Intensive Immunosuppressive Therapy Research Articles

Increased prevalence of polyomavirus BK viruria that correlates with thrombocytopenia in patients with systemic lupus erythematosus on intensive immunosuppressive therapy

The prevalence of polyomavirus BK (BKV) reactivation is high in patients with systemic lupus erythematosus (SLE) on long-term immunosuppressants compared to normal population. However, only a few studies are available for the possible correlation of BKV reactivation and clinical manifestations in SLE patients. In the present study, we tried to correlate BKV viruria, clinical manifestations, laboratory findings, and medications in patients with SLE. The urine BKV viral DNA copies were detected from 95 patients with SLE and 32 healthy volunteers by real-time PCR. We found that the prevalence rate of BKV viruria in SLE patients was significantly higher than normal group (71.6% vs. 18.6%, p < 0.001) as well as the urine BKV DNA viral load (4.74 ± 3.17 vs. 1.08 ± 2.33 by log scale, p < 0.001). Interestingly, BKV viruria (+) SLE patients had more thrombocytopenic events than BKV viruria ( − ) group (32.4% vs. 3.7%, p = 0.008 after adjustment by age and sex). The patients with BKV viruria DNA copy number >3,200,000/ml exhibited more thrombocytopenia risk than BKV viruria ≦3,200,000 copy number/ml or BKV viruria ( − ). The use of potent immunosuppressants may increase BKV viruria. In a refractory thrombocytoponeic case, the add-on of anti-BKV medication, leflunomide 20 mg/day rapidly decreased BKV viruria and recovered platelet counts. In conclusion, our study demonstrated that patients with SLE had higher prevalence rate of BKV reactivation that is correlated with thrombocytopenic episode. Intensive immunosuppressive therapy in SLE may increase the risk of BKV viruria.

Successful treatment with intensive immunosuppressive therapy and mechanical ventilation for idiopathic pneumonia syndrome following allogeneic bone marrow transplantation

Successful treatment with intensive immunosuppressive therapy and mechanical ventilation for idiopathic pneumonia syndrome following allogeneic bone marrow transplantation

中枢神経症状で発症した再発性多発軟骨炎にともなう血管周囲炎を主体とした髄膜脳炎の１剖検例

A 76-year-old woman presented with decreased spontaneous speech and voluntary behavior. She developed impaired consciousness, as well as swelling of her ears, with subsequent gradual worsening of such symptoms. Prolonged fever, nuchal rigidity, hearing loss, and elevated plasma CRP and erythrocyte sedimentation rate were observed. CSF showed elevation of protein and IgG, and pleocytosis. Cranial MRI showed progressive brain atrophy and multiple high intensity lesions in the white matter on T2-weighted imaging and FLAIR imaging. The histopathology of biopsy sample from auricular cartilage was consistent with the relapsing polychondritis (RP). Accordingly, the diagnosis of meningoencephalitis associated with RP was made. Impaired consciousness was transiently improved by steroid pulse therapy, but subsequently worsened in spite of intensive immunosuppressive therapy with prednisolone, methotrexate and cyclosporine. Histological examination of the autopsied brain revealed perivascular lymphocyte infiltration in the pia mater and the cerebrum white matter, and inflammatory destruction of the myelin sheath. Meningoencephalitis of this case was thought to be caused by RP-associated perivascular inflammation.

Posaconazole as Prophylaxis in Immunocompromised Patients: A Single Center Experience

