Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.

Ockham's razor defeated: about two atypical cases of hemolytic uremic syndrome.

BACKGROUND: Medical investigation is a favorite application of Ockham's razor, in virtue of which when presented with competing hypotheses, the solution with the fewest assumptions should be privileged. Hemolytic uremic syndrome (HUS) encompasses diseases with distinct pathological mechanisms, such as HUS due to shiga-like toxin-producing bacteria (STEC-HUS) and atypical HUS, linked to defects in the alternate complement pathway. Other etiologies such as Parvovirus B19 infection are exceptional. All these causes are rare to such extent that we usually consider them mutually exclusive. We report here two cases of HUS that could be traced to multiple causes. CASES PRESENTATION: Case 1 presented as vomiting and diarrhea. All biological characteristics of HUS were present. STEC was found in stool (by PCR and culture). After initial remission, a recurrence occurred and patient was started on Eculizumab. Genetic analysis revealed the heterozygous presence of a CFHR1/CFH hybrid gene. The issue was favorable under treatment. In case 2, HUS presented as fever, vomiting and purpura of the lower limbs. Skin lesions and erythroblastopenia led to suspect Parvovirus B19 primo-infection, which was confirmed by peripheral blood and medullar PCR. Concurrently, stool culture and PCR revealed the presence of STEC. Evolution showed spontaneous recovery. CONCLUSIONS: Both cases defy Ockham's razor in the sense that multiple causes could be traced to a single outcome; furthermore, they invite us to reflect on the physiopathology of HUS as they question the classical distinction between STEC-HUS and atypical HUS. We propose a two-hit mechanism model leading to HUS. Indeed, in case 1, HUS unfolded as a result of the synergistic interaction between an infectious trigger and a genetic predisposition. In case 2 however, it is the simultaneous occurrence of two infectious triggers that led to HUS. In dissent from Ockham's razor, an exceptional disease such as HUS may stem from the sequential occurrence or co-occurrence of several rare conditions.

Kidney Diseases Associated With Parvovirus B19, Hanta, Ebola, and Dengue Virus Infection: A Brief Review.

Viral infection-associated kidney diseases are an emerging public health issue in both developing and developed countries. Many new viruses have emerged with new paradigms of kidney injury, either directly through their cytopathic effect or indirectly through immune-mediated glomerulopathy, tubulointerstitial disease, and acute kidney injury as part of multiorgan failure. Herein, we will discuss Parvovirus, which causes glomerulopathy, and Hanta, Ebola, and Dengue viruses, which cause viral hemorrhagic fever and acute kidney injury. Clinical manifestations also depend on extrarenal organ systems involved. Diagnosis of these viral infections is mainly based on a high index of suspicion, serologic testing, and isolation of viral DNA/RNA. Management is largely conservative, as specific antiviral agents are unavailable.

[Erythrovirus B19 infections. Six years of follow-up in adults and children]. / Infecciones por Erythrovirus B19. Seis años de seguimiento en población adulta y pediátrica.

INTRODUCTION: The aetiological agent of erythema infectiosum is Erythrovirus B19 (also known as parvovirus B19), frequently found in children and adolescents, but also associated with arthropathy, aplastic crisis, and abortion in adults. MATERIAL AND METHODS: A retrospective study of Erythrovirus B19 cases in the years 2010-2015. RESULTS: Of the 56 cases of Erythrovirus B19 diagnosed, 34 were adults (32 women and 2 men) and 22 younger than 18 years (12 girls and 10 boys). Six cases were in pregnant women. Infections mainly occurred between spring and summer. In childhood, fever (64%), rash (50%), and anaemia (55%) were the most frequent symptoms. However, arthralgia (59%) was the most frequent symptom in adults, and less frequent were anaemia (41%), fever (32%), and rash (29%). CONCLUSIONS: The characteristic clinical presentation in childhood was rash and fever, whereas in adults it was arthralgia. Anaemia is also frequent, but only severe in previous haematological disease. It should be pointed out that Erythrovirus B19 infection during pregnancy could severely affect the foetus.

