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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2019  |  Volume : 30  |  Issue : 5  |  Page : 1179-1183
Cryptococcosis masquerading as disseminated tuberculosis in a patient on chronic hemodialysis

1 Department of Nephrology, Sir Gangaram Hospital, New Delhi, India
2 Department of Pathology, Sir Gangaram Hospital, New Delhi, India

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Date of Submission11-Sep-2018
Date of Acceptance10-Oct-2018
Date of Web Publication4-Nov-2019


Chronic hemodialysis (HD) recipients are nearly ten times more prone to fungal infections compared to the general population. However, infections such as cryptococcosis usually affect immunocompromised patients, unusual in otherwise immunocompetent patients. Here, we describe a unique case of cryptococcosis in a human immunodeficiency virus negative end-stage renal disease (ESRD) patient. A 26-year-old female patient, diagnosed with ESRD, on maintenance HD for the past six months, presented with pyrexia of unknown origin associated with cervical lymphadenopathy, biopsy of which showed granulomatous inflammation. The patient was initiated on anti-tubercular treatment but did not respond to treatment. A month later, she developed skin lesions; biopsy and culture from scrapings of the lesions were suggestive of infection with Cryptococcus neoformans. She responded to antifungal therapy very well, with a resolution of fever and skin lesions within a month. This is a unique case report, in which cryptococcosis mimicked tuberculosis in an otherwise immunocompetent patient with ESRD.

How to cite this article:
Meena P, Gupta A, Gaur L, Shingada A, Gupta P, Bhargava V, Rana DS. Cryptococcosis masquerading as disseminated tuberculosis in a patient on chronic hemodialysis. Saudi J Kidney Dis Transpl 2019;30:1179-83

How to cite this URL:
Meena P, Gupta A, Gaur L, Shingada A, Gupta P, Bhargava V, Rana DS. Cryptococcosis masquerading as disseminated tuberculosis in a patient on chronic hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2021 Sep 25];30:1179-83. Available from: https://www.sjkdt.org/text.asp?2019/30/5/1179/270278

   Introduction Top

End-stage renal disease (ESRD) patients worldwide routinely undergo hemodialysis (HD). HD is associated with disturbances in both innate and adaptive immunity leading to increased susceptibility to infections.[1] Infections constitute a major cause of morbidity and death in HD patients, second only to cardiovascular diseases. In addition to bacterial and viral infections, fungal infections are becoming increasingly frequent among HD patients. Chronic HD recipients are nearly 10 times more prone for fungal infections compared to general population.[2] Fungal infections like cryptococcosis usually affect immunocompromised patients like acquired immunodeficiency syndrome, and unusual in otherwise immunocompetent patients.[3] Here, we describe a unique case of cryptococcosis in a human immunodeficiency virus negative ESRD patient, with a rare manifestation.

   Case Report Top

Informed consent was obtained from the patient before presenting the report.

A 26-year-old female patient, who was diagnosed with chronic kidney disease of unknown etiology (CKDu) six months back, was on regular maintenance HD for five months, from our hospital. She was admitted to the hospital with chief complaints of fever, decreased appetite, and malaise for one month. Fever was initially intermittent, low grade, however, progressed to high grade, daily fever spike of peak 102°F. She gave a history of significant weight loss of 4 kg in a period of one month. There was no history of cough, expectoration, pain in abdomen, burning micturition, oral ulcers, headache, or altered sensorium. On examination, she was found to have bilateral cervical lymphadenopathy involving the deep cervical lymph nodes, which were discrete, nontender, firm in consistency, approximately 2 cm × 2 cm in diameter. Mild pallor and bilateral pedal edema were also noted, but there was no icterus, cyanosis, or clubbing. AV fistula site on the left forearm was healthy and patent. On systemic examination, no other abnormality was detected.

