There is limited information on the characteristics, prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with COVID-19. This retrospective case series investigated 167 patients reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in March and April, 2020. Outcomes were compared with 167 randomly selected, contemporary, age-/sex-matched noncancer patients with COVID-19 admitted at six participating hospitals. Among MM and noncancer patients, median age was 71 years, and 57% of patients were male; 75 and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate–severe in 77 and 89% of patients and critical in 8 and 4%, respectively. Supplemental oxygen was required by 47 and 55% of MM and noncancer patients, respectively, and 21%/9% vs 8%/6% required noninvasive/invasive ventilation. Inpatient mortality was 34 and 23% in MM and noncancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19. This rapidly evolved into a pandemic of the heterogeneous clinical disease named coronavirus disease 2019 (COVID-19) that has challenged healthcare systems and led to thousands of deaths worldwide. The clinical presentation is highly variable, ranging from asymptomatic cases to severe respiratory infections. It is associated with a pro-inflammatory status, leading to cytokine release syndrome and hypercoagulation, with multi-organ damage and fatal outcome2. It was soon recognized that various factors, including increased age , male sex, and presence of comorbidities  contributed substantially to the severity of COVID-19. Investigations of novel strategies for the prevention and treatment of COVID-19 , together with appropriate intensive supportive care, have aimed to improve patient outcome4. There are cumulative data indicating that patients with cancer may be at increased risk for more severe COVID-19 and associated complications, including those receiving or not receiving treatment within the month prior to infection6, although other recent results suggest mortality may be primarily associated with age, male sex, and comorbidities7.In December 2019, a cluster of patients with pneumonia linked to a previously unknown coronavirus, now named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was detected in Wuhan, China8. Some MM treatments may also positively or negatively impact the immune system. The most common side-effect of MM treatment is the induction of cytopenia, which is clearly associated with increased susceptibility to bacterial and viral infections. Chemotherapy, particularly high-dose melphalan, results in these side effects. Corticosteroids have well-established immunosuppressive effects. Proteasome inhibitors induce T-cell dysfunction and are associated with an increased risk for varicella-zoster virus reactivation9. Immunomodulatory drugs may have a protective effect by increasing natural killer (NK) and T-cell function but are also associated with cytopenia and an increased risk for venous thromboembolism10. CD38 monoclonal antibodies reduce NK and immunosuppressive regulatory T cells, and are associated with higher incidences of viral and bacterial infections12.Multiple myeloma (MM) is a malignant proliferation of clonal B lymphoid cells at the last stage of maturation (plasma cells) that are responsible for the secretion of immunoglobulins (Igs). Impairment of Ig production, with the coexistence of a monoclonal component (M-component) plus immunosuppression of normal Igs, leads to severely impaired humoral immunity. Additionally, MM patients display dysfunctional cellular and innate immunity; this complex failure of immunosurveillance mechanisms makes MM patients highly susceptible to viral and bacterial infections13 and a small UK series of 75 heterogeneous patients that did not report a non-MM reference group of patients with COVID-1914. Several international and national guidelines have been reported19, providing guidance to physicians on the management of patients with MM during the COVID-19 pandemic; however, these recommendations are based on consensus and general disease concepts, and lack specific data derived from infected patients. To our knowledge, this is the first large case-series study to describe comprehensively the clinical characteristics of COVID-19 in hospitalized MM patients, compare outcomes with a noncancer cohort of COVID-19 patients, and identify preadmission prognostic factors of inpatient mortality.To date, there is very limited information regarding characteristics and outcomes of MM patients with COVID-19, with only a single case report20/Grupo Español de Mieloma8). The study was approved by the Institutional Review Board (IRB) of Hospital Universitario 12 de Octubre (n 20/208). This case-series study includes MM patients who were admitted to a participating hospital with a SARS-CoV-2 polymerase chain reaction (PCR)-positive test between March 1 and April 30, 2020. Additionally, a series of patients with no cancer history, matched by age and sex, were randomly selected from cohorts of COVID-19 patients admitted during the same time period at six participating hospitals.This multicenter case-series analysis was performed at a national level by the Spanish Myeloma Collaborative Group -PCR diagnostic assay was performed.A modified version of a questionnaire proposed by the International Myeloma Society was used for