Abstract
Background
X-linked agammaglobulinemia is a primary immunodeficiency associated with mutations in the B cell tyrosine kinase (BTK) gene leading to failure in B cell maturation and defective antibody production. Campylobacter and closely related Helicobacter species can cause persistent bacteremia, enteritis and cellulitis in patients with XLA and are difficult to diagnose and eradicate. In this context, detection of circulating microbial cell-free DNA (mcfDNA) by next-generation sequencing (NGS) can be used to identify infectious agents in susceptible immunocompromised hosts.
Methods
We report 4-year-old fraternal twins with XLA presenting with disparate clinical manifestations due to C. upsaliensis and coinfection with C. upsaliensis and H. canis respectively.
Results
Patient #1 was diagnosed with XLA at 11 months-old and was started on weekly immunoglobulin replacement. At 2.5 yo he developed recurrent fever, abdominal pain and diarrhea. Endoscopy/colonoscopy revealed focal ileocolitis without ulceration or granulomas. Stool infectious workup, including bacterial stool cultures, was negative. At 3 yo he developed gram- rod bacteremia that was not further identified but successfully treated with ceftriaxone. He presented 2 months later with fever and diarrhea; blood cultures were negative, but stool culture grew C. jejuni. His symptoms recrudesced after two months and he was treated for presumed recurrent Campylobacter infection. Intermittent fevers and diarrhea recurred, and repeat stool culture grew C. upsaliensis identified by MALDI-TOF resulting in a 3-month course of azithromycin. Stool PCR remained positive for Campylobacter species after one month of therapy. Fever and diarrhea recurred after completion of therapy and stool culture again grew C. upsaliensis but sensitivities could not be obtained. McfDNA testing confirmed C. upsaliensis and therapy with ertapenem, ciprofloxacin, amoxicillin and doxycycline was initiated. He remained symptom free three months into therapy.
Patient #2 was diagnosed with XLA at 1 yo and started weekly immunoglobulin replacement. At 3.5 yo he developed fever, erythema nodosum (EN) and arthritis. Given his twin’s diagnosis of Campylobacter enteritis with likely bacteremia, a presumptive diagnosis of Campylobacter related reactive arthritis and EN was made. Treatment with Naprosyn and 14 days of azithromycin failed to prevent the return of EN post therapy. He had multiple courses of azithromycin each followed by return of EN rash. Following completion of therapy, he presented with high fevers, worsening rash, leukocytosis and elevated ESR. Blood and stool cultures were obtained and returned negative. Despite completion of a 3 month course of azithromycin, stool PCR remained positive for Campylobacter species and his symptoms persisted. The recrudescence of fevers and worsening rash 2 months after completion of therapy prompted repeat blood and stool cultures that returned negative. McfDNA testing was obtained in that context and identified Helicobacter canis and Campylobacter upsaliensis. Treatment with ertapenem, ciprofloxacin, amoxicillin and doxycycline was initiated and he remained symptom free three months into therapy.
Conclusions
Physicians should be aware of the varied presentations of chronic Campylobacter and Helicobacter infection in XLA patients. Plasma NGS for circulating mcfDNA in immunocompromised patients offers a rapid, non-invasive means of detecting these fastidious organisms that can be difficult to diagnose using more conventional means.
Old questions, new tools: does next-generation sequencing hold the key to unraveling intestinal B-cell responses?