Nodular Lymphocytic Predominant Hodgkin’s Lymphoma


Hodgkin lymphoma (HL) is of two types. Classical (cHL) and nodular lymphocyte predominant (NLPHL). NLPHL is rarer and runs a more indolent clinical course.

Epidemiology

NLPHL accounts for about 5% of all HL.

Age: The disease is characterised by two peaks. The first one in childhood and the second between the ages of 30-40.

Gender: NLPHL shows a male predominance. About three-fourth of the patients are males. Male preponderance is less marked in blacks.

Racial Differences: Black patients are younger, more often female and more often present with axillary involvement. Little is known of NLPHL in other races (Cancer 2015; 121:3472-80).

Familial Susceptibility: Family members of patients with NLPHL at increased risk NLPHL. The standardised incidence ratio in one study was reported to be 19 (J Clin Oncol 2013; 31;938-43).

Histology

The normal architecture of the node is effaced and replaced by large nodules. Occasionally there may be large nodules with diffuse areas. Sometimes uninvolved nodal tissue may be seen. This is usually located peripheral in a sub-capsular area.

Microscopically NLPHL shows the malignant cell, LP cell, in a background mainly made up of small lymphocytes and with a prominent follicular dendritic cell (FDC) network. The follicular dendritic cell meshwork is absent from the diffuse areas. Unlike most other malignancies (and like cHL and T cell/Histolytic rich large B cell lymphoma) the normal reactive cells form the bulk of the enlarged node.

The LP cell has a nucleus that shows complex lobulation. It resembles a exploded kernel of corn and hence the cell is also referred to as the popcorn cell. The nucleolus is smaller than that of the RS cell and lies peripherally and is basophilic. There is a thin rim of cytoplasm.

The infiltrate in a nodule mainly consists of small lymphocytes. Unlike cHL, Eosinophils and plasma cells are occasional or may be absent. Most of the small lymphocytes making up the nodule are CD20+, CD79+ small B lymphocytes. The LP cells is however immediately surrounded by CD20, CD3+ T helper cells that express PD-1 and CD57. Diffuse area have CD4+ T cells and areas between nodes have CD3+ parafollicular T cells.

Varient histological patterns are known, associated with adverse prognosis and should be reported (Am J Surg Pathol 2003;27:1346-56).

Immunophenotype helps in diagnosis and has given clues to the origin of LP cells. The LP cells show a B cell phenotype and express CD20, CD79, CD22, PAX-5 and CD45. They express BCL-6 indicating the germinal centre origin. They do not express BCL-2. They strongly express the B cell transcription factor OCT-2 and its cofactor BOB.1. This distinguishes then from the Reed-Sternberg (RS) cells of cHL. RS cells show a weak expression or do not express these factors. RS cells express CD15, CD30 and fascin that are not expressed by the LP cells. About a fifth of the patients express IgD. These patients tend to be male, present with cervical adenopathy and have a greater risk of having a variant histology.

The normal counterpart of the LP cell appears to be the germinal centre B cell at the cenrtoblastic stage of differentiation.

NLPHL as well as cHL are diseases characterised by malignant cells surrounded by an infiltrate of normal cells. Unlike other cancers, the normal cells form the bulk of the tumour mass in both the cases. The malignant cells affect and are affected by the normal cells surrounding them. LP cells, like normal germinal centre cells, appear to depend on normal immunoglobulin receptor signalling. RS cells depends on other signalling receptors e.g. CD30 and CD40. The growth of normal germinal centre cells depends on The FDC and follicular T cells. These cells also support the growth of LP cells. The LP cell do not produce cytokines at levels seen in the RS cell. B symptoms are less common NLPHL less common than cHL.

 

 

Clinical Presentation

The most common presentation of NLPHL is isolated lymphadenopathy, most often in the cervical, axillary or the inguinal region. The swelling is usually present for a long time and has been growing slowly. About 80% of the patients present with localised disease and less than 20% with stage III/IV (Ann Hematol. 2016; 95: 417–423). B symptoms are uncommon (about 5%). Extranodal disease is very uncommon.

