Minimal Change Disease is the most common cause of Nephrotic Syndrome in the paediatric population. It may be caused by NSAID use. Electron microscopy shows the fusion of foot processes while light microscopy will appear normal.

Focal segmental glomerulosclerosis causes Nephrotic Syndrome in adults. It is associated with Heroin use and HIV infection. There is a limited response to steroids, and the disease progresses to end-stage renal failure in 5-10 years.

Diabetic nephropathy occurs after a long period of diabetes due to the deposition of amyloid protein leading to a decrease in glomerular filtration.

There is no history of Hepatitis B in this patient and no symptoms of liver disease such as jaundice.

Membranous glomerulonephritis would present with features of Nephritic Syndrome. These would be oedema, haematuria; red blood cell casts in the urine and hypertension.

IgA is the major Ig in secretions, particularly from the gastrointestinal tract (but also in saliva, tears, sweat and breast milk).
IgE is important for mast cell degranulation in allergic and antiparasitic response. In the allergic response, the plasma cell produces IgE-antibodies, which, like antibodies of other immunoglobulin isotypes, are capable of binding a specific allergen via its Fab portion.
IgG is the most abundant in plasma (comprising 80% of normal serum immunoglobulin) and the main circulatory Ig for the secondary immune response.

Haemorrhage occurs into the fracture site from the ruptured vessels in the bone marrow and those supplying the periosteum immediately after fracture. This hematoma formation is the first phase of bone healing.

The 4 stages of bone healing are:
Haematoma at the fracture site (provides a framework for healing)
Callus formation
Lamellar bone formation
Remodelling

Petechiae are small red or purple spots on the skin measuring less than 3 mm, caused by minor haemorrhages which do not blanch on applying pressure.
Purpura measures between 3mm and 1 cm in diameter, while ecchymoses are greater than 1 cm in diameter. Both are caused due to haemorrhage.

Erythema is the generalised redness of the skin.

A macule is a flat, discoloured area of the skin measuring less than 1 cm in diameter.

A diagnosis of Haemophilia is supported in this patient by the family history and the presence of hemarthrosis-both characteristics of Haemophilia. Haemophilia A is caused by Factor VIII deficiency, leading to impaired coagulation. This disease typically presents after six months when the child starts crawling.

Von Willebrand disease presents with nosebleeds and hematomas. Idiopathic thrombocytopenic purpura presents with bruises that resemble a rash.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency presents with haemolytic anaemia induced by specific drugs or foods.

Factor V Leiden mutation causes blood clotting rather than bleeding.

ALL is the most common leukaemia in children, with a peak incidence between the ages of 2 and 5.
ALL has a wide range of clinical symptoms, but many children present with an acute illness that resembles coryza or a viral infection. ALL also has the following features:
Weakness and sluggishness all over
Muscle, joint, and bone pain that isn’t specific
Anaemia
Petechiae and unexplained bruising
Oedema
Lymphadenopathy
Hepatosplenomegaly

The following are typical features of a full blood count in patients with ALL:
Anaemia (normocytic or macrocytic)
Leukopenia affects about half of the patients (WCC 4 x 109/l).
Around 25% of patients have leucocytosis (WCC > 10 x 109/l).
Around 25% of patients have hyperleukocytosis (WCC > 50 x 109/l).
Thrombocytopaenia

Classic signs:
Rubor (redness)
Calor (heat)
Dolour (pain)
Tumour (swelling)
Functio laesa (loss of function)
These classic signs are produced by a rapid vascular response and cellular events. The main function of these events is to bring elements of the immune system to the site of injury and prevent further tissue damage.

CML is a myeloproliferative disorder characterised by an abnormal pluripotent haemopoietic stem cell. A cytogenetic abnormality known as the Philadelphia chromosome, which results from a reciprocal translocation between the long arms of chromosomes 9 and 22, causes more than 80% of cases of CML.

CML is a disease that develops slowly over several years. This is known as the ‘chronic stage.’ This stage is usually asymptomatic, and 90 percent of patients are diagnosed at this point, with the disease being discovered frequently as a result of a routine blood test. During this stage, the bone marrow contains less than 10% immature white cells (blasts).

