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Fulminant sepsis due to disseminated histoplasmosis in renal transplantation: A diagnostic challenge
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Journal of Acute Medicine 2 (2012) 55e57 www.e-jacme.com
Case Report
Fulminant sepsis due to disseminated histoplasmosis in renal transplantation: A diagnostic challenge Omkar Ulhas Vaidya a,*, Anwita Omkar Vaidya b, Harshal Rohidas Patil a, Heidi Huseth a a
Department of Internal Medicine, Univsersity of MissourieKansas City, Kansas City, Missouri, United States b Clinical Research Consultants, Kansas City, Missouri, United States Received 12 February 2012; accepted 13 March 2012 Available online 2 June 2012
Abstract Disseminated histoplasmosis can be extremely life threatening if not identified and treated promptly. Diagnosing fungal infections in patients receiving solid organ transplants and in those who are immunosuppressed is pivotal in prevention of fungal sepsis. These patients may present with subtle chronic symptoms prior to sepsis. The patient, a 77-year-old woman who had a kidney transplant from a living related donor about 26 years previously, presented with recurrent skin rash and muscle weakness for 4 months. Her skin biopsy showed nonspecific granulomas prior to admission. On presentation she remained critically ill, and her radiographic imaging or cultures did not show specific abnormalities throughout the disease course, except for a positive urine histoplasma antigen and serum histoplasma polymerase chain reaction. Her clinical status deteriorated eventually leading to death. This case highlights the importance of rapid diagnostic tests in the early diagnosis of disseminated histoplasmosis, which could potentially prevent fulminant sepsis. Copyright Ó 2012, Taiwan Society of Emergency Medicine. Published by Elsevier Taiwan LLC. All rights reserved. Keywords: Fulminant sepsis; Histoplasmosis; Renal transplant
1. Introduction Certain infections in renal transplant patients may have an atypical symptomatic presentation secondary to immunosuppression. Histoplasmosis is found all over the world, although it is mostly predominant in the midwestern United States and Central America.1,2 Generally, the presentation in immunocompetent patients varies. In immunocompromised patients with histoplasmosis, the disease does not follow a defined pattern, and patients may exhibit an array of clinical symptoms like fever, weight loss, pneumonitis, cough, and lymphatic tissue enlargement.2,3 Disseminated histoplasmosis is a life threatening infection and requires early diagnosis and prompt treatment.
* Corresponding author. 4401 Wornall Road, Kansas City, Missouri 64111, United States. E-mail address: [email protected] (O.U. Vaidya).
We report a patient with disseminated histoplasmosis who presented with recurrent skin rash and proximal muscle weakness for 4 months prior to development of sepsis. 2. Case report A 77-year-old woman who had a renal transplant from a living related donor about 26 years previously was referred to our tertiary care center from the rural Midwest region of the United States. Her renal history was significant for end-stage renal disease from polycystic kidney disease. She also had a history of fibromyalgia. Her primary complaints included a bilateral lower extremity skin rash and proximal muscle weakness for approximately 4 months. A painful pruritic rash with indurated plaques was more prominent on the left lower extremity than the right. She had episodes of spontaneous remission and recurrence of symptoms. Her records showed a history of multiple admissions to an outside facility for the same symptoms, where she was presumably treated for cellulitis. Laboratory tests were not indicative of any
2211-5587/$ - see front matter Copyright Ó 2012, Taiwan Society of Emergency Medicine. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.jacme.2012.03.002
56
O.U. Vaidya et al. / Journal of Acute Medicine 2 (2012) 55e57
pancytopenia corresponding to these admissions. The patient had a normal blood cell count during these admissions. She was on immunosuppression therapy, including azathioprine and prednisone. A skin biopsy performed about 1 month prior to her admission had demonstrated granulomas, although all special stains showed no abnormalities. An increase in mucin was observed throughout the subcutaneous fat. After consultations with three different dermatopathologists, a likely infectious etiology was derived, although an autoimmune etiology could not be ruled out (Fig. 1). The autoimmune examination, which included rheumatoid factor, antiribonucleoprotein antibodies, anticyclic citrullinated protein antibodies, antinuclear antibodies, antidouble-stranded DNA antibodies, cytoplasmic antineutrophil cytoplasmic antibodies, perinuclear antineutrophil cytoplasmic antibodies, and anti Jo-1 