NLPHL runs a more indolent course that cHL. It is characterised by a relapses and transformation to high grade lymphoma diffuse large B cell lymphoma (including T cell/ histiocyte rich large B cell lymphoma). Relapses usually respond to treatment.

Staging

NLPHL, like cHL is classified by the Ann Arbor staging system with Cotswolds modifications. The stages are summarised below. A more detailed staging can be found here.

  1. Stage I: Involvement of one nodal region, lymphoid structure or one extra-nodal site
  2. Stage II: More than one region involved but disease limited to one side of the diaphragm.
  3. Stage III: Disease on both sides of the diaphragm but limited to the lymphoid system.
  4. Stage IV: Disease disseminated to one or more extra nodal organs.

Patients with fever with hight sweats and significant (>10% in the preceding 6 months) are said to have B symptoms.

The staging workup should include clinical examination, haemogram, ESR and biochemistry. NLPHL is PET avid. PET-CT is better than CT for staging. It is of value in to exclude diseases dissemination in patients where observation or local treatments are being considered. The value is interim PET-CT is NLPHL is uncertain. The bone marrow is very uncommonly involved (about 1-2%). Only patients with advanced disease should be subjected to bone marrow examination.

 

Differential Diagnosis

  1. Lymphocyte Rich Classical Hodgkin lymphoma
  2. T cell/ Histiocyte Rich Large B Cell Lymphoma
  3. Progressively Trasnformed germinal centres
  4. Follicular Lymphoma
  5. Mantle cell Lymphoma

 

Treatment

Early disease (Stage I/IIA)

Patients who have undergone excision biopsy that has resulted in a complete removal of all disease may be observed. Despite a lower progression free survival the patients who are observed do not show an inferior overall survival. This indicates that delaying treatment (radiation, chemotherapy or both as may be appropriate) does not hamper it’s efficacy.

Advanced Disease (Stage IIB, III, IV)

These patients need chemotherapy with the anti-CD20 antibody, rituximab. Three approaches are possible

  1. Classical Hodgkin lymphoma like therapy with Rituximab with ABVD: R-ABVD (Rituximab, doxorubicin, bleomycin, vinblastine and dacarbazine) should be administered to patients needing chemotherapy.
  2. B cell non-Hodgkin Lymphoma like therapy: R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is the standard treatment for high grade B cell non-hodgkin lymphoma. R-CHOP has been shown to effective in disease control and reducing the risk of transformation. It may be preferred in patients at a high risk of transformation, though there is not comparative trial with R-ABVD. Males and those with variant histology are at a higher risk of transformation. Models for predicting transformation are available.
  3. Single agent Rituximab: Single agent rituximab is indicated in patients with co-morbidities. The risk of relapse remains high.

Treatment of Relapse

Relapses must be rebiopsied to confirm NLPHL and to exclude transformation to a high grade lymphoma. Localized relapses may be treated with radiation. Chemotherapy should be used for other patients. Patients who have a chemosensitive relapse may be considered for allogenic stem cell transplant (Am J Haematol 2017 Oct 3. doi: 10.1002/ajh.24927).

Treatment of Transformation

Patients who undergo transformation are treated with regimen for regimens for high grade B cell lymphoma. The limited data suggests that the outcome is no different from that of de novo large B cell lymphoma.

 

Prognosis

The prognosis of NLHPL is better than conventional HL partially because of a more favourable disease profile – early stage, no B symptoms, no Bulky disease. One study showed a 94% overall survival at 10years (Ann Hematol. 2016; 95: 417–423). The progression free survival was 75% indicating relapses are common but are curable. Progression to diffuse large B cell lymphoma is seen in 5-10% of the patients. Atypical histology increases the risk of relapse (Blood. 2013 Dec 19;122(26):4246-52).

 

 

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Drugs and Eosinophilia


Drugs, prescription and non-prescription,  and nutritional supplements are a common cause of eosinophilia across the world. In regions with a low prevalence of parasitic infestations drugs are the leading cause of eosinophilia.

