Cytomegalovirus induced refractory TTP in an immunocompetent individual: a case report.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare, potentially fatal disease with multisystem involvement. Cytomegalovirus (CMV) infection as a cause of refractory TTP, has been reported only in immunocompromised individuals. We report a case of CMV-induced refractory TTP in an immunocompetent individual. CASE PRESENTATION: A 35-year-old, previously healthy Sri Lankan man, presented with fever for 3 days with gum bleeding and progressive drowsiness. His Glasgow coma scale score was 10/15. He did not have papilloedema or neck stiffness. Laboratory evaluation showed a severe thrombocytopenia with microangiopathic haemolytic anaemia. There was marginal renal impairment and normal coagulation profile. Non-contrast CT scan of brain was normal. A diagnosis of thrombotic thrombocytopenic purpura was made. Despite daily plasma exchanges and high-dose steroids, he failed to achieve the expected therapeutic response, thus demonstrating refractory TTP. On exploring for possible causes of refractoriness to treatment, a clinically significant PCR titre of CMV was detected. Treatment of CMV infection lead to complete recovery of TTP. His disease course was further complicated with spontaneous spinal haemorrhage leading to neurological sequelae. DISCUSSION AND CONCLUSIONS: This is the first report of CMV induced refractory TTP in an immunocompetent adult. It is also the first report of clinically significant spontaneous spinal haematoma in TTP. These two rare occurrences should be considered when patients with refractory TTP do not improve as expected.

Parvovirus B19 infection associated with hemolytic anemia and cranial polyneuropathy.

Parvovirus B19 (PB19) is a common, widespread, small, single-stranded DNA virus which has been linked with a broad spectrum of clinical illnesses, including a variety of neurological complications such as encephalitis, meningitis, myelitis, stroke, cerebellar ataxia, and neuropathy. The authors describe a case of PB19 infection associated with hemolytic anemia and cranial polyneuropathy involving the second and third cranial nerves in a 23-year-old immunocompetent woman. The diagnosis of acute PB19 infection was established with detection of positive DNA and anti-PB19 IgM antibodies in blood samples. Antiganglioside antibody studies were performed and serum anti-GD1b IgG was strongly positive. Further investigation was normal or negative, excluding other infectious or autoimmune disorders. The patient was initially treated with a 5-day course of intravenous immunoglobulin (IGIV). Because of incomplete neurological recovery, methylprednisolone was also administered 7 days after IGIV therapy initiation. Complete resolution of clinical symptoms was observed 3 months after disease onset at follow-up visit, despite the persistence of PB19 DNA and anti-PB19 IgM antibodies in serum 5 months after the initial presentation. Our report provides evidence that PB19 could affect both the central and peripheral nervous system, possibly by triggering an autoimmune mechanism that leads to autoantibody production.

Haemolytic anaemia: don't leave it out in the cold.

This clinical case highlights the diagnostic odyssey of an adolescent girl presenting to A&E with non-specific headaches and chest pain. The case will describe the steps in decision making from admission to follow-up.

Induction of Heme Oxygenase-1 Deficiency and Associated Glutamate-Mediated Neurotoxicity Is a Highly Conserved HIV Phenotype of Chronic Macrophage Infection That Is Resistant to Antiretroviral Therapy.

UNLABELLED: Expression of the cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly reduced in the brain prefrontal cortex of HIV-positive individuals with HIV-associated neurocognitive disorders (HAND). Furthermore, this HO-1 deficiency correlates with brain viral load, markers of macrophage activation, and type I interferon responses. In vitro, HIV replication in monocyte-derived macrophages (MDM) selectively reduces HO-1 protein and RNA expression and induces production of neurotoxic levels of glutamate; correction of this HO-1 deficiency reduces neurotoxic glutamate production without an effect on HIV replication. We now demonstrate that macrophage HO-1 deficiency, and the associated neurotoxin production, is a conserved feature of infection with macrophage-tropic HIV-1 strains that correlates closely with the extent of replication, and this feature extends to HIV-2 infection. We further demonstrate that this HO-1 deficiency does not depend specifically upon the HIV-1 accessory genes nef, vpr, or vpu but rather on HIV replication, even when markedly limited. Finally, antiretroviral therapy (ART) applied to MDM after HIV infection is established does not prevent HO-1 loss or the associated neurotoxin production. This work defines a predictable relationship between HIV replication, HO-1 loss, and neurotoxin production in MDM that likely reflects processes in place in the HIV-infected brains of individuals receiving ART. It further suggests that correcting this HO-1 deficiency in HIV-infected MDM could provide neuroprotection above that provided by current ART or proposed antiviral therapies directed at limiting Nef, Vpr, or Vpu functions. The ability of HIV-2 to reduce HO-1 expression suggests that this is a conserved phenotype among macrophage-tropic human immunodeficiency viruses that could contribute to neuropathogenesis. IMPORTANCE: The continued prevalence of HIV-associated neurocognitive disorders (HAND) underscores the need for adjunctive therapy that targets the neuropathological processes that persist in antiretroviral therapy (ART)-treated HIV-infected individuals. To this end, we previously identified one such possible process, a deficiency of the antioxidative and anti-inflammatory enzyme heme oxygenase-1 (HO-1) in the brains of individuals with HAND. In the present study, our findings suggest that the HO-1 deficiency associated with excess glutamate production and neurotoxicity in HIV-infected macrophages is a highly conserved phenotype of macrophage-tropic HIV strains and that this phenotype can persist in the macrophage compartment in the presence of ART. This suggests a plausible mechanism by which HIV infection of brain macrophages in ART-treated individuals could exacerbate oxidative stress and glutamate-induced neuronal injury, each of which is associated with neurocognitive dysfunction in infected individuals. Thus, therapies that rescue the HO-1 deficiency in HIV-infected individuals could provide additional neuroprotection to ART.