Parvovirus B19 infection during pregnancy and risks to the fetus.

Parvovirus B19 infects 1 to 5% of pregnant women, generally with normal pregnancy outcomes. During epidemics, the rate of infection is higher. Major congenital anomalies among offspring of infected mothers are rare, as the virus does not appear to be a significant teratogen. However, parvovirus B19 infection may cause significant fetal damage, and in rare cases, brain anomalies and neurodevelopmental insults, especially if infection occurs in the first 20 weeks of pregnancy. Parvovirus B19 is also an important cause of fetal loss, especially in the second half of pregnancy when spontaneous fetal loss from other causes is relatively rare. Parvovirus B19 infection may affect many fetal organs and can cause severe anemia, following fetal erythroid progenitor cells infection and apoptosis, especially in fetuses, that have shortened half-life of erythrocytes. Severe anemia may cause high output cardiac failure and nonimmune hydrops fetalis. In addition, parvovirus B19 may directly infect myocardial cells and produce myocarditis that further aggravates the cardiac failure. Intrauterine fetal transfusion is commonly used for the treatment of severe fetal anemia with survival rates of 75 to 90% and significant reduction of fetal morbidity. Only 66 cases were evaluated neurodevelopmentally, of which 10 (16%) had slight or severe neurodevelopmental problems. Because parvovirus B19 infection can cause severe fetal morbidity and mortality, it should be part of the routine work-up of pregnant women who have been exposed to the virus or of pregnancies with suspected fetal hydrops. Assessment for maternal infection during pregnancy is especially important during epidemics, when sero-conversion rates are high. Birth Defects Research 109:311-323, 2017. © 2017 Wiley Periodicals, Inc.

Betaferon in chronic viral cardiomyopathy (BICC) trial: Effects of interferon-ß treatment in patients with chronic viral cardiomyopathy.

BACKGROUND: Chronic viral infections of the heart are considered one antecedent event leading to progressive dysfunction of the myocardium, often with an impaired prognosis due to a virus- or immune-mediated myocardial injury. Symptomatic treatment does not influence the viral cause of heart failure, and the effect of antiviral treatment has not been determined, yet. METHODS AND RESULTS: In this phase II study 143 patients with symptoms of heart failure and biopsy-based confirmation of the enterovirus (EV), adenovirus, and/or parvovirus B19 genomes in their myocardial tissue were randomly assigned to double-blind treatment, and received either placebo (n = 48) or 4 × 10(6) (n = 49) and 8 × 10(6) IU (n = 46) interferon beta-1b (IFN-ß-1b) for 24 weeks, in addition to standard heart failure treatment. Patients with active myocarditis or other specific causes of heart failure were excluded. Compared to placebo, virus elimination and/or virus load reduction was higher in the IFN-ß-1b groups (odds ratio 2.33, p = 0.048), similarly in both interferon groups and both strata. IFN-ß-1b treatment was associated with favourable effects on NYHA functional class (p = 0.013 at follow-up week 12), improvement in quality of life (Minnesota Heart Failure score; p = 0.032 at follow-up week 24) and patient global assessment (follow-up week 12 to follow-up week 24; p = 0.039). The frequency of adverse cardiac events was not higher in the IFN-ß-1b groups compared to the placebo group. CONCLUSIONS: Immunomodulatory IFN-ß-1b treatment is a well-tolerated and safe treatment option, leading to effective virus clearance or reduction of the virus load in patients with chronic viral cardiomyopathy. Favourable clinical effects assess quality of life, NYHA functional class, and patient global assessment. ClinicalTrials.gov identifier: NCT001185250.

Pediatric parvovirus B19: spectrum of clinical manifestations.

