually have a much better prognosis.
There are four main syndromes: CML (associated with the
Philadelphia chromosome and discussed earlier), essential
thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis associated with JAK2 mutation.
Polycythaemia vera
In PV there is an increased number of circulating erythrocytes (raised haematocrit). PV can also result in raised
numbers of WBCs and platelets. Primary PV is associated
369
Haematological disorders
with low levels of EPO, caused by a mutation of a tyrosine
kinase gene (JAK2) which results in overproduction of cells
independently of EPO.
The usual age of presentation is between 65 and 74years,
and patients can be asymptomatic. The disease starts with a
plethoric stage and then moves on to the spent stage. The
array of signs and symptoms seen include:
• symptoms of raised haematocrit (headache, weakness,
sweating, dizziness)
• symptoms of thrombosis (deep vein thrombosis (DVT),
myocardial infarction, stroke, Budd–Chiari syndrome)
• arthralgia and pruritus
• plethora (red complexion) and the presence of
splenomegaly
On investigation, there is raised haematocrit, thrombocytosis and leucocytosis.
Management aims to control cardiovascular risks and is
with venesection (to lower the haematocrit) and low-dose aspirin. In high-risk patients, cytoreductive treatment is also recommended, and includes hydroxycarbamide and interferon alfa.
Essential thrombocythaemia
In ET the platelet count is markedly elevated and the
platelets are functionally abnormal. The mean age at diagnosis is 60years, but initial stages of the disease can be
asymptomatic.
Clinical features are related to increased tendency of
bleeding and thrombosis, and include:
• a headache, lightheadedness or syncope
• burning pains, arthralgia, swollen digits
• transient ischemic episodes and parasthesiae
• bleeding gums or gastrointestinal bleeds
• splenomegaly and hepatomegaly
Investigations in a patient with suspected ET include FBC,
which usually shows elevated platelet levels (>600 × 109/L).
A blood film may show bizarre-looking platelets and platelet aggregates.
Treatment is with observation alone in patients with low
risk of thrombosis. Low-dose aspirin can also be used. In
high-risk patients cytoreductive therapy (e.g. with hydroxyurea) is necessary.
Primary myelofibrosis
In primary myelofibrosis there is proliferation of abnormal
cells in all three cell lines, accompanied by release of growth
factors, which cause bone marrow fibrosis. There is a characteristic leucoerythroblastic blood film appearance and
elevated levels of various cytokines. The disease can present
in a patient with no previous associated condition (primary
myelofibrosis) or develop secondarily (e.g. from PV or ET).
The disease may be asymptomatic initially, and clinical
features are variable. They may reflect progressive anaemia,
leucopenia or leucocytosis, thrombocytopenia or throm-
bocytosis and multiorgan extramedullary haemopoiesis
(mostly hepatomegaly and/or splenomegaly). Organ enlargement can cause symptoms due to a mass effect, including spinal cord compression or seizures. Constitutional
symptoms, including fatigue, weight loss and night sweats,
are common.
The only curative treatment is with allogeneic stem
cell transplantation. General management otherwise is
palliative and concentrated around symptomatic control.
Hydroxyurea has traditionally been the preferred agent,
and is often effective at relieving symptoms and reducing
splenomegaly.
BLEEDING DISORDERS
An increased tendency for bleeding can result from abnormalities of platelets, the coagulation pathway or blood
vessels. The differential diagnosis, clinical findings and
investigation of these disorders are discussed in detail in
Chapter26. Specific conditions and their management are
considered here.
Haemophilia A
Haemophilia A is a bleeding disorder caused by deficiency
of clotting factor VIII. It affects 1 in 4000–5000 males worldwide. The vast majority of cases result from an X-linked recessive mutation, meaning males are affected from carrier
mothers. There is usually a strong family history predicting
the condition. Females born to affected fathers can have
mild symptoms because of homozygosity.
The disease can have marked phenotypical variability,
leading to a wide spectrum of severity. In severe disease,
the presentation is usually apparent in infancy. Signs and
symptoms can include excessive bleeding on minor procedures or trauma, spontaneous haemarthroses, intramuscular or intracranial haemorrhage and haematuria. Moderate
disease often becomes apparent with excessive bleeding at
venepuncture or during surgery. In mild forms, only major
trauma or a surgical procedure will cause excessive bleeding.
