By Dean L. Winslow, MD, FACP, FIDSA, FPIDS

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: A previously healthy 4-year-old boy with no prior serious illnesses was diagnosed with disseminated coccidioidomycosis with prominent skin and bone involvement. Despite treatment with liposomal amphotericin B, antifungal azoles, and surgical debridement, the patient developed progressive disease. Treatment with interferon-gamma slowed disease progression, and later treatment with interleukin-4 and interleukin-13 blockade induced remission of his infection.

SOURCE: Tsai M, Thauland TJ, Huang AY, et al. Disseminated coccidioidomycosis treated with interferon-γ and dupilumab. N Engl J Med 2020;382:2337-2343.

A previously healthy 4-year-old boy who lived in an area endemic for coccidioidomycosis presented with prominent skin and bone involvement due to disseminated coccidioidomycosis. The patient had clinical and serological evidence of disease progression despite treatment with liposomal amphotericin B, various azoles, and surgical debridement of bony lesions. The investigators carefully evaluated the child’s immune system and found no clear genetic abnormalities to explain the child’s severe, progressive disease.

Like most patients with disseminated coccidioido-mycosis, the child exhibited no genomic evidence of any known, rare immune disease. However, comprehensive immunologic testing using functional assays showed exaggerated production of interleukin-4 and reduced production of interferon-gamma. Additional studies showed that in functional assays, it was demonstrated that the child’s cells produced aberrantly high levels of the short, nonfunctional isoform of IL12RB1, leading to impaired interleukin-12 signaling and type 1 immunity. Treatment of the child with interferon-gamma appeared to slow, but not halt, disease progression. The addition of interleukin-4 and interleukin-13 blockade with dupilumab resulted in rapid resolution of the child’s clinical symptoms.

COMMENTARY

I trained on the East Coast and in Louisiana, so I saw a lot of histoplasmosis and some blastomycosis. Then I practiced in Delaware during the first half of my career and saw only one case of coccidioidomycosis in a returning traveler during those years. When I returned to academic medicine in 2003 at our county hospital in San Jose, CA, (where Dr. David Stevens and his protégé, Dr. Larry Mirels, had established a center of excellence for the treatment of coccidioidomycosis years before), I had the privilege of helping them care for many complicated and uncomplicated patients over the next 10 years. I quickly gained a lot of respect for this disease. Since I was trained in both adult and pediatric infectious disease, I attended regularly on the inpatient pediatric infectious disease consult service. I am still heartbroken when I remember the case of a beautiful 4-year-old boy from the San Francisco Bay Area who traveled to Phoenix for Christmas with his family and returned severely ill with disseminated coccidioidomycosis and central nervous system (CNS) involvement. The diagnosis was somewhat delayed but eventually was made at an outside hospital, and the patient was transferred to our hospital for higher-level care. Working with our pediatric colleagues, we treated him aggressively with liposomal amphotericin B, fluconazole, and even intrathecal amphotericin B. His course was complicated by stroke and significant hydrocephalus. I recommended a ventricular-peritoneal shunt be placed, and sadly, his surgery was complicated by perioperative cerebral hemorrhage, and he was placed on comfort care and died.

With my colleagues at Stanford, currently I am involved in the management of three adult patients with longstanding complicated CNS coccidioidomycosis. Although it has been known for some time that patients with disseminated coccidioidomycosis seem to have a disproportionate Th2 > Th1 response to C. immitis, the genetic basis for this still is not entirely clear in most patients. Dr. Steve Holland and his colleagues at the National Institute of Allergy and Infectious Diseases currently are conducting a large multicenter study collecting plasma and cells from patients with disseminated coccidioidomycosis to try to better characterize the subtle immune deficits these patients have to explain their susceptibility to disseminated disease. We have sent specimens on our patients to the National Institutes of Health, but no results have been published yet.

The use of interferon-gamma plus dupilumab dramatically helped the child described in this case report, but clearly larger studies with immunomodulators (tailored to the functional defects found in each patient) need to be performed since it is clear that this particular treatment will not necessarily help all patients with disseminated coccidioidomycosis.