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Lifesaver cells

 

 

It’s an immense responsibility to treat children, especially when the child’s life is at stake. People wresting babies from death’s grip are seen almost as gods. Such doctors can be found at the University Children’s Hospital Zurich, one of the world’s leading pediatric centers. You’ll find out how they manage to fight and defeat such terrible diseases as septic granulomatosis in this interview with Doctor Mathias Hauri-Hohl.

– Doctor Hauri-Hohl, your department specializes in stem cell transplantation. When is this method especially effective?

– Hematopoietic stem cell transplantation is used for the treatment of an increasing number of diseases of genetic or malignant origin. Historically, it was developed for the treatment of hematological malignancies (such as leukemia), that would not respond to conventional treatment. This remains an important indication for hematopoietic stem cell transplantation (HSCT). However, for several reasons an increasing number of non-malignant diseases (such as primary immunodeficiencies, aplastic anemia, metabolic diseases) can be cured with HSCT. Besides these different indications, we have put our focus on the treatment of chronic granulomatous disease (CGD), an inherited primary immunodeficiency.

Affected patients usually demonstrate normal numbers of neut rophil granulocytes, yet their function is severely impaired. Neutrophil granulocytes are a particular cell type in the blood, specialized in the rapid elimination of pathogens such as bacteria and fungi. Thus, patients with impaired granulocyte function (aka CGD) are susceptible to invasive, lifethreatening infections by bacteria and fungi. Generally, they are only diagnosed after one or more episodes of severe infections. These patients require rapid and appropriate antimicrobial treatment for an acute infection. In addition, patients often suffer from inflammatory conditions, such as inflammatory bowel disease. The patients need to change their lifestyle in order to minimize environmental exposure to fungal pathogens. Furthermore, they require life-long antimicrobial prophylaxis. Despite these measures, life expectancy of CGD patients is limited, as they eventually succumb to invasive infections. Currently, the only curative treatment is hematopoietic stem cell transplantation.

– To what extent is it a rare disease?

– It is found in approximately one in two to five hundred thousand people. Rare diseases such as CGD can be tricky to diagnose and require a high level of suspicion and thus often go unnoticed by physicians.

– What’s the key point of stem cell treatment?

– Blood consists of diverse, highly specialized cell types. For example, red blood cells transport oxygen throughout the body, and blood platelets are responsible for coagulation. Phagocytes (such as neutrophil granulocytes) rapidly remove bacteria and fungi. Other immune cells (such as T and B cells) take care of viral infections. Genetic diseases may only affect one particular cell type. However, all of these cell types continuously develop from a pool of hematopoietic stem cells in the bone marrow throughout life. It is not (yet) possible to replace a particular cell type long-term. The cure therefore requires the replacement of the patient’s hematopoietic system with stem cells derived from a healthy donor. Over time, these donor cells will replace the patient’s blood cells and consequently establish a healthy state.

Since with HSCT we introduce foreign cells into the patient’s body, we have to trick both the patient and the donor’s immune cells to become tolerant of each other. Otherwise, serious complications can arise, such as rejection of the transplanted cells or an immune reaction known as graftversushost disease.

– What other illnesses does stem cell transplantation help to fight?

– In our department, roughly 40 percent of patients undergoing HSCT suffer from malignant diseases, primarily leukemia (blood cancer). The remainder consists of patients with hematological diseases (such as aplastic anemias or red blood cell disorders (e.g. sickle cell disease)) and primary immunodeficiencies (in particular, CGD). A minority suffers from certain metabolic disorders amenable to being cured via HSCT.

 

 

– What is the age range of your patients?

– In our pediatric unit we treat children aged from a few months to 16 years old. This range of children requires personalized medical care and specialized nursing. Our overall goal is to provide a durable cure and obtain a quality of life and life expectancy in our patients that is comparable to their peers.

– Tell us, please, in more detail, about transplantation and the preparations necessary.

