13-year old Ciara (name changed) lived in Mauritius. She had been suffering from repeated skin rashes and kidney and lung ailments since she was 2 years old and was diagnosed with systemic lupus erythematosus and class IV lupus nephritis. She was being symptomatically treated for her skin conditions, nephritis, as well as pulmonary hypertension. In spite of being treated with 12 different medications, including steroids, immunosuppressants as well as anti-hypertension pills, her condition was not improving. She had undergone multiple kidney biopsies which showed no improvement even after the medication. More recently, she had started facing a stiffening of her lower limbs, that was affecting her ability to walk. Ciara’s family were desperately trying to get appropriate treatment for her when they brought her to Bangalore from Mauritius in search of a paediatric immunologist. Here they were fortunate to consult the only Pediatric Immunologist in Bangalore, Dr Sagar Bhattad, at Aster CMI Hospital.
After reviewing the case history, Dr Bhattad immediately recognized that, while the case was correctly diagnosed as systemic lupus erythematosus, this was in an unusual form. Systemic lupus erythematosus symptoms typically do not kick in until 8-10 years of age. However, in Ciara’s case, she had been suffering since she was 2. He concluded that there must be other underlying causes that needed to be identified for appropriate treatment. It so happened that Dr Bhattad had previously encountered 2 similar cases during his post-graduate training and had in fact written his MD thesis on the topic. This is why he was almost sure that the underlying reason was some form of primary immunodeficiency disease.
Primary immunodeficiency diseases are disorders in which the immune system is weakened allowing for infections and other health issues. Typically, symptoms start during infancy and often worsen progressively. Multiple organs may be involved and it can eventually involve even the neurological system, often resulting in irreversible neurological damage. Majority of primary immunodeficiency diseases are inherited and caused due to mutations in the genes encoding for key proteins involved in maintaining immunity. Dr Bhattad, therefore, recommended genetic testing to confirm his suspicion and identify the cause of Ciara’s condition.
It took 6 weeks for the results to come back, but it was worth the wait. Genetic test results confirmed that Ciara was suffering from a very rare complement deficiency, caused due to a homozygous mutation on exon 2 of the Complement Component 1q or C1q gene. C1q is part of a protein complex C1 that plays a key role in the innate immune system. C1 binds to antibody-antigen complexes to trigger the complement system during an infection, resulting in activating phagocytosis, inflammation, and subsequent lysis of bacteria. Thus, C1q forms an integral part of the immune system and a deficiency in functional C1q has been associated with glomerulonephritis, recurrent skin lesions, systemic lupus erythematosus (SLE) or SLE-like diseases. Ciara had a mutation that resulted in the loss of C1q protein, which explained her symptoms.
While C1q deficiency is rare and treatment options are limited, a bone marrow transplant was done for this disorder for the first time in the UK in 2014 and fewer than 10 successful bone marrow transplant cases have been carried out worldwide since. Bone marrow transplantation comes with its own complications, the primary one being the availability of an HLA matched donor for the bone marrow. Thankfully, Ciara’s father turned out to be a perfect match and Dr Bhattad proceeded to plan and collaborate with Drs Stalin Ramprakash and CP Raghuram, bone marrow transplant experts at Aster CMI Hospital, to perform this transplant.
Ciara was admitted to the hospital about 2 weeks prior to the transplantation so that all tests could be carried out and she could be closely monitored. She was again kept in the hospital for 2-3 weeks after the transplant to ensure that there were no adverse effects and she did not get any infections immediately after the transplantation.
Many factors contribute to the success of transplantation. HLA donor matching and the underlying condition of the patient play major roles in success, and the patient must be closely monitored post the transfer of the bone marrow. These factors, along with the age and weight of the patient as well as kidney involvement, contribute to a decision on the medical treatment that follows transplantation. Due to Ciara’s kidney and lung involvement, medications were carefully planned. Complications were also anticipated as preexisting organ damage increases the risk of complications during and after the transplant, making the technique complex and one requiring meticulous planning.
Ciara underwent successful transplantation and is doing very well so far. She will need to be closely monitored for the next 3 months and be on immunosuppressants for the next 6 months. Dr Bhattad calls it the ‘100 day’ period post-transplantation when there is a high risk of infection and chances of transplant rejection. However, after the ‘100 day’ period, the new bone marrow starts to function completely, and the immunosuppressant doses can be decreased.
Aster CMI in Bangalore has a dedicated Immunology and Bone Marrow Transplant Unit (BMT) which encounters many children with immune deficiencies, as in Ciara’s case. Dr Bhattad reiterates that “Primary immune deficiencies are actually quite common, but often undiagnosed. It should particularly be considered in case of repeated infections and multiple hospitalizations, ideally before irreversible organ damage occurs. Awareness of such deficiencies is particularly important, especially now that the required diagnostics and therapeutics are available. Eyes see only what the mind knows.”
Only when doctors start looking for these conditions in their patients will they be able to make an early diagnosis. Increasing awareness of these diseases is the need of the hour.