Disseminated histoplasmosis and haemophagocytic syndrome in two kidney transplant patients
Histoplasmosis diseminada y síndrome hemofagocítico en dos pacientes trasplantados renales
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"apellidos" => "Serna-Higuita" "email" => array:1 [ 0 => "lm.serna@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] 5 => array:3 [ "nombre" => "Gustavo" "apellidos" => "Zuluaga-Valencia" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Unidad de Nefrología, Hospital Pablo Tobón Uribe, Medellín, Antioquia, Colombia, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Unidad de Nefrología, Facultad de Medicina. Universidad de Antioquia, Medellín, Antioquia, Colombia, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Histoplasmosis diseminada y síndrome hemofagocítico en dos pacientes trasplantados renales" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11508_16025_36073_en_t111508.jpg" "Alto" => 531 "Ancho" => 1442 "Tamanyo" => 279620 ] ] "descripcion" => array:1 [ "en" => "Diagnostic criteria for haemophagocytic syndrome" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">To the Editor:</span></p><p class="elsevierStylePara">There are very few reports of haemophagocytic syndrome and infection by histoplasmosis in transplanted patients.<span class="elsevierStyleSup">1 </span>We present the cases of two renal transplant patients who, after suffering acute organ rejection and therefore needing more immunosuppression, developed disseminated infection of histoplasmosis. Their clinical and laboratory data were compatible with haemophagocytic syndrome.<span class="elsevierStyleSup"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Case 1. </span>30-year-old female with chronic end-stage renal failure (CRF) secondary to hyperoxaluria. The patient receives a renal transplant from a deceased donor; alemtuzumab induction and maintenance with mycophenolate-cyclosporine. Twelve moths later the patient presents acute rejection 1B and cyclosporine is replaced by tacrolimus. Six months later, the patient comes into a consultation due to fevers, arthritis and a generalized maculopapular rash. Clinical analysis report leucocytes: 1400/mm<span class="elsevierStyleSup">3</span>, platelets: 100,000/mm<span class="elsevierStyleSup">3</span>, creatinine: 4,3mg/dl, blood urea nitrogen (BUN): 75mg/dl, total bilirubin: 2,41mg/dl and direct: 2,15mg/dl, gamaglutamil-transferase: 552U/l, oxaloacetic transaminase: 839U/l, glutamic pyruvic transaminase: 348U/l, ferritin: 372,522ng/ml, triglycerides: 462mg/dl, fibrinogen: 213, chest tomography with ground glass pattern and areas of consolidation, abdominal ultrasound with splenomegaly. Polyculture is performed; we start to administer meropenem, linezolid and doxycycline. Studies for cytomegalovirus (CMV), toxoplasmosis, human immunodeficiency virus (HIV), hepatitis A, B and C, rickettsia, leptospirosis, tuberculosis, cryptococcus, Epstein-Barr virus (EBV) all returned negative. Patient requires ventilator support and renal replacement therapy (RRT) due to further clinical downturn. Three days later, haemocultures and myelogram isolate intracelullar yeasts compatible with histoplasm. We start to administer amphotericin B, and then intraconazole. The patient improves, with partial recovery of renal function; final creatinine level: 2.3mg/dl. RRT is suspended and immunosuppression resumes.