On investigation, activated partial thromboplastin time
(APTT) is usually prolonged and factor VIII level is low.
Management is divided into prophylaxis and treatment.
Prophylaxis includes recombinant factor VIII infusion in
severe disease and maintenance of treatment to control the
symptoms. In episodes of acute bleeding, management is
with factor VIII and fresh frozen plasma, and at times with
desmopressin and antifibrinolytic agents to boost factor
VIII activity.
Special care is needed in haemophilia A patients when
surgery or pregnancy is planned. A specialist multidisciplinary team should be involved, and intensive monitoring is necessary to ensure the minimum patient risk
and complications. With current therapies and specialist
370
Disseminated intravascular coagulation
3636
multidisciplinary team support, life expectancy for patients
is normal. Any pregnant woman with a family history of the
condition should be offered genetic screening.
Haemophilia B (Christmas disease)
This is caused by a deficiency in clotting factor IX. As in
haemophilia A, this is also an X-linked recessive condition
but it is about five times less prevalent than haemophilia A.
The clinical features of haemophilia B are similar to those of
haemophilia A but less severe.
On investigation, APTT is prolonged and on factor IX
assay, factor IX activity is low.
Treatment with recombinant factor IX is the first-line
therapy. If this is unavailable, plasma-derived factor IX can
be used. Additional treatment with antifibrinolytic therapy
can be used in cases of acute bleeding. Care should be taken
to monitor patients for the development of inhibitors to
factor IX. The risk of an immune response to factor IX is
higher than in haemophilia A and can cause a severe anaphylactic reaction.
Von Willebrand disease
Von Willebrand disease (vWD) is the most common coagulopathy worldwide. It occurs in 1%–2% of the general population and is more common in females, and is more severe
in people with blood group O. In most of those with vWD,
it is an inherited, autosomal dominant condition (rarely
autosomal recessive) or in some cases it can be acquired
(pseudo-vWD, associated with myeloproliferative disease
or solid tumours). It results from the abnormal function, or
deficiency of von Willebrand factor (vWF).
Von Willebrand factor (vWF) is a plasma protein that
mediates platelet adherence to the subendothelium and
platelet aggregation. It also binds and stabilizes factor VIII,
preventing its clearance from plasma.
Presentation differs according to the severity of the deficiency, and in many cases remain occult, until an episode of
abnormal bleeding occurs.
Most patients present with bleeding characterized by
platelet disorders: bruising, bleeding into the skin, mucosal bleeding (epistaxis, bleeding gums, gastrointestinal
bleeding). Spontaneous bleeding (e.g. into joints) or internal bleeding occurs only in severe cases. Menorrhagia and
bleeding following surgery, dental extractions, trauma and
delivery are common.
Investigations include prolonged APTT and low vWF
level. Since vWF binds factor VIII and prevents its breakdown, vWD can also lead to factor VIII deficiency, and this
can also be measured.
Management includes education regarding avoidance
of precipitating factors. Minor disease may not require any
other intervention except patient education. Treatment to
achieve haemostasis includes tranexamic acid, desmopressin and vWF factor administration.
Immune thrombocytopenia
Immune thrombocytopenia (ITP) is an autoimmune condition that results in low platelet levels. There is antibodymediated destruction of platelets in the spleen and liver and
antibody-mediated reduced platelet production. This can
happen alone (primary ITP) or can be associated with other
conditions (secondary ITP). The cause is often unclear, but
it may occur following viral illnesses, in the context of other
autoimmune diseases (such as SLE) or lymphoproliferative
disease, or following administration of certain drugs.
ITP can be acute or chronic, and it can affect both adults
and children. The presentation can be relatively mild with
clinical features including:
• easy bruising, petechial or purpuric rash
• mucosal bleeding and menorrhagia
• haematuria and gastrointestinal bleeding (less common)
• splenomegaly, which rarely occurs in isolated ITP
and should prompt consideration of an underlying
diagnosis if it is present
Treatment is considered on the basis of symptoms and factors such as platelet count, patient age and comorbidities.
