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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2020  |  Volume : 31  |  Issue : 4  |  Page : 868-873
Disseminated Histoplasmosis Masquerading as Significant Weight Loss Eight Years Post Renal Transplant


Department of Nephrology, Medical Division, Command Hospital Air Force, Bengaluru, Karnataka, India

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Date of Submission31-May-2019
Date of Decision12-Jul-2019
Date of Acceptance14-Jul-2019
Date of Web Publication15-Aug-2020
 

   Abstract 


With the advent of potent immunosuppressive therapies, renal transplant recipients are more susceptible to a variety of infections with atypical pathogens and presentations. In the setting of many years post-renal transplant, weight loss may be due to occult systemic fungal infection and if left untreated it may evolve with multisystem involvement. We describe a case with significant weight loss who got admitted for the evaluation for post-transplant lympho- proliferative disorder. The 30-year-old male patient presented with weight loss eight years post- renal transplant and detailed evaluation revealed systemic fungal infection involving cutaneous, pulmonary, and hematopoietic systems.

How to cite this article:
Jha VK, Mahapatra D. Disseminated Histoplasmosis Masquerading as Significant Weight Loss Eight Years Post Renal Transplant. Saudi J Kidney Dis Transpl 2020;31:868-73

How to cite this URL:
Jha VK, Mahapatra D. Disseminated Histoplasmosis Masquerading as Significant Weight Loss Eight Years Post Renal Transplant. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Oct 27];31:868-73. Available from: https://www.sjkdt.org/text.asp?2020/31/4/868/292324



   Introduction Top


Although histoplasmosis is the most common endemic mycosis among immunocompromised patients in general, the frequency of histo- plasmosis among solid organ transplant (SOT) recipients appears to be low. In a study performed in an area hyperendemic for histoplasmosis, no cases were observed among 586 SOT recipients after a mean follow-up of 16 months.[1] In another study, the incidence of posttransplantation histoplasmosis was one case per 1000 person-years.[2] The disease manifestation can vary from subtle clinical manifestations often misdiagnosed as tuberculosis to severe disseminated disease with very high mortality. We describe a case who got admitted for evaluation of significant weight loss for post-transplant lymphoproliferative disorder (PTLD) and turned out to be a systemic fungal infection. The diagnosis of histoplasmosis was made by histopathological examination of the lesion in lung and skin. The patient was detected to have multisystem involvement in the form of the cutaneous, pulmonary, and hematopoietic system.


   Case Report Top


Written informed consent was obtained from the patient before reporting the case.

This 30-year-male, a living related donor renal transplant recipient, was transplanted in August 2008 with mother as the donor. The native kidney disease was presumed chronic glomerulonephritis. Pre transplant period, he did not receive any induction and was on triple drug immunosuppressants (tacrolimus/myco- phenolate mofetil/steroid) with baseline serum creatinine of 1.3–1.4 mg/dL. In the immediate post-transplant period, he had urinary tract infection (Pseudomonas aeruginosa) which was managed conservatively. He was admitted about eight years postrenal transplantation with significant weight loss (his actual weight was 42 kg, which came down to 36 kg within two months) and intermittent loose motions for three months. He had generalized weakness and nonproductive cough for one month. He also had skin lesions on the right hand, left thigh, and upper lip region for the past two months which was painless and non-itchy [Figure 1]. There was no history of abdominal pain, blood/mucus in stool, hematemesis, melena, fever, hemoptysis, breathlessness, orthopnea, and other complaints. He denied any history of urinary complaints/exposure to commercial sex workers, drug abuse, or intake of drugs other than prescribed. Clinically on admission, he was afebrile, normotensive, had no pedal edema and lymphadenopathy. He was evaluated in detail for his weight loss. Initial evaluation revealed normal hemogram and urine examination. His serum creatinine was 1.8 mg/dL with tacrolimus level being 4.3 ng/mL.
Figure 1: Clinical photograph showing ulceration over medial aspect of right wrist joint with surrounding erythema.