Previous work up for CKD etiology was reviewed, including markers for vasculitic diseases (ANA, dsDNA, ANCA, PANCA) which were negative. Her kidney biopsy done five months back was suggestive of diffuse glomerulosclerosis and chronic interstitial fibrosis, without accompanying endocapillary proliferation or fibrinoid necrosis. Her hematological investigations were within the normal limits, except low hemoglobin level of 9.2 g/dL, and raised ESR of 98 mm in the 1st h. Her serum CRP was also raised 340 mg/L. Her creatinine was 497 μmol/L, blood urea nitrogen 48.7 mmol/L, serum potassium 4.2 mmol/L, and serum albumin was 3.2 g/dL. Serology for HBsAg, anti-HCV antibody, and HIV was negative. Her serum glucose level and HbA1c were normal. Chest X-ray was suggestive of left-sided pleural effusion. Pleural fluid analysis revealed exudative nature, with protein being 3.8 g/dL, glucose 62 mg/dL, and normal ADA level 32 U/L. Pleural fluid cytology revealed total cell count 50 cells/mm3 with predominantly lymphocytes. Blood, urine, and pleural fluid culture were sterile. Mantoux tuberculin test and Interferon Gamma Release Assay (QuantiFERON TB Gold), both were positive. Excisional biopsy of cervical lymph node was done which was suggestive of granulomatous inflammation; however, Ziehl–Neelsen staining for acid-fast bacilli was negative. With the clinical and histopathological findings, a diagnosis of probable tubercular lymphadenitis was made and she was initiated on antitubercular drugs (ATT) (rifampicin, isoniazid, ethambutol, and pyrazinamide in renal modified dose) and was discharged. Patient was on regular follow-up. During the next four weeks of follow-up, she did not show any significant improvement. She was again readmitted due to persistent fever and the absence of weight gain. She also developed skin lesions over her left leg which gradually involved both lower limbs and then all over the body [Figure l]a. Examination revealed multiple tender nodules each measuring 2–3 cm in diameter, located over dorsal aspect of lower limbs, back, and face. Few nodules in the legs had ulcerated with serosanguinous discharge. This time we decided to stop ATT and to investigate further for other granuloma causing infections. A repeat LN biopsy and skin biopsy from lesion was performed. Skin biopsy revealed the presence of an abscess cavity lined with a palisade arrangement of histiocytes/epitheloid cells in the dermis. Few ill-formed epithelioid cell granulomas with many admixed giant cells were present [Figure l]b. Biopsy stained negative for AFB. LN biopsy also showed ill-formed noncaseating granuloma. Meanwhile, culture for fungal organisms was also sent. Interestingly, the skin tissue and LN tissue both culture grew milky colonies of Cryptococcus neoformans. Further the skin biopsy was also stained for fungal organism which shows numerous yeast form of Cryptococcus [Figure l]c. On subsequent evaluation, she denied any such previous skin lesions. She also denied the use of steroids, including the use of native medicines (which could potentially contain unscrupulously added steroids). HIV was tested negative on repeat testing with ELISA as well as by Western blot. Her CD4 and CD8 Τ Cell counts in blood were within the normal limits. Apart from end-stage kidney disease, she was “apparently” immunocompetent. Considering the cohabitation of blue rock pigeons (Columbia livia) and humans in this part of the Indian subcontinent, it is likely that the patient acquired the infection through exposure to pigeon excreta.
Figure 1: (a) Skin ulcers on left leg, (b) skin biopsy H and E, ×100: low power view showing granuloma with epitheloidgiant cell and histiocytic collection within dermis, and (c) skin biopsy mucicarmine stain showing numerous yeast form of Cryptococcus (×400).

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To rule out disseminated disease, evaluation was done, including blood and urine culture, fungal antigen in serum and all were returned negative. The patient was initially managed with liposomal amphotericin (3 mg/kg IV) daily for four weeks; however, flucytosine was not administered in view of potential bone marrow suppression, particularly more pronounced in patients with renal insufficiency; then, she was discharged on oral fluconazole 400 mg daily. The patient improved significantly with a resolution of ulcers over the next four weeks. She had weight gain of six kg, improvement in appetite and regression of lymph nodes. The patient is on regular follow-up with no recurrence of fever or skin lesions even after six months.

   Discussion Top

Eleven to thirteen percent of the world population is affected with chronic kidney disease with majority of patients belonging to stage 3.[4] Worldwide prevalence of ESRD patients on dialysis is more than one million.[5] Various studies has shown that higher prevalence of infections among ESRD patients, associated with impaired innate as well as acquired immune system.[1] Patients on chronic HD therapy are at increased risk of fungal infections (nearly ten times),[2] as well as tubercular infection (3-25-fold),[6] as compared with the general population.

Although tuberculosis is considered to be the most common cause of granulomatous inflammation, other infections such as fungal, Toxoplasma, Tularemia,  Yersinia More Details, and  Brucella More Details are also known to cause granuloma, indistinguishable from tuberculosis.[7] In our case, presumptive diagnosis of tuberculosis was made due to epidemiological and clinical profile of the patient. Our patient was kept on close follow-up due to high suspicion of other infections. The unique presentation of cryptococcosis in our patient lead to delay in diagnosis, but timely treatment leads to rapid recovery.

c. neoformans has a complex polysaccharide capsule with antiphagocytic properties. Although exposure in some regions of the world is nearly ubiquitous, this organism rarely causes clinically important infection in immunocompetent hosts. In contrast, it has become a notable opportunistic infection in those possessing a compromised cell-mediated immune response. Disseminated cryptococcosis is defined by (1) a positive culture from at least two different sites or (2) a positive blood culture.[8] In the current case, positive cultures were obtained from two sites.