General measures include advice and close monitoring. If
pharmacological treatment is indicated, first-line measures
include steroids, intravenously administered immunoglobulin and intravenously administered anti-D. If these prove
ineffective, splenectomy or biological agents (e.g. rituximab) can be indicated.
DISSEMINATED INTRAVASCULAR
COAGULATION
Aetiology
The condition is characterized by a specific haematological
response to a secondary disease. There are no predisposing
factors in terms of sex, age and race. Risk factors include:
• infection: septicaemia, most commonly gram-negative
sepsis;
• malignancy: mainly leukaemias;
• some connective tissue disorders: antiphospholipid
syndrome;
• obstetric complications: amniotic fluid embolism,
placental abruption, preeclampsia, HELLP syndrome,
septic abortion;
• major trauma causing tissue damage;
• immunological factors: incompatible blood transfusion,
drug reaction, anaphylaxis;
• other factors: snake bites, acute pancreatitis, heat stroke.
Pathology
In DIC, normal haemostasis and processes of coagulation
and fibrinolysis are dysregulated. There is an inappropriate,
371
Haematological disorders
diffuse activation of the clotting cascade (especially thrombin) in response to an insult. This may lead to acute or
chronic thrombosis that compromises tissue oxygenation
and leads to organ damage. Moreover, because of thrombosis exhausting the supply of clotting factors, severe haemorrhage can occur.
Initially, intravascular coagulation is precipitated by
release of tissue factor from injured or malignant cells.
This glycoprotein is present on the surface of many cells,
including endothelial cells, monocytes and macrophages,
and is not normally in contact with the general circulation unless vascular damage has occurred. On exposure
to blood and platelets, tissue factor binds activated factor
VII, triggering the common coagulation pathway and formation of thrombin and fibrin. As a result, thrombi form
throughout the microcirculation, causing ischaemia and
infarction.
Simultaneously, an excess of thrombin leads to activation of plasmin so as to commence fibrinolysis. Fibrin
breakdown leads to formation of fibrin degradation products, which have further anticoagulant properties contributing to haemorrhage.
Clinical features
Since DIC is a manifestation of a primary disease, usually the most immediate signs and symptoms are those
of the underlying condition. Additionally, large bruises
and spontaneous bleeding (e.g. from sites of venepuncture) may be apparent. In subacute and chronic cases the
clinical presentation is usually associated with thrombosis; however, in acute settings various features can be
found:
• Bleeding from at least three unrelated sites (e.g. nose,
ears, respiratory tract or gastrointestinal tract)
• Fever and confusion
• Thrombosis can cause widespread ischaemia or
infarction leading to renal failure, liver failure and
central nervous involvement
Investigations will show
• low platelet count
• prolonged prothrombin time and APTT
• low fibrinogen levels
• high D-dimer/fibrin degradation product levels
Treatment and prognosis
Treatment of the underlying disease is the first priority and
may resolve the DIC. Replacement of platelets and clotting
factors (fresh frozen plasma or cryoprecipitate) may be
used if there is haemorrhage or a risk of haemorrhage (e.g.
in surgery). Pharmacological inhibitors of coagulation or
fibrinolysis (e.g. heparin or tranexamic acid) may be beneficial in certain circumstances.
DIC is associated with high mortality. It commonly
results in organ failure and long-term complications.
Prognosis is based on the nature of the underlying condition, comorbidities and the severity of DIC.
THROMBOTIC DISORDERS AND THROMBOEMBOLISM
HINTS AND TIPS
The causes of thromboembolism can be broken
down by the Virchow triad:
• changes in the vessel wall
• changes in the blood flow
• changes in the composition of the blood
Aetiology
Risk factors for venous thromboembolism are outlined in
Table. 36.11. Venous thromboembolism most commonly oc-
curs in the deep veins of the lower limbs and pelvis. Clots in the
CNS, lungs, renal vessels or mesenteric vessels are less common.
Pathology
• Clotting of blood can be caused by abnormal vessel
walls, venous stasis or hypercoagulable blood.
• Thrombosis may be precipitated by a specific event such
as surgery or a physiological state such as pregnancy.