data extraction. A common set of demographic, clinical, laboratory, treatment, and outcome variables were collected for the MM and noncancer cohorts of hospitalized COVID-19 patients. Specific disease status and treatment data were obtained for MM patients. Data extraction was performed locally by hematology departments in participating hospitals and centrally processed by the PETHEMA/GEM data-monitoring unit. Hospital outcome status was defined as discharge from the hospital or receiving ongoing care (survivor group) or death (non-survivor group).21. We assessed internal validity with a bootstrapping procedure that used 500 replicate samples to gain insight into the stability of the reference model22. Analyses were generated using SAS/STAT software, Version 9.4, SAS Institute Inc.Demographic, clinical, laboratory, and therapy covariates and hospital outcomes were summarized using descriptive statistics. Continuous variables were reported as the median and interquartile range (IQR). Generic COVID-19 patient characteristics and specific MM features were analyzed according to the two hospital outcome categories. Crude and adjusted odd ratios (OR) with 95% confidence intervals (CI) were estimated with logistic regression analysis for a predefined set of well-established prognostic factors. Preadmission characteristics, MM status, and comorbidities constituted the reference model and were used to adjust the association of relevant MM features with mortality. To limit model overfitting, the number of events per candidate variable was restricted to >10. Calibration and discrimination of the resulting models were assessed using the Hosmer–Lemeshow goodness-of-fit test and the c-statisticBetween March 1 and April 30, 2020, 216 patients with MM and SARS-Cov-2 infection detected by RT-PCR were reported from 73 healthcare centers. Thirty patients were excluded because of a diagnosis of a plasma cell disorder other than MM; 19 patients were excluded because they did not require hospital admission  diagnosed between January and April 2020 (during the emerging pandemic) did not survive COVID-19. To understand this high mortality rate, we analyzed the characteristics of the cohort. Of note, 10 (83%) of the 12 non-survivors were male, 11 (92%) had a M-component other than IgG, 9 (75%) had international staging system stage III disease, 7 (58%) presented with renal impairment, and 7 (58%) had active disease. By contrast, 82% of patients who had received autologous stem cell transplantation (ASCT) survived COVID-19, while 41% of the non-ASCT group died  vs noncancer patients (23%). The main predictors of inpatient mortality for MM were male sex, age >65 years, renal disease, and active/progressive disease.This is a highly representative series for gaining insights into the impact of COVID-19 in the MM population; all Spanish hospitals were put under the governance of the Ministry of Health, and the structure of PETHEMA/GEM includes most centers treating MM patients within Spanish territory. The selected time-frame corresponded to peak COVID-19 incidence and population excess mortality in Spain. Additionally, to gain a more precise picture of the differential features of these patients, we obtained clinical and laboratory characteristics and hospital outcomes from a concomitant series of SARS-CoV-2-infected noncancer patients. To assure uniformity, the study focused solely on patients requiring hospital admission—we did not include MM patients who were treated as outpatients for COVID-19 and either was PCR-positive or just had COVID-19-compatible symptomatology since, in such a population, obtaining a complete case history could not be guaranteed.n = 73) ensured a representative mix of cases. The central data-monitoring unit worked closely with local sites to confirm data and on patient follow-up. Participating centers were long-term contributors to the PETHEMA/GEM research program; local data extractors at each site implemented common data element definitions.Participating centers covered the whole geographical territory of Spain, although half of the cases were reported from the Madrid region, where a higher number of COVID-19 cases were confirmed at the national level. A large number of participating hospitals  and hematologic diseases (33%), as well as immunocompromised patients (27.8%)27.As noted, inpatient mortality was higher in MM vs noncancer patients. This occurred despite the similarity between groups in the clinical severity of COVID-19. Rates of comorbidities appeared comparable between groups, except for renal disease, which has emerged as a critical feature in the outcome of SARS-CoV-2-infected MM patients. Interestingly, the presence of lymphopenia and higher levels of D-dimers and ferritin, laboratory findings associated with higher mortality rates in several global COVID-19 patient series28. By contrast, hypertension as a comorbidity was not a significant factor in the adjusted model. Other MM features such as high-risk cytogenetics and immunoparesis did not influence the outcome; the latter is of interest since humoral immunodeficiency, which is common in MM, would be considered a potential factor for elevated risk. Additionally, we observed that IgG isotype and stage I disease were associated with lower mortality.The higher inpatient mortality rate