When CML cells expand, symptoms typically begin to appear. The ‘accelerated stage’ is what it’s called. Approximately 10% of people are diagnosed at this point. During this stage, between 10% and 30% of blood cells in the bone marrow are blasts. During this stage, common clinical features include:
Fatigue and exhaustion
Night sweats and fever
Distension of the abdomen
Pain in the left upper quadrant (splenic infarction)
Splenomegaly (commonest examination finding)
Hepatomegaly
Bruising is simple.
Gout is a type of arthritis that affects (rapid cell turnover)
Hyperviscosity is a condition in which the viscosity of (CVA, priapism)
A small percentage of patients experience a ‘blast crisis’ (blast stage). More than 30% of the blood cells in the bone marrow are immature blast cells at this stage. Patients with severe constitutional symptoms (fever, weight loss, bone pain), infections, and bleeding diathesis typically present at this stage.

In CML, laboratory findings include:
White cell count is abnormally high (often greater than 100 x 109/l).
Increased number of immature leukocytes causes a left shift.
Anaemia that is mild to moderately normochromic and normocytic.
Platelets can be low, normal, or elevated, and the Philadelphia chromosome can be found in > 80% of patients.
Serum uric acid and ALP levels are frequently elevated.
Tyrosine kinase inhibitors (TKIs), such as imatinib and dasatinib, are the current mainstay of CML treatment.
Allogenic bone marrow transplantation is now only used in cases where TKIs have failed to work.

The most common type of adult leukaemia is chronic lymphocytic leukaemia (CLL). It develops as a result of relatively mature lymphocytes clonally proliferating. The B-cell lineage accounts for approximately 95% of cases. CLL is primarily a disease of adult men, with men over the age of 50 accounting for more than 75% of CLL patients.

It is the most indolent form of chronic leukaemia, and it is frequently discovered by chance when blood counts are taken for other reasons, such as ‘well man’ screening tests. The patient may develop lymphadenopathy, hepatosplenomegaly, anaemia, and infections as the disease progresses.

The following are examples of CLL laboratory findings:
Clonal B cell lymphocytosis (diagnosed at greater than 5 x 109/l, but can reach 300 x 109/l)
In advanced disease, normocytic, normochromic anaemia is present.

Patients with autoimmune-related haemolytic anaemias have a positive direct antiglobulin test (DAT).

Although bone marrow aspiration is not always required, it can aid in the diagnosis of CLL. If there has been rapid lymph node enlargement, a lymph node biopsy is required to rule out Richter’s syndrome. This is the transition from low-grade lymphoma to high-grade lymphoma, which is characterised by fever, weight loss, and pain.

Although there is no cure for CLL, it can be managed with chemotherapy regimens that help patients live longer. Early treatment has no benefit, and the standard treatment for early disease is to watch and wait, with examinations and blood counts every 3 to 12 months. Chemotherapy is usually reserved for patients who have a disease that is active and causing symptoms.

The following is the overall prognosis for CLL:
1/3 will not require treatment and will live a long time.
1/3 will go through an indolent phase before the disease progresses.
1/3 of patients will have an aggressive disease that requires immediate treatment.

Chronic myeloid leukaemia is most common in middle-aged and elderly people. It is responsible for 20% of all leukemias. The majority of CML patients experience fatigue, weight loss, and excessive sweating.

The Philadelphia chromosome is found in over 90% of CML cases. A balanced translocation between chromosomes 9 and 22 is known as the Philadelphia chromosome.

Because white cells produce a B12 binding protein, serum B12 levels in CML are typically high.

In CML, the neutrophil alkaline phosphatase score is usually low.

Almost all patients with CML eventually progress to blast crisis, though this can take up to ten years. If any of the following features are present in a CML patient, a blast crisis is diagnosed:
In the blood or bone marrow, there are more than 20% myeloblasts or lymphoblasts.
On a bone marrow biopsy, large clusters of blasts were discovered.

CML can be treated with tyrosine kinase inhibitors like imatinib and dasatinib if a chloroma (a solid tumour made up of myeloblasts that grows outside of the bone marrow) is present.

Compression of the thecal sac causes metastatic Spinal Cord Compression (MSCC) due to a Metastatic tumour and its components. It can cause symptoms of limb weakness, sensory disturbances and back pain depending on the extent and level of Compression.

The most common source of a tumour causing MSCC is a prostate carcinoma that metastasized to the spinal cord via the vertebral venous plexus.

Aspirin irreversibly inhibits cyclooxygenase and blocks the platelet production of thromboxane A2 (TXA2), thus inhibiting platelet aggregation.

Neutrophil polymorphs are the predominant type of white cells in an acute reaction. They pass between endothelial cell junctions to invade damaged tissue so that the effects of injury can be combated. Extravasation occurs with the movement of leukocytes out of the vessel lumen, and is achieved in five phases which are margination, ‘rolling’, adhesion, transmigration and chemotaxis.