Clinical Spectrum of Drug Induced Eosinophilia

The spectrum of drug induced eosinophilia extends from an asymptomatic eosinophilia discovered on a routine haemogram to a a serious disorder like drug induced drug reaction with eosinophilia and systemic syndromes (DRESS). Eosinophilia associated with specific organ complications includes

  1. Eosinophilic pulmonary infiltrates associated with the use of sulfadsalazine, nitrofurantoin and non-steroidal anti-inflammatory drugs (NSAID)
  2. Acute interstitial nephritis with eosinophilia  associated with the use of semisynthetic penicillins, cephalosporins, NSAID, sulphonamides, phenytoin, cimetidine and allopurinol
  3. Eosinophilia-myalgia syndrome (EMS) presents with increased eosinophil counts associated with  severe myalgia, neuropathy, skin rash and multi-system complications. The cause of EMS is not known but L-tryptophan has been implemented.
  4. Drug reaction with eosinophilia and systemic symptoms /Drug induced hypersensitivity syndrome (DRESS/DIHS): The syndrome is a form of delayed drug hypersensitivity the presents with fever lymphadenopathy and end organ damage. The spectrum of end-organ damage includes hepetitis, interstitial nephritis, pneumonitis and carditis. The drugs implicated in DRESS/DIHS include
    1. Anti-infective
      1. Antibiotics: Cephalosporins, doxycycline, fluoroquinolone, linezolid, metronidazole, nitrofurantoin, penicillins, tetracycline
      2. Sulfomaides: Sulfasalazine trimethoprim-sulfamethoxozole
      3. Sulfones: Dapsone
      4. Antiviral: Abacavir, Nevirapine
    2. Anti-epileptic: Carbamazepine, lamotrigine, phenobarbital, phenytoin, , valproate
    3. Anti-depressants: Amitriptyline, desimipramine, fluoxetine
    4. Anti-inflammatory: Diclofenac, ibuprofen, naproxen, piroxicam
    5. Antihypertensives: ACE inhibitors, β-blockers, hydrochlorthiazide
    6. Others:  Allopurinol, cyclosporine, ranitidine

Management

The incriminating drug should be withdrawn in symptomatic patients. Asymptomatic eosinophilia does not necessitate discontinuation of therapy. If equally effective therapy is available it is preferable to stop therapy. If this is not the case the drug may be continued with careful monitoring for symptoms.

Sickle β-Thalassaemia


Sickle cell anaemia and β-thalassaemia are two common haemoglobinopathies. Co-inheritance of the two is called sickle β-thalassaemia. Sickle β-thalassaemia seen in Africa, throughout the  Mediterranean, Arabian Peninsula and sporadically in india. It has heterogeneous clinical presentation. The severity depends on the severity of the thalassaemia allele and the extent to which the impaired haemoglobin synthesis is compensated by foetal haemoglobin synthesis.

Pathophysiology

With a very few exceptions (Blood 1989; 74: 1817-22) the sickle cell and the thalassaemia gene are arranged in trans i.e on different chromosomes (βsthal). One allele is inherited from the mother and one from the father. One parent carries the a β-thalassaemia trait the other parent has a sickle cell disease that may be sickle cell anaemia, sickle β-thalassaemia or a trait. Sickle β-thalassaemia in Africa and India/Arabia is mild whereas the patients from the Mediterranean region have severe disease. As mentioned above the differences in severity have to do with severity of the β-thalassaemia and the degree to which the impaired haemoglobin A synthesis is compensated by HbF. Weatherall suggested that patients with HbA <15% follow a course similar to severe HbA and those with HbA 20-30% follow a mild course.

  1. African sickle β-thalassaemia: African patients have a mild β-thalassaemia resulting in a relatively higher HbA level and a lower risk of sickling. These patients run a mild clinical course.
  2. Arab/Indian sickle β-thalassaemia: Patients from India and the Arabian peninsula have a sickle cell haplotype that is associated with a high HbF production. The HbF retards sickling. High levels of HbF attenuate symptoms. Patients carrying this haplotype have mild symptoms even when the inherit a severe β- chain defect. Another reason of a mild phenotype in India is the interaction with α thalassaemia.
  3. Mediterranean sickle β-thalassaemia: Mediterranean patients usually inherit a severe form of  β-thalassaemia. These patients have severe sickling because there is very little HbA or HbF to offset inhibit the crystallisation of HbS. Despite only one chromosome carrying HbS the phenotype of these patients resembles sickle cell anaemia.