in MM vs noncancer patients can be explained through patient-related factors and MM features, besides the biology of the disease itself. Regarding patient-related factors, age >65 years and male sex emerged as two of the most important risk factors predicting inpatient mortality. Notably, and in contrast to noncancer COVID-19 populations, in which 75 years has been reported as the cutoff predicting peak risk of death, the mortality rate in MM did not differ above 65 years of age, suggesting that there are other factors intrinsic to MM that influence the outcome. Regarding MM features, renal insufficiency is a major hallmark of MM (one of the four myeloma-defining events); in the present series, its presence at hospital admission for COVID-19 emerged as the most important factor for survival (OR = 3.8). Renal impairment at diagnosis was also an adverse factor, but this significance was lost in the adjusted multivariate analysis. However, the strength of association with inpatient mortality of renal insufficiency at admission increased, and the independent prognostic value was retained in the multivariate analysis. Indeed, kidney disease as a prognostic factor predicting increased inpatient mortality rate in a general patient population has been previously described in a single-center study in ChinaRegarding MM status at hospital admission for COVID-19, as would be expected, the presence of uncontrolled disease had a detrimental effect on survival (OR = 2.6) and was one of the independent factors predicting outcome. This would help explain the significantly higher mortality rate observed in patients diagnosed at the time of pandemic (January–April 2020), since in most their disease was not adequately controlled; it is well known that newly diagnosed patients have an elevated risk of mortality due to infectious complications in the first 3 months of treatment. The benefit of disease control  in the context of COVID-19 would likewise explain the favorable outcome observed in patients who had previously received ASCT since most of them were in response.The non-participation of MM patients with unconfirmed COVID-19 or who were not hospitalized is a limitation in terms of the broader applicability of the study results. Further studies could be conducted to implement our analysis protocol in a less restricted population of patients. Another limitation is that our study is not able to identify optimal management and treatment of newly diagnosed MM patients with COVID-19.In conclusion, MM patients hospitalized with SARS-CoV-2 infection have a higher inpatient mortality rate than noncancer patients. This had been suspected since the beginning of the COVID-19 pandemic, and consequently national and international societies have published or made general recommendations about optimal management of MM patients. Our study assessed the impact of prior MM treatments based on immunomodulatory drugs, proteasome inhibitors, or monoclonal antibodies, and none of these influenced in the inpatient mortality rate. Although we cannot answer the question of whether to treat or not—and how—during the pandemic, we can stress the need for appropriate disease control in all patients, to minimize hospital visits, particularly in the most vulnerable MM populations such as male patients, those aged >65 years , and those with renal impairment, which is the most critical factor. Accordingly, MM patients requiring treatment due to active disease should be tested for COVID-19 by PCR and, if negative, we should proceed to optimize treatment in the most protective environment possible. In patients with the non-active disease, MM treatment could be postponed for 1–2 months; however, if patients are receiving maintenance therapy, treatment should continue. Further research is required to identify the most effective treatments for COVID-19, as well as vaccination strategies that should be employed as early as possible in the most vulnerable patients. Future studies should validate criteria for stratifying MM patients who are at greater risk in a healthcare crisis such as the COVID-19 pandemic and who could benefit from reducing their risk-exposure through a more stringent preventive strategy.


Maternal HIV coinfection is a key factor for mother-to-child transmission (MTCT) of HCV. However, data about HCV MTCT in HIV/HCV-coinfected pregnant women on combined antiretroviral treatment (ART) are scarce. This study assessed the HCV MTCT rate in the Madrid Cohort of HIV-infected women.Retrospective study within the Madrid Cohort of HIV-infected pregnant women (2000–2012). Epidemiological, clinical and treatment related variables were analysed for the mother and infant pairs. HCV MTCT rate was determined.Three hundred thirty-nine HIV/HCV-coinfected women and their exposed infants were recorded. A total of 227 (67%) paired mother-children had available data of HCV follow-up and were included for the analysis. Sixteen children  were HCV infected by 18 months of age, none of them coinfected with HIV. HIV/HCV-coinfected pregnant women were mostly of Spanish origin with a background of previous injection drug use. HCV-genotype 1 was predominant. The characteristics of mothers that transmitted HCV were similar to those that did not transmit HCV with respect to sociodemographic and clinical features. A