</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Case 2. </span>41-year-old female with end-stage CRF of unknown aetiology and renal transplant from donor deceased 4 years prior. She received induction with alemtuzumab and tacrolimus-mycophenolate maintenance. Four months before, she presented cellular acute rejection 1A and required an increase of immunosupressive medication. She is hospitalized due to fifteen days of fever, ulcers in pubic areas and maculopapular rash. The paraclinical exams show haemoglobin: 7.58g/dl, haematocrit: 22.5%, leukocytes: 2520/mm<span class="elsevierStyleSup">3</span>, platelets: 7000/mm<span class="elsevierStyleSup">3</span>, creatinine: 5,8mg/dl, BUN: 68mg/dl, ferritin: 28,805ng/ml, lactate dehydrogenase: 314U/l, triglycerides: 352mg/dl, fibrinogen: 305, normal thorax radiography and abdominal ultrasound with hepatosplenomegaly. Studies are run on the patient to test for dengue, toxoplasma, haemoparasites, HIV, hepatitis A, B, and C, EBV, rickettsia, leptospira, cryptococcus, all negative. Polyculture is performed and antibiotic treatment begins with unfavourable evolution which progresses quickly into organic multisystemic failure. Patient then requires RRT and ventilator support. Three days later the haemocultures report histoplasma, that same day the patient passed away.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleItalic">Histoplasma capsulatum</span> is a dismorphic fungus that causes endemic systemic mycosis in certain areas of America, Africa and Asia.<span class="elsevierStyleSup">2</span> It is a granolumatous disease that affects mainly the lungs and the immune system. It is found in caverns and abandoned construction sites, especially where deposits of birds and bat faeces can be seen.<span class="elsevierStyleSup">3</span></p><p class="elsevierStylePara">The infection is acquired by inhaling their spores.<span class="elsevierStyleSup">2.</span>The severity of the disease depends on the number of spores inhaled and the immune state of the host organism; in healthy patients the infection is asymptomatic or similar to a flu syndrome.<span class="elsevierStyleSup">4-6 </span>However, in patients with immune system deficits the infection can lead to haematogenous spread involving the lungs, liver, spleen, bone marrow, and central nervous system (CNS).</p><p class="elsevierStylePara">In patients with renal transplant, the clinical frame is not specific.<span class="elsevierStyleSup">6</span> 50% of patients develop respiratory symptoms and 75% disseminated histoplasmosis<span class="elsevierStyleSup">5</span>, characterized by the involvement of at least two organs.<span class="elsevierStyleSup">4</span> 25% to 60% of patients have hepatosplenomegaly. Frequently there is septic shock.<span class="elsevierStyleSup">5 </span>The CNS manifestation is observed on less that 10% of cases<span class="elsevierStyleSup">6</span>; other symptoms can include paniculitis, orofacial complications, ileal perforation and meningitis.<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">Although histoplasmosis in transplanted patients is uncommon, and it has been prevalent in patients with hepatic or renal transplant,<span class="elsevierStyleSup">6</span> the reported incidence is between 1-5 cases in 3436 transplant patients and for a maximum period of 75 years.<span class="elsevierStyleSup">1,4</span></p><p class="elsevierStylePara">When it comes to the diagnosis, the culture, though sensitive and specific, requires several weeks for correct identification. Though the antibodies are not reliable, the detection of the urine antigen for this fungus is one of the fastest and most sensitive methods: it finds 90% of patients with disseminated infection and 75% with acute pulmonary histoplasmosis.