– In order for donor stem cells to grow in the patient’s bone marrow, the patient’s bone marrow cells have to be eliminated by a pre-treatment known as conditioning. In non-malignant diseases such as CGD, this conditioning should be strong enough to effectively remove the host’s hematopoiesis. However, it should be mild enough not to negatively affect the vital organs. We have developed a conditioning regimen (the socalled Reduced Intensity Conditioning) that is both highly effective and well tolerated in non-malignant diseases. This conditioning regimen takes about 7–8 days. Transplantation of donor hematopoietic cells is done via an intravenous infusion. The donor stem cells will thereafter find their way into the empty niches in the bone marrow via the bloodstream and start producing blood cells within 2–4 weeks.

The use of reduced intensity conditioning mitigates or prevents short- and long-term side effects. After stem cell transplantion, children are closely monitored by specialized doctors for at least four to six months.

– Which side effects are likely and how do you deal with them?

– Common side effects early after transplantation include mucositis (inflammation of the mucosa of the gastrointestinal tract), which can be pretty severe in heavily pretreated children with malignant diseases. In addition, pathogens can enter the body through the affected mucosa, leading to systemic infections, or viruses having remained silent for years may reactivate and can be harmful during the phase of heavy immunosuppression. On rare occasions, the residual immune cells of the host mount an immune response towards the donor cells and reject the graft. On the other hand, the donor’s immune cells may react against the host tissues (Graft-versus-Host Disease). Prompt diagnosis of the condition and appropriate treatment are essential during this phase.

Long-term complications – mainly occurring after high-dose chemotherapy or irradiation therapy – may include poor growth, heart or lung dysfunction, secondary tumors and infertility.

Some of the drugs used for conditioning are metabolized with varying speeds in different patients. Thus it is important to assess the metabolism of these drugs in every patient and adapt the dose accordingly, to avoid over- or undertreatment, which can result in more severe side effects or graft failure respectively.

– Do patients from other countries come to you?

– The department of pediatric stem cell transplantation is the largest of its kind in Switzerland. We perform 30–40 transplants annually. Of course, it is our duty primarily to treat patients from Switzerland. However, since we are renowned for our experience in the treatment of patients with CGD, we get referrals for HSCT from other centers (e.g. Russia, Slovenia, Saudi Arabia, Germany, France,…). In addition, we get requests for our advice in the conservative treatment of children with CGD.

 

 

– When you get a sick child, where do you start treatment?

– During the initial consultations we review the medical history (infectious and inflammatory complications, growth and development, medications, preemptive measures, psychosocial issues…). The treatment of ongoing inflammation or infection, adaptation of prophylactic treatment, instructing the parents and patients to lower the risk of exposure to environmental pathogens… these are all steps to improve the course of the disease. Since HSCT is currently the only curative option, we perform a search for related (mainly siblings) or unrelated donors.

– Is there a global donor base?

– Roughly 25 million volunteers have registered in many registries worldwide. With the consent of the parents, the patient is registered in the Swiss registry and considering the information from the histocompatibility typing, a search is initiated throughout the registries. With this large body of volunteer donors there is a fair chance of finding a suitable donor (70–80%).

– And do the other twenty percent remain without a donor?

– In certain cases it can be very difficult to find a suitable donor. In these cases one of the parents can serve as a donor. New developments in conditioning regimens and graft manipulation including our own have drastically decreased the rate of complications (mainly graft rejection and graft-versus-host disease) in this setting.

– What happens next – after you have found the donor?

– Approximately 10 days before the scheduled transplantation, the patient is hospitalized. First, a central venous access line is installed. Then the patient receives the conditioning chemotherapy, which usually takes no more than 8 days. During conditioning and 4–6 weeks after transplantation, the child remains in a room with filtered air. This and the strict preemptive measures help prevent infectious complications in this phase, where the patient is heavily immunosuppressed. Should the patient show any signs of infection (bacterial, viral) he is rapidly treated. Within 10–14 days the donor cells start to appear in the blood and soon thereafter phagocytes reach sufficient levels to provide a first line of defense against bacteria and fungi. Once the production of platelets and red blood cells is sufficiently stable, the patient may leave the protective environment. However, immunosuppressive medication is still required for another 4–5 months. During this time certain precautions have to be taken. Weekly or biweekly checks in our outpatient clinic are necessary during this time, to check for infectious or immunological complications. Normally, monthly and later quarterly follow-up visits are sufficient. Vaccinations will have to be repeated.