high rate (50%) of preterm deliveries was observed. Infants infected with HCV were similar at birth in weight, length and head circumference than those uninfected.MTCT rates of HCV among HIV/HCV-coinfected women on ART within the Madrid cohort were lower than previously described. However, rates are still significant and strategies to eliminate any HCV transmission from mother to child are needed. Hepatitis C virus (HCV) infection has been recognised as a worldwide health problem in both adults and children, being the most common cause of chronic liver disease ,2. It isAfter the implementation of universal testing of blood transfusion products, mother-to-child transmission (MTCT) became the leading source of HCV infection in children ,4. MTCT However, many of these studies were performed before the combined antiretroviral therapy (ART) era, when women were more likely to be immunocompromised during pregnancy. Although antiretroviral therapy has no direct effect on HCV replication, the improved immunological condition or other unknown factors might contribute to a reduction of the vertical transmission rate reported in the natural history of the disease.Fewer studies have examined the rates of MTCT of HCV among HIV-coinfected women with well-controlled HIV disease. In a previous study among HIV/HCV-coinfected mothers from Latin American and the Caribbean, a rate of MTCT of HCV of 8.5%  was observed . This raTherefore, HCV MTCT among HIV/HCV coinfected women on stable antiretroviral treatment may be lower than reported in other coinfected population, presenting current rates of MTCT of HCV that are similar to those monoinfected. The primary objective of this study was to assess the MTCT rate of HCV among HCV/HIV-coinfected women, among infants with follow up testing available, in the ART era in Madrid, Spain.S1 Fig. A total of 227 (66.8%) paired mother and children with available data from HCV diagnostic tests (serology and molecular) were analysed. Mother-infant pairs without available information (n = 112) about HCV serology or PCR in children were compared with those included in the study (S1 Table). In this cohort, HCV PCR was performed per protocol at 3–6 months and HCV serology from 12–18 months of age, simultaneously to HIV serology. Absence of HCV infection was considered as both HCV negative and negative PCR in the first eighteen months. Infants were considered to be HCV-infected if HCV PCR was detected in at least 1 sample and they had persistence of HCV antibodies after 18 months of age. Infants with HCV RNA-positive samples followed by subsequent HCV RNA-negative results at the 6-month visit were classified as having transient HCV infection. Two comparisons were performed: mothers who had transmitted HCV to their infants (n = 16) versus mothers who had not (n = 211), and children with HCV infection (n = 16) versus non-infected (n = 211).This was a retrospective study within the Madrid cohort of HIV-infected pregnant women from 2000 to 2012. The Madrid Cohort of HIV-infected mother-infant pairs is a multicenter, prospective and observational study of HIV-1 infected women and their children. Since 2000, mother and infants pairs have been recruited from 8 hospitals in Madrid. The characteristics of the Madrid Cohort have been previously described elsewhere . All HIVWritten informed consent was obtained for all mother infant pairs. This study was reviewed and approved by the Ethics Committee from Hospital Universitario de Getafe, Madrid.Chi-squared and Fisher tests were applied to assess differences among the groups for categorical variables. For continuous variables, Student t-test and U-Mann Whitney were applied when appropriate. To estimate the effect of the different sociodemographic, epidemiological and clinical-virological variables, odds ratios (ORs) were calculated and 95% confidence intervals (95% CIs) were assessed using logistic regression. Statistical analysis and graphs were performed using R Software (R Core Team (2018), version 3.5.2, Vienna, Austria. ..All HIV/HCV-coinfected mothers from the Madrid cohort of HIV-infected pregnant women were included. A total of 227 paired mother and children were studied. HIV/HCV-coinfected mothers not included in the study due to absence of HCV diagnosis information, had lower HCV VL during pregnancy and were exposed to more rates of ART, compared to the HIV/HCV-coinfected mothers studied vs. 34 [31.5–36.5] years) and gestational age (38 [36–38] vs. 37.5 [36.8–39] weeks), with almost 50% of preterm births in both groups .The studied population was mainly from Spain 202/227 (88.9%), Caucasian 206/227 (90.7%), and mostly HIV-infected by parenteral drug use (IVDU) 148/227 (65.2%) and sexual transmission 58/227 (25.5%). Mothers that gave birth to HCV infected children were similar in terms of sociodemographic characteristics, with respect to the non-HCV transmitters. Both groups had similar age at delivery .Analysing the immunologic and virologic status, HCV transmitters mother presented a slightly lower measurement of CD4 and higher HIV viral load than the non-HCV transmitters mothers. However, these differences did not reach statistical significance , last CD4 count before delivery , or vaginal delivery .In terms of delivery-associated characteristics, there were not consistent differences between