antibodies, showed no abnormalities. On presentation, she had a high grade 38.8 C fever. She was then started on broad-spectrum antibiotics, vancomycin 15 mg/kg intravenously every 8 hours, and piperacillin/tazobactam 3.375 mg intravenously every 6 hours. Her complete blood count results ranged as follows: platelets, 97e50 109/ L; white blood cells, 4.5e2.4 109/L; hemoglobin 10.1e9.0 g/dL; creatine kinase 1.70 U/L (0e2.37 U/L); and thyroid stimulating hormone 1.94 mIU/L. Blood and sputum cultures were negative. Roentgenography of the chest showed essentially insignificant for any specific finding (Fig. 2). Computerized tomography of the chest showed no infiltrates or lymphadenopathy. On the following day, she had hypotension and atrial fibrillation. On examination, she was found to be hemodynamically unstable and was treated with mechanical ventilation. After intubation, she underwent a bronchoscopy. A silver stain revealed a budding yeast infection, fungal organisms consistent with Candida and atypical squamous cells, and, hence, she was also started on antifungal intravenous fluconazole 400 mg empirically.
Fig. 1. A hematoxylin and eosin stain of the skin biopsy demonstrating two granulomas, one at 12 o’clock and the other at 6 o’clock. Also shown is the lymphocytic inflammation. An increase in mucin is observed throughout the subcutaneous fat.
Fig. 2. Chest roentgenogram shows a right basilar subsegmental atelectasis and a very small left pleural effusion.
Histoplasma antigen in the urine was elevated to more than 39 enzyme immunoassay (EIA) units (reference range: < 2.0 EIA units). Her antifungal therapy was then immediately changed to intravenous amphotericin B to 1 mg/kg per day. She continued to require vasopressor support and mechanical ventilation. Aggressive supportive measures were discontinued as per the patient’s wish and the family’s decision on the second day. She became hemodynamically unstable and died the same night. Bone marrow biopsy reports after the patient’s death showed megakaryocytes, no lymphoproliferative disorder, and a fungal yeast infection consistent with histoplasmosis. Her serum DNA probe test was positive for histoplasma. Fungal blood cultures remained negative throughout the course of the disease. 3. Discussion Histoplasmosis is also known as Ohio Valley fever. Its causative organism, Histoplasma capsulatum, is seen all over the world. It is common in Central America and the United States (most predominantly in Ohio, Mississippi, and the Midwest).1,2 Clinically, it may present with variable clinical symptoms like fever, weight loss, cough, pneumonitis, and lymphatic tissue enlargement.2,3 In a multicentric study the cumulative incidence of endemic fungal infections was 0.50%. The combined incidence of blastoplasmosis and histoplasmosis was less than 1% (median time to disease onset after transplant was 10.5 months).4 Histoplasma is a dimorphic fungus and the infection is acquired by inhalation of conidia. Infection can be acquired from inhalation of these conidia, which are commonly present in cave-dwelling bats and soils inhabited by chickens.5 Histoplasmosis has various forms of presentation ranging from being asymptomatic to cutaneous manifestations like panniculitis and myositis.6 Cutaneous manifestations of histoplasmosis have been reported, especially in transplant recipients,7 but our case was unique because it presented 26 years after a renal transplant. Urinary histoplasma antigen has very high sensitivity and specificity, and it is very useful as a diagnostic tool,8 especially since the results of fungal
O.U. Vaidya et al. / Journal of Acute Medicine 2 (2012) 55e57
cultures and skin biopsy generally take a few days. Also, a polymerase chain reaction of whole blood plays a significant role in the facilitation of diagnosis even when blood cultures are negative.9 Amphotericin B is reserved for the initial treatment of moderately severe or severe infection because of its potential toxicity.10 Oral therapy with itraconazole is appropriate for patients not requiring hospitalization and for continuation of outpatient therapy in those initially treated with amphotericin B.10 4. Conclusion This case highlights the importance of urinary histoplasmosis antigen as a rapid diagnostic tool. Immunosuppression puts renal transplant patients at a risk of developing opportunistic and fungal infections. Early consideration of histoplasmosis in immunosuppressed patients, especially in endemic regions, can help prevent devastating effects from otherwise treatable infectious etiologies. In this case, the patient’s skin biopsy showed granulomas but all special stains were negative for any organisms. She had fibromyalgia that also added to the challenge in early diagnosis. Obtaining a urine histoplasma antigen and DNA probe may have helped in the early diagnosis and treatment of the disease.