Our patient was otherwise clinically non-immunocompromised other than by virtue of uremia which is associated with impaired cellmediated immunity, and impaired Chemotaxis of neutrophils. She had neither received any immunosuppressive drugs nor had HIV positive status. Her CD4 count was also normal. Cryptococcosis in apparently immunocompetent patients possesses both diagnostic and therapeutic challenges. Here, we described the cutaneous lesions by Cryptococcus in a patient of ESRD who was getting treatment for tuberculosis. Among the fungal infections in ESRD patients, Candida (70%) is the most overwhelming pathogen followed by Cryptococcus (6%) and then Coccidioides (4%). In patients with impaired cell-mediated immunity, dissemination can occur to central nervous system, skin, bones, lungs, and other organs. Cutaneous infections can occur through both primary or systemic hematogeneous, later being rarer.[9] Outdoor activities predisposes for risk of infection with soil contaminated with bird dropping.[10] After extensive literature review, we found only eight case reports of cryptococcal infection in HIV negative dialysis patients with a single case report describing cutaneous cryptococcosis.[3] However, our case is unique in the presentation as it mimicked tuberculosis.

Involvement of skin and soft tissue is relatively uncommon (10%–20%).[10] Cutaneous presentation is variable; lesions can be in form of papules, abscesses, ulcers, nodules, pustules because of clinically indistinguishability, they pose a difficult diagnostic challenge.[10] Histopathology of affected tissue assisted by culture, serology, and polymerase chain reaction can help to aid the diagnosing such masquerading lesions.[11]

Management of cryptococcosis is a chai-lenging issue. Treatment recommendations are specific for unique risk populations, such as pregnant women, nonHIV patients, and are also specific for sites of infection involved.[12]

This case report describes the importance of considering the diagnosis of this potentially devastating, although treatable infection in patients with ESRD. A high degree of clinical suspicion may be required for early detection of rare organisms including tuberculosis as early treatment may limit dissemination and associated morbidity and mortality.

Conflict of interest: None declared

   References Top

Kato S, Chmielewski M, Honda H, et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008; 3:1526 33.  Back to cited text no. 1
Abbott KC, Hypolite I, Tveit DJ, et al. Hospitalizations for fungal infections after initiation of chronic dialysis in the United States. Nephron 2001;89:426-32.  Back to cited text no. 2
Hong N, Chen M, Fang w, et al. Cryptococcosis in HIV-negative patients with renal dialysis: A Retrospective analysis of pooled cases. Mycopathologia 2017;182:887-96.  Back to cited text no. 3
Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease – A systematic review and meta-analysis. PL0S One 2016:11 :e0158765.  Back to cited text no. 4
Grassmann A, Gioberge s, Moeller s, Brown G. ESRD patients in 2004: Global overview of patient numbers, treatment modalities and associated trends. Nephrol Dial Transplant 2005;20:2587-93.  Back to cited text no. 5
Romanowski k, Clark EG, Levin A, Cook VJ, Johnston JC. Tuberculosis and chronic kidney disease: An emerging global syndemic. Kidney Int 2016;90:34-40.  Back to cited text no. 6
Asano S. Granulomatous lymphadenitis. J Clin Exp Hematop 2012;52:1-6.  Back to cited text no. 7
Meesing A, Jittjareon A, Pornpetchpracha A, Tassaneetrithep B, Phuphuakrat A, Kiertiburanakul s. Disseminated cryptococcosis in an HIV-seronegative pregnant woman with transient T-lymphocytopenia: A case report and review of the literature. Southeast Asian J Trop Med Public Health 2014;45:647-53.  Back to cited text no. 8
Christianson JC, Engber w, Andes D. Primary cutaneous cryptococcosis in immunocompetent and immunocompromised hosts. MedMycol 2003:41:177-88.  Back to cited text no. 9
Du L, Yang Y, Gu J, Chen J, Liao w, Zhu Y. Systemic review of published reports on primary cutaneous cryptococcosis in immunocompetent patients. Mycopathologia 2015; 180:19-25.  Back to cited text no. 10
Perfect JR, Bicanic T. Cryptococcosis diagnosis and treatment: What do we know now. Fungal Genet Biol 2015:78:49-54.  Back to cited text no. 11
Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious diseases society of America. Clin Infect Dis 2000:30: 710-8.  Back to cited text no. 12

Correspondence Address:
Priti Meena
Department of Nephrology, Sir Gangaram Hospital, New Delhi - 110 060
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DOI: 10.4103/1319-2442.270278

PMID: 31696861

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