• Small clots may break off and embolize to other organs
(e.g. the lungs (pulmonary embolus)) or, very rarely,
cause cerebral infarction by paradoxical embolus in
patients with a patent foramen ovale.
Clinical features
• DVT causes local pain, swelling, redness and oedema.
• The diagnosis can be difficult to make on clinical
grounds.
• Pulmonary embolus classically causes sudden onset of
pleuritic chest pain, dyspnoea and haemoptysis.
• Patients with inherited hypercoagulable states may
present with venous thromboses without obvious
precipitants, in unusual places (e.g. Budd–Chiari
syndrome), at an early age or with spontaneous
abortions.
• Antiphospholipid syndrome and
hyperhomocysteinaemia increase the risk of arterial as
well as venous thromboses.
372
Thrombotic disorders and thromboembolism
Table36.11 Risk factors for thromboembolic events
Cause Risk factor Associated factors
Inherited (decreasing order of
thrombotic risk)
Acquired Physiological Pregnancy
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden mutation (activated
protein C resistance)
Prothrombin 20210A mutation
Hyperhomocysteinaemia
Dysfibrinogenaemia (10% have
thrombophilia, 90% have coagulopathy)
Obesity
Increasing age
Initiating events (immobilization) Surgery
Trauma
Long-distance travel
Pathological Malignancy
Venous trauma
Oestrogens
Nephrotic syndrome
Antiphospholipid syndrome
Hyperviscosity syndromes
Paroxysmal nocturnal haemoglobinuria
Inflammatory bowel disease
3636
Table36.12 Wells score algorithm
Score 1 point for each of the following. Subtract 2 points if
an alternative diagnosis is considered.
A risk of DVT is likely if the score is 2 or more
1. Ongoing malignancy (current, previous 6months or
palliative)
2. Paralysis, paresis or recent immobilization of legs with,
e.g. plaster
3. Recently bedridden for 3days or more, or major
surgery within last 12weeks under general anaesthesia
4. Pitting oedema in the symptomatic leg
5. Localized tenderness along deep veins
6. Swollen entire leg
7. Calf swollen by more than 3 cm when compared with
the asymptomatic leg
8. Collateral superficial veins
9. Previous DVT
DVT, Deep vein thrombosis.
A careful clinical examination should be performed in any
patient suspected of having thrombotic disease to look for
an underlying cause such as malignancy, and investigations
should be requested appropriately. The pretest probability of venous thromboembolism should be evaluated with
an accepted scoring system (e.g. Wells score for DVT; see
Table36.12). If concerns arise, appropriate imaging such as
ultrasound scan or CT pulmonary angiogram scan can be
considered. If the patient is young, ask if there have been
recurrent episodes, recurrent spontaneous abortions or a
family history of thromboembolism, and consider hereditary thrombophilia.
Treatment and prognosis
Although local protocols may differ, general management
considerations for patients who have thrombotic disease
should include appropriate anticoagulation and lifestyle advice. Compression stockings and avoidance of risk factors
is very important. Use of low-molecular-weight heparin
should be started in the acute phase, and unfractionated
373
Haematological disorders
heparin should be considered in patients with a high risk
of bleeding.
When you are considering long-term management,
treatment with warfarin and regular monitoring with the
international normalized ratio is slowly being replaced with
treatment with novel oral anticoagulant medications. These
agents do not need regular monitoring but are expensive
and there are no immediate antidotes available currently,
which increases the risk if bleeding occurs.
The length of treatment is variable and depends on the
cause of the thrombus. When you are considering DVT
and pulmonary embolus, treatment is initially continued
for 3months, after which it is re-evaluated on the basis of
comorbidities, current patient status and the cause of the
initial event.
HINTS AND TIPS
Warfarin alone is a procoagulant when used initially
because of its more rapid inhibition of protein C
and protein S.
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura is a rare form
of thrombotic microangiopathy. It is more common in
adults (peak occurrence in the fourth decade of life), although cases in children and neonates have been reported.
Pregnancy and the postpartum period account for 10%–
25% of cases, and it has higher prevalence in autoimmune
disease and cancer.