Delayed haemolytic transfusion reactions (DHTRs) commonly occurs 4-8 days after blood transfusion, but can occur up to a month after. Signs and symptoms include jaundice, fever, an inadequate rise in PCV, reticulocytosis, a positive antibody screen and a positive Direct Antiglobulin Test (Coombs test). DHTRs usually have a benign course and require no treatment but sometimes, life-threatening haemolysis with severe anaemia and renal failure can occur so haemoglobin levels and renal function should be monitored.

Acute haemolytic reaction aka immediate haemolytic transfusion reaction presents with fever, chills, pain at transfusion site, nausea, vomiting, dark urine and feeling of ‘impending doom’. Often, it occurs due to ABO incompatibility.

Febrile transfusion reaction presents with a 1 degree rise in temperature from baseline during transfusion. Patient may have chills and malaise. It is the most common transfusion reaction (1 in 8 transfusions) and is usually caused by cytokines released from leukocytes in transfused red cell or platelet components.

Transfusion-associated circulatory overload (TACO) presents as acute or worsening respiratory distress within 6 hours of transfusion of a large volume of blood. It is common in patients with diminished cardiac reserve or chronic anaemia. Elderly patients, infants and severely anaemic patients are particularly susceptible. Clinical features of TACO include: Acute respiratory distress, Tachycardia, Hypertension, Acute/worsening pulmonary oedema on chest X-ray. The BNP is usually raised to at least 1.5 times the pre-transfusion baseline.

Graft versus host disease(GVHD) is an immune mediated condition that arises from a complex interaction between donor and recipients adaptive immunity. It presents as dermatitis, hepatitis and enteritis developing within 100 days after stem cell or bone marrow transplant.

All the Haemophilia’s have an X-linked recessive inheritance pattern, so they only manifest in male patients. Diseases with a mitochondrial inheritance pattern include MELAS syndrome, Leigh syndrome, LHON and MERRF syndrome. Autosomal dominant disorders include Huntingdon disease and Marfan syndrome. X-linked dominant diseases include Fragile X syndrome. Autosomal recessive diseases include cystic fibrosis and sickle cell disease.

In 2016 the SOFA guideline was introduced, also called the Sepsis-related Organ Failure Assessment, to make a sepsis diagnosis easier and prevent mortality.

According to this guideline, sepsis was defined as a life-threatening organ dysfunction due to a dysregulated host response to infection.

Septic shock was defined as a subset of sepsis in which the circulatory and metabolic abnormalities would lead to a greater risk of mortality than sepsis alone. Patients with septic shock would be clinically identified by a need for vasopressors to maintain MAP greater than 65 mmHg and serum lactate greater than two mmol/L.

Functional hyposplenism is characterised by the blood film findings of Howell-Jolly bodies or siderotic granules on iron staining. The most frequent cause is surgical removal of the spleen e.g. after traumatic rupture, but hyposplenism can also occur in sickle cell anaemia, gluten-induced enteropathy, amyloidosis and other conditions.

Hodgkin’s lymphoma is a malignant tumour of the lymphatic system that is characterised histologically by the presence of Reed-Sternberg cells (multinucleated giant cells). The peak incidence is in young adults aged 20-35, and there is a slight male predominance.

The following are recognised risk factors for Hodgkin’s lymphoma:
Male gender
Age 20-35
Positive family history
Epstein-Barr virus infection
Immunosuppression including HIV infection
Prolonged use of human growth hormone
Most patients present with an enlarged, but otherwise asymptomatic lymph node. The most commonly affected lymph nodes are in the supraclavicular and lower cervical areas. Other common clinical features include shortness of breath and chest discomfort secondary to mediastinal mass. Mediastinal masses are sometimes discovered as incidental findings on routine chest X-rays. Approximately 30% of patients with Hodgkin’s lymphoma develop splenomegaly.
‘B’ symptoms occur in approximately 25% of patients. The ‘B’ symptoms of Hodgkin’s lymphoma are:
Fever (>38ºC)
Night sweats
Weight loss (>10% over 6 months)
Pain after alcohol consumption is a pathognomonic sign of Hodgkin’s lymphoma, it is, however, not a ‘B’ symptom. It is rare though, only occurring in 2-3% of patients with Hodgkin’s lymphoma.