Efficacy of posaconazole was recently demonstrated in the prevention of invasive fungal infections (IFI) in recipients of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with GVHD and in patients undergoing intensive chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes.Between Jan 2007 and April 2008, 54 patients had received posaconazole prophylaxis (200 mg t.i.d orally) either during induction chemotherapy (33 pts) or because of GVHD (25 pts). Four patients belong to the two subgroups. We analyze these two subgroups separately. IFI were defined as possible/probable/proven according to EORTC/MSG criteria. Prophylaxis with posaconazole was performed to 33 patients undergoing induction chemotherapy (29 AML, 3 MDS, 1 aplastic anemia), (19F/14M), median age 67 years ( range 21 – 81). The median duration of neutropenia (ANC< 500 cells/mm3 ) was 39 days (range10 – 278 days). Median duration of posaconazole prophylaxis was 27 days (range 4 – 203 days), early discontinuation of prophylaxis was observed in 20 patients because of progression to IFI in 5 cases, empirical antifungal therapy for persistent fever (11 cases), mucositis (3 cases) and hepatic toxicity (1 case). Possible or probable IFI was diagnosed in 5/33 (14%) patients (3 possible and 2 probable pulmonary aspergillosis). Five deaths were occurred, only one was related to the IFI, other causes of death were intercurrent disease in 3 patients and one septic choc. Twenty five patients with GVHD treated with intensive immunosuppressive therapy had received posaconazole prophylaxis (13F/12M), median age 52 years (range21– 70), one patient had a prior diagnosis of IFI and was in complete resolution. RIC allo-HSCT was performed to 12 patients,10 sibling donors,14 MUD, one patient received umbilical cord blood transplantation. Acute GVHD grade II to IV and chronic extensive GVHD were reported in 16 and 9 patients respectively. All patients had received high dose corticosteroids (0.5 to 2 mg/Kg/d), the majority of them (21) had two or more immunosuppressive agents. The median duration of posaconazole prophylaxis was 110 days (range 19 days - 10 months), 6 patients are still receiving prophylaxis, 4 premature discontinuations due to hepatic toxicity in one case, progression to IFI in 2 cases and diet because of severe digestive GVHD in one case. Two patients (8%) developed IFI ( 1 possible and 1 probable pulmonary aspergillosis) during prophylaxis period. One patient died from IFI. IFI-unrelated death occurred in 5/25 (20%) patients.Conclusions: We observed 6% (2/33) probable/proven IFI in AML patients undergoing intensive chemotherapy and 4% (1/25) in GVHD patients witch is comparable to the incidence reported in recent studies (Oliver et al., NEJM 2007; 356:348–59/Andrew et al., NEJM 2007; 356:335–47). These results suggest that posaconazole prophylaxis is effective in reducing the incidence of IFI in this high risk population.

Reduced-Intensity Unrelated Cord Blood Transplantation for Adult Patients with Severe Aplastic Anemia

Although unrelated cord blood transplantation (UCBT) has become a viable therapeutic option widely applicable for adult patients with hematological diseases, UCBT for severe aplastic anemia (SAA) remains to be controversial due to higher incidence of graft failure (GF) relative to the other stem cell sources. To evaluate the feasibility of UCBT for SAA, we retrospectively analyzed results for 11 adult patients with SAA who received first UCBT after reduced-intensity conditioning regimen (RI-UCBT) in Toranomon Hospital. Median age was 49 years (range, 20–70). Nine of them were non-responders to intensive immunosuppressive therapy and were multiply transfused, and two patients were fulminant type with no neutrophils in peripheral blood at diagnosis. The conditioning regimen consisted of fludarabine 125mg/m2, melphalan 80mg/m2, and 4 Gy of total body irradiation. Graft-versus-host disease prophylaxis was composed of cyclosporine alone (n=2), tacrolimus alone (n=2), and tacrolimus plus mycophenolate mofetil (n=7). Median total nucleated cell number and median CD34+ cell number were 2.65 × 107/kg (range, 1.83–4.39) and 0.70 × 105/kg (range, 0.27–1.52), respectively. Serological HLA disparities were as follows; 6/6 (n=3), 5/6 (n=2), and 4/6 (n=6). Ten of the 11 patients achieved primary neutrophil and platelet engraftment. Median time to an absolute neutrophil count > 0.5×109/liter and an unsupported platelet count > 20×109/liter were 18 days (range, 12–28) and 42.5 days (range, 26–64) respectively. All patients who achieved engraftment resulted in complete hematological recovery with complete donor chimerism, except for one patient who developed late GF at three years after UCBT. All 2 who experienced GF (1: primary GF, 1: late GF) were rescued by second RI-UCBT. Two of the 11 patients died from IPS (n=2), and remaining 9 patients are alive, having survived for 18.7 months (range, 2–71 months). Six out of 7 patients who survived more than 6 months were free from immunosuppressant. The probabilities of overall survival and event-free survival at 2 years after UCBT were 77.8% and 68.2%, respectively. Our results here strongly indicated feasibility and effectiveness of RI-UCBT for adult SAA patients with high engraftment rate and low treatment-related mortality. RI-UCBT could be considered as a viable therapeutic option for those who lack suitable HLA-matched sibling donors and failed immunosuppressive therapy.