Neonatal outcome after fetal anemia managed by intrauterine transfusion.

UNLABELLED: In-utero transfusion is now well under control and improves the survival of foetuses monitored for fetal anemia with a survival rate of more than 80 %. The aim was to evaluate short-term neonatal outcome after fetal severe anemia managed by intrauterine transfusions. We did a retrospective study of all neonates born after management of severe fetal anemia (n = 93) between January 1999 and January 2013 in our regional center. The two main causes of anemia were maternal red blood cell alloimmunization (N = 81, 87 %) and Parvovirus B19 infection (N = 10, 10.8 %). In the alloimmunization group, phototherapy was implemented in 85.2 % of cases with a maximum level of bilirubin of 114.4 ± 60.7 (mg/dl). Transfusion and exchange transfusion were, respectively, required in 51.9 % and in 34.6 % of cases. One neonate presented a convulsive episode, and we observed three neonatal deaths. In the parvovirus group, none of the child had anemia at birth and no management was necessary. CONCLUSION: Contemporary management of Rhesus disease is associated with encouraging neonatal outcomes. In case of Parvovirus infection, no specific management is necessary at. But, in all cases of fetal anemia, children should be followed up with particular attention to neurologic development. WHAT IS KNOWN: • In-utero transfusion is now well under control and improves the survival of fetuses monitored for fetal anemia. • Limited studies are available on the effect of IUT on postnatal outcome in infants with a history of fetal anemia. What is New: • Contemporary management of severe Rhesus disease is associated with encouraging neonatal outcomes. • The majority of infants can be managed with phototherapy and a limited number of top-up transfusions and exchange transfusions. In case of Parvovirus infection, the short-term neonatal outcome is excellent.

[Aplastic crisis due to parvovirus B19 and Epstein-Barr virus in a patient with hereditary spherocytosis]. / Crisis aplásica por Parvovirus B19 y virus de Epstein-Barr en paciente con esferocitosis hereditaria.

Anemic syndrome in childhood requires a diagnosis and urgent treatment guided by systematic protocols that can avoid unnecessary additional testing. The case of a 4 year-old girl with fatigue and intermittent fever of 7 days duration, accompanied by abdominal pain is presented. She had regular general health status, with mucocutaneous jaundice, a grade III/VI/iv murmur, and painful abdomen with hepatosplenomegaly. The blood analysis showed a hypo-regenerative anemia with increased LDH and indirect bilirubin. The Coombs Test was negative, with spherocytes being observed in the peripheral blood smear. The IgM and IgG were positive for parvovirus B19 IgM and Epstein Barr virus, leading to the diagnosis of aplastic crisis in a patient with hereditary spherocytosis. No specific treatment was required. Under the suspicion of anemic syndrome in emergencies, the ABCDE sequence must be followed. Through the history, physical examination and basic laboratory tests, an initial diagnostic approach can be made. Specific etiological tests should be based on this first study.

ITPA genotype protects against anemia during peginterferon and ribavirin therapy but does not influence virological response.

