One you may have missed

April 2008

A 17-year-old girl presented to our service for evaluation of immunodeficiency and assistance with treatment. During the next several weeks, her respiratory status continued to worsen despite routine therapies including assistance with pulmonary clearance and various intravenous antibiotics.

Eventually, the diseased middle and upper lobes of her right lung were removed due to progressive consolidation without an etiology, and cultures were positive for Mycobacterium avium complex (MAC). Because the diseased lung had been removed, she was not treated with anti-mycobacterials. However, about two months later, she developed a second pneumonia and persistent fevers. Lesions in her liver and her tibia were biopsied and grew M. avium as well. She responded well to a prolonged three-drug anti-mycobacterial regimen.

She first presented to her home hospital with bronchiolitis when she was 16 months old. At 4 years old, she developed abdominal swelling and was found to have multiple enlarged abdominal lymph nodes. Culture was positive for M. kansasii, and IV amikacin was added to a three-drug oral regimen with good response. Since that time, she has had many recurrences of pulmonary, lymph node and bone nontuberculous mycobacterial infections with isolates including M. kansasii, M. fortuitum and MAC (Figure 1).

Figure 1

She had been treated with combinations of anti-mycobacterials (including macrolides, rifampin, ethambutal, fluoroquinolones, amikacin and clofazamine) as well as a trial of granulocyte-macrophage colony–stimulating factor. However, whenever antimicrobials were discontinued or narrowed, recurrences or new mycobacterial infections occurred.

Her past medical history showed no recurrent infections or opportunistic infections other than mycobacteria. She had a right-eye hemangioma as an infant that was surgically removed. When she was 8 years old, she had a presumed stroke that was thought to be due to an infected embolus, but neither the source nor the organism was ever proven.

She has never been vaccinated. She has no family history of immunodeficiency, and her parents are not known to be related.

What is the most likely immune deficiency for this girl?

1. Cystic fibrosis
2. HIV
3. Interferon gamma receptor deficiency
4. Severe combined immunodeficiency (SCID)

Answer

The correct answer is (C) interferon gamma receptor deficiency. This girl was found to be a compound heterozygote, meaning that she carried two different mutations (one on each allele) in the interferon gamma receptor 1, the protein responsible for binding to interferon gamma.

Host control of mycobacterial and intracellular bacteria, such as Salmonella, is largely driven by the interferon (IFN) gamma/interleukin (IL) 12 pathway. Once the macrophage ingests mycobacteria or Salmonella, it secretes IL 12, which then activates T cells and natural killer cells through the IL 12 receptor leading to IFN gamma production and secretion. IFN gamma then binds to the IFN gamma receptor, which is a heterodimer of IFN gamma receptor 1 and IFN gamma receptor 2, eventually leading to signal transducer and activator of transcription 1 phosphorylation and transcription of the genes involved in bacterial killing. Disruption of multiple points along this pathway, as demonstrated by “X” in the figure, may result in recurrent mycobacterial and/or Salmonella infections.

There are two forms of IFN gamma receptor 1 deficiency: autosomal dominant and autosomal recessive. The dominant form is much milder, as there is some residual IFN gamma receptor activity. It typically presents at an older age, especially if the bacille Calmette-Guérin (BCG) vaccine is not given, and with more focal disease, such as nontuberculous mycobacterial osteomyelitis. Augmenting antimicrobial therapy with exogenous IFN gamma is often effective in controlling the dominant form of the disease. For those with the recessive form of the disease, presentation is usually within the first few years of life, as was seen in our patient, and there is typically more systemic disease, such as her concurrent liver, bone and lung disease. Treatment with exogenous IFN gamma is usually not helpful, and bone marrow transplantation should be considered in addition to multiple antimicrobials. As exemplified in this patient, other opportunistic infections are not usually seen, although there may be more trouble with viral infections such as cytomegalovirus as well as intracellular bacterial infections including Salmonella.

Pulmonary nontuberculous mycobacterial infection can occur with cystic fibrosis. This patient tested negative for cystic fibrosis as a young child during her first prolonged pulmonary infection. Nontuberculous mycobacterial infection typically occurs in the teenage years in this population but does not occur outside of the lung, making the course very different than for our patient. HIV should be considered in any individual presenting with recurrent or opportunistic infections, and our patient tested negative. However, with infection progressing to the point of disseminated MAC during several years, one would expect other manifestations such as recurrent bacterial, viral or fungal infections. Other than vaccine BCG, disseminated nontuberculous mycobacterial infections are typically not seen in SCID. Other opportunistic infections, such as Pneumocystis jiroveci pneumonia, viral infections and mucosal candidiasis, are common. Disseminated BCG is often observed in individuals with SCID who are born in countries administering this vaccine at birth.

The research for this patient was funded by NCI Contract N01-CO-12400.

For more information:

• Alexandra Freeman, MD, and Steve Holland, MD, both work for the Laboratory of Clinical Infectious Diseases, NIAID, NIH. Holland is chief of the laboratory.
• Doffinger R, Patel SY, Kumararatne DS. Host genetic factors and mycobacterial infections: lessons from single gene disorders affecting innate and adaptive immunity. Microbes and Infection. 2006;8:1141-1150.
• Dorman SE, Picard C, Lammas D, et al. Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet. 2004;364:2113-2121.