Neuromyelitis optica associated with systemic autoimmune diseases in children

Case reports Neuromyelitis optica (NMO, Devic's disease) is a severe autoimmune disorder predominantly involving optic nerves and spinal cord [1]. Usually isolated, it has been associated with systemic autoimmune diseases in adult patients [2]. We report 2 children with a systemic autoimmune disease who developed NMO. Patients were female; NMO symptoms started at age 8 and 12 years. Patient 1 had a diagnosis of Systemic Lupus Erythematosus (SLE) (fever, cytopenias, mesangeal glomerulonephritis, positive ANA, anti-DNA, anti-Sm). She developed vomiting, tremor, hyperreflexia, paresthesia, neurogenic bladder and progressive vision loss 2 years after SLE onset. Neuroradiological investigations disclosed longitudinally extensive transverse myelitis and bilateral optic nerve involvement. Patient 2 had recurrent parotitis for 1 year before she developed vision loss, papilitis, dystonia and paresthesia. She exhibited positive ANA, anti-Ro and antiLa, and objective eye dryness. MRI evidenced lesions in brainstem and spinal cord, and evoked potentials revealed optic nerve involvement. A diagnosis of Sjogren's Syndrome (SS) associated with NMO was made. NMO-Ig was detected in both patients' sera. Intravenous and p.o. high dose steroids, a 6-month course of monthly I.V. cyclophosphamide (up to 1 g/m2/dose), followed by azathioprine (2–3 mg/Kg/day) as maintenance therapy, were used in both (plasmapheresis in one). Visual, motor and sensitive symptoms dramatically improved. Mild relapses occurred in both children; they were successfully treated with steroids. Patients are currently well, with improved vision and residual lesions in MRI. Conclusion NMO can occur in the setting SLE or SS in children. Intensive immunosuppressive therapy may induce remission and prevent visual loss.

A Case Report of Successful Treatment With Immunoadsorption Onto Protein A in Mixed Connective Tissue Disease in Childhood

An 11-year-old male patient suffering mixed connective tissue disease with life-threatening pulmonary arterial hypertension, progressive heart failure (New York Heart Association class III-IV), skin ulcers, Raynaud's phenomenon and arthritis, showing no improvement after intensive immunosuppressive therapy or high dose steroids, was treated with immunoadsorption onto protein A. With a combined therapy of low-dose cortisone and bosentan and 22 sessions of immunoadsorption, his condition improved significantly and he continues in clinical remission. At the time of writing no further immunosuppressive therapy or immunoadsorption had been necessary. The patient is now 15 years old and healthy with an age-based constitution comparable to the normal population.

Life threatening pneumonia in a lupus patient: a case report

We report a case of systemic lupus erythematosus (SLE) in a 44-year old Caucasian woman complicated with pneumonia and severe respiratory failure requiring ICU treatment and mechanical ventilation. Symptoms developed in a generally well controlled SLE course after sudden stop in immunosupresant therapy (methotrexate, cyclosporin and methylprednisolone). A fulminant course of the disease, an interstitial pattern in a high resolution computed tomography (HRCT) and negative repeated sputum, blood and bronchoaspirate cultures enabled diagnosis of fulminant lupus pneumonitis. The response to pulses of cyclophosphamide and methylprednisolone was good but complicated with a significant leukopenia. HRCT confirmed significant remission of pulmonary changes. Fulminant lupus pneumonitis is a rare but potentially life threatening complication of SLE. Differential diagnosis requires exclusion of pneumonia induced by pathogens such as Pneumocystis jirovevecii (carinii) and Mycobacterium sp. Intensive immunosuppressive therapy and close cooperation between ICU, pulmonology and rheumatology departments is necessary in such a case to minimalize the risk of fatal outcome.

Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura

AbstractDiscoveries during the past decade have revolutionized our understanding of idiopathic thrombotic thrombocytopenic purpura (TTP). Most cases in adults are caused by acquired autoantibodies that inhibit ADAMTS13, a metalloprotease that cleaves von Willebrand factor within nascent platelet-rich thrombi to prevent hemolysis, thrombocytopenia, and tissue infarction. Although approximately 80% of patients respond to plasma exchange, which removes autoantibody and replenishes ADAMTS13, one third to one half of survivors develop refractory or relapsing disease. Intensive immunosuppressive therapy with rituximab appears to be effective as salvage therapy, and ongoing clinical trials should determine whether adjuvant rituximab with plasma exchange also is beneficial at first diagnosis. A major unanswered question is whether plasma exchange is effective for the subset of patients with idiopathic TTP who do not have severe ADAMTS13 deficiency.

Case Report: Successful Treatment of Posttransplant Lymphoproliferative Disorder and Quiescence of Dermatomyositis With Rituximab and Sirolimus

Posttransplant lymphoproliferative disorder (PTLD) remains one of the most important complications of intensive immunosuppressive therapy. A 65-year-old Caucasian woman received a primary en bloc kidney transplant from a deceased 2-year-old donor. After antithymocyte globulin induction she was treated with a maintenance regimen including cyclosporine and mycophenylate mofetil (MMF). She had a history of recurrent dermatomyositis, suggesting a flawed immune system. After a benign course for 9 months and after an increase in MMF from 2 to 3 g daily, she presented with pneumonia owing to Candida albicans, which was responsive to antibiotics, as was the PTLD. Persistent fever led to a diagnosis of PTLD. The immunosuppressive regimen was converted to sirolimus (SRL) and rituximab, with over 90% necrosis of the neoplasm at 1 month. However, owing to concern at exploration, the allografts were extirpated. This case documented the benefit of the rituximab–SRL combination to treat PTLD while maintaining dermatomyositis in remission.

Fatal Kikuchi–Fujimoto disease associated with SLE and hemophagocytic syndrome: a case report

Kikuchi-Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis is a rare, benign, autoimmune condition characterized by lymphadenopathy, fever, and neutropenia. KFD can frequently mimic various diseases including infection, malignancy, and autoimmune disease. KFD has also been infrequently reported in association with SLE, which can be diagnosed previously, simultaneously, or after the diagnosis of SLE. The author presents here the first case of fatal KFD simultaneously occurred with SLE complicated with hemophagocytic syndrome and severe infection. The recognition of this association is of significance for management of affected patients with early intensive immunosuppressive therapy for favorable outcome.

Hepatitis B reactivation after chemotherapy: two decades of clinical research.

Hepatitis due to hepatitis B virus reactivation after cytotoxic or immunosuppressive therapy is a serious cause of liver-related morbidity and mortality. With the characterization of the underlying pathogenesis, much progress in the management of this important clinical problem has been made in the past 2 decades. By year 2008, it is mandatory to screen for hepatitis B surface antigen status before initiating intensive chemotherapy or immunosuppressive therapy. All those who are hepatitis B surface antigen positive should be started on preemptive nucleos(t)ide analogues. However, there remains important issues, such as the type and duration of nucleos(t)ide analogue therapy, which need to be understood. As not all hepatitis B surface antigen-positive patients will suffer from HBV reactivation, it is therefore useful to identify risk factors related to HBV reactivation so that patients will not be treated unnecessarily with nucleos(t)ide analogues. To date, a high baseline level of viral replication, as reflected by high serum HBV DNA level, positive serum hepatitis B e antigen, and a high intrahepatic covalently closed circular DNA level, is the most important predictor for HBV reactivation. Recently, there has been an increased awareness of reactivation of occult hepatitis B virus, especially in hepatitis B virus endemic area, such as the Asia-Pacific region. Careful epidemiological study will be needed to clarify the impact of occult hepatitis B infection in patients treated with cytotoxic or immunosuppressive therapy.