Clinical Picture of Sickle-β Thalassaemia

The features of sickle-β thalassaemia resemble those of other sickling disease. It is a chronic haemolytic anaemia the course of which is interrupted by acute exacerbations known as crisis. The manifestations include haemolytic anaemia, painful and other crisis, leg ulcers, priapism and complications of pregnancy. The severity of symptoms is variable. One end of the spectrum are patients, usually of origin Mediterranean descent, whose presentation is indistinguishable from sickle cell anaemia. These patients have inherit severe forms of β (β0) chain defects. Those with sickle cell-β+ thalassaemia have milder symptoms. These patients are typically of African ancestory. Unlike patients with sickle cell anaemia patients with sickle-β thalassaemia may have splenomegaly that is more prominent patients with sickle cell-β+ thalassaemia. The spleen is usually moderately enlarged but massive splenomegaly that may be associated hypersplenism neccesisating splenectomy has been reported. The effect of co-inheritance of α-thalassaemia is small. A decrease in the frequency of acute chest syndrome and leg ulcers and a higher persistence of splenomegaly is seen. Co-inheritance of α thalassemia is one of the reasons that sickle-β thalassaemia runs a milder course in India (the other being the high HbF due to the Arab-Indian haplotype of HbS).

Diagnosis

The haematological findings vary with severity. More severe phenotypes shows greater anaemia, lower MCHC, higher reticulocytes, HbF and HbA2. A variable number of sickle cells may be found. Unlike sickle cell anaemia both forms of sickle cell-β thalassaemia have an elevated HbA2. The distribution of HbA2 is very similar to heterozygous β thalassaemia. The levels of HbF are variable. High levels are found in patients with the Arab-Indian and Senegal haplotype of HbS.

Sickle cell-β0 thalassaemia needs to be differentiated from sickle cell anaemia. The presentation of both may be identical. However an offspring of a sickle cell-β0 thalassaemia patients and a carrier of β-thalassamia trait has a 25% risk of suffering from β-thalassaemia major. The offspring of a patients with sickle cell anaemia and a carrier of β thalassaemia trait does not carry the risk of β thalassaemia major. Though sickle cell-β0 thalassaemia is characterised by an elevated HbA2 and splenomegaly this can not be relied upon to differentiate between the two conditions. Family and DNA studies are needed. If the studies show one parent to be heterozygous for HbS and the other a carrier of β thalassaemia trait no further studies are needed. If any of the parent has a phenotype of sickle cell anaemia DNA studies may be the only way to make the diagnosis.

Sickle Cell β thalassaemia in cis

Almost all patients with sickle-β thalassaemia have the disorder in trans i.e. the one β globin gene is thalassaemic and the other has a the sickle mutation. Patients with HbS and thalassaemia gene in cis have been described. These patients have a mild hemolysis, HbA2 levels were 6%–7%, HbF approximately 3% and HbS of 10%–11%.

Treatment

The symptoms of sickle-β thalassaemia are due to sickling need to be treated accordingly.

Primary Cutaneous DLBCL – Leg Type


The first description of a primary cutaneous diffuse large B cell lymphoma was by Willemze et al in 1987 who described a group of elderly women with cutaneous large cell lymphomas with tumours in the legs and a worse prognosis ( Am J Pathol. Feb 1987; 126(2): 325–333).

Primary cutaneous diffuse large B cell lymphoma, leg type is a type of high grade cutaneous B cell lymphomas that was included as a separate entity in the WHO 2008 lymphoma classification. It forms about 20% of all cutaneous B cell lymphomas and about 4% of all cutaneous lymphomas. It is more common in women and the median age of occurrence is the 7th decade.

Pathology

Primary cutaneous large B cell lymphoma is characterized by a monotonous, diffuse, non-epidermotrophic infiltrate that is CD 20 and CD79a positive. and almost always express BCL2, IRF4/MUM1 and FOX-P1. The latter three markers are not expressed in in the primary cutaneous follicular centre cell lymphoma  another type of primary cutaneous B cell lymphoma. BCL6 is usually expressed but CD10 is not. 