<span class="elsevierStyleSup">5</span></p><p class="elsevierStylePara">With the appropriate therapy, the prognosis for the disseminated form of the infection is excellent given that mortality in the absence of treatment is 80%.<span class="elsevierStyleSup">5</span> The initial treatment for severe infections, besides decreasing inmunosuppresion,<span class="elsevierStyleSup">6</span> is amphotericin B dose of 1mg/kg per day until observed improvement of the disease, usually for 1-2 weeks, continuing with 200mg itraconazole 2 times a day for 12 months. In moderate infection, we start with itraconazole 3 times a day during 3 days as loading doses, followed by 200mg, twice a day for 12 months.<span class="elsevierStyleSup">4,6</span></p><p class="elsevierStylePara">Haemophagocytic lymphohistiocytosis (HL) or haemophagocytic syndrome is characterised by an extensive inflammatory response to a variety of infections or immune system abnormalities,<span class="elsevierStyleSup">7-9</span> with excessive cytokine production which leads to activation of T lymphocytes and macrophages in liver, spleen and bone marrow. For its diagnosis, at least five criteria are required (Table 1). Other findings include lymphadenopathy, rash and neurological symptoms. In suspected cases, bone marrow biopsy can confirm diagnosis with the presence of haemophagocytosis in red blood cells and other blood elements;<span class="elsevierStyleSup">9</span> however, a negative result does not exclude the diagnosis. A valuable sign of this disease, though not specific, is ferritin: the higher its level, the greater the possibility of having the syndrome. On this report the diagnosis of haemophagocityc syndrome was performed with five clinical criteria because we could not find phagocytes in the bone marrow.</p><p class="elsevierStylePara">HL may be inherited but the most commonly acquired form is caused by immunodeficiencies, haematological malignancy or secondary to infectious processes especially EVB, CMV and fungus.<span class="elsevierStyleSup">9</span> Mortality in transplanted patients nears the 50%. In case it is associated to histoplasmosis, optimal treatment is based in support measures and the adequate anti fungal therapy.<span class="elsevierStyleSup">1,7,9</span></p><p class="elsevierStylePara">This revision seeks to draw attention to the possible association between disseminated histoplasmosis and haemophagocytic syndrome in renal transplant patients which may induce a multi organic failure, a fact that increases its lethality.<span class="elsevierStyleSup">11</span> Timely diagnosis and treatment could improve the final prognosis.<span class="elsevierStyleSup">9</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The authors have no conflict of interests to declare.</p><p class="elsevierStylePara"><a href="grande/11508_16025_36073_en_t111508.jpg" class="elsevierStyleCrossRefs"><img src="11508_16025_36073_en_t111508.jpg" alt="Diagnostic criteria for haemophagocytic syndrome"></img></a></p><p class="elsevierStylePara">Table 1. Diagnostic criteria for haemophagocytic syndrome</p>" "pdfFichero" => "P1-E543-S3700-A11508-EN.pdf" "tienePdf" => true "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11508_16025_36073_en_t111508.jpg" "Alto" => 531 "Ancho" => 1442 "Tamanyo" => 279620 ] ] "descripcion" => array:1 [ "en" => "Diagnostic criteria for haemophagocytic syndrome" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:11 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Lo MM, Mo JQ, Dixon BP,\u{A0}Czech KA. Disseminated histoplasmosis associated with hemophagocytic lymphohistiocytosis in kidney transplant recipients. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 9 | 1 | 10 |
