Q&A: Awareness essential to diagnosis, treatment of rare primary immunodeficiency
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Warts, hypogammaglobulinemia, infections and myelokathexis — or WHIM — syndrome is a rare but important primary immunodeficiency that leaves some patients susceptible to life-threatening infections as well as to cancer.
Healio spoke with Teresa Kathleen Tarrant, MD, associate professor in rheumatology and immunology at Duke University School of Medicine, to find out more about the disease, including its diagnosis, treatment and how doctors can better help patients who have been diagnosed with it.
Healio: How does WHIM syndrome fit into the range of primary immunodeficiency disorders (PIDs)?
Tarrant: The spectrum of an immunodeficiency can include anything that is wrong with your immune system. In PIDs, they are immunodeficiency diseases that tend to have genetic causes. Sometimes we don’t know the gene, but in the case of WHIM syndrome, we often know the gene or genes to look at. Its genetics have been better defined.
WHIM syndrome runs in some families because it has an autosomal dominant inheritance for many patients. In this scenario, one parent has it and gives one copy of their abnormal gene to their child, and that is all you need to have the expression of the disease.
However, people also can be born with a spontaneous mutation. In this scenario, nobody in their family has the abnormal gene, but something happened when they were developing that led to a spontaneous mutation in that gene. In most patients, but not all, it’s the CXCR4 gene that has become affected. What that looks like clinically is a very broad spectrum.
In some cases, WHIM syndrome can be first diagnosed in early age as recognized by an excessive number of warts and many infections. Testing often reveals neutropenia, a low level of infection-fighting neutrophils, and sometimes low antibody levels, or hypogammaglobulinemia.
These patients oftentimes will get a bone marrow aspirate. The hematopathologist will look at the white blood cells in the bone marrow and in their blood and see that they do not look like cancer, but their neutrophils don’t look normal.
Patients also have hypercellular marrow, meaning there are many blood cells inside the bone marrow – this is what is called “myelokathesis” and is the “M” of WHIM. Further testing reveals low levels of blood cells in the blood despite many inside the bone marrow. The immune cells are being made, but they’re trapped.
Having a cellular problem and an antibody problem, which can be seen in WHIM, is called a combined immunodeficiency. We like to group immunodeficiencies by whether or not there are cellular problems or antibody problems so you can understand the pattern of infections that they may suffer from and formulate a treatment plan.
Healio: How does WHIM syndrome manifest in terms of symptoms?
Tarrant: That spectrum can be very broad. In childhood and adolescence, there can be lots of infections in the sinuses or pneumonia that occurs from low antibodies or from low blood counts. They can have skin infections from the low white blood cell counts, particularly low neutrophils. But some children are healthy, and you wouldn’t know that they have a problem.
Although some children and young adults may have a noticeable increase in warts on their body, WHIM patients may also have only have a few warts, which can be common in kids, and wouldn’t necessarily be thought of as abnormal.
There are some individuals with WHIM who may not have severe infection or warts, so some of these individuals don’t get diagnosed until later, especially if they don’t have a family history of problems.
An unusual type of blood cancer or papilloma-virus cancer manifesting in a young or middle aged person can invite clinical attention, particularly if it is associated with low neutrophils in the blood.
Some people are screened for WHIM, even if they are healthy, because they’re looking for that defect on purpose, because a family member has it.
As we increase awareness about primary immunodeficiencies, it probably will be on the radar of more physicians to investigate or to refer to an allergist or immunologist. If someone has abnormal blood or antibody levels and infections, in general, that’s when you would start involving a specialist to help you evaluate a patient.
Healio: What role does genetic testing play in this diagnosis?