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Other investigations were serum calcium 7.0 mg/dL, phosphate 1.7 mg/dL, serum alkaline 463 IU/L, serum protein 6.1 g/dL, serum albumin 4 g/dL, serum bilirubin 0.8 mg/dL, aspartate transaminase/alanine transaminase of 14/16 IU/L, lactate dehydrogenase of 264 IU/L, total serum cholesterol 67 mg/dL, serum triglyceride 69 mg/dL, low-density lipoprotein of 39 mg/dL, high-density lipoprotein of 64 mg/dL, Vitamin D3 7.90 ng/mL, and intact parathormone of 343.10 pg/mL. Repeated stool routine/microscopic examination showed no ova or cyst. Thyroid profile was normal. Cytomegalovirus serology was negative. Serum IgA tissue transglutaminase for celiac sprue was normal. Serum immunoglobulin profile was normal. Ultrasound of abdomen revealed mild non-homogeneous parenchymal echotexture of the liver and grade 2 hydro- nephrosis with calculi 6 mm in size in upper pole of the right kidney; the transplant kidney was normal. Chest X-ray [Figure 2] showed the left apical lung lesion with cavitation. Upper gastrointestinal endoscopy was normal and D2 biopsy was suggestive of plasma cell infiltrates in lamina propria with positive staining for IgG and IgA. There was partial villous shortening. Occasional lymphoepithe- lial lesions were also seen [Figure 3]. In view of suspicion of plasma cell disorder, serum protein electrophoresis, serum immune fixation, and free light chain assay were done, which were normal. Bone marrow aspiration and biopsy were normal. His whole-body positron emission tomography scan revealed focal areas of ileal wall thickening with increased fluorodeoxy- glucose (FDG) uptake in the right iliac fossa and metabolically active consolidation in left lung apex. Subpleural fibronodular opacities were noted in the left lung with no FDG uptake [Figure 4]. High resolution computed tomography of the chest revealed patchy areas of consolidation in both lungs with cavitation in the left upper lobe and multiple ground- glass nodules. Few centrilobular nodules with the tree in bud appearance were noted in the right lower lobe [Figure 5]. Computed tomography-guided lung biopsy revealed numerous histiocytes and mononuclear cells with numerous intracytoplasmic multiple fungal bodies surrounded by clear halo, morphologically suggestive of histoplasmosis ([Figure 6] and [Figure 7]). The rK39 serology, to rule out cutaneous leishmaniasis, was negative. Serum galacto- mannan was strongly positive (OI = 8.9). Skin biopsy revealed pan-dermal thinned inflammatory cell infiltrate comprising of foamy histiocytes, polymorphs, and lymphocytes.
Figure 2: Chest X-ray showing left apical lung lesion with cavitation.

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Figure 3: Duodenal biopsy showing plasma cell infiltrates in lamina propria on staining for IgG and IgA. Partial villous shortening and occasional lympho-epithelial lesions were also seen.

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Figure 4: Positron emission tomography scan showing focal areas of ileal wall thickening with increased fluorodeoxyglucose uptake in the right iliac fossa.

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Figure 5: High resolution computed tomography scan of the chest showing patchy areas of consolidation in both lungs with cavitation in left upper lobe and multiple ground glass nodules.

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Figure 6: Computed tomography guided lung biopsy showing numerous histiocytes and mononuclear cells with numerous intracytoplasmic multiple fungal bodies surrounded by clear halo morphologically suggestive of histoplasmosis.

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Figure 7: Lung biopsy – Gomoris silver stain showing multiple intracytoplasmic fungal bodies.

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However, no organisms were seen. Special stain for fungi was negative. Since the lung biopsy was suggestive of histoplasmosis, he was put on intravenous amphotericin B. After few days, he developed progressive pancytopenia (hemoglobin 6.1 g/dL, total leukocyte count 1700/mm3, and platelet 17,000/mm3) and amphotericin B was stopped, after a total dose of 210 mg, and itraconazole started. The patient had a downhill course during hospitali- zation and had progressive pancytopenia requiring two leukodepleted red blood cell and six platelet-rich plasma transfusions. Within 11 days of starting itraconazole, the patient had an improvement in hematological parameters and he was put on intravenous ampho- tericin B again. With the due course, he had a remarkable improvement in the form of weight gain, the disappearance of skin lesions and normal hematological parameters. He was discharged from the hospital on itraconazole.