Parvovirus B19 (PVB19) infection has a varied spectrum of clinical manifestations, ranging from subclinical infection to skin and joint symptoms to hematologic effects with potential fatality. The most common manifestation of PVB19 infection in children is erythema infectiosum (EI). Also known as fifth disease or slapped cheek syndrome, EI presents as an erythematous exanthem limited to the malar eminences that follows a mild prodromal illness. In healthy children, infection is selflimiting and has an excellent prognosis; however, in high-risk pediatric groups (eg, immunocompromised patients, children with hemolytic anemia or prenatal infection), clinical manifestations are hematologic in nature and typically are more severe. Diagnosis often is made clinically. Serologic testing can be confirmatory. Treatment is aimed at symptomatic relief, and a vaccine currently is under investigation.

Human parvovirus B19 infection causes cell cycle arrest of human erythroid progenitors at late S phase that favors viral DNA replication.

Human parvovirus B19 (B19V) infection has a unique tropism to human erythroid progenitor cells (EPCs) in human bone marrow and the fetal liver. It has been reported that both B19V infection and expression of the large nonstructural protein NS1 arrested EPCs at a cell cycle status with a 4 N DNA content, which was previously claimed to be "G2/M arrest." However, a B19V mutant infectious DNA (M20(mTAD2)) replicated well in B19V-semipermissive UT7/Epo-S1 cells but did not induce G2/M arrest (S. Lou, Y. Luo, F. Cheng, Q. Huang, W. Shen, S. Kleiboeker, J. F. Tisdale, Z. Liu, and J. Qiu, J. Virol. 86:10748-10758, 2012). To further characterize cell cycle arrest during B19V infection of EPCs, we analyzed the cell cycle change using 5-bromo-2'-deoxyuridine (BrdU) pulse-labeling and DAPI (4',6-diamidino-2-phenylindole) staining, which precisely establishes the cell cycle pattern based on both cellular DNA replication and nuclear DNA content. We found that although both B19V NS1 transduction and infection immediately arrested cells at a status of 4 N DNA content, B19V-infected 4 N cells still incorporated BrdU, indicating active DNA synthesis. Notably, the BrdU incorporation was caused neither by viral DNA replication nor by cellular DNA repair that could be initiated by B19V infection-induced cellular DNA damage. Moreover, several S phase regulators were abundantly expressed and colocalized within the B19V replication centers. More importantly, replication of the B19V wild-type infectious DNA, as well as the M20(mTAD2) mutant, arrested cells at S phase. Taken together, our results confirmed that B19V infection triggers late S phase arrest, which presumably provides cellular S phase factors for viral DNA replication.

Long-term neurodevelopmental outcome after intrauterine transfusion for fetal anemia.

The long-term neurodevelopmental outcome of children born after intrauterine blood transfusion (IUT) for red cell alloimmunization is considered favorable. Severe hydrops has been identified as a strong predictor for neurodevelopmental impairment. However, the long-term outcome of survivors of IUT for congenital Parvovirus B19 infection and fetomaternal hemorrhage is not well known. Limitations of the follow-up studies to date are small sample size, lack of controls, unclear criteria for impairment and lack of standardized developmental tests. Future research should take into account more subtle impairments, since cognitive functioning <-1 SD, behavioral and learning problems already have a significant impact on care requirements and future socio-economic potential. A better understanding of the effect of IUT and fetal anemia on child development over time will allow more accurate parental counseling and targeted interventions to optimize child development when needed.

Adult human parvovirus-B19 infection presenting with hearing difficulty and dizziness.