Clinical Features

DLBCL-LT is a disease of elderly women (M:F:12-4, median age 70 years). Though called leg type, only 85-90% of the primary cutaneous DLBCL, leg type occur in the legs. The remaining occur at other sites. Patients present with a rapidly growing red or reddish blue nodule on one or both the legs. Patients may have ulceration and may be confused with venous ulcer. Unlike other cutaneous lymphomas primary cutaneous DLBCL, leg type disseminates to non-cutaneous sites.

Treatment

Radiotherapy

As DLBCL-LT has a tendency to disseminate to extra-cutaneous sites than other cutaneous lymphomas radiation is less effective in this disease. . A complete response rate of 88%  with a high (58%) relapse rate has been reported. relapses are in the in field and extra-cutaneous.

Chemotherapy

R-CHOP is the standard first line therapy. Dose reduction may be needed in elderly. Single agent rituximab is also an option but is associated with a high rate of recurrences. Linelidomide has been used in patients with relapse.

Hyperleukocytosis and Leukostasis


Leukostasis is a oncological emergency seen in patients with leukaemia who present with pronounced leucocytosis. It is seen in about 5-30% of adult acute leukaemia cases. It results from slugging of microcirculation by leucocytes.  It is associated with a mortality of 20-40%.

Pathogenesis of Leukostasis

Manifestations of leukostasis result from impaired circulation in the affected vascular bed. Leukocytosis impairs circulation because of

  1. Increased viscosity
  2. Formation of intravascular leukocyte aggregates (white bland thrombi)
  3. Increased adhesion of blasts to the endothelium

Cells increase the viscosity of blood hampering flow through microcirculation. Pliability of blood cells is important for maintaining blood flow in microvasculature. The biconcave shape of the erythrocytes provides them with deformability allowing smooth passage through the microvasculature. Leukocytes are less pliable than erythrocytes.  Normally the number of leucocytes is a small fraction of the number of erythrocytes. The contribution of leucocytes to blood viscosity in minimal.

Blood viscosity increases with leucocytosis. The increase is related to the leucocyte count, size of the leukocytes and the deformability of the leucocytes. Blasts are less deformable than mature cells. Myeloblasts are larger and less deformable than lymphoblasts. Cells of the monoblastic series are the least deformable. Lymphocytes are the smallest and have the least impact on the viscosity amongst all leucocytes.

Blasts secrete cytokines like IL-1β  and TNF-β. These lead to up regulation of adhesion molecules like ICAM-1, VCAM-1 and E-selectin that increases the adhesion of blasts to the endothelium. Adhesions of blasts to microvasculature further diminish blood flow.

The vascular beds most commonly affected are the lung, CNS and the eye. Tissue hypoxia resulting from impaired circulation is believed to contribute to elevated LDH seen in acute leukaemias. 

Clinical Features

About 5-13% of acute myeloid leukaemia and 10-30% of acute lymphoblastic leukaemia have hyperleukocytosis. The symptoms of leukostasis are related to the ischaemia in the affected circulatory bed. The commonest vascular beds affected and the symptoms attributable to these beds are listed below.

Organ Manifestation
Brain Stupor
Eyes Blurring of vision
Lungs Dyspnoea
Kidney Azoaemia
Heart Arrhythmia
Penis Priapsim

Examination of the fundus shows papilledema, blurred disc margins, dilated blood vessels, and retinal haemorrhages.

The leukocyte count  at which symptoms develop depends on the type of leukaemia. Symptoms develop at the lowest counts in acute myeloid leukaemia. Patients of chronic lymphocytic leukaemia may not have symptoms of hyperleukocytosis at leucocyte counts as high as 400X109/L. Leukostasis is associated with increased morbidity and mortality.