It is characterized by a pentad of features:
• thrombocytopenia and excessive bleeding
• microangiopathic haemolysis that can result in
jaundice and abdominal pain
• neurological abnormalities such as lethargy, confusion,
headache and seizures
• renal dysfunction and acute kidney injury
• pyrexia that is not caused by infection
Clinical examination can also show purpuric rash and
splenomegaly.
These features may not all be present, and clinical suspicion is necessary. The diagnosis should be considered a
medical emergency.
Investigations include:
• blood film: shows the fragmented RBCs (schistocytes),
which are characteristic of the disease.
• renal function tests, which can show elevated creatinine
level.
• measurement of bilirubin and LDH levels, which will
rise because of haemolysis.
Treatment is with intravenous plasma exchange, and this
has vastly improved the prognosis and allowed most
patients to achieve a lasting response. Immunosuppression
with glucocorticosteroids and biological drugs is also used.
Haemolytic uraemic syndrome
Haemolytic uraemic syndrome is the most common cause
of acute kidney injury in children, and 90% of cases occur
following a diarrheal illness, particularly with pathogenic
Escherichia coli. This organism is able to release a toxin that
then damages endothelial cells. This occurs particularly in
the renal system, gastrointestinal system and CNS. Damage
to the microvasculature causes deposition of thrombin and
fibrin and narrowing of the blood vessels. Erythrocytes are
unable to pass through the vessels and become damaged,
causing haemolysis.
The remaining 10% of cases can be due to a variety of
causes, including viruses, drugs and cancer.
It is a systemic disease classically presenting with profuse
diarrhoea that becomes bloody at 1–3days. There is often
abdominal pain, vomiting and fever.
Investigations include:
• FBC: anaemia and thrombocytopenia;
• biochemistry: renal impairment, raised LDH level,
raised bilirubin level;
• blood film: RBC fragments, reticulocytes.
Typical haemolytic uraemic syndrome (following diarrhoea) is usually self-resolving with supportive care.
Dialysis is sometimes required. Plasma exchange or immunosuppression may be required in severe cases.
Chapter Summary
• Haematological diseases are a group of conditions primarily affecting blood. They can be
roughly divided into myeloid disease, including haemoglobinopathies, anaemias,
myeloproliferative disorders, coagulopathies and/or disorders that reduce the number of
blood cells (e.g. myelodysplastic syndrome or thrombocytopenia) and haematological
malignancies. The malignancies include lymphomas, leukaemias and myelomas.
Miscellaneous haematological diseases can be acquired (e.g. hyposplenism due to
splenectomy), related to other underlying conditions (e.g. anaemia of chronic disease) or
caused by genetic abnormalities (e.g. haemochromatosis).
374
Infectious diseases
37
GENERAL OVERVIEW
Infections affecting specific systems have been discussed in
the appropriate chapters. This chapter considers other important and very different infections – human immunodeficiency virus (HIV) infection, malaria and infection with
drug-resistant bacteria.
HIV AND AIDS
Epidemiology and aetiology
Public Health England estimates that around 100,000 adults
in the United Kingdom are infected with HIV. The World
Health Organization (WHO) states that around 36.7 million people worldwide are infected with HIV, of whom an
estimated 70% live in sub-Saharan Africa. It is believed
deaths from HIV-related disease reached 1.1 million in
2015, and in some countries it is threatening the stability of
society. There has been a huge drive to increase the provision of antiretroviral therapies, and currently more than 18
million people are receiving treatment. The development of
effective strategies, however, remains difficult.
Two HIV types have been identified: HIV-1 and HIV-2.
HIV-1 was first identified in 1983 and is found throughout
the world. It is the main cause of HIV-related disease in humans. HIV-2 has lower infectivity and relatively poor capacity for transmission compared with HIV-1 and is confined
to West Africa, where it is endemic. It accounts for around
5% of HIV infections worldwide.
HIV can be transmitted by sexual, parenteral and vertical routes (Tables 37.1 and 37.2).