Human parvovirus B19 (HPV-B19), a small and non-enveloped DNA virus, causes erythema infectiosum (EI) in children. In adults, however, it is known to cause a variety of symptoms. A 39-year-old woman visited our hospital because of low-grade fever, diarrhea, bilateral leg edema, and numbness in the right arm, one and a half months after her daughter developed EI. We diagnosed her as HPV-B19 infection after her daughter's history and positive test for serum HPV-B19 IgM antibody, together with the continued observations. Two weeks later, she developed dizziness and left hearing difficulty. However, we did not give her any medication. HPV-B19 IgM antibody value (2.4) measured after one month of the onset was decreased to 1.7, 1.1, and 0.9 after two, three, and five months of the onset, respectively. Thus, it took 5 months for the IgM antibody value to become negative. Her symptoms gradually improved along with the decrease in HPV-B19 antibody without any medication. Hearing difficulty and dizziness are not categorized as manifestations of HPV-B19 infection, because these symptoms are very rare. The present report indicates that the symptoms related to inner ear dysfunctions should be added to those associated with adult HPV-B19 infection. In conclusion, we should consider HPV-B19 infection when we evaluate patients with causeless hearing difficulty and dizziness.

Clinical findings in parvovirus B19 infection in 30 adult patients in Kyoto.

To relate the clinical findings of parvovirus B19 infection to the phase of the disease, we performed a retrospective chart review of 30 adult patients who tested positive for IgM antibody against parvovirus B19 at our hospital from March 2003 to November 2008. Median patient age was 38 years, with 86.7% aged between 26 and 45 years. The male-to-female ratio was 4:26 (86.7% female). Symptoms in the first phase were mainly flu-like, including fever, headache, or myalgia. Symptoms in the second phase were arthralgia in 24 (85.7%) and rash in 23 (82.1%). Fever was observed in 21 (70.0%), and 22 (75.9%) were found to be lymphopenic. The onsets in 73.3% of cases were concentrated within 10.1% of the study period, an observation nearly consistent with an outbreak of erythema infectiosum. Three patients had symmetrical swelling of joints, all of whom also had rash. Most patients visited the hospital within a week of onset and prognosis was favorable. In the parvovirus B19 infection, flu-like symptoms were frequent in the first phase, while rash and arthralgia were common in the second. Female sex, age between 26 and 45, and presence of rash, arthralgia, fever, and lymphopenia were clinical findings with a high frequency (≥70%), and these factors may contribute to diagnosis. In an era when early diagnosis and therapy is required in rheumatoid arthritis, it is important to recognize the parvovirus B19 infection with a presentation of acute arthritis and a favorable prognosis.

Papular-purpuric gloves and socks syndrome associated with B19V infection in a 6-year-old child.

A 6 year-old girl was admitted for evaluation of a fever associated with a petechial rash of 2 days' duration. She was in good general condition with no acute distress. Inspection of the skin revealed an amazing papular and purpuric rash of predominantly acral and symmetrical distribution and sharply demarcated on the ankles. All laboratory tests were found normal. Rash and fever completely resolved in less than 3 days. Serological testing for parvovirus B19 (B19V) antibodies was positive for IgM but negative for IgG. Moreover, B19V DNA was detected in serum with a viral load of 2.24 x 10(8) copies per mL. So we concluded of a paediatric case of popular-purpuric gloves and socks syndrome (PPGSS) associated with B19V infection. PPGSS is an idiosyncratic reaction to viral infection. The syndrome has been associated with several viruses such as HHV6, measles, coxsackie B6, and above all B19V. PPGSS occurs mostly in young adults. It is characterised by a typical papular and purpuric rash with an acral distribution and a sharp demarcation on the wrists and ankles. The rash is often pruritic and can be accompanied by mucosal lesions and/or systemic symptoms such as fever, asthenia and lymphadenopathy. Most of the time, the disease is self-limited with a short course and a benign prognosis. A very similar disease has been described in some children. The distinctive clinical characteristics of PPGSS in children should be recognized by paediatrician in particular at the emergency room in order to avoid superfluous explorations.

Symptoms associated with parvovirus B19 infection in adults: a pilot study.

