By Purvi Parikh, MD
On a cold, blustery Cleveland day when I was a resident, a forty-year-old man walked into our infectious disease clinic at the Cleveland Clinic Foundation. The patient was undergoing routine visits in preparation for a kidney transplant. This poor man had been hospitalized six months earlier at another hospital where he caught a terrible infection and was re-admitted in septic shock and multi-organ failure. Luckily he survived, but in the process lost some of his toes as well as his kidney function. Thus, he was now on dialysis and awaiting a new kidney. The organism to blame was streptococcus pneumoniae, which causes pneumonias and ear infections but isn’t deemed life threatening in healthy individuals. Moreover, most of us are vaccinated against this as babies and again as adults.
An astute internal medicine resident in the clinic noticed the rarity of this case and decided to pursue a work-up of his immune system. An HIV test, which commonly is checked when there is suspicion of immunocompromise, was negative. Luckily, this young doctor went one step further and checked this patient’s immuglobulins and vaccine titers. Surprisingly, his total immunoglobulin G (IgG) and immunoglobulin A (IgA) were very low. The patient did not show any positive vaccine titers for things he had been vaccinated against such as Hepatitis B and pneumococcus. Upon further probing of his history, it was found that he had had an autoimmune disorder as a young adult called immune/idiopathic thrombocytopenic purpura: his platelets were attacked by his own immune system. He also had his spleen and lymph nodes removed as a child because his parents had been told they were enlarged. With this history now complete, the patient was appropriately referred to Cleveland Clinic’s allergy-immunology clinic for further evaluation. There, the diagnosis of common variable immunodeficiency (CVID) was made, which explained all of his lifelong ailments by one unifying diagnosis. The patient has since been started on monthly replacements of intravenous gamma globulin therapy.
The young doctor in the story, who was my co-resident at the time, knew I was going into allergy and immunology and told me about the patient. More than anything else, this case alerted me to the severity of the disease, and how under recognized it was. The patient had been showing symptoms since childhood, yet it had escaped diagnosis, with serious consequences to the patient and costs to the healthcare system.
CVID is one of the most common primary immunodeficiency syndromes. Its prevalence ranges from 1 in 25,000 to 50,000 and affects nearly every organ system, causing significant morbidity and mortality. Although it is about as prevalent as some leukemias, even specialists frequently fail to spot it. The average CVID patient goes 8-10 years from onset of classic symptoms until a diagnosis is made. These patients generally present between ages 20-40 but the condition can present at nearly any age. Immunoglobulins are vital antibodies made by our immune system to fight disease such as infections, autoimmunity, and malignancy. CVID patients commonly have a deficiency in IgG and/or IglA and IgM. They lack the ability to make antibody titers against both protein and polysaccharide vaccines. These features leave these patients very vulnerable to certain types of sinopulmonary infections, lymphomas, and autoimmune diseases.
CVID is just one of 150 primary immunodeficiency syndromes that occur at various stages of life. Of all the immunodeficiencies, those involving antibodies are most common and luckily they are less severe than some immunodeficiencies that involve T cells and B cells. IgA deficiency is the most common and affects approximately 1 in 500 people. It is also the mildest form of immunodeficiency and most patients live very full lives. They are, however, predisposed to more infections and more antibiotic use than their healthy counterparts. They are also at greater risk for autoimmune diseases such as celiac disease and have difficulty responding to certain vaccinations, like our patient in Cleveland.
New York State, where I practice, joined other states recently in instituting a newborn blood screen that can pick up those with one of the more deadly immunodeficiencies – Severe Combined Immunodeficiency. Thanks to this program, these newborns can get the emergent bone marrow transplants they need sooner and avoid problems down the line. From this program, it seems that even SCID is far more common than we initially thought. Through this program they have also identified other diseases early, such as DiGeorge Syndrome and a congenital leukemia.
The immune system is the most nimble, diverse, and complex organ we possess. Outside of immunodeficiency, the immune system is responsible for inflammation related to very prevalent conditions such as diabetes and heart disease. In fact, some of our patients with complement deficiencies are at risk of developing heart attacks as young as their 20s and 30s because their immune system is not able to clear atherosclerotic plaques that can clog their coronary arteries.