57
References 1. Kibria R, Bari K, Ali SA, et al. “Ohio River valley fever” presenting as isolated granulomatous hepatitis: a case report. South Med J. 2009 Jun;102:656e658. 2. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115e132. 3. Chang MR, Taira CL, Paniago AM, et al. Study of 30 cases of histoplasmosis observed in the Mato Grosso do Sul State, Brazil. Rev Inst Med Trop Sao Paulo. 2007;49:37e39. 4. Grim SA, Proia L, Miller R, et al. A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation. Transpl Infect Dis. 2012;14:17e23. 5. Ferreira MS, Borges AS. Histoplasmosis. Rev Soc Bras Med Trop. 2009;42:192e198. 6. Farr B, Beacham BE, Atuk NO. Cutaneous histoplasmosis after renal transplantation. South Med J. 1981;74:635e637. 7. Marques SA, Hozumi S, Camargo RM, et al. Histoplasmosis presenting as cellulitis 18 years after renal transplantation. Med Mycol. 2008;46:725e728. 8. Connolly PA, Durkin MM, Lemonte AM, et al. Detection of histoplasma antigen by a quantitative enzyme immunoassay. Clin Vaccine Immunol. 2007;14:1587e1591. 9. Qualtieri J, Stratton CW, Head DR, et al. PCR detection of Histoplasma capsulatum var. capsulatum in whole blood of a renal transplant patient with disseminated histoplasmosis. Ann Clin Lab Sci. 2009;39:409e412. 10. Mocherla S, Wheat LJ. Treatment of histoplasmosis. Semin Respir Infect. 2001;16:141e148.
Journal of Acute Medicine 2 (2012) 55e57 www.e-jacme.com
Case Report
Fulminant sepsis due to disseminated histoplasmosis in renal transplantation: A diagnostic challenge Omkar Ulhas Vaidya a,*, Anwita Omkar Vaidya b, Harshal Rohidas Patil a, Heidi Huseth a a
Department of Internal Medicine, Univsersity of MissourieKansas City, Kansas City, Missouri, United States b Clinical Research Consultants, Kansas City, Missouri, United States Received 12 February 2012; accepted 13 March 2012 Available online 2 June 2012
Abstract Disseminated histoplasmosis can be extremely life threatening if not identified and treated promptly. Diagnosing fungal infections in patients receiving solid organ transplants and in those who are immunosuppressed is pivotal in prevention of fungal sepsis. These patients may present with subtle chronic symptoms prior to sepsis. The patient, a 77-year-old woman who had a kidney transplant from a living related donor about 26 years previously, presented with recurrent skin rash and muscle weakness for 4 months. Her skin biopsy showed nonspecific granulomas prior to admission. On presentation she remained critically ill, and her radiographic imaging or cultures did not show specific abnormalities throughout the disease course, except for a positive urine histoplasma antigen and serum histoplasma polymerase chain reaction. Her clinical status deteriorated eventually leading to death. This case highlights the importance of rapid diagnostic tests in the early diagnosis of disseminated histoplasmosis, which could potentially prevent fulminant sepsis. Copyright Ó 2012, Taiwan Society of Emergency Medicine. Published by Elsevier Taiwan LLC. All rights reserved. Keywords: Fulminant sepsis; Histoplasmosis; Renal transplant
1. Introduction Certain infections in renal transplant patients may have an atypical symptomatic presentation secondary to immunosuppression. Histoplasmosis is found all over the world, although it is mostly predominant in the midwestern United States and Central America.1,2 Generally, the presentation in immunocompetent patients varies. In immunocompromised patients with histoplasmosis, the disease does not follow a defined pattern, and patients may exhibit an array of clinical symptoms like fever, weight loss, pneumonitis, cough, and lymphatic tissue enlargement.2,3 Disseminated histoplasmosis is a life threatening infection and requires early diagnosis and prompt treatment.
