How do you get Neutropenia?

There are quite a few types of neutropenia and various ways that you can get them:-

• • Neutropenias present at birth:
  • Severe Congenital neutropenia (Kostmann syndrome)
  • Cyclic neutropenia
  • Metabolic diseases associated with neutropenia:
  • Shwachman-Diamond syndrome
  • Glycogen-storage disease type 1b
  • Neutropenias that are acquired during life:
    • Idiopathic neutropenia
    • Autoimmune neutropenia

      To meet normal physiologic needs, a healthy adult produces roughly 60 billion neutrophils each day. While neutrophils are produced by the bone marrow at a prodigious rate, their blood half-life is short – on the order of approximately 8 hours in a normal individual. Hence, erythrocytes, with a far longer lifespan, vastly outnumber neutrophils by a ratio of about one thousand to one in the peripheral blood. Under normal physiologic conditions, as stable equilibrium exists between marrow neutrophil production and peripheral utilization. When the production of neutrophils by the bone marrow is out spaced by utilization in the periphery, the number of circulating neutrophils in the peripheral blood decreases and Neutropenia results.

      Normal neutrophil levels vary with age and race. In general, these counts range from 1.8 to 7.0 x 10⁹/L, with a mean of approximately 4.0 x 10⁹/L. Infants between 2 weeks and 1 year of age have neutrophil counts that are normally somewhat lower than older individuals. Additionally, people of African origin have normal neutrophil counts that are slightly lower than those seen in Caucasians. When a patient is found to be neutropenic, the peripheral blood neutrophil count serves as a rough guide to the relative seriousness of the disorder. This degree of Neutropenia can be “mild” (1.0 – 1.8 x 10⁹/L), “moderate” (0.5 – 1.0 x 10⁹/L), or “severe” (less than 0.5 x 10⁹/L). It should be emphasized, however, that the duration of Neutropenia, the function of neutrophils and other host defences, and the capacity of the bone marrow to respond also contribute considerably to the relative susceptibility of a patient to infection.

      Patients with severe Neutropenia, and particularly those with neutrophil levels less than 0.2 x 10⁹/L, have a significantly increased risk of infection due to invasion of surface bacteria in the mouth, intestinal tract or skin. Such patients frequently demonstrate mucosal inflammation, particularly of the gingival and perirectal areas and often manifest cellulitis, abscesses, furunculosis, pneumonia or septicaemia. Unlike normal individuals, infections in these individuals often lack the fluctuance, induration, and exudate that typically accompany a normal inflammatory response. While superficial infections cause substantial morbidity in these patients, deep-tissue infections of the sinuses, lungs, liver and blood pose the greatest risk. Resistant organisms caused by the repeated use of broad spectrum antibiotics often complicate treatment.

      Acquired non-malignant Neutropenia occurs much more commonly than chronic Neutropenia. In children, the acute forms are most frequently seen in association with viral infection. Neutropenia in this setting usually develops over one to two days and can persist for up to a week without serious sequelae. Since concomitant diminution of other cell lines in this setting is unusual, evaluation for malignancy should be considered if the red cell or platelet compartment are also significantly decreased. In the seriously ill patient – particularly the neonate – sepsis can cause acute Neutropenia. Since such patients can deplete their neutrophil reserves during an overwhelming infection, granulocyte transfusions may be life-saving.

Free resources

There are many apparently authoratitive resources that can be found on the internet, however the one that is the most widely regarded as the leading authority is published by the Severe Chronic Neutropenia International Registry which is based in the US. It is a useful document to present to doctors and other interested parties for specialist reading and we would recommend every sufferer reads this to get a full understanding. The SCNIR can be contacted directly for specific questions and they will liaise with UK medical professionals if needs be though they do have a UK representative who is based in Leeds, Professor Sally Kinsey.  For registration or clinical questions please contact  Audrey Anna Bolyard at bolyard@u.washington.edu.

Link to their handbook: https://depts.washington.edu/registry/

National Neutropenia Network

Another organisation based in the US, who work closely with the SCNIR and who have a mountain of information can be found at: http://www.neutropenianet.org/

 

Health & Lifestyle Management

There are a variety of supportive therapies; only the most important are addressed below:

• Mouth Care: This should include regular dental check ups. Excellent oral hygiene is very important and the use of an antibacterial mouthwash is recommended.
• Immunizations and Vaccinations: People with SCN have an intact immune system that allows them to make normal antibodies protecting from the devastating effects of viral illnesses. Therefore all routine immunizations according to the standard vaccination schedule of your country are recommended.
• Monitoring Temperature: If you have a fever above 38.5°C/101.3°F you must seek medical attention. Not all Neutropenics however have temperatures with infection, therefore please be aware of other symptoms
• General Hygiene: This includes thorough hand washing and attention to scrapes and cuts on the skin. Some sufferers like to carry and hang antibacterial hand gel though the jury is out on whether this prevents you from building up an immunity. We would suggest common sense prevails.
• Oral Prophylaxis: Antibiotics/antifungals, either oral or intravenous, may be given to SCN patients but this is very much based on individual medical specialist choice.
• Prompt Contact of Hospital / Clinic: It’s important to have the contact telephone numbers of your haemotologist and clinic.
• Foreign Travel: Travel is an option but should always be considered with advice from your specialist. Always declare Neutropenia under any travel insurance to ensure adequate cover is in place.