– Are there any cases that you particularly remember?

– Of course, behind these ‘cases’ there are unique human beings and their families. One particular family has become very close to me. They lost their first-born baby girl due to a severe bacterial infection. We can only assume that she was suffering from undiagnosed chronic granulomatous disease. The second girl was later diagnosed with CGD after repeated severe infections and an ongoing inflammatory bowel disease. They sought our advice and the child is now scheduled for a transplantation from a matched unrelated donor in January. Caring for such patients and their families is very rewarding and touching, especially if the transplantation is successful and without major adverse events. Hopefully, we will manage to save the child and provide her with the opportunity to live a normal life.

 

 

Mathias Hauri-Hohl

Doctor of Medicine. Transplant physician and head of research in the department of stem cell transplantation at the University Childrens’ Hospital Zurich. In 2002, he graduated from Basel University School of Medicine. In 2008, he was awarded a Doctor of Natural Sciences in Biomedical Research and Immunobiology. He is a boardcertified pediatrician and a member of the Swiss Society of Pediatrics. His research focuses on the improvement of transplantation tolerance and the restoration of the immune system after stem cell transplantation. In addition, prevention of conditioning-related side effects is part of his ongoing research.

 

 

Professor Tayfun Güngör: head of The Department of stem cell transplantation at The University children’s hospital Zurich.  

– Professor Tayfun Güng.r, what are the main tasks of your department?

– The main thing is to guarantee stem cell transplantation at a national level for the treatment of malignant and non-malignant diseases. Over the past 25 years, we have accumulated vast expertise in the treatment of certain diseases – in particular, chronic granulomatous disease. Children are sent to us with this rare diagnosis from other clinics in Switzerland and from abroad. Thus, we have gained vast experience in stem cell transplantation for this disease. Fortunately, chronic granulomatous disease is a very rare disease, so there are only a few patients with this diagnosis. We transplant roughly 5–6 patients with CGD per year.

– Do topics of scientific research concern only this area?

– The conditioning regimen we developed for the curative treatment of chronic granulomatous disease can be applied to other diseases, such as immunodeficiencies and blood disorders (e.g. sickle cell anemia or betathalassemia). More than 300 immunodeficiency disorders are known to date. I am sure that hematopoietic stem cell transplantation is an effective method of treating a large number of these diseases.

– And can these diseases be successfully treated in cancer centers?

– Cancer centers in general are very experienced in the treatment of aggressive tumors. However, non-malignant diseases require a more differentiated approach to prevent unnecessarily harsh conditioning therapy of the patient.

– Is it possible to achieve such results that all children can be saved thanks to the methods of treatment used in your clinic?

– We strive to further reduce the risks, to minimize complications and losses. Unfortunately, many factors influence the outcome, including the donor. For example, sibling donor transplantations yield very favorable outcomes, with a complication-free survival rate of roughly 95%. But we still have much research to do in order to improve the outcome of this therapy!

– Do you cooperate with colleagues from other countries?

– Ever since the first transplantations in 1991 in our center, we have had a number of longstanding partners in transplant centers in England, France, Germany, the USA, Australia and South America.

– Why do you think your department has become the leading one in this sphere?

– The reason is simple: we concentrated on one particular disease very early on and began to conduct research in this particular area. These insights made it possible to obtain very good transplant results. By the way, this is the current trend in medicine – more and more centers are specializing in some kind of disease and in technologies for its treatment. This helps to achieve substantial results in fighting against these serious diseases and to achieve the main goal – a complete recovery of the child and an excellent quality of life.

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