HCV transmitters and non-transmitters with regards to the type of delivery or ART Among 227 children included in the study, 16 were vertically HCV infected. All of them had a HCV PCR detected in at least 1 sample and a persistence of HCV antibodies after 18 months of age; thus, the HCV transmission rate from HIV/HCV-coinfected women in this cohort was 7.0 (95%CI 3.7–10.4%).Table 2).Newborns vertically HCV infected were similar in gender and physical examination  at birth with respect to non-HCV newborns (n = 211). No differences were found between groups  transmission rate, which appears to be lower than the rate reported in the literature previous to the extended use of ART ,12. We aOur study does not have the power to answer the question if HCV MTCT was lower in HIV/HCV-coinfected mothers due to improved access to ART, since most women received ART, and no comparisons could be made with HIV/HCV women not on ART. Our results may support the hypothesis of lower rates of HCV transmission in the current era as there is an accompanying lower rate of HIV transmission with better maternal HIV infection control during pregnancy. Although the HCV perinatal transmission rate shown in our study of 7.0% is lower than the previously reported in other studies and in a large meta-analysis , the broAmong risk factors, the majority of studies with scheduled Caesarean delivery in women with HCV infection, with or without HIV coinfection, have found that the procedure does not reduce the risk of perinatal transmission of HCV ,21. ThesThere is no consensus on the definition of MTCT of HCV. The definitions of HCV infection (ie viremic or non viremic) and of MTCT differ between studies and this may account for some of the variations between MTCT rates between publications. Nevertheless, it is commonly accepted that MTCT of HCV occurs if there is persistence of anti-HCV antibodies in a child over 18 months of age or the presence of HCV RNA in an infant older than 2 months of age in two different sampling occasions. Since 20% of infants born to HCV infected pregnant mothers may have spontaneous viral clearance, it is important to test for HIV RNA in plasma during the first months of life. Most studies suggest testing for HCV RNA at the age of 2–6 months to early detect HCV infection, along with serum anti-HCV during follow up at 18–24 months in order to verify the persistence or clearance of HCV antibodies ,12,27. SAlthough our study shows a HCV MTCT lower than the reported in the pre-ART era, it is consistent with current evidence in coinfected ART treated women in Europe and USA . NeverthPreterm deliveries proportion in this study (50%) were higher than the reported in this global same cohort (21.5%) , probablLimitations of this study included low sample size and the high percentage of missing diagnosis (30%) in children, which means that a significant number of women with a known HCV infection gave birth to children that remain untested. This fact has already been reported in other cohorts ,28. HoweAlthough multi cohort studies with a higher sample size are needed, this is a wide descriptive group that provides an relevant insight in HCV MTCT among HIV/HCV-coinfected women in the ART era. In conclusion, MTCT rates of HCV among HIV/HCV-coinfected women on ART within the Madrid cohort were lower than previously described. However, rates are still significant and strategies to eliminate any HCV transmission from mother to child are needed.S1 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Consistency among clinical symptoms, laboratory results and autopsy findings can be a quality measure in the diagnosis of coronavirus disease 2019 (COVID-19). There have been classic clinical cases that have met the case definition of COVID-19 but real-time reverse-transcription polymerase chain reaction (rRT-PCR) tests of nasopharyngeal swabs were negative.This study aimed to share pathological observations of autopsies performed at the 37 Military Hospital’s Department of Anatomical Pathology on three presumed COVID-19 cases in Accra, Ghana.Complete autopsies with detailed gross and histopathological analysis were conducted between April 2020 and May 2020 on three suspected COVID-19 cases, of which two had initial negative (rRT-PCR) nasopharyngeal tests. Postmortem bronchopulmonary samples of two cases were collected and tested by rRT-PCR for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).The two postmortem bronchopulmonary samples tested for SARS-CoV-2 by rRT-PCR were positive. Though no postmortem bronchopulmonary sample was taken from the third case, a close contact tested positive for SARS-CoV-2 in later contact tracing. For all three cases, lung histopathological findings were consistent with Acute Respiratory Distress Syndrome.The outcome of COVID-19 testing is dependent on the sample type and accuracy of sampling amongst other factors. Histopathological findings vary and may be dependent on a patient’s modifying factors, as well as the duration of infection. More autopsies are required to fully understand the pathogenesis of this disease in Ghanaians. As at the end of May 2020, over 7303 cases, 34 deaths and 2412 recoveries had been recorded.2 COVID-19 emerged from Wuhan, Hubei Province, China in December 2019, and is clinically associated with viral pneumonia.4 