Diagnosis

Leukostasis is clinical diagnosis of exclusion. It should be considered in any patients with lung or CNS symptoms who has hyperleukocyosis. Hyperleukocytosis has been variably defined as a count of 50X109/L or 100X109/L. Symptoms are likely to occur at lower counts in patients with acute myeloblastic leukaemia particularly when there is a monocytoid component. Patients with chronic lymphoblastic leukaemia tolerate counts as high as 400X109/L without symptoms. The conditions that can mimic leukostasis include

  1. Pulmonary infection
  2. Pulmonary embolism
  3. Pulmonary oedema
  4. Pulmonary haemorrhage
  5. Transfusion-related acute lung injury  is blood products have been transfused
  6. CNS infections – meningitis and encephalitis
  7. Conditions causing acute mental status change

The x-ray findings include diffuse interstitial or alveolar infiltrates. It can be normal in early stages. Examination of the fundus is important.

Treatment

Leukostasis is associated with a mortality of 20-40%. The treatment of leukostatsis is to rapidly reduce the leukocyte count. Three methods of rapidly reducing leucocyte counts are induction chemotherapy, leukocytopheresis or low dose chemotherapy. Each of these methods are supported by theoretical arguments. Induction chemotherapy is the definitive therapy for leukaemia. Whether leukocytopheresis or hydroxyurea add to the benefit of induction chemotherapy is not clear. The use of hydroxyurea and leukocytopheresis is dictated by the experience of the treating centre. The procedures are usually resorted to with the belief that induction therapy with a very high leucocyte count may increase the risk of tumour lysis. 

Leukocytopheresis: Leukocytopheresis is used because it rapidly brings down the leucocyte count without causing lysis of blasts. It has the theoretical advantage of reducing the risk of tumour lysis and reducing mortality. This has never been proven in clinical trials. Two procedures needed about 12-24 hour apart. Leukocytopheresis is indicated in

  1. Symptomatic patients with AML with leucocyte counts more than 50X109/L and ALL with counts more than 150X109/L.
  2. Asymptomatic patients with AML and leucocyte  counts >100 X 109/L
  3. Asymptomatic patients with ALL with leucocyte counts >300 X 109/L
  4. CML patients who are symptomatic with leucocyte counts greater than 150X109/L,
  5. CLL patients who are symptomatic with leucocyte counts greater than 500X109/L. 
  6. It should not be performed in patients with acute promyelocytic leukaemia symptomatic or asymtomatic

The procedure involves insertion of a catheter. This may be associated with an increased risk of bleeding as these patients have thrombocytopenia.

Low Dose Chemotherapy: Like leukocytopheresis the value of low dose chemotherapy has not been proven. The following interventions may be used (with leukocytopheresis)

  1. Acute myeloid leukaemia should be treated with hydroxyurea in a dose of 50-100mg/Kg. It may be administered as a single or multiple doses.
  2. Acute lymphoblastic leukaemia may be treated with steroids with or without vincristine. 

Induction chemotherapy: Induction chemotherapy is the definitive therapy for acute leukaemia. High counts are associated with a higher risk of tumour lysis resulting in an apprehensions of starting chemotherapy in patients with very high leucocyte counts.

Other measures: Cranial irradiation and dexamethasone has been used in patients with CNS symptoms. Blood transfusions can increase viscosity and may worsen symptoms of leukostasis. One needs to be conservative about red cell transfusions till the leukocyte counts become normal. Transfusions in patients with symptoms attributable to anaemia should not be held back. 

 

Overwhelming Post-Splenectomy Infection (OPSI)


Splenectomy is a treatment for haematological disorders, palliation of hypersplenism, symptom relief in patients with symptomatic splenomegaly, splenic trauma and as a diagnostic procedure when tha pathology can not be ascertained by any other intervention. Sickle cell anaemia results in “autosplenectomy” and loss of splenic function. One of the risk of loss of splenic function is overwhelming post-splenectomy sepsis, a condition that proceeds from a mild flu-like illness to fulminating sepsis in a short time and when fully established has a mortality of 50-80%.

Pathogenesis

Microbiology

Pneumococcus is the commonest organism responsible for about 50-90% of the infections.  H. influenza, Meningococcus, Streptococcus, Staphylococcus and E. Coli are the other organisms responsible for OPSI.