BACKGROUND AND OBJECTIVES: The clinical features of parvovirus B19 infection in adult patients have not been well described. The aim of this prospective study was to clarify the clinical features of adult patients with parvovirus B19 infection in primary care settings. METHODS: The study subjects were adults over age 18 years who had visited one primary care clinic over a period of one year. They were chosen if they had at least two of the following three symptoms: edema, joint pain, and rash, and if they had contact with children with erythema infectiosum. The diagnosis was confirmed if anti-parvovirus B19 antibodies were identified. The process of these symptoms was recorded until they resolved. RESULTS: Twenty patients met the inclusion criteria, and 14 (70%) patients were diagnosed with parvovirus B19 infection. The 14 adult patients consisted of two men and twelve women ranging from 33 to 63 years (median, 38 years). The patients consisted of two groups. In the first group, they presented with the first phase of infection showing symptoms such as malaise, muscle pain, and fever, and in the second phase presented with edema, rash, and joint pain that developed within two days of the first phase. In the second group, the first and second phases were clearly separated. CONCLUSIONS: Parvovirus B19 infection in adults can be efficiently diagnosed in primary care settings by observing clinical symptoms such as edema, joint pain, and rash, and by asking patients about their contact with children who have erythema infectiosum.

[Parvovirus B19: importance of diathesis in the clinical expression of a common infection]. / Le parvovirus B19 ou de l'importance du terrain dans l'expression clinique d'une infection fréquente.

Symptomatic manifestations of parvovirus B19 infection range from harmless conditions such as 5th disease of the child or arthropathy of the middle-aged woman to life threatening disease such as transient aplastic crisis during sickle cell disease, chronic anaemia in immunodeficiency states or hydrops foetalis during pregnancy. Increasing knowledge of parvovirus B19 has led to a better understanding about how a single and unvariant erythrovirus causes such a variety of diseases. The importance of age, hematopoietic and immune status has been raised and besides, effective diagnostic assays, treatments and possibly vaccine have been developed that can be rationally used at the light of this knowledge.

The usual childhood diseases: forgotten but not gone.

With the advent of vaccine protection for many diseases, many of today's practitioners have never seen cases of what were the common childhood diseases. If any of these diseases returns, there is a risk that the practitioner will not recognize it. This article tries to establish why the diseases may return and to describe the diseases with photographs.

Parvovirus B19 infection and autoimmune disease.

Human parvovirus B19 infections may cause a widespread benign and self-limiting disease in children and adults, known as erythema infectiosum or fifth disease. A variety of further manifestations are associated with the infection such as arthralgias, arthritis, leukopenia and thrombocytopenia, anemia and vasculitis, spontaneous abortion and hydrops fetalis in pregnant women. Both in children and adults parvovirus B19 infections have been frequently implicated as a cause or trigger of various forms of autoimmune diseases affecting joints, connective tissue and large and small vessels. In addition, autoimmune neutropenia, thrombocytopenia and hemolytic anemia are known as sequelae of B19 infection. The molecular basis of the autoimmune phenomena and resultant pathogenesis is unclear. The involvement of molecular mimicry between cellular and viral proteins, the induction of enhanced cytokine production via the viral transactivator protein NS1 and the phospholipase A2-like activity of the capsid protein VP1 may contribute to the induction of autoimmune reactions. All the known data and the potential mechanisms involved in the pathogenesis will be discussed in this review.

Neurological manifestations of human parvovirus B19 infection.

Since its discovery, human parvovirus B19 has been linked with a broad spectrum of clinical syndromes. An aetiological role for the virus has been confirmed in erythema infectiosum, transient aplastic crisis, persistent infection manifesting as pure red cell aplasia in immunocompromised persons, non-immune hydrops fetalis and arthritis. Less commonly recognised, but receiving increasing attention recently, are the neurological manifestations, a variety of which have been described in patients with either clinically diagnosed or laboratory confirmed B19 infection. The purpose of this review is to summarise present knowledge of B19, its known and potential pathogenic mechanisms and its association with human diseases, particularly those with neurological manifestations. The outcome of the review supports an aetiological role of the virus in neurological disease. However, the pathogenesis remains unknown and elucidating this is a priority.