In every field of medicine from Cardiology, to Oncology to Gastroenterology to Neurosurgery, the immune system is being studied now for novel cures to benefit patients. Thus you can imagine what a detriment it is when this system is lacking or not functioning properly. The delay in diagnosis does not only adversely affect patients, but is a costly burden on our healthcare system. Improving both clinician awareness and patient awareness of these diseases can help patients avoid many complications throughout their lives. For the patient I mentioned, it could have saved his kidneys in the first place, and his chances of a transplant in the second. His dialysis alone will cost the healthcare system upwards of $60,000 per month. The price paid on the quality of his life is, sadly, immeasurable.
I will always be grateful to my colleague at Cleveland Clinic for telling me about this case. In this, you can see how much doctors are a function not only of what we are taught, but also the other doctors we meet along the way. As a physician practitioner, I find it very rewarding to treat and help any patient, but when patients have been lost in the medical system with multiple serious ailments throughout their lives, being the one to find the one unifying diagnosis provides special satisfaction. The patients I have seen in my first year of private practice can’t have the lost opportunities restored to them, but putting a name to something elusive gives them relief and peace of mind. Getting them on the appropriate, even life-saving treatments is a palpable joy for them and for me.
Usually their cases are also very complicated and they are much sicker than the typical allergy patient. They don’t always present in the same way, which makes each case a mystery of its own. For this reason it is also humbling as I realize how little we still know about immunology and how far we have to go.
Dr. Purvi Parikh is an adult and pediatric allergist and immunologist. She completed her fellowship training in allergy and immunology at Albert Einstein College of Medicine’s Montefiore medical center following her residency at the Cleveland Clinic and is board certified by the American Board Allergy and Immunology, as well as the American Board of Internal Medicine.
Dr. Parikh has published articles on allergy, asthma and immunodeficiency syndromes in the Annals of Allergy, Asthma and Immunology, The Journal of Gastrointestinal Cancer and is currently writing a chapter for an otorhinolaryngology textbook. Dr. Parikh has also presented research at various national and international meetings.
She is passionate about health policy and sits on the health and public policy committee for the American College of Physicians. She also is a board member and founder of the Share and Care Foundation’s young professional committee, which raises money for underprivileged women and children in India.
My son, Rick Atkins, born 5/2/1975, diagnosed at age 2 as Buckleys Syndrome, aka Hyper Ige, Jobs Syndrome, lived 30 years.
He was under the care of Dr. Finklestein of Long Beach Children’s Hospital and later Dr Stiehm and Dr Roberts at UCLA Medical Hospital. He had lots of allergies, rashes and frequent pneumonias, sometimes pseudomonas. Eventually his lungs, kidneys and heart gave out.
My question is, what kinds of improvements have been made in this field to help these people ?
Dear Diane,
First, I am very sorry to hear about the loss of your son. I cannot imagine what that was like for your family. I hope you can take some solace in knowing that the immunologists you named, especially Dr. Stiehm, are the foremost authorities and experts on immunodeficiency and thus your son was in excellent hands. Job’s syndrome as you know is a rare yet complex disease where people have very high levels of IgE or immunoglobulin E, eczematous rashes and are predisposed to many problems such as infections of the skin, lungs, malignancies, and brittle bones to name a few. There are two types – an autosomal dominant form and an autosomal recessive form depending on which gene (STAT 3 for dominant and DOCK 8 for recessive) is affected. I am not sure which type your son had but for the dominant form usually treatment is supportive by giving aggressive antibiotics when patients are ill, replacing antibodies if unable to respond to vaccines, and at times lung transplantation if it is warranted. Evidence for prophylactic treatments either with antibiotics or interferon gamma is still lacking but some practitioners will use it. In the recessive form of the disease, bone marrow transplantation can be helpful or curative but is not recommended for the autosomal dominant form. Many treatments come with risks too, especially in our immunocompromised patients, so a risk vs. benefit analysis is important on each patient.
Hopefully current research can guide us in terms of gene therapy and an eventual cure. We learn the most about immunology and these rare diseases from people like your son, so rest assured his life has made a larger impact than you may realize. Thank you for writing.
Dr. Purvi Parikh