The Ann Arbour clinical staging is as follows:
Stage I: one involved lymph node group
Stage II two involved lymph node groups on one side of the diaphragm
Stage III: lymph node groups involved on both sides of the diaphragm
Stage IV: Involvement of extra-nodal tissues, such as the liver or bone marrow
Diagnosis is made by lymph node biopsy, which should be taken from a sufficiently large specimen or excisional biopsy, as opposed to a fine needle biopsy. The Reed-Sternberg cell is the most useful diagnostic feature. This is a giant cell with twin mirror-image nuclei and prominent ‘owl’s eye’ nucleoli.
The Reed-Sternberg cell of Hodgkin’s Lymphoma
Histological typing depends upon the other cells within the diseased tissue. Nodular sclerosing is the most common type of Hodgkin’s lymphoma. Lymphocyte-depleted and lymphocyte-predominant are rare subtypes.
The majority of cases can be successfully treated, and unlike many other malignancies even if the first-line treatment fails, a cure can often be achieved with second-line therapies. Stage 1 Hodgkin’s lymphoma is usually treated with radiotherapy alone, but more advanced stages require combination chemotherapy. In localised disease treated with irradiation, there is a 5-year survival rate of greater than 80%. In disseminated disease treated with chemotherapy, the 5-year survival falls to around 50%. Overall, a 5-year survival of >70% should be achieved.

IgA is the predominant antibody class in secretions and tremendous quantities are secreted into various body spaces and onto mucosal surfaces (the gut lumen, the pharynx and sinuses, the larger airways, although not the alveoli).
Because of its size, the majority of IgM is found in the circulation.

Along with IgM, IgD is predominant among the surface receptors of mature B cells, where it plays a key role in B cells activation.

IgE has the lowest concentration in normal human serum. It plays a prominent role in immune responses to helminth parasites, and in allergic reactions.
IgG is the most abundant immunoglobulin and constitutes 75 percent of serum immunoglobulin in an adult human

Natural Killer (NK) Cells are lymphocytes in the same family as T and B cells, which come from a common progenitor. They are cytotoxic CD8 positive cells that do not have the T-cell receptor. They are very big cells with cytoplasmic granules and are designed to kill target cells with a low level of expression of HLA class I molecules.
Examples include during a viral infection or on a malignant cell. NK cells display several receptors for HLA molecules on their surface, and when HLA is expressed on the target cell, these deliver an inhibitory signal into the NK cell. Absent HLA molecules on the target cell cause this inhibitory signal to get lost and as a result, the NK cell can then kill its target. Also, NK cells display antibody-dependent cell-mediated cytotoxicity, where antibody binds to antigen on the surface of the target cell. The NK cells then bind to the Fc portion of the bound antibody and kill the target cell.

The LDH level is usually markedly increased in severe megaloblastic anaemia. Reticulocyte counts are inappropriately low, representing a lack of production of RBCs due to massive intramedullary haemolysis. These findings are characteristics of ineffective haematopoiesis that occurs in megaloblastic anaemia as well as in other disorders such as thalassemia major.
The common feature in megaloblastosis is a defect in DNA synthesis in rapidly dividing cells. To a lesser extent, RNA and protein synthesis are impaired. Unbalanced cell growth and impaired cell division occur since nuclear maturation is arrested. More mature RBC precursors are destroyed in the bone marrow prior to entering the bloodstream (intramedullary haemolysis).

A type IV hypersensitivity reaction occurred in this patient. Allergic contact dermatitis is an inflammatory skin reaction occurring in response to an external stimulus, acting either as an allergen or an irritant, caused by a type IV or delayed hypersensitivity reaction. They usually take several days to develop.

Acute lymphoblastic leukaemia (ALL) is caused by an accumulation of lymphoblasts in the bone marrow and is the most common malignancy of childhood. The incidence of ALL is highest at 3 – 7 years, with 75% of cases occurring before the age of 6. There is a secondary rise after the age of 40 years. 85% of cases are of B-cell lineage and have an equal sex incidence; there is a male predominance for the 15% of T-cell lineage.

Anaemia of chronic disease is one of the most common causes of normocytic anaemia. The anaemia is usually mild (Hb > 90 g/L) and non-progressive. Anaemia of chronic disease is usually associated with low serum iron, low transferrin saturation, and a low total iron binding capacity (TIBC) with normal or raised ferritin which differentiates it from iron deficiency anaemia.

Anaphylaxis is an example of a type I hypersensitivity reaction.

It is IgE mediated.

It requires a prior exposure to the antigen. The initial exposure sensitizes the body to the antigen and a second exposure to that antigen leads to an anaphylactic reaction.

