AOSD is a diagnosis of exclusion. The patient had few atypical features of AOSD, namely, a pruritic rash that did not parallel the febrile episodes and absence of typical twice a day fever spikes. However, the presence of prolonged fever, sore-throat, large joint arthritis, lymphadenopathy, hepatomegaly, elevated inflammatory markers including ferritin, neutrophil leukocytosis, elevated liver enzymes, negative antinuclear antibodies and rheumatoid factor along with exclusion of neoplasms (imaging and histology), other infections (imaging and culture) and autoimmune disorders (negative autoantibody profile) confirmed the diagnosis of AOSD. The systemic score was 4.0 predicting favourable outcome [3].
Isolation of the organism by culture is the gold standard for diagnosing melioidosis. Specificity and positive predictive value of melioidosis antibody testing are modest (68.7–91.3% sensitivity, 17.5–40.9% positive predictive value) and depends on assay methods [4]. False positive results in melioidosis serology have been reported in disease endemic areas [4,5,6]. However, progressive rise and subsequent decline in antibody titre makes it unlikely to be due to background exposure in our patient.
The mechanism by which the patient produced a serological response against B pseudomallei can be three-fold. First, this may have been a false positive result due to antibodies produced by activated polyclonal B cells in AOSD. Second, onset of AOSD would have led to reactivation of latent melioidosis infection. Third, meliodosis infection would have triggered an immune dysregulation and precipitated the onset of AOSD.
Autoimmune disorders are characterized by production of autoantibodies that target self-antigens. It is possible that these antibodies cross react with microbial antigens and produce a false positive result when tested for microbial antibodies. Examples include false positive HIV antibodies in systemic lupus erythematosus (SLE), discoid lupus and mixed connective tissue disease [7], measles antibodies in SLE and chronic active hepatitis [8] and falsely positive fluorescent treponemal antibody absorption in SLE [9, 10].
However, unlike many other autoimmune disorders, AOSD is an auto-inflammatory disease characterized by dysregulation of innate immune system and over expression of chemokines such as IL-1, IL-6 and IL-17 [11]. It is not associated with autoantibody production, although rare cases of AOSD with positive ANA [12] and positive anti-golgi antibodies [13] have been reported. Dysregulated innate system and over-expressed chemokines can activate memory B cells previously sensitized against melioidosis to produce antibodies. IL-6, a key pathogenic mediator in AOSD [11], promotes polyclonal B cell maturation to plasma cells [14] leading to hypergammaglobulinaemia. It is possible that in our patient, plasma cells producing melioidosis antibodies were activated. A report of false positive Treponema pallidum haemagglutination following treatment with intravenous immunoglobulin therapy, provides further evidence to the possibility of having specific antibodies in a non-specific hypergammaglobulinaemic state [15].
Alternatively, the patient may have had latent melioidosis infection which reactivated with the onset of AOSD and dysregulation of innate immune system which would have held the latent infection quiescent. Aggressive and prolonged antibiotics would have controlled the infection while fever persisted due to AOSD that remained untreated. Although classical presentation of melioidosis is with pneumonia or multiple abscesses, altered innate system would have blunted the host’s ability to mount a pyogenic immune response and abscess formation.
Finally, primary meliodosis infection in this patient would have triggered an innate immune system dysregulation precipitating the auto-inflammatory response resulting in AOSD. Antibiotic therapy would have treated the infection. In fact possible infectious aetiologies have been proposed in AOSD including several viruses and bacteria including Mycoplasma pneumonia, Chlamydia pneumonia, Brucella abortus, Borrelia burgdorferi, Bartonella henslae and Yersinia enterocolitica [15]. B. pseudomallei has not been described before as a possible aetiology of AOSD. However, other similar gram negative bacteria have potentially been linked to causation of AOSD, a feature B pseudomallei may also share. In fact, Burkholderia species have been causatively linked to a cutaneous vasculitis [16].
Considering the parallel changes of ferritin and melioidosis antibody titre (Fig. 1), it is unlikely that infection preceded and triggered the onset of AOSD. Reactivation of melioidosis with onset of AOSD also appears less likely given the poor response the antibiotics and prompt response to steroids. False positive rise of melioid antibodies therefore remains the most likely explanation for this observation.