Pathology
HIV is a lentivirus that belongs to a subgroup of human
retroviruses, which means that its genetic information is
stored in a single strand of ribonucleic acid (RNA). Three
specific HIV genes produce proteins essential for virus survival (Table37.3). HIV can infect any cells expressing CD4
receptor (notably central to the immune response T-helper
cells) as well as macrophages, monocytes and microglia. The
CD4 receptor has affinity for glycoprotein 120 on the viral
envelope, allowing the virus to enter the cell. Coreceptors
such as CXCR4 and CCR5 are currently being explored as
potential therapeutic targets.
Virus replication involves the enzyme reverse
transcriptase. It makes DNA copies of the virus RNA, which
Table37.1 Risk of HIV transmission
Type of exposure (source
known to be HIV positive) Risk of transmission (%)
Needlestick 0.2–0.4
Mucosal membrane
exposure
Receptive oral sex 0–0.04
Insertive vaginal sex ≤0.1
Insertive anal sex ≤0.1
Receptive vaginal sex 0.01–0.15
Receptive anal sex ≤3
IDUs sharing needles 0.7
Transfusion 90–100
IDU, Intravenous drug user.
Table37.2 Routes of HIV transmission
Route Examples
Sexual Vaginal intercourse, anal intercourse
Parenteral IV drug abuse, blood transfusion,
Vertical (i.e. from
mother to fetus)
IV, Intravenous.
Table37.3 HIV genes and the proteins they encode
Gene Protein
pol Reverse transcriptase (makes DNA copies of
the viral RNA) and integrase (for insertion into
host DNA)
gag Core protein p24
env Glycoprotein 41, a transmembrane
protein, and glycoprotein 120, an external
glycoprotein (for fusion with host cell)
then becomes integrated into the host cell's genome and results in the production of viral particles. This disrupts the
normal function of the infected cells, and the host cells are
eventually destroyed.
Because the principal cells affected are those of the immune system, HIV infection is characterized by diseases
resulting from immunodeficiency (e.g. infections and
malignancies).
needlestick injury
During gestation or delivery, via
breast milk
0.1
375
Infectious diseases
Clinical features
Diagnosis is usually made by HIV antibody tests. These antibodies may be undetectable for up to 3months after infection, which presents a window for false-negative results.
Once a diagnosis has been confirmed, disease activity can
be assessed by quantification of HIV RNA viral load and
CD4+ cell count (Table37.4).
There are currently two main systems in use for staging
and surveillance of HIV and HIV-related disease. The US
Centers for Disease Control and Prevention (CDC) staging system uses the CD4 count and the presence of certain
HIV-related illness to classify the clinical stage as A, B or
C (Table37.5). When the CD4 count is not available, the
WHO system is used: this describes primary infection and
stages 1–4 (see later).
It is estimated that 50% of untreated patients will develop acquired immunodeficiency syndrome (AIDS) after
10years. A minority remain asymptomatic for many years
without treatment.
Primary HIV infection
In most patients, primary HIV infection results in a 'seroconversion illness' occurring between 1 and 6weeks after
infection. The symptoms are similar to those seen with
other viral infections, including fever, arthralgia, headaches,
rash, generalized lymphadenopathy and occasional neurological abnormalities. The illness is self-limiting, and usually resolves in 1–2weeks.
Clinical stage 1
The patient is either asymptomatic or has persistent generalized lymphadenopathy: rubbery, mobile, enlarged lymph
nodes at multiple sites. Biopsy shows nonspecific reactive
histiocytosis.
Clinical stage 2
During this stage (which broadly resembles CDC stage B)
the illness is symptomatic. It corresponds to mild mucocutaneous manifestations and recurrent upper respiratory
tract infections. Although many of these may occur in other
clinical situations, they are severer in the context of HIV.
Constitutional symptoms are common (Table37.6).
Clinical stages 3 and 4
In stages 3 and 4 (CDC stage C) constitutional symptoms
may be severer, and the conditions that occur indicate that
the immunosuppression is more profound. The appearance
of these conditions is a guide to initiating or changing treatment. Any system can be affected. Malignancies are seen
with increased frequency, and may be associated with specific viral infections (Table37.7).