   Discussion Top


The incidence of histoplasmosis is estimated to be low among SOT recipients, with only a few case series, mostly among renal and liver transplant recipients reported.[3],[4],[5],[6] The median time interval from transplantation to diagnosis of histoplasmosis was ~17 months, similar to a previous report by Wheat et al,[4] with a broad range from two months to seven years. In a recent large series of 152 cases of histo- plasmosis, the median time from transplant to diagnosis was 27 months, but 34% were diagnosed in the 1st year after transplant.[5] This study concluded that although late cases may occur, the 1st year after SOT is the period of highest risk for histoplasmosis. The presentation in the index case was quite late, i.e., almost eight years after renal transplant. The clinical features of disseminated histoplasmosis in SOT recipients are nonspecific and similar to many other disseminated infections. The most common symptoms are fever and shortness of breath, but mild symptoms may also be present, and disseminated disease may not be apparent from the initial evaluation. Disseminated disease is marked by fever, weight loss, weakness, fatigue, and mild respiratory symptoms and is often associated with cutaneous and subcutaneous lesions. In our case, patient presented with generalized weakness, weight loss and vague symptoms after eight years post-renal transplantation. Clinical features in the form of chronic diarrhea and weight loss in view of so many years post-transplant, prompted us to rule out PTLD. We got features of immunoproliferative small intestinal disease (IPSID) in D2 biopsy; however, serum immuno- fixation was negative. The patient was put empirically on doxycycline in view of the possibility of IPSID. The chest X-ray features of nonhomogenous opacity with cavitation was more in favor of tuberculosis or PTLD but lung biopsy gave us a different diagnosis. A transplant physician should therefore be aware of this uncommon pathogen to diagnose histo- plasmosis and utilize the available investigative modalities and initiate appropriate treatment. Serological diagnosis of disseminated histoplasmosis appears to be of limited value for immunosuppressed patients, with only one- third of the patients in one series being positive. However, seroconversion or a 4-fold increase in titers strongly suggests a diagnosis of histoplasmosis.[7] When chest infection is present, chest radiographic findings include diffuse, nodular, patchy, or military infiltrates; hilar adenopathy is uncommon.[7] Chronic syndromes present as cavitatory lung disease, calcified lymph nodes, and mediastinal fibrosis. Primary infection is acquired by inhalation of infectious microconidia, by direct inoculation into the skin, or through an infected allograft. Once the microconidia are lodged in the alveolar and interstitial spaces, it becomes a yeast, multiplies intracellularly and disseminates until cell-mediated immunity develops (2–10 weeks).[8],[9] Cutaneous lesions in disseminated histoplasmosis include papules, nodules, plaques, erythema multiforme-like lesions, and exfoliative dermatitis.[10] Erythema nodosum, a hypersensitivity-mediated panni- culitis in which the organisms are not present has also been described.[11] Multiple cutaneous lesions in this patient also did not reveal any fungus in special stain but it was highly suggestive of histoplasmosis accompanied by hypersensitivity-mediated panniculitis. Gomori’s methenamine silver stain is the best stain for H. capsulatum. The organisms are seen as numerous, small (2–4 μm), oval yeast-like fungi within the cytoplasm of macrophages in the dermis and subcutaneous tissue.

Histoplasmosis despite its worldwide distribution, has been uncommonly reported from India.[12] The organism is a dimorphic fungus, present as a mold in its natural reservoir, soil contaminated with bird droppings and converts to a budding yeast form in tissues during the invasive disease. The diagnosis is made on histopathology of affected areas, most often with the demonstration of intracellular yeasts, the presence of budding and a distinct capsule seen best on the PAS or Gomori’s Silver stain, all of which were seen in our patient. The recommended treatment for acute or disseminated histoplasmosis of moderate-to-severe disease is liposomal amphotericin B products followed by itraconazole; itraconazole alone is recommended in less severe cases of acute disease.[8] In our case, the patient was initially put on plain amphotericin B showing good response in the form of his general well-being but developed pancytopenia presumed to be either drug-induced or progression of the disease. He was taken off mycophenolate mofetil after admission. He was switched to itraconazole 200 mg twice a day with close monitoring of tacrolimus level (dose of tacrolimus 0.5 mg/day, tacrolimus trough level 4.3 ng/mL). His serum creatinine remained around 1.2–1.4 mg/dL during his hospital stay while on treatment. The treatment was again changed to amphotericin B in view of severe disseminated disease after recovery from pancytopenia. Recommendations for the duration of treatment vary from 12 weeks for the acute disease to > 12 months for progressive disseminated disease. The treatment should be individualized on the basis of diagnosis, immunosuppression status, and potential consequences of the location of the disease. In our case, the patient showed significant positive response in the form of weight gain, the disappearance of cutaneous lesion and improvement in hematological parameters.