| 2024 October | 70 | 59 | 129 |
| 2024 September | 86 | 44 | 130 |
| 2024 August | 84 | 80 | 164 |
| 2024 July | 57 | 31 | 88 |
| 2024 June | 79 | 39 | 118 |
| 2024 May | 93 | 39 | 132 |
| 2024 April | 66 | 40 | 106 |
| 2024 March | 68 | 26 | 94 |
| 2024 February | 46 | 36 | 82 |
| 2024 January | 62 | 42 | 104 |
| 2023 December | 43 | 31 | 74 |
| 2023 November | 68 | 41 | 109 |
| 2023 October | 97 | 35 | 132 |
| 2023 September | 52 | 34 | 86 |
| 2023 August | 80 | 19 | 99 |
| 2023 July | 83 | 40 | 123 |
| 2023 June | 88 | 26 | 114 |
| 2023 May | 73 | 42 | 115 |
| 2023 April | 64 | 649 | 713 |
| 2023 March | 69 | 26 | 95 |
| 2023 February | 59 | 29 | 88 |
| 2023 January | 82 | 26 | 108 |
| 2022 December | 73 | 16 | 89 |
| 2022 November | 81 | 40 | 121 |
| 2022 October | 61 | 63 | 124 |
| 2022 September | 71 | 22 | 93 |
| 2022 August | 60 | 87 | 147 |
| 2022 July | 56 | 58 | 114 |
| 2022 June | 109 | 38 | 147 |
| 2022 May | 74 | 46 | 120 |
| 2022 April | 88 | 43 | 131 |
| 2022 March | 79 | 43 | 122 |
| 2022 February | 57 | 57 | 114 |
| 2022 January | 52 | 31 | 83 |
| 2021 December | 58 | 43 | 101 |
| 2021 November | 57 | 41 | 98 |
| 2021 October | 63 | 28 | 91 |
| 2021 September | 59 | 48 | 107 |
| 2021 August | 72 | 36 | 108 |
| 2021 July | 98 | 30 | 128 |
| 2021 June | 64 | 29 | 93 |
| 2021 May | 67 | 32 | 99 |
| 2021 April | 116 | 63 | 179 |
| 2021 March | 69 | 41 | 110 |
| 2021 February | 83 | 24 | 107 |
| 2021 January | 69 | 26 | 95 |
| 2020 December | 80 | 16 | 96 |
| 2020 November | 47 | 16 | 63 |
| 2020 October | 48 | 12 | 60 |
| 2020 September | 54 | 9 | 63 |
| 2020 August | 42 | 9 | 51 |
| 2020 July | 48 | 7 | 55 |
| 2020 June | 44 | 10 | 54 |
| 2020 May | 78 | 16 | 94 |
| 2020 April | 40 | 18 | 58 |
| 2020 March | 54 | 10 | 64 |
| 2020 February | 58 | 18 | 76 |
| 2020 January | 75 | 22 | 97 |
| 2019 December | 57 | 14 | 71 |
| 2019 November | 58 | 20 | 78 |
| 2019 October | 59 | 8 | 67 |
| 2019 September | 50 | 25 | 75 |
| 2019 August | 34 | 19 | 53 |
| 2019 July | 45 | 29 | 74 |
| 2019 June | 36 | 12 | 48 |
| 2019 May | 38 | 33 | 71 |
| 2019 April | 80 | 33 | 113 |
| 2019 March | 48 | 38 | 86 |
| 2019 February | 34 | 40 | 74 |
| 2019 January | 45 | 35 | 80 |
| 2018 December | 87 | 42 | 129 |
| 2018 November | 146 | 17 | 163 |
| 2018 October | 108 | 12 | 120 |
| 2018 September | 92 | 12 | 104 |
| 2018 August | 71 | 14 | 85 |
| 2018 July | 58 | 12 | 70 |
| 2018 June | 63 | 9 | 72 |
| 2018 May | 60 | 14 | 74 |
| 2018 April | 69 | 13 | 82 |
| 2018 March | 61 | 4 | 65 |
| 2018 February | 61 | 10 | 71 |
| 2018 January | 50 | 2 | 52 |
| 2017 December | 78 | 12 | 90 |
| 2017 November | 61 | 8 | 69 |
| 2017 October | 51 | 6 | 57 |
| 2017 September | 58 | 21 | 79 |
| 2017 August | 37 | 6 | 43 |
| 2017 July | 44 | 5 | 49 |
| 2017 June | 50 | 4 | 54 |
| 2017 May | 61 | 5 | 66 |
| 2017 April | 68 | 6 | 74 |
| 2017 March | 42 | 4 | 46 |
| 2017 February | 50 | 8 | 58 |
| 2017 January | 39 | 5 | 44 |
| 2016 December | 64 | 4 | 68 |
| 2016 November | 57 | 6 | 63 |
| 2016 October | 131 | 7 | 138 |
| 2016 September | 168 | 2 | 170 |
| 2016 August | 208 | 4 | 212 |
| 2016 July | 182 | 4 | 186 |
| 2016 June | 162 | 0 | 162 |
| 2016 May | 154 | 0 | 154 |
| 2016 April | 102 | 0 | 102 |
| 2016 March | 88 | 0 | 88 |
| 2016 February | 139 | 0 | 139 |
| 2016 January | 115 | 0 | 115 |
| 2015 December | 114 | 0 | 114 |
| 2015 November | 106 | 0 | 106 |
| 2015 October | 112 | 0 | 112 |
| 2015 September | 86 | 0 | 86 |
| 2015 August | 74 | 0 | 74 |
| 2015 July | 81 | 0 | 81 |
| 2015 June | 43 | 0 | 43 |
| 2015 May | 50 | 0 | 50 |
| 2015 April | 5 | 0 | 5 |
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