Prevalence of Pneumocystis jirovecii and Mycoplasma pneumoniae in patients presenting with pneumonia at hospitals in Port Elizabeth

Pneumocystis jirovecii, an opportunistic fungus, is the causative agent of Pneumocystis pneumonia (PcP) in humans, and is an important cause of morbidity and mortality among immunocompromised persons, AIDS-related or patients receiving prolonged corticosteroid or intensive immunosuppressive therapies. PcP also remains a significant cause of mortality where access to ealthcare/antiretroviral therapy is limited and when P. jirovecii has not been diagnosed or prophylaxis not recommended. Mycoplasma pneumoniae is a common cause of acute upper and lower respiratory tract infections, particularly in children, young adults and the elderly, and community-acquired pneumonia which often results in hospitalisation due to the severity of the illness. Prevalence of M. pneumoniae infections within healthy populations can vary from between 13.5-34% to 45% in adults with asthma. As delayed treatment of pneumonia increases the risk for mortality, rapid and accurate identification is crucial to the establishment of informed prognosis and facilitation of early appropriate treatment.

Interstitial Lung Disease in Dermatomyositis and polymyositis-analysis of 23 Cases

Objective: To characterize the clinical, laboratory, immunological, image, and pathological features inpatients of dermatomyositis (DM)/polymyositis (PM) with interstitial lung disease (ILD). Methods: We searched the data base of National Taiwan University Hospital between 1989 and 2006 for DM/PM patients with ILD. The medical records were reviewed. Results: Twenty-three DM/PM patients fulfilling Bohan and Peter's criteria with image-proved ILD were enrolled. Seven, 16 and no patients were classified into the rapid progression, slow progression and asymptomatic group, respectively. There were significantly more DM-ILD patients compared to PM-ILD patients in the rapid progression group than in the slow progression group (4/3 vs. 2/14, p=0.045). In the rapid progression group, 6 patients (85.71%) died and only one patient, receiving aggressive combination of immunosuppressive agents, survived at the end of study with improved pulmonary function test results. The survival of the rapid progression group was significantly lower than the slow progression group (mean survival time: 6±4 months vs. 69 ± 8 months, p=0.001; frequency of death due to ILD progression: 85.71% vs. 25%, p=0.019). Conclusion: There are significantly more DM-ILD patients with rapid progression of pulmonary symptoms than PM-ILD patients. DM/PM patients with rapid progressive ILD are with poorer prognosis, despite with intensive immunosuppressive therapy.

Toxoplasmosis encephalitis following severe graft‐vs.‐host disease after allogeneic hematopoietic stem cell transplantation: 17 yr experience in Fukuoka BMT group

Toxoplasmosis is a rare but rapidly fatal complication that can occur following hematopoietic stem cell transplantation (HSCT). Over a 17-yr period at our institutions, a definite diagnosis of toxoplasmosis was made in only two of 925 allogeneic HSCT recipients (0.22%) and none of 641 autologous HSCT recipients. These two patients received a conventional conditioning regimen followed by transplantation from an HLA-matched donor; however, they developed severe graft-vs.-host disease, which required intensive immunosuppressive therapy. Despite prophylactic treatment with trimethoprim/sulfamethoxazole, their immunosuppressive state, as indicated by a low CD4(+) cell count, might have resulted in toxoplasmosis encephalitis. Rapid and non-invasive methods such as a polymerase chain reaction (PCR) test of their cerebrospinal fluid for Toxoplasma gondii and magnetic resonance imaging of the brain were useful for providing a definitive diagnosis and prompt therapy in these patients: one patient stabilized and survived after responding to treatment with pyrimethamine/sulfodiazine whereas the other died of bacterial infection. In addition, retrospective PCR analyses of the frozen stored peripheral blood samples disclosed that detection of T. gondii preceded the onset of disease, indicating routine PCR testing of peripheral blood specimens may be an early diagnostic tool. It should be noted that when patients receiving HSCT have an unexplained fever and/or neurological complications, PCR tests should be considered to avoid cerebral lesions and improve the outcome of the patients.

