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Table of Contents
CASE REPORT
Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 27-29

A rare case of disseminated histoplasmosis with oral manifestations in a rheumatoid arthritis patient treated with rituximab: Diagnostic and management challenges – A review


Division of Rheumatology and Clinical Immunology, Medanta - The Medicity, Gurugram, Haryana, India

Date of Submission22-Jan-2020
Date of Acceptance19-Feb-2020
Date of Web Publication07-Jul-2020

Correspondence Address:
Dr. Shruti Bajad
Room No. 13, 4th Floor, Medanta - The Medicity, Gurugram, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AMJM.AMJM_5_20

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  Abstract 


Disseminated histoplasmosis happens to be a rare complication that rheumatologists come across in their clinical practice. Biologics, mainly tumor necrosis factor blockers, have been mentioned as one of the causative factors in invasive histoplasmosis, and there are few case reports to support that. However, rituximab use has not been reported with histoplasmosis infection frequently. The association of such novel biologic agents with serious infections such as histoplasmosis needs further exploration as timely management and intervention can be life-saving for the patient. We report about a 69-year-old female, diagnosed with rheumatoid arthritis, who was treated with rituximab and subsequently developed disseminated histoplasmosis. She was successfully managed with antifungals. Here, we discuss the latest evidence-based treatment modalities for such patients with special reference to rheumatoid patients on biologic therapy.

Keywords: Biologics, histoplasmosis, rheumatoid arthritis, rituximab


How to cite this article:
Bajad S, Durgarao Yadavalli J N, Tanna D, Ekbote G, Kazi W, Gupta R. A rare case of disseminated histoplasmosis with oral manifestations in a rheumatoid arthritis patient treated with rituximab: Diagnostic and management challenges – A review. Amrita J Med 2020;16:27-9

How to cite this URL:
Bajad S, Durgarao Yadavalli J N, Tanna D, Ekbote G, Kazi W, Gupta R. A rare case of disseminated histoplasmosis with oral manifestations in a rheumatoid arthritis patient treated with rituximab: Diagnostic and management challenges – A review. Amrita J Med [serial online] 2020 [cited 2020 Aug 8];16:27-9. Available from: http://www.ajmonline.org.in/text.asp?2020/16/1/27/289139




  Introduction Top


Rheumatoid arthritis (RA) patients have an underlying higher risk of opportunistic infections, partly due to the nature of the disease and partly due to immunosuppressive medication. Even subtle signs of illness should not be ignored. The patient should undergo appropriate evaluation according to the presenting clinical symptoms to look for differentials including infection. Here, we describe a case where the patient suffered from disseminated histoplasmosis postrituximab infusion on the background of seropositive erosive RA.


  Case Report Top


A 69-year-old female, a diagnosed case of anti-cyclic citrullinated peptide antibody positive erosive RA for 15 years with persistent disease activity despite being on varied doses of combination disease-modifying antirheumatic drugs (DMARDS), last dose – glucocorticoids (GCs) at 5 mg daily, methotrexate at 25 mg weekly, and leflunomide at 20 mg daily. Her history was unremarkable, and there were no comorbidities. She had a positive family history of RA. There was no history of travel to any endemic area of histoplasmosis.

Her complaints started with painless red eyes without any blurring of vision or discharge, nonitchy purpuric lesions over both upper limbs, anterior chest, and back. Furthermore, there were recurrent oral ulcers. Skin biopsy was suggestive of lymphocytic nonnecrotizing vasculitis. The patient was started on GCs in tapering doses and colchicine. She did not respond to the treatment, and subsequently, thalidomide was added for recurrent oral ulcers, to which also she showed a suboptimal response. Meanwhile, in view of persistently active RA, the patient was given injection rituximab 1 g. Later, the patient started having dysphagia to both solids and liquids, persistent oral ulcers along with tongue enlargement. She had a weight loss of 5 kg over 3 months, but other systemic manifestations were absent.

