This is an extraordinary time of rapid advances in understanding the causes and consequences of neutropenia and immunodeficiency diseases. New developments in genetics and genomics now allow us to pinpoint precisely the specific mutations causing most of these diseases. Although advances in treatment lag behind basic understanding, novel therapies are also emerging. In this issue, experts review the cellular, molecular, and genetic features for several diseases affecting host defense mechanisms: leukocyte adhesion deficiency, Barth syndrome, Gaucher's disease, and other immunodeficiency syndromes. Although these conditions are all quite rare, each teaches the critical nature of the individual components of the immune system and how single mutations affecting the host-defense network can have devastating consequences for our patients.
We recognize that most of the content in this issue is very specialized information, and for many of us the information is not very relevant on a day-to-day basis. However, if you or your child has one of these conditions, it is very pertinent. It is also this kind of information that provides the essential framework on rare diseases for early and proper diagnosis, understanding of treatment options and consequences, and good clinical decisions by patients, parents, and healthcare organizations.
The organizational framework for improving care for immunodeficiency diseases consists of four parts:
- screening and early diagnosis;
- clinical analysis and genetic counselling;
- longitudinal registries and repositories;
- cooperative trials to identify novel therapies.
In this issue, the article by Borte et al. ‘Guidelines for newborn screening of primary immunodeficiency diseases’, carefully summarizes recent advances in genetic and molecular diagnosis for these conditions. Screening of newborns with a drop of blood is the most important step for early diagnosis for some, but not yet all, of these conditions. Changes are coming rapidly with clinical applications of exome and whole genome sequencing. Skillful obstetricians and neonatologists often quickly recognize major abnormalities of the newborn, but genetic screening leads to more precise diagnoses. Screening programs are particularly important because affected children are often born far away from geneticists and other experts. Neutropenia, immunodeficiency, and marrow failure syndromes often go unrecognized in newborns, but improvements are coming.
One of the biggest challenges is how to interpret the rapidly burgeoning information on the basis of neutropenia and immunodeficiency syndromes. Medical advice and genetic counseling depend upon understanding the consequences of genetics and molecular findings. A report by Robert Sokolic on ‘Neutropenia in primary immunodeficiency syndromes’ provides such insights. The immunodeficiency syndromes primarily affect adaptive immunity, but neutropenia may also occur. Understanding its frequency and consequences is very important to patients. We are also gradually discovering the specific genotype/phenotype relationships that are associated with the varied clinical patterns of these conditions.
Giving good advice requires knowing how to predict the course of the patient. The knowledge base for giving good advice is longitudinal databases of disease-specific clinical information. For instance, if a child is neutropenic at birth, can we predict the neutropenia will improve, worsen, or remain the same? For immunodeficiency syndromes, it is extremely important to know the best ways to protect the patient from infections. The report by Guy Zimmerman succinctly and critically summarizes what we know about leukocyte adhesion deficiency syndromes, but there are still gaps in our knowledge, especially as patients live longer and some reach adulthood. Patients and parents want accurate prognostic information, and the best source of this information is through the creation of repositories and registries. These resources are needed to know the natural history and to define treatment outcomes.
Improving care also depends on translational research focused on finding new therapies. Ideally, new treatments come from molecular understanding of diseases, but they also occur through serendipity and astute clinical observations. For rare diseases, such as those described in this issue of Current Opinion in Hematology, progress also depends on recruitment of patients and cooperation among patients, their families, researchers, and clinicians. The time is ripe for simplifying the clinical research infrastructure and regulations to facilitate clinical trials for rare diseases, such as those which have led to better treatments for the congenital neutropenias and Gaucher's disease.
Advances in screening and early diagnosis, medical expertise, genetic counseling, registries to define the natural history of rare diseases and research to identify new and effective therapies are the cornerstones for improving care for neutropenia and immunodeficiency. We have seen enormous progress, but there are still many opportunities and much yet to be done.
Conflicts of interest
D.C.D. serves as a consultant and/or receives research funding from Amgen, Cellerant, Eisai, Galderma, Merck, Phillips Home Healthcare, Sanofi-Aventis, and Tarix. He currently serves as an editor for Lippincott, Williams and Wilkins and Wolters Kluwer and on the Editorial Advisory Board for Medscape.