Mouth and Genital Ulcers With Inflamed Cartilage (MAGIC) Syndrome Complicated by Aneurysmal Aortitis

"MAGIC syndrome" (Mouth And Genital ulcers with Inflamed Cartilage) has been proposed to describe patients with clinical features of both relapsing polychondritis and Behcet disease. A total of 18 cases have been reported with only 1 case associated with aneurysmal aortitis described in 1997. Herein, we describe a patient with MAGIC syndrome complicated by aneurysmal aortitis requiring cardiothoracic surgery and intensive immunosuppression. Monitoring for the possible development of inflammatory aortic aneurysms should thus be considered in patients with MAGIC syndrome who have persistently elevated serum inflammatory markers. If an aortic aneurysm is detected, cardiothoracic surgical referral is necessary, close monitoring for enlargement is mandatory, and intensification of immunosuppressive therapy should be considered.

Acute motor axonal neuropathy during intensive immunosuppressive therapy for macrophage activation syndrome

We describe a 2-year-old girl with refractory macrophage activation syndrome (MAS), which is a serious complication of inflammatory disorders associated with rheumatic disease in children. Although she was treated with intensive immunosuppressive therapies such as immunoglobulin, plasma exchange, dexamethasone, methotrexate, cyclosporine, and etoposide, she subsequently developed motor deficit with the abolition of deep tendon reflexes. Since nerve conduction study revealed low-amplitude compound muscle action potentials and motor conduction slowing, she was diagnosed as having acute motor axonal neuropathy (AMAN) associated with refractory MAS. This is the first report of AMAN occurring during immunosuppressive therapy for extremely refractory MAS, suggesting that hypercytokinemia or activated macrophages may have played a critical role in the pathogenesis of AMAN in this patient.

Successful treatment of disseminated fusariosis with posaconazole during neutropenia and subsequent allogeneic hematopoietic stem cell transplantation

We report the case of a 16-year-old girl with acute myelogenous leukemia with disseminated fusariosis, who responded to salvage posaconazole therapy. She subsequently received additional cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation with posaconazole continued as secondary prophylaxis. Despite intensive immunosuppressive therapy for graft-versus-host disease, no recrudescence of infection occurred.

A case of life-threatening refractory polychondritis successfully treated with combined intensive immunosuppressive therapy with methotrexate

Relapsing polychondritis (RP) is a rare disease of unknown etiology causing systematic inflammation and resulting in destruction of cartilaginous tissues. We describe here an 18-year-old Japanese woman who developed severe airway stenosis as the initial symptom with auricular, nasal, and ocular inflammation. The effect of high dose oral steroid, methylprednisolone pulse therapy, and cyclophosphamide was temporary and her conditioning was worsening. Finally we added methotrexate to the immunosuppressive treatment and achieved reduction of disease activity. This case illustrates the potentially fatal sudden onset of airway inflammation that can occur with this disorder, and the effectiveness of methotrexate.

Les microangiopathies thrombotiques. Incidence, physiopathologie, tableau clinique, prise en charge thérapeutique et pronostic

IntroductionThe objective of this work was to review current data about the pathophysiology, clinical features, and treatment of thrombotic microangiopathies. Current knowledgeThrombotic microangiopathies are microvascular occlusive disorders characterized by systemic or intrarenal aggregation of platelets, thrombocytopenia, and mechanical injury to erythrocytes. In thrombotic thrombocytopenic purpura, systemic microvascular aggregation of platelets causes ischemia in the brain and other organs. In the hemolytic–uremic syndrome, platelet–fibrin thrombi occlude predominantly the renal circulation. Thrombotic microangiopathy is a rare disorder whose varied clinical manifestations result from the formation of platelet-rich thrombi within the microvasculature and consequent tissue ischemia. The clinical features are acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. This diagnosis is of considerable importance because of the possible fulminant clinical course. Some atypical forms may be unrecognized. Plasma exchange is the current reference treatment of thrombotic thrombocytopenic purpura. However, in the light of recent publications, either infusions of concentrates of purified enzyme or more intensive immunosuppressive therapy would be more specific.