Tarrant: Genetic testing has evolved for all PIDs. For many of these diseases, we now can identify the genetic defect and the family members who have it, and we can order a workup to confirm a suspected diagnosis. There’s a lot less resistance or trepidation around ordering that type of testing now, and there are many ways that you can order genetic testing. A lot of it depends on your institution. Some doctors will order an immunodeficiency panel that will highlight the published genes of many different immunodeficiencies. You might send that off because you know your patient has an immunodeficiency, but you don’t want to sequence every gene and rather focus on the immune ones. Other doctors might order what’s called whole-exome sequencing, where they’re ordering all the coding sequences of your DNA. Some doctors sequence everything, both coding and noncoding, which is whole-genome sequencing.
So, there’s a range of genetic testing that is available and different ways that it is done. But in general, the cost of it has come down considerably, and most immunologists feel it’s a very valuable piece of the diagnostic workup.
Sometimes people have a novel genetic mutation, which means it’s a gene mutation no one has ever seen before, but it doesn’t necessarily cause disease. This is called a VUS or variant of unknown significance. Sometimes genetic testing says the gene is normal, but the patient has all the features of the disease. Thus, genetic testing isn’t perfect, because it may not capture people who have new gene defects in the same way, and it may not capture people who have perhaps a different gene involved in what we think is the typical gene but looks very similar to that disease. Then some people can have very, very mild disease, whereas other people can have very severe disease with both having the same genetic mutation. This is something we don’t understand well, but more research is investigating. It’s not necessarily as easy as saying the gene is good or bad. There’s still a lot of gray.
Healio: Once that diagnosis has been made, what kind of treatment follows?
Tarrant: There is no one protocol for everyone. A lot of it is symptom-based and personalized medicine. If a patient is having problems with infections, you are going to be quicker to start antibiotics, because they have an immune defect and they are going to need a little more help to fight those infections. If they have very low neutrophil counts, some of those patients can take an injectable medicine that will increase their neutrophil numbers from the bone marrow. Some patients with low antibody levels will go on infusion therapy to replace the antibodies. Then you would obviously be screening these patients more often for cancers. Because they have more problems with warts, we typically would recommend the HPV and pneumonia vaccines to strengthen their immune systems as much as possible. There are currently no therapies that treat the cause of the disease, but some options are currently being evaluated to target some of the genetic causes discussed previously.
Healio: Which doctors would be managing this treatment?
Tarrant: It depends on where the patient is presenting, but oftentimes an allergist immunologist or hematologist oncologist could take the lead. The clinical problems tend to involve multiple specialties. Many patients with PIDs don’t have one doctor, but several. If warts are a critical problem, including a dermatologist would be helpful. If they’re having lots of sinus problems, you may include an otolaryngologist or ENT doctor to help manage that. If they are having cervical cancer or pelvic issues related to HPV, you may involve an OB/GYN. Oftentimes for PIDs, it’s a coordinated effort of primary care and specialists.
Healio: What are the primary takeaways that doctors need to know to better recognize and treat WHIM syndrome?
Tarrant: If you’re looking at a patient who has an unusual degree of warts that are not responding to standard therapies, you might want to have this on your radar. An easy screen for a lot of these patients is to get a complete blood count with a differential. It lets you know how many white blood cells you have, particularly neutrophils.
If somebody with warts has lower than normal neutrophils, you may want to ask the patient more about prior infections and family history of infections and warts. Is this someone who has had more sinus infections than usual? Have they had pneumonia, which is unusual for young, healthy people? If those things look abnormal, you could consider referring them to an allergist/immunologist or a hematologist to evaluate whether the patient needs additional testing.
Healio: Do you have anything else you would like to add?
Tarrant: PID doesn’t get a lot of coverage. The more people know about these diseases, the more likely we are to recognize and diagnose them more quickly. PID has, in the published literature, a delay in diagnosis. Usually, the delay has a lot to do with the fact that we aren’t recognizing the symptoms of the disease. So, the more we inform people about what that looks like, how you can get information, and who you should refer to, we can get patients diagnosed more quickly and, hopefully, treated sooner.
For more information:
Teresa Kathleen Tarrant, MD, can be reached at teresa.tarrant@duke.edu.