UNLABELLED: On-treatment anemia is associated with higher sustained virological response (SVR) rates during peginterferon plus ribavirin (RBV) therapy. Inosine triphosphatase (ITPA) variants causing ITPase deficiency have been shown to protect against RBV-induced anemia. However, ITPase activity has not been associated with SVR. To study this discrepancy, we examined the relationships between ITPase activity, on-treatment anemia, SVR, and RBV levels in hepatitis C virus genotype 1 (HCV-1) patients from the CHARIOT study. ITPA genotype (rs7270101, rs1127354) was used to define ITPase activity in 546 patients. Plasma RBV levels were measured using high-performance liquid chromatography (HPLC). Relationships between ITPase activity, on-treatment hemoglobin (Hb) levels, RBV levels, and SVR were tested using regression modeling, survival analysis, and locally weighted scatterplot smoothing (LOWESS) plot analysis. Hb decline was independently associated with SVR (P<0.0001). ITPase deficiency was present in 35%. ITPase deficiency strongly protected against Hb decline (P<0.0001), but was not associated with SVR (P=0.28). The probability of SVR increased with lower nadir Hb for both wild-type and deficient ITPase activity, but the association curve shifted to describe a parallel relationship at higher Hb levels in patients with ITPase deficiency. In a subset (n=203), we tested the hypothesis that the association between Hb decline and SVR reflected RBV levels rather than actual Hb level. RBV levels were associated with on-treatment Hb decline and SVR, but not ITPase activity. In regression models, adjustment for RBV levels attenuated the association between Hb decline and SVR. CONCLUSION: ITPase deficiency protects against RBV-induced anemia, but is not associated with SVR. Our data suggest that the relationship between Hb decline and SVR is not mechanistic, but is linked to RBV levels.

ADAMTS13 activity levels in patients with human immunodeficiency virus-associated thrombotic microangiopathy and profound CD4 deficiency.

BACKGROUND: Thrombotic microangiopathy (TMA) encompasses a number of disorders with hemolytic anemia and thrombocytopenia, including thrombotic thrombocytopenic purpura (TTP). A deficiency in ADAMTS13 enzyme levels, along with an inhibitory antibody, is found in most patients with idiopathic TTP. Patients with human immunodeficiency virus (HIV) infection can have a TTP-like illness; however, it appears to have a different etiology. METHODS: A retrospective review of patients who had an ADAMTS13 activity level performed from 2005 through 2007 was completed. Patients with a diagnosis of HIV infection with TMA were investigated. RESULTS: Two patients were identified. Case 1: a 47-year-old man with HIV infection and a CD4 count <10/microL presented with altered mental status, pneumonia, acute renal failure, thrombocytopenia, and anemia. The ADAMTS13 level was 71%. He was treated with plasma infusion. Two days after admission, he expired because of respiratory distress syndrome and metabolic lactic acidosis. Case 2: a 39-year-old man with HIV infection and a CD4 count of 9/microL presented with chest pain, acute renal failure, thrombocytopenia, and anemia. The ADAMTS13 level was 65%. He received multiple units of fresh frozen plasma without significant improvement in his platelet count. Six days after admission, the patient began highly active antiretroviral therapy, which resulted in a rapid increase in his platelet count. CONCLUSIONS: HIV-associated TMA is postulated to have a different pathophysiology than idiopathic TTP. This study supports that assumption because both patients exhibited many of the classic findings of TTP but did not have a deficiency of ADAMTS13.

Hemolytic anemia presenting with idiopathic intracranial hypertension.

We report on an 8-year-old girl with hemolytic anemia because of infection with parvovirus B19 and increased intracranial pressure. She presented acutely with headache, vomiting, and mild scleral and mucosal icterus. Upon evaluation, the patient exhibited profound hemolytic anemia, papilledema, and increased intracranial pressure. The patient was treated with intravenous immunoglobulin, prednisone, and packed red blood cells. Concurrent with an improvement of her anemia, she experienced a gradual resolution of her headache, vomiting, and optic-disc swelling. Signs of idiopathic intracranial hypertension may occur as a consequence of severe anemia, and are reversible upon correction of the underlying hematologic disorder.

Transient parvovirus-associated hypoplasia of multiple peripheral blood cell lines in children with chronic hemolytic anemia.

Human parvovirus infection typically causes transient red blood cell aplasia. However, contrary to common perceptions, the hematopathologic effects of parvovirus infection are not always limited to the erythroid lineage. We describe here a consecutive series of 17 patients with chronic hemolytic anemia hospitalized for aplastic crisis, of whom 13 had transient hypoplasia of multiple peripheral blood cell lines.

Parvovirus B19 infection in children with a variety of hematological disorders.