Treatment and prognosis
Currently, there is no effective cure or vaccine for HIV infection, even though in the last decade treatment of HIV
infection has changed dramatically. At present, mainstay
treatment concentrates around antiretroviral medication,
Table37.4 Investigations at different stages of HIV infection
Phase Viral replication p24 HIV antibodies CD4+ count
Primary infection High Detectable until HIV
Stage 1
(WHO)/A (CDC)
(asymptomatic/PGL)
Advanced,
symptomatic stages
CDC, Centers for Disease Control and Prevention; PGL, persistent generalized lymphadenopathy; WHO, World Health Organization.
Table37.5 Centers for Disease Control and Prevention staging of HIV infection
CD4+ count (cells/μL)
>500 A1 B1 C1
200–499 A2 B2 C2
<200 A3 B3 C3
PCL, Persistent generalized lymphadenopathy.
Low Undetectable as
High Detectable Detectable Falls; when <200/μL, the risk
A: asymptomatic,
acute HIV or PGL
antibodies appear
antibody in excess
to antigen
B: symptomatic conditions, not
AIDS defining C: AIDS indicator illness
Detectable3weeks
to 3months after
exposure
Detectable Normal
Transient fall because of
high viral load, but returns to
normal when HIV antibodies
appear
of infection is very high and
development of AIDS is likely
376
HIV and AIDS
Table37.6 Features of symptomatic HIV infection
Organ/system WHO stage Example
Mouth 2 Angular stomatitis, recurrent oral ulceration, parotid enlargement
3 Oral hairy leucoplakia, oral candidiasis, necrotizing gingivitis/
periodontitis
4 Chronic oral herpes simplex infection
Gastrointestinal 2 Hepatosplenomegaly
3 Persistent diarrhoea or malnutrition
4 HIV wasting syndrome, HIV rectal fistula, esophagitis (HSV, CMV,
Candida)
Not in WHO staging Hepatobiliary disease (Mycobacteria, hepatitis B virus, CMV,
microsporidia), colitis (Campylobacter, Salmonella, Shigella,
Cryptosporidium, Giardia), anal carcinoma
Cardiovascular 4 HIV-associated cardiomyopathy
Not in WHO staging Pericardial effusions, conduction abnormalities, dilated
cardiomyopathy, pulmonary hypertension, noninfectious endocarditis
Respiratory 2 Recurrent upper respiratory tract infection (e.g. tonsillitis, sinusitis)
3 Pulmonary TB, severe recurrent bacterial pneumonia, lymphoid
interstitial pneumonitis, chronic HIV-associated lung disease (e.g.
bronchiectasis)
4 Lower respiratory tract candidiasis, Pneumocystis jirovecii
pneumonia
Not in WHO staging Fungal pneumonia
Neurological 4 CNS toxoplasmosis, cryptococcal meningitis, HIV
encephalopathy, progressive multifocal leucoencephalopathy,
CNS lymphoma
Not in WHO staging Myelopathy, peripheral neuropathy, inflammatory demyelinating
polyneuropathy, retinitis (e.g. CMV)
Renal 4 HIV-associated nephropathy
Severe nephrotic syndrome with characteristic FSGS
Haematological 3 Unexplained anaemia, neutropenia or thrombocytopenia
4 B-cell non-Hodgkin lymphoma
Not in WHO staging Burkitt lymphoma, immunoblastic lymphoma
Dermatological 2 Herpes zoster, fungal nail infections (Candida, tinea), seborrheic
dermatitis, itchy papular eruptions, extensive molluscum
contagiosum
4 Kaposi sarcoma, genital herpes simplex
Not in WHO staging Squamous cell carcinoma, crusted scabies
Reproductive Not in WHO staging Invasive cervical carcinoma
Other/systemic 2 Weight loss <10%
3 Persistent fever
4 Disseminated TB, disseminated non-TB mycobacterial infection,
recurrent severe bacterial infection (not pneumonia), disseminated
fungal infection (e.g. histoplasmosis), cryptosporidiosis, visceral
herpes simplex, CMV infection other than liver/spleen/lymph
nodes, Kaposi sarcoma
AIDS-indicator illnesses (Centers for Disease Control and Prevention 1993, stage C) are shown in bold.
CIAV, Chicken infectious anaemia virus; CMV, cytomegalovirus; FSCS, focal segmental glomerulosclerosis; HSV, herpes simplex virus.
3737
377