Treatment

Granulocyte-Colony Stimulating Factor (G-CSF)

G-CSF is a cytokine normally produced by the human body itself. Cytokines are proteins and peptides that allow cells to communicate with one another. They act like hormones and neurotransmitters and are involved in a variety of immunological, inflammatory, and infectious diseases. The type of G-CSF which is given as treatment is not from human beings but is safely made by genetic engineering to produce an identical substance which acts like the naturally occurring cytokine.

G-CSF stimulates the production and enhances the activity of mature neutrophils to improve their bacteria-killing function. SCN patients produce their own G-CSF, but for unknown reasons it does not produce the normal effects within the blood system so extra G-CSF is required.

The dose and frequency of injection of G-CSF varies widely. For most patients, 5-20 micrograms (mcg) per kilogram (kg) of body weight of G-CSF given as a daily subcutaneous injection is usually sufficient. Sometimes certain patients need very high doses, even up to 120/mcg/kg/day and others will require very low doses, as low as 0.01 mcg/kg/day.

For some patients with severe chronic Neutropenia the dosage frequency of G-CSF may be required less than daily, but short-term amendments may be necessary if infections occur.

G-CSF is usually administered by an injection just under the skin in areas such as the abdomen below the naval, upper outer arms, and upper outer thighs. It is possible to self-administer G-CSF depending on the age of the patient. The injection is not usually very painful but, occasionally, a stinging sensation may be experienced for a short period of time.

G-CSF treatments can be expensive, up to $4000 a month in the US, though are charged for in the UK under the NHS guidelines. However, it might be possible to get financial help with G-CSF supplies in the US.

Effects and Side Effects

Administration of G-CSF may result in a dramatic increase in the numbers of neutrophils in the blood and is without a doubt, the most effective therapy in treating SCN. Some SCN patients receiving G-CSF report bone or muscle pain and splenomegaly (enlargement of spleen). Other side effects are infrequent but few patients have experienced some of the following:

• Thrombocytopenia (Low platelet levels)
• Injection site reactions such as rash
• Hepatomegaly (liver enlargement)
• Arthralgia (joint pain)
• Osteoporosis (reduced bone density)
• Cutaneous vasculitis (renal disease)
• Haematuria/ proteinuria (blood or serum in urine)
• Alopecia (hair loss)
• Exacerbation of some pre-existing skin disorders (e.g. psoriasis).

Other Treatments

Bone Marrow Transplant

BMT is a treatment option for SCN. It may be considered for failure to respond to treatment, or for patients who develop leukemia or MDS in the course of their disease. BMT is a very intensive procedure, carrying serious risks and therefore it is not recommended as first choice treatment. Your haemotologist will be able to discuss this with you.

Corticosteroids

In some conditions steroids have long been effective at increasing neutrophil counts in the blood. Steroids work by encouraging neutrophils to leave the bone marrow and enter the blood stream. However, they do not induce the production of new neutrophils in the bone marrow. They may even decrease the number of other types of white cells increasing the risk of infection.

In general, steroids have not proven useful for patients with SCN, except for very few SCN patients not responding to other therapies.

How are you tested for Neutropenia?

Blood Testing

Early misdiagnosis is a common issue for patients and families with Neutropenia. In order to officially determine Neutropenia a medical specialist will need to run a Complete Blood Count (CBC),  also known as a Full Blood Count (FBC). These tests directly measure the neutrophil count.

Patients with Severe Chronic Neutropenia (SCN) may have a neutrophil count which varies slightly.

Though, in contrast to Cyclic Neutropenia it always remains at a very low level. With Cyclic Neutropenia counts can test normal due to a cyclical change, but may test very low at other times. Testing for Cyclic usually involves CBCs taken three times per week for at least six weeks to see if a regular cyclical pattern of neutrophil counts.

Medical professionals should also do a blood test to exclude autoimmune Neutropenia by testing for neutrophil antibodies.

Bone Marrow Testing

If initial blood tests indicate Neutropenia the next step in diagnosis is a bone marrow examination. Neutropenia can be determined by viewing a sample of marrow under a microscope.

Bone marrow cells are usually taken from the large pelvic bone, the ilium or the sternum. The patient is usually asleep under general anesthetic or under local anesthetic with sedation.

There are two different methods of examining bone marrow. First, marrow cells can be taken out like taking a blood sample from a vein (bone marrow aspirate) from the middle of the bone. Secondly, a small piece of the solid, bonier part of bone marrow is taken (bone marrow biopsy) and processed to look at the architecture of the marrow structure.

Cytogenetic and Molecular Testing

A subset of Cytology (the study of cells and their structures) cytogenetics involves the study of the hereditary properties of cells and chromosomes.

Any morphological or structural abnormality of the marrow cells may be preceded by a change in cytogenetics. There are additional techniques by which some cytogenetic changes can be monitored depending on the physician testing.