* Corresponding author. 4401 Wornall Road, Kansas City, Missouri 64111, United States. E-mail address: [email protected] (O.U. Vaidya).
We report a patient with disseminated histoplasmosis who presented with recurrent skin rash and proximal muscle weakness for 4 months prior to development of sepsis. 2. Case report A 77-year-old woman who had a renal transplant from a living related donor about 26 years previously was referred to our tertiary care center from the rural Midwest region of the United States. Her renal history was significant for end-stage renal disease from polycystic kidney disease. She also had a history of fibromyalgia. Her primary complaints included a bilateral lower extremity skin rash and proximal muscle weakness for approximately 4 months. A painful pruritic rash with indurated plaques was more prominent on the left lower extremity than the right. She had episodes of spontaneous remission and recurrence of symptoms. Her records showed a history of multiple admissions to an outside facility for the same symptoms, where she was presumably treated for cellulitis. Laboratory tests were not indicative of any
2211-5587/$ - see front matter Copyright Ó 2012, Taiwan Society of Emergency Medicine. Published by Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.jacme.2012.03.002
56
O.U. Vaidya et al. / Journal of Acute Medicine 2 (2012) 55e57
pancytopenia corresponding to these admissions. The patient had a normal blood cell count during these admissions. She was on immunosuppression therapy, including azathioprine and prednisone. A skin biopsy performed about 1 month prior to her admission had demonstrated granulomas, although all special stains showed no abnormalities. An increase in mucin was observed throughout the subcutaneous fat. After consultations with three different dermatopathologists, a likely infectious etiology was derived, although an autoimmune etiology could not be ruled out (Fig. 1). The autoimmune examination, which included rheumatoid factor, antiribonucleoprotein antibodies, anticyclic citrullinated protein antibodies, antinuclear antibodies, antidouble-stranded DNA antibodies, cytoplasmic antineutrophil cytoplasmic antibodies, perinuclear antineutrophil cytoplasmic antibodies, and anti Jo-1 antibodies, showed no abnormalities. On presentation, she had a high grade 38.8 C fever. She was then started on broad-spectrum antibiotics, vancomycin 15 mg/kg intravenously every 8 hours, and piperacillin/tazobactam 3.375 mg intravenously every 6 hours. Her complete blood count results ranged as follows: platelets, 97e50 109/ L; white blood cells, 4.5e2.4 109/L; hemoglobin 10.1e9.0 g/dL; creatine kinase 1.70 U/L (0e2.37 U/L); and thyroid stimulating hormone 1.94 mIU/L. Blood and sputum cultures were negative. Roentgenography of the chest showed essentially insignificant for any specific finding (Fig. 2). Computerized tomography of the chest showed no infiltrates or lymphadenopathy. On the following day, she had hypotension and atrial fibrillation. On examination, she was found to be hemodynamically unstable and was treated with mechanical ventilation. After intubation, she underwent a bronchoscopy. A silver stain revealed a budding yeast infection, fungal organisms consistent with Candida and atypical squamous cells, and, hence, she was also started on antifungal intravenous fluconazole 400 mg empirically.
Fig. 1. A hematoxylin and eosin stain of the skin biopsy demonstrating two granulomas, one at 12 o’clock and the other at 6 o’clock. Also shown is the lymphocytic inflammation. An increase in mucin is observed throughout the subcutaneous fat.
Fig. 2. Chest roentgenogram shows a right basilar subsegmental atelectasis and a very small left pleural effusion.