At the time of presentation to the hospital, she was febrile and appeared distressed. There was right supraclavicular lymphadenopathy along with angular cheilitis and multiple oral ulcerations. The tongue was grossly enlarged with furrowing and on palpation was hard and indurated. Her basic investigations were normal except for erythrocyte sedimentation rate – 58 mm/h, C-reactive protein – 148.1 mg/dL, and albumin – 2.96 g/dL. The autoimmune panel, including antinuclear antibodies and ANCA, were negative, and chest X-ray was normal. In view of these findings, her methotrexate was stopped, GC dose was decreased, and hydroxychloroquine was continued. Due to dysphagia, feeding was initiated with Ryle's tube. Magnetic resonance imaging of the brain, face, and orbits showed ill-defined short-tau inversion recovery hyperintense signal showing diffuse contrast-enhancement intrinsic muscles of the tongue on either side of midline suggestive of probable inflammatory etiology without the involvement of mylohyoid or floor of the tongue. Later, tongue biopsy was done which showed completely ulcerated epithelium with sheets of macrophages, filled with tiny, capsulated organisms, surrounding a mixed inflammatory infiltrate. These organisms were Grocott's Methenamine Silver and periodic acid-Schiff positive suggestive of tongue histoplasmosis [Figure 1] and [Figure 2].
Figure 1: Multiple ulcers over the dorsum of the tongue

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Figure 2: (a) Periodic acid–Schiff stain showing small round-to-oval basophilic bodies surrounded by a clear halo characteristic of histoplasmosis. (b) Grocott Methenamine Silver stain showing small round-to-oval basophilic bodies surrounded by a clear halo characteristic of histoplasmosis

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Contrast-enhanced computed tomography of the chest and abdomen showed few ill-defined peribronchial and subpleural opacities in both lungs suggestive of infective etiology. Left adrenal was bulky. Thus, the diagnosis of disseminated histoplasmosis was made. Her DMARDS were discontinued, and she was started on liposomal amphotericin B. Her oral and cutaneous lesions showed signs of improvement, and tongue size also decreased. After 2 weeks, she was shifted to itraconazole. Dysphagia improved, and her Ryle's tube was removed, and oral feeds were started slowly. The patient was closely followed during the recovery course, and she exhibited an encouraging response to the treatment.


  Discussion Top


RA patients often have dysfunctional immunity owing to the disease itself and concomitant use of immunosuppressants including steroids. Thus, the incidence of infections has been reported as high as two times as compared to the normal population.[1] Although novel treatment strategies such as tumor necrosis factor (TNF) blockers have been quite useful in disease control in RA patients, serious infections have noted with their use, with the prevalence of 6%–18% and an incidence of 6/100 patient years.[2],[3]

There is no denial from the recent controlled trial that rituximab has been successfully used in refractory RA.[4] An increased incidence of infections in patients with lymphomas and RA being treated with rituximab has been reported.[5],[6] Pooled data from 356 patients who received rituximab monotherapy showed that the incidence rate of infectious events was 30% out of which 1% were serious fungal infections.[7]

Histoplasmosis is an opportunistic fungal infection which is frequently caused by the inhalation of Histoplasma capsulatum microconidia, endemic to the Ohio and Mississippi river valleys in Central America, the USA, and certain parts of parts of southern Europe, Asia, and Africa.[8] It is a dimorphic fungus having worldwide distribution and spread by the inhalational route. In India, most histoplasmosis cases have been reported from the Gangetic delta belt.[9]

The first reported case of histoplasmosis was done by Panja and Sen in India in 1959. It is considered endemic in certain Indian states, namely West Bengal, from where the prevalence of skin positivity of 9.4% to histoplasmin antigen has been reported. Few sporadic case reports from other parts of India have been reported as well.[10]

An optimal host defense against H. capsulatum requires interaction between macrophages and T-cells. Thus, immunocompromised people are more susceptible to this infection. Histoplasmosis may be challenging to diagnose in immunocompromised patients. The diagnosis can be made by the visualization of yeast on histopathology, isolation of the organism in culture, or detection of histoplasmosis antigens in body fluids. Histopathology and culture are the gold standards for the diagnosis. H. capsulatum can take at least 4 weeks to be detected in cultures, and DNA probes may be used to assist with the diagnosis. Antigen testing is noninvasive, and combining serum and urine antigen testing can increase the sensitivity. The sensitivity of the antigen test is higher in more severe or disseminated infections. Serology may also help to make the diagnosis, but it may not be reliable in patients who cannot produce antibodies due to immune defects. The disease should be suspected in patients with risk factors such as HIV-positive patients, extremes of age, immunosuppressive medications, exposure-related factors with clinical features such as fever, fatigue, weight loss, lymphadenopathy, organ-related manifestations, and imaging features.[11],[12]