Types of Neutropenia

There are four main types of Neutropenia: Autoimmune, Congenital, Idiopathic & Cyclic;

• Autoimmune – involves antibodies in the blood that actually attack the body’s own neutrophils. Granulocyte-specific antibodies are detectable by different immunological blood tests that can be performed. If these antibodies are identified, the patients should be kept under medical care, but may not necessarily require treatment with antibiotics or G-CSF. Depending on the frequency of infections and the neutrophil counts, prophylaxis with an oral antibiotic may be considered.
• Congenital – This type of Neutropenia is generally present at birth and is often called Kostmann Syndrome. It is usually very severe since neutrophils are often completely absent. Patients neutrophils rarely fully mature into the cells that are capable of fighting infections. This type is known to often benefit from G-CSF treatments.
• Idiopathic – This type of Neutropenia may occur at any time in life for unknown reasons. The onset of idiopathic Neutropenia is possible in both, children and adults. Most patients respond well to G-CSF treatment but require long-term treatment.
• Cyclic – Cyclic Neutropenia is when a cyclic pattern of varying neutrophil count shows with a typical cycle length of 21 days. These cycles vary from patient to patient with some individuals being neutropenic during the whole cycle and others who have low neutrophil counts for only a few days and normal blood counts during the rest of the time. This Neutropenia occurs because cell production rates fluctuate by the bone marrow stem cells.

 

We will be looking at how Neutropenia is tested in the next blog, however if you have any experiences of neutropenia and would like to be considered as a contributor to this blog site, please feel free to contact us at ukneutropeniasg@gmail.com – thank you.

What is Neutropenia?

Neutropenia is a disorder of the blood when the number of neutrophils are too low. The body protects itself against the constant risk of infection by making a lot of neutrophils. They are your main defences against infections. With lower numbers of neutrophils, it is harder to fight infections, particularly bacterial and fungal infections.

People with neutropenia get infections easily and often if left untreated. Most of the infections occur in the lungs, mouth and throat, sinuses and skin. Painful mouth ulcers, gum infections, ear infections and periodontal disease are also very common. Severe, life-treating infections may also occur. Often the sufferer must be admitted to hospital and receive intravenous antibiotics. Your doctor uses blood tests to find out whether you have enough neutrophils and there are other tests to find out more about the type of Neutropenia that you have too.

The severity of neutropenia generally depends on the absolute neutrophil count (ANC) and is described as follows:

• Mild neutropenia, when the ANC falls below a lower limit of 1500 per mm3 (1.5 x 109 /1), but remains higher than 1000 per mm3 (1.0 x 109 /1).
• Moderate neutropenia, when the ANC falls between 500 per mm3 and 1000 per mm3 (0.5 x 109 /1 – 1.0 x 109 /1)
• Severe neutropenia, when the ANC falls below 500 per mm3 (0.5 x 109 /1)

So, can it be treated? Yes, though this depends on many factors – age, type of neutropenia, whether you get a haemotologist who knows much about Neutropenia, what the financial budget is like for the NHS in your area as treatment is expensive, and more importantly whether it would be beneficial for you.

So read on to find out about types of neutropenia…..

UK Neutropenia Support Group – Who we are and what we stand for.

Welcome to the first blog for the UK Neutropenia Support Group…..

……we are a small friendly group dedicated to raising the profile of Neutropenia in the UK, and to provide a support network for sufferers, friends and families of the condition Neutropenia.

We started initially with a Facebook group a couple of years ago, which has slowly but steadily grown with interest and support from people across the globe, not just in the UK. We have a twitter feed also, and hope that this year we will be able to become an organisation with charitable status (or similar) so that we can fund raise for better research and education within the UK. We already have the back up of the UK member of the SCNIR (Severe Chronic National International Registry), Professor Sally Kinsey and we hope to gain further support from other professionals across the UK.

The story so far comprises several strands for sufferers in the UK;

• Neutropenia in its own right is a rare disease and therefore frequently misunderstood, misdiagnosed and mistreated.
• Neutropenia can be debilitating and life threatening.
• There is little knowledge ‘out there’ about the condition, nor is there much support and sufferers and their families often feel isolated.
• The NHS can be a bit of a postcode lottery in regard to diagnosis & treatment due to funding issues across the country.

With all of the above in mind, the facebook group was launched and a small group formed and grew. Over time it has become clear that variances across the country via the NHS mean that everyone is getting different advice and treatment – some better than others, dependent on the knowledge of the professionals involved. It has become clear that there are a lot of differences in procedures, opinions, diagnoses & treatment.

I write as a sufferer, formally diagnosed several years ago, though it now appears from my medical records I may have had this condition much much longer…..the jigsaw pieces over the years are starting to come together and what many people thought of as hypochondriac-ism, is now being proven as actual illness with genuine and now validated reason for this constant in my life.

This all sounds a bit cryptic to those who have no idea what Neutropenia is perhaps…..all shall become clear in my next blog post so please keep on reading and do sign up for future instalments.

Please feel free to follow the group on Twitter @UKneutropeniasg and join our facebook group http://on.fb.me/1xvDani