This study was carried out to detect Parvovirus B19 (PB19) DNA together with its antibodies in the sera of children with a range of hematological disorders to clarify the contribution of this infection to changes observed in hematological picture in those populations. This study included 85 pediatric patients with different hematological disorders. Twenty healthy subjects with matched age and sex were included as controls. Patients were classified into four groups; group I included 25 patients with hemolytic anemia in aplastic crisis, group II included 20 patients with hemolytic anemia without aplastic crisis, group III included 20 acute leukemia patients under chemotherapy, group IV included 20 patients with recently diagnosed acute leukemia. Virological study for PB19 included determination of specific IgG & IgM together with viral DNA by polymerase chain reaction (PCR). In all groups of patients with positive markers for PB19, there were statistically significant differences in the mean Hb concentration and RBC count (P < 0.001 for each), presence of neutropenia (P = 0.003) and lymphocytosis (P < 0.001) compared to controls. There was statistically significant difference in the prevalence of PB19 IgM, IgG and PCR among studied groups compared to control group. In group I and group II IgG had the highest positive rate (56 and 35%, respectively). In group III IgG also had a high positive rate (45%). However, in group IV IgM had the highest positive rate (50%) followed by PCR (45%) then IgG (40%). In conclusion, PB19 infection is detected in high rates among children with hematological disorders. PB19 must be suspected and screened for when there is anemia in those patients associated with neutropenia and lymphocytosis. In patients with acute leukaemia under chemotherapy who have unexpected anemia, neutropenia and lymphocytosis Parvovirus infection should be considered before a change of chemotherapy protocol. Screening of blood for PB19 may be helpful in understanding the epidemiology of infection with this virus. The direct detection of DNA by PCR in sera needs to be coupled with serology for a more reliable diagnosis of PB19 infections in these children.

Russia's imperial blood: was Rasputin not the healer of legend?

The only son of Russia's last Tsar, a great-grandson of Queen Victoria, continues to be used as the favorite example of the X-linked inheritance of hemophilia, in spite of the fact that this popular historical diathesis has never been confirmed by any form of modern medical laboratory testing. Certain to be controversial, a new study of the symptoms that were witnessed by those who were closest to the teenaged Russian heir now raises the possibility that his blood disorder might well have been something other than hemophilia. The key to discovering Tsarevich Alexei's true diagnosis is found in those now legendary allegations that the infamous "Mad Monk", Grigory Rasputin, had possessed a power of healing that was somehow responsible for the young boy's mysterious history of spontaneous recoveries. If we are to accept the popular diagnosis of history and call it a clotting factor deficiency, then the boy's now famous sudden recoveries will remain a complete mystery. The so-called "Mad Monk" Rasputin, as a direct result of the revolutionary propaganda of the time, is then overblown into a larger-than-life legend. If, however, we are to change the diagnosis and call it a platelet disorder, then the air is let out of the legend, and Rasputin is revealed to have been nothing more than a very ordinary middle-aged Siberian hippie who did not possess any healing powers at all.

Human parvovirus B19 infection among patients with chronic blood disorders.

OBJECTIVE: In a normal host, parvovirus infection can be asymptomatic or can result in erythema infectiosum or arthropathy. Patients with underlying hematologic and immunologic disorders who become infected with this virus are at risk for aplastic anemia. This small study attempts to confirm this relation between the human parvovirus B19 infection as one of the predisposing factor of aplastic crisis in patients with hemolytic disorders. METHODS: The laboratory records of 73 patients' serum samples, which were tested for detection of specific Immunoglobulin M and Immunoglobulin G antibody by means of the recurrently available indirect enzyme linked Immunoassay during the period from March 1998 to March 2001, were reviewed retrospectively at the Armed Forces Hospital, Riyadh, Kingdom of Saudi Arabia. RESULTS: For all patients there were 11 (15%) who were diagnosed as acute infections while 50 (68%) had serological evidence of previous exposure. Eight out of the 11 acute patients had chronic hemolytic disorder as the underlying disease while, the 3 other patients were organ transplant and connective tissue disease patients. CONCLUSION: Seventy-eight percent of our infected patients were known to have an underlying blood disorder, while 22% had immunosuppressed disorders such as organ transplant and connective tissue disorder. Parvovirus B19 can be considered as one of the predisposing factors of hemolytic crisis in patients with chronic hemolytic disease.

Post renal transplantation human herpesvirus 8-associated lymphoproliferative disorder and Kaposi's sarcoma.

Post-transplantation lymphoproliferative disorders (PTLDs) and Kaposi's sarcoma (KS) are immunosuppression-related tumours developing in solid organ transplant patients. Although the Epstein-Barr virus (EBV) is detected in the majority of the PTLDs during the first year after transplantation, the proportion of EBV-negative PTLDs has increased in recent years. We report a case of a 17-year-old man who developed severe immune haemolytic anaemia, KS and human herpesvirus 8 (HHV-8)-associated, polymorphic-type PTLD 9 months after allogeneic renal transplantation from his HHV-8-seropositive father. It is suggested that: (i) HHV-8 may be associated with EBV-negative, polymorphous-type PTLD occurring less than 1 year after transplantation, and (ii) PTLD may be listed among other tumours, including KS, Castleman's disease and primary effusion lymphoma (PEL), that are related to HHV-8 infection.