Reintroduction of immunosuppressive medications in pediatric rheumatology patients with histoplasmosis: a case series

The often-chronic nature of fungal and rheumatic therapies make selecting compatible medications critical. In severe DH, initial therapy may begin with intravenous amphotericin transitioning to oral itraconazole, with a total antifungal duration of at least 12 months [7, 21]. Itraconazole is an effective antifungal, but it potently inhibits the CYP3A4 pathway, thereby decreasing steroid metabolism [8, 9, 11, 12]. Nevertheless, adjunctive corticosteroids may still be indicated for fungal infections and other inflammatory states, like rheumatic flares [1, 7, 8]. Furthermore, systemic or local corticosteroid use by itself can also cause iatrogenic Cushing’s syndrome, although drug interactions increase risk [9, 28, 29]. Shortly following IASIs, 44 % of our cRD developed non-allergic adverse reactions with prominent Cushingoid features. To our knowledge, this is the first description of Cushing’s syndrome in cRD undergoing itraconazole treatment following IASI and systemic steroids. However, previous reports associating itraconazole and steroid therapy with hypothalamic-pituitary-adrenal (HPA) axis suppression and, more infrequently, overt Cushing’s syndrome have been published, usually for patients with cystic fibrosis taking inhaled steroids [9, 10, 13, 15].

The somewhat surprisingly high fraction of patients presenting with overt Cushingoid features in our report could perhaps be due to differences in systemic steroid levels, route of steroid administration, type of steroid, underlying disease, and/or drug interactions. For example, a study comparing the effects of itraconazole on a single dose of methylprednisolone versus prednisone in healthy volunteers indicated prednisone’s pharmacokinetics were unaffected while methylprednisolone concentration increased [12]. In our limited cohort, is difficult to draw firm conclusions about what/if combinations of corticosteroids and itraconazole place patients at greatest risk for HPA axis-related syndromes. High dose steroidal bursts combined with IASI perhaps contribute, but more research is needed, for example, to determine if route of steroid administration matters and if underlying comorbidities affect risk. Regardless, there is an urgency to determine optimal strategies of IM usage in the setting of concurrent histoplasmosis that facilitate histoplasmosis recovery and rheumatic disease management. Moreover, perhaps HPA axis monitoring should be considered in patients needing itraconazole and steroids [13].

Acute DH develops in about 1 of every 2000 acute histoplasmosis cases, and most acute DH occurs in immunosuppressed patients [30]. Markedly, immunocompromised patients (e.g., AIDS) have a 10-fold increased risk for developing DH compared to immunocompetent persons, and DH mortality rates in severely immunocompromised patients can reach 30 % [31‐33]. Chu et al. noted that in 111 pediatric cases of histoplasmosis requiring hospitalization, 32 % of these patients were immunocompromised and/or had a comorbidity with an overall pediatric mortality of 5 % [33]. Likewise, a review of 73 pediatric histoplasmosis cases by Ouellette et al. reported immunocompromised children had a 2.5X higher rate (56 % vs. 21 %) of developing DH [34]. In line with these findings, in our series most (66 %) PH cases were in patients without prior IM, while all patients with DH were receiving prior combination or DMARD therapy.

Studies assessing post-histoplasmosis care in patients experiencing TNFai complicated by histoplasmosis are limited [19, 20, 22, 23]. Notably, Vergidis et al. described outcomes of 98 patients with various autoimmune diseases diagnosed with histoplasmosis, wherein 3/98 patients continued non-combination TNFai, 11/58 patients continued DMARDs, and 13/23 patients continued corticosteroids. The 3 histoplasmosis cases maintaining TNFai, which is not the standard of care, were described as “mild” and all patients achieved remission after 6–10 months of itraconazole. During follow-up (median 32 months), 2/25 patients resuming TNFai (and 1/49 who had not) developed histoplasmosis recurrence with 1 fatality (taking TNFai). Follow-up data were unavailable for the other patients, and resumption information on DMARDs and corticosteroids was not reported [22]. Furthermore, after TNFai was held in 14/15 adult patients with RA, 4 resumed them at least 5 months FHD. The patient continuing TNFai, whose lung biopsy showed inactive disease, did well, while one patient who resumed TNFai developed clinical recurrence, permanently halted it, and recovered [23]. In our case series, persistent rheumatic disease activity led to resumption of biologics and non-HCQ DMARDs in 1 cSLE and 6 JIA patients FHD. However, no patients were restarted on TNFai due to safety concerns even if histoplasmosis disease was mild. One JIA patient did not require IM and the patient with MCTD proceeded on their pre-histoplasmosis regimen of HCQ and maintenance steroids. The 3 patients resuming MTX had favorable outcomes. HCQ was continued without issue for the cSLE and MCTD patients, and HCQ was an alternative (or additive) treatment option for JIA patients. Unlike some evidence on MTX, HCQ does not increase infection risk, but all 3 patients starting either medicine cleared their histoplasmosis without recurrence.

Considering timing of biologic reinitiation FHD, 5 cRD began the non-TNFai ABA before [2] or following [3] HC, while the initiations of tocilizumab or ustekinumab were only after HC. Although no patients were receiving ABA, tocilizumab, or ustekinumab prior to their histoplasmosis diagnosis, all 4 cRD beginning them have remained free of histoplasmosis recurrence and neither patient starting ABA while still antigen positive experienced worsening of their histoplasmosis. Moreover, 1 of these 2 ABA patients has achieved HC to date. Despite the small numbers, the use of ABA in these cRD resulted in good rheumatologic outcomes without exacerbating the infection, suggesting that ABA may be an option for treating rheumatic patients with histoplasmosis. The inability to support some cRD without higher tier medications underscores the need to promote infection safety while controlling rheumatic disease. For example, considering lower risk (non-TNFai) biologics, like ABA, for patients in endemic fungal areas such as the Ohio and Mississippi River Valleys where histoplasmosis is the most frequent TNFai-associated endemic fungal infection [6]. While screening for histoplasmosis prior to beginning biologics is not routinely recommended, nevertheless physicians prescribing IM must be aware of histoplasmosis presentations and risk factors [1].