Role of spleen in Immunity

The spleen is involved in production of IgM producing memory cells to polysaccharide antigens. These responses are T cell independent. The spleen also produces the following molecules

  1.  Properdin which is an activator of C3 by the alternate pathway
  2. Tuftsin a tetrapeptide that stimulates phagocytosis
  3. C3a is a chemotactic factor
  4. Factor B is a component of the alternate complement pathway

Splenectomized individuals have a defect in cell mediated immunity because of depletion of CD45RA+

Clinical Presentation
The risk of OPSI appears to vary with the underlying pathology. Conditions that impair immunity are associated with a higher risk of OPSI. The risk is about 1-2% in splenectomies because of trauma or idiopathic thrombocytopaenic purport, 6% in Hodgkin Lymphoma and increases to as high 11% in patients with thalassaemia.

The risk diminishes with age at splenectomy. Infants have a risk of 15%, children 10.4% older children 4.4% and adults about 0.9%. Splenectomized patients are at a higher risk of death from infection. Though the adults with splenectomy as predisposed to infection as those without splenectomy the risk of mortality in those with splenectomy is 58 times higher than those without.

About half the infections occur within 2 years and about three-fourth within 5 years of splenectomy. However OPSI may be seen decades after splenectomy.

OPSI presents as a mild illness upper respiratory infection that rapidly progresses to a fulminant illness. The patients develop septic shock, multi system organ failure and disseminated intravascular coagulation within hours. Early suspicion and initiation of antibiotics is the key to success.

Investigations

The focus of management of patients with OPSI is early initiation of antibiotics. When recognised early the mortality of OPSI can be reduced to 10%. There is no test that can predict the risk of OPSI. Haematological and biochemical test as appropriate for patients with sepsis should be performed. Blood culture should be performed to identify the organism. Antibiotics therapy should be initiated immediately and not await the results of blood culture.

Management

Patient Education: The key to successful treatment of  OPSI is the timely initiation of antibiotics. The importance of seeking medical consultation as soon as symptoms occur should be emphasised to the patient. The patient must carry a card or a bracelet identifying him/her as a person who has undergone splenectomy.

Initial Antibiotics: The antibiotics chosen for initial treatment of OPSI are directed against pneumococcus, H. Influenzae and meningococcus. Penicillin for many years was the drug of choice but with the emergence of penicillin resistant pneumococcus it is no longer an appropriate first line antibiotic in OPSI. The patient should be instructed to take oral antibiotics at the first sign of infection making it very clear that this is not a substitute for seeking immediate medical consultation. This strategy ensures that some effective antibiotic is administered at the earliest but these antibiotics are insufficient to treat OPSI. The oral antibiotics recommended include a combination of amoxicillin and clavlunate, cefuroxime aexetil or a fluoroquinolone with a gram positive cover like moxifloxacin. If a patient of suspected OPSI is seen in the clinic an intramuscular dose ceftriaxone 100mg/kg (maximum 2g) should be administered before immediately transporting the patient to the nearest intensive care facility for further treatment.

The initial choice of antibiotics for OPSI is as follows

  1. Patient not Hypersensitive to β-lactams: Vancomycin 10–15mg/kg  i.v. every 12 hours (maximum 1g, dose to be adjusted according to creatinine clearance) with Ceftriaxone 2g i.v. daily (50mg/kg i.v. every 12 hours for children)
  2. Patients Hypersensitive to β-lactams: Vancomycin 10–15mg/kg  i.v. every 12 hours (maximum 1g, dose to be adjusted according to creatinine clearance) with Levofloxacin 750mg i.v. q 24h

The local treatment recommendations need to be followed in case of a significant prevalence of penicillin resistant pneumococci. The therapy should be modified according to microbiological results and antibiotic sensitivity.

Prevention of OPSI

Prevention of OPSI rests on patient education, vaccination and use of prophylactic antibiotics.

Patient Education

The patients must be made aware of the symptoms of OPSI. The importance of seeking prompt professional opinion in case of fever. They should carry a card/bracelet identifying them as patients having undergone splenectomy. They should keep a supply of antibiotics listed above to be taken immediately in case of fever.

Vaccination

(See British Committee for Standards in Haematology guidelines for prevention and treatment of infection  in patients with an absent or dysfunctional spleen)

Patients should be vaccinated against pneumococcus, meningococcus and H. influenzae. The three vaccines may be administered together but at different locations.