Histoplasma antigen in the urine was elevated to more than 39 enzyme immunoassay (EIA) units (reference range: < 2.0 EIA units). Her antifungal therapy was then immediately changed to intravenous amphotericin B to 1 mg/kg per day. She continued to require vasopressor support and mechanical ventilation. Aggressive supportive measures were discontinued as per the patient’s wish and the family’s decision on the second day. She became hemodynamically unstable and died the same night. Bone marrow biopsy reports after the patient’s death showed megakaryocytes, no lymphoproliferative disorder, and a fungal yeast infection consistent with histoplasmosis. Her serum DNA probe test was positive for histoplasma. Fungal blood cultures remained negative throughout the course of the disease. 3. Discussion Histoplasmosis is also known as Ohio Valley fever. Its causative organism, Histoplasma capsulatum, is seen all over the world. It is common in Central America and the United States (most predominantly in Ohio, Mississippi, and the Midwest).1,2 Clinically, it may present with variable clinical symptoms like fever, weight loss, cough, pneumonitis, and lymphatic tissue enlargement.2,3 In a multicentric study the cumulative incidence of endemic fungal infections was 0.50%. The combined incidence of blastoplasmosis and histoplasmosis was less than 1% (median time to disease onset after transplant was 10.5 months).4 Histoplasma is a dimorphic fungus and the infection is acquired by inhalation of conidia. Infection can be acquired from inhalation of these conidia, which are commonly present in cave-dwelling bats and soils inhabited by chickens.5 Histoplasmosis has various forms of presentation ranging from being asymptomatic to cutaneous manifestations like panniculitis and myositis.6 Cutaneous manifestations of histoplasmosis have been reported, especially in transplant recipients,7 but our case was unique because it presented 26 years after a renal transplant. Urinary histoplasma antigen has very high sensitivity and specificity, and it is very useful as a diagnostic tool,8 especially since the results of fungal
O.U. Vaidya et al. / Journal of Acute Medicine 2 (2012) 55e57
cultures and skin biopsy generally take a few days. Also, a polymerase chain reaction of whole blood plays a significant role in the facilitation of diagnosis even when blood cultures are negative.9 Amphotericin B is reserved for the initial treatment of moderately severe or severe infection because of its potential toxicity.10 Oral therapy with itraconazole is appropriate for patients not requiring hospitalization and for continuation of outpatient therapy in those initially treated with amphotericin B.10 4. Conclusion This case highlights the importance of urinary histoplasmosis antigen as a rapid diagnostic tool. Immunosuppression puts renal transplant patients at a risk of developing opportunistic and fungal infections. Early consideration of histoplasmosis in immunosuppressed patients, especially in endemic regions, can help prevent devastating effects from otherwise treatable infectious etiologies. In this case, the patient’s skin biopsy showed granulomas but all special stains were negative for any organisms. She had fibromyalgia that also added to the challenge in early diagnosis. Obtaining a urine histoplasma antigen and DNA probe may have helped in the early diagnosis and treatment of the disease.
57
References 1. Kibria R, Bari K, Ali SA, et al. “Ohio River valley fever” presenting as isolated granulomatous hepatitis: a case report. South Med J. 2009 Jun;102:656e658. 2. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115e132. 3. Chang MR, Taira CL, Paniago AM, et al. Study of 30 cases of histoplasmosis observed in the Mato Grosso do Sul State, Brazil. Rev Inst Med Trop Sao Paulo. 2007;49:37e39. 4. Grim SA, Proia L, Miller R, et al. A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation. Transpl Infect Dis. 2012;14:17e23. 5. Ferreira MS, Borges AS. Histoplasmosis. Rev Soc Bras Med Trop. 2009;42:192e198. 6. Farr B, Beacham BE, Atuk NO. Cutaneous histoplasmosis after renal transplantation. South Med J. 1981;74:635e637. 7. Marques SA, Hozumi S, Camargo RM, et al. Histoplasmosis presenting as cellulitis 18 years after renal transplantation. Med Mycol. 2008;46:725e728. 8. Connolly PA, Durkin MM, Lemonte AM, et al. Detection of histoplasma antigen by a quantitative enzyme immunoassay. Clin Vaccine Immunol. 2007;14:1587e1591. 9. Qualtieri J, Stratton CW, Head DR, et al. PCR detection of Histoplasma capsulatum var. capsulatum in whole blood of a renal transplant patient with disseminated histoplasmosis. Ann Clin Lab Sci. 2009;39:409e412. 10. Mocherla S, Wheat LJ. Treatment of histoplasmosis. Semin Respir Infect. 2001;16:141e148.