   Conclusion Top


Although the risk of disseminated fungal infection is usually more in initial years post- SOT, it should be considered even in later years post-transplant in appropriate clinical setting. Weight loss as a manifestation in a renal transplant recipient can be due to occult systemic fungal infection and may not be always be due to malignancy/tuberculosis. With due course, in the absence of appropriate therapy, it may evolve with multisystem involvement. A high degree of suspicion should be present to rule out disseminated fungal infection many years post-renal transplant and appropriate therapy with close monitoring is associated with a good outcome.

Conflict of interest: None declared.



 
   References Top

1.
Vail GM, Young RS, Wheat LJ, Filo RS, Cornetta K, Goldman M. Incidence of histo- plasmosis following allogeneic bone marrow transplant or solid organ transplant in a hyperendemic area. Transpl Infect Dis 2002; 4:148-51.  Back to cited text no. 1
    
2.
Cuellar-Rodriguez J, Avery RK, Lard M, Budev M, Gordon SM, Shrestha NK, et al. Histoplasmosis in solid organ transplant recipients: 10 years of experience at a large transplant center in an endemic area. Clin Infect Dis 2009;49:710-6.  Back to cited text no. 2
    
3.
Peddi VR, Hariharan S, First MR. Disseminated histoplasmosis in renal allograft recipients. Clin Transplant 1996;10:160-5.  Back to cited text no. 3
    
4.
Wheat LJ, Smith EJ, Sathapatayavongs B, Batteiger B, Filo RS, Leapman SB, et al. Histoplasmosis in renal allograft recipients. Two large urban outbreaks. Arch Intern Med 1983;143:703-7.  Back to cited text no. 4
    
5.
Assi M, Martin S, Wheat LJ, Hage C, Freifeld A, Avery R, et al. Histoplasmosis after solid organ transplant. Clin Infect Dis 2013;57: 1542-9.  Back to cited text no. 5
    
6.
Oh YS, Lisker-Melman M, Korenblat KM, Zuckerman GR, Crippin JS. Disseminated histoplasmosis in a liver transplant recipient. Liver Transpl 2006;12:677-81.  Back to cited text no. 6
    
7.
Kauffman CA. Diagnosis of histoplasmosis in immunosuppressed patients. Curr Opin Infect Dis 2008;21:421-5.  Back to cited text no. 7
    
8.
Farr B, Beacham BE, Atuk NO. Cutaneous histoplasmosis after renal transplantation. South Med J 1981;74:635-7.  Back to cited text no. 8
    
9.
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. 9
    
10.
Newman SL. Cell-mediated immunity to Histoplasma capsulatum. Semin Respir Infect 2001;16:102-8.  Back to cited text no. 10
    
11.
Ramdial PK, Mosam A, Dlova NC, B Satar N, Aboobaker J, Singh SM. Disseminated cutaneous histoplasmosis in patients infected with human immunodeficiency virus. J Cutan Pathol 2002;29:215-25.  Back to cited text no. 11
    
12.
Gopalakrishnan R, Nambi PS, Ramasubramanian V, Abdul Ghafur K, Parameswaran A. Histoplasmosis in India: Truly uncommon or uncommonly recognised? J Assoc Physicians India 2012;60:25-8.  Back to cited text no. 12
    

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Correspondence Address:
Vijoy Kumar Jha
Department of Nephrology, Command Hospital Air Force, Bengaluru - 560 007, Karnataka
India
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DOI: 10.4103/1319-2442.292324

PMID: 32801251

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]



 

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