  1. Pneumococcal Vaccination: Two pneumococcal vaccines are available. The 23 valent polysaccharide vaccine  (PPV) and the 13 valent protein conjugated vaccine (PCV).  PPV is ineffective in children younger than two years. The vaccination should be administered at least two weeks, ideally six weeks before the splenectomy. In case it is not possible, vaccinations should be delayed to two weeks after splenectomy. The vaccination schedule in the link mentioned above may be followed.
  2. H. Influenzae: H. Influenzae vaccine is a conjugate between capsular polysaccharide of H. influenzae type b and either non-toxic variant of diphtheria toxin or tetanus toxoid. Hib is a part of primary vaccination. If splenectomy is performed before primary immunisation is completed the primary vaccination should be continued as per schedule. If splenectomy is performed after completion of primary immunisation an additional dose of Hib vaccination should be given
  3. Meningococcus: Meningococcal vaccines may be polysaccharide or conjugated. Conjugated vaccines may be monovalent only against serogroup C or quadravalent against serogroups A, C, W and Y. Patients should be vaccinated at least 2 weeks (6 weeks) before splenectomy.

Prophylactic Antibiotics

Despite there being no evidence to prove their efficacy, most agree with the use of prophylactic antibiotics in patients with splenectomy. The main concern is infection by resistant stains. While the British Committee for standards in Haematology has taken the position that antibiotic prophylaxis should be administered lifelong (Br J Haematol 2011;155:308-17), the American and the French advocate use of prophylactic antibiotics in adults for 1-2 years after splenectomy when the risk of infection is the highest (Mayo Clin Proc. 2011; 86: 686–701). Children with splenectomy should be administered antibiotics directed against Pneumococcus till the age of 5 years. If the child remains free of infection one may consider discontinuation of antibiotics.  Penicillin V (125mg twice a day till the age of 3 and 250mg twice a day thereafter) is the drug of choice in areas where penicillin resistant pneumococcus are not prevalent. Other antibiotics including macrolides, co-trimoxazole and a fluoroquinolone with a gram positive cover like moxifloxacin may be used where penicillin resistant pneumococcus is prevalent.

Osteonecrosis in Acute Lymphoblastic Leukaemia (ALL)


Corticosteroids are an important component of treatment of childhood ALL. The use of corticosteroids ahs been associated with osteonecrosis. The estimates of osteonecrosis have varied from 7.4%-44%.  About 25% of these patients need surgical intervention for symptom or functional deficit.

Factors Predisposing to Osteonecrosis

  1. Age: Increasing age predisposes to ON. ON is uncommon below the age of 10 years and increases thereafter. The extent of ON is adults with ALL is not characterized.
  2. Gender: Females are at a greater risk of ON than males.
  3. Steroid Use:  ON is more common with the use of dexamethasone. Administering dexamethasone on alternate weeks in late intensification has been shown to be associated with a lower incidence of osteonecrosis. Patients who have a poor  dexamethasone clearance have a higher risk of ON.
  4. Other Factors: ON has been reported to be more common in patients with a low albumin and elevated. High body-mass index is associated with increased risk of ON.

Mechanism of Osteonecrosis

The mechanism of ON in ALL patients is unknown. The proposed etiologies are:

  1. Steroid induced hypercoagulable state resulting in the development of microthrombi
  2. Steroid induced intramedullary lipocyte proliferation and hypertrophy causing a reduced blood flow
  3. Suppression of osteoblasts and apoptosis of osteocytes

Clinical Presentation

The median time to occurrence of symptoms is 14-27 months. Ninety-five percent of the patients have ON of weight-bearing joints The usual presentation if of pain in the hip and knees. In severe cases the joints may collapse.

Management

The treatment of ON is mainly supportive. Surgical intervention, including joint replacement where needed, may be needed in a about one-fourth of the patient for pain or functional deficit.  Bisphosphonates have been used to slow progression but their role is uncertain. The value of discontinuing steroids is not certain but most discontinue steroids but most discontinue steroids.

Prevention and Monitoring

MRI can detect ON before it becomes symptomatic but it’s use outside clinical trials is not recommended.