Clinical, laboratory and radiological features for COVID-19 are non-specific; features are similar to other respiratory tract infections.5 Thus, mild symptoms of COVID-19 such as fever, cough, dyspnoea, myalgia and fatigue were initially treated and managed as pneumonia symptoms by healthcare workers.The global estimate of confirmed cases of coronavirus disease 2019 (COVID-19) as of 27 May 2020 stood at over 5.5 million in approximately 213 countries and territories with over 349 190 deaths, giving a mortality rate of 15.7%.The World Health Orginization (WHO) Situation Report 94 defines a suspected COVID-19 case as:A] person presenting with acute respiratory illness  AND no aetiology that fully explains the clinical presentation; OR A patient with an acute respiratory illness AND has been in contact with a confirmed or probable case of COVID-19 in the last 14 days before the onset of symptoms; OR A patient with severe acute respiratory illness  AND in the absence of an alternative diagnosis that fully explains the clinical presentation. [7 However, there is an instance where DAD was not reported.8 Other pathological features that have been reported in the lung include: oedema, fibrinous exudates, reactive hyperplasia limited to some type II pneumocytes and patchy inflammatory changes with scattered multinucleated giant cells.7 Others report pathological similarities between these coronavirus infections: COVID-19, Severe Acute Respiratory Syndrome (SARS) and Middle Eastern respiratory syndrome.3The clinical presentation of COVID-19 infection varies from mild to moderate to severe. The severe presentation is reportedly characterized by Acute Respiratory Distress Syndrome. In line with this, diffuse alveolar damage (DAD) is a reported postmortem pathological feature of COVID-19; DAD is the histological correlate of Acute Respiratory Distress Syndrome. In the acute stage, DAD is characterized by hyaline membrane formation in the alveoli and the organizing stage by interstitial widening due to oedema and fibroblast proliferation.9 The authors suggested that infection with SARS coronavirus 2 (SARS-CoV-2) results in endotheliitis in several organs from the involvement of the virus and as part of the host inflammatory response. The authors hypothesized that a strategy that targets endotheliitis in susceptible patients  is likely to improve survival in such patients.9Though other pathological features have been reported in other organs, including the liver and heart, the changes in these organs have been less significant than those reported in the lung. The prominent role of endotheliitis in COVID-19 infection was highlighted in one such publication that reported the presence of viral inclusion in endothelial cells.10 The specificity of most real-time reverse-transcription (rRT) PCR tests is estimated at 100%, because the design of the primers is specific for the genome sequence of SARS-CoV-2. However, false-negative reports may occur and have been associated with intended and non-intended activities during case detection, patient preparation, sample collection, packaging, storage, transport and reporting.11Among nucleic acid tests, the polymerase chain reaction (PCR) method is considered the ‘gold standard’ for the detection of COVID-19, and it is characterized by rapid detection, high sensitivity and high specificity.11 Howbeit, the positivity rates of these samples vary; bronchoalveolar lavage has the highest positivity rate. In one study of 205 confirmed COVID-19 infections, the rRT-PCR positivity rate of bronchoalveolar lavage, sputum, nasal and oropharyngeal specimens were 93%, 72%, 63% and 32%, respectively.3The nasopharyngeal swabs or other upper respiratory tract specimens, including throat swabs or, more recently, saliva are the commonly used specimens for rRT-PCR diagnosis of COVID-19.Although confirmed deaths due to COVID-19 are being recorded, autopsy findings of COVID-19 reported deaths in Africa, including Ghana, are largely unavailable. This report shares pathological observations of autopsies performed at the 37 Military Hospital’s J.M. Wadhwani Department of Anatomical Pathology on three presumed COVID-19 cases. It also highlights the challenges associated with managing presumed cases.Due to the emergency nature of the pandemic, ethical review and approval was not conducted. However, all identifiers were removed from the report and verbal consent was also sought from the relations of the deceased, where required.The 37 Military Hospital, a 600-bed tertiary facility, is one of the largest hospitals in Ghana. Annually, the J.M. Wadhwani Department of Anatomical Pathology of the hospital conducts approximately 1500 hospital, medico-legal or coroner’s autopsies in its standard morgue facility.12The notices of death were received by the Department of Anatomical Pathology for two presumed COVID-19 cases who were being managed within the 37 Military Hospital. Also received at the department was a case referred from a peripheral hospital for a medico-legal or coroner’s autopsy to determine the cause of death. All cases were received between April 2020 and May 2020 and met the clinical case definition of COVID-19; antemortem SARS-CoV-2 tests of the two tested cases were negative. All cases were transported to the morgue under COVID-19 recommended protocols