There have been reports in the literature stating histoplasmosis infection with TNF blockers; but to the best of our knowledge, we report first case of postrituximab oral histoplasmosis in a RA patient residing in nonendemic areas. There have been sporadic cases of disseminated histoplasmosis after abatacept and use of TNF inhibitors.[13],[14] The most recent IDSA clinical practice guidelines on the management of patients with histoplasmosis recommend 12 months of azole treatment for disseminated disease. More severe infections require treatment with amphotericin B. Itraconazole treatment should be continued until clinical and laboratory findings normalize. Life-long itraconazole therapy would be necessitated for patients who require continued immunosuppressive therapy which is likely in cases such as RA. Furthermore, a patient needing long-term immunosuppression may need 2 years of azole prophylaxis before the initiation of immunosuppression in endemic areas.[15]


  Conclusion Top


Patients suffering from autoimmune disorders and especially those on higher immunosuppression are at a higher risk for rare infections and one should keep their eyes open to look for uncommon causes and try to catch them at earliest.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Doran MF, Crowson CS, Pond GR, O'Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: A population-based study. Arthritis Rheum 2002;46:2287-93.  Back to cited text no. 1
    
2.
Kroesen S, Widmer AF, Tyndall A, Hasler P. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology (Oxford) 2003;42:617-21.  Back to cited text no. 2
    
3.
Listing J, Strangfeld A, Kary S, Rau R, von Hinueber U, Stoyanova-Scholz M, et al. Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 2005;52:3403-12.  Back to cited text no. 3
    
4.
Pescovitz MD. Rituximab, an anti-cd20 monoclonal antibody: History and mechanism of action. Am J Transplant 2006;6:859-66.  Back to cited text no. 4
    
5.
Aksoy S, Dizdar O, Hayran M, Harputluoǧlu H. Infectious complications of rituximab in patients with lymphoma during maintenance therapy: A systematic review and meta-analysis. Leuk Lymphoma 2009;50:357-65.  Back to cited text no. 5
    
6.
Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Sieper J, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2007. Ann Rheum Dis 2007;66 Suppl 3:iii2-22.  Back to cited text no. 6
    
7.
Kimby E. Tolerability and safety of rituximab (MabThera). Cancer Treat Rev 2005;31:456-73.  Back to cited text no. 7
    
8.
Kauffman CA. Histoplasmosis: A clinical and laboratory update. Clin Microbiol Rev 2007;20:115-32.  Back to cited text no. 8
    
9.
Subramanian S, Abraham OC, Rupali P, Zachariah A, Mathews MS, Mathai D. Disseminated histoplasmosis. J Assoc Physicians India 2005;53:185-9.  Back to cited text no. 9
    
10.
Joshi SA, Kagal AS, Bharadwaj RS, Kulkarni SS, Jadhav MV. Disseminated histoplamosis. Indian J Med Microbiol 2006;24:297-8.  Back to cited text no. 10
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11.
Wheat LJ, Azar MM, Bahr NC, Spec A, Relich RF, Hage C. Histoplasmosis. Infect Dis Clin North Am 2016;30:207-27.  Back to cited text no. 11
    
12.
Azar MM, Hage CA. Clinical perspectives in the diagnosis and management of histoplasmosis. Clin Chest Med 2017;38:403-15.  Back to cited text no. 12
    
13.
Jain N, Doyon JB, Lazarus JE, Schaefer IM, Johncilla ME, Agoston AT, et al. A case of disseminated histoplasmosis in a patient with rheumatoid arthritis on abatacept. J Gen Intern Med 2018;33:769-72.  Back to cited text no. 13
    
14.
Gundacker ND, Baddley JW. Fungal Infections in the Era of Biologic Therapies. Curr Clin Micro Rpt 2015;2:76.  Back to cited text no. 14
    
15.
Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25.  Back to cited text no. 15
    


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