Massive calcium influx into the cells leads to mast cell degranulation.

The Immunoglobulin antigen complex binds to Fc receptors on the surface of mast cells. The result is mast cell degranulation and release of histamine, proteoglycans and serum proteases from cytoplasmic granules.

Interleukin-1, which is released by leukocytes and acts on the thermoregulatory centre of the hypothalamus, causes fever. Because prostaglandins mediate this process, antipyretics such as NSAIDs, paracetamol, and aspirin reduce prostaglandin levels by inhibiting cyclooxygenase enzymes. Malignant disease secretes interleukins, which cause the B-symptoms seen in lymphoma, for example. Bacterial toxins can also cause interleukins to be produced.

Pyrexia of unknown origin (PUO) is defined as a fever of greater than 38.3 degrees Celsius that lasts for more than 2-3 weeks with no clear diagnosis despite extensive investigation.

Investigation necessitates a thorough understanding of the conditions that can cause febrile illness, which may be missed during an initial investigation, as well as a thorough history, examination, and investigation centred on that list.

Pyrexia of unknown origin has a wide differential diagnosis, which includes:
Infection
Bacterial
Pyogenic abscess
Tuberculosis
Infective endocarditis
Brucellosis
Lyme disease
Viral
HIV
Epstein Barr Virus
Cytomegalovirus
Parasite
Toxoplasmosis
Malignancy
Leukaemia
Lymphoma
Renal cell carcinoma
Hepatocellular carcinoma
Vasculitides
Still’s disease
Granulomatosis with polyangiitis (formerly Wegener’s)
Systemic lupus erythematosus
Giant cell arteritis
Rheumatoid arthritis
Polymyalgia rheumatica
Miscellaneous
Drug induced fevers
Familial Mediterranean fever
Thyrotoxicosis
Inflammatory bowel disease
Sarcoidosis
Factitious fever
Exaggerated normal circadian fluctuation

The patient might need to be admitted to the hospital for observation and further investigation. Because infection is still a possibility, blood cultures should be repeated on a regular basis, and inflammatory markers should be closely monitored. CT, PET, and MRI imaging have largely replaced diagnostic laparotomy as a diagnostic tool.

In February 2016 the Society of Critical Care Medicine published a JAMA article reformatting the definitions of sepsis in an attempt to overcome the shortcomings of the old definitions.
The main changes are a new definition of sepsis, the replacement of the SIRS criteria with the quick Sepsis-related Organ Failure Assessment (qSOFA), and the complete removal of “severe sepsis” as an entity.
The new definition of sepsis is that it is “life-threatening organ dysfunction caused by a dysregulated host response to infection.”
Septic shock is “a subset of sepsis in which underlying circulatory and cellular metabolism abnormalities are profound enough to increase mortality.”
In essence this means that septic shock is sepsis plus the following, despite adequate fluid resuscitation:
Vasopressors required to maintain a MAP > 65 mmHg
Serum lactate > 2 mmol/l
The qSOFA score is a bedside prompt designed to identify patients with suspected infection who are at greater risk for a poor outcome outside of the intensive care unit. It uses the following three criteria:
Hypotension (SBP < 100 mmHg)
Tachypnoea (RR > 22)
Altered mental status (GCS < 15)
The presence of 2 or more of the qSOFA criteria near the onset of infection is associated with greater risk of death or a prolonged intensive care unit stay.

The process of fracture healing occurs naturally after traumatic bone disruption and begins with haemorrhage, then progresses through Inflammatory, reparative, and remodelling stages

Average healing times of common fractures are:
Femoral shaft: 12 weeks
Tibia: 10 weeks
Phalanges: 3 weeks
Metacarpals: 4-6 weeks
Distal radius: 4-6 weeks
Humerus: 6-8 weeks

Non-specific signs of anaemia include:
1. pallor of mucous membranes or nail beds (if Hb < 90 g/L),
2. tachycardia
3. bounding pulse
4. wide pulse pressure
5. flow murmurs
6. cardiomegaly
7. signs of congestive cardiac failure (in severe cases)

An opsonin is any molecule that enhances phagocytosis by marking an antigen for an immune response, for example, immunoglobulin or complement. Opsonisation is the molecular mechanism whereby molecules, microbes, or apoptotic cells are chemically modified to have a stronger attraction to the cell surface receptors on phagocytes and natural killer cells. With the antigen coated in opsonins, binding to immune cells is greatly enhanced. Opsonisation also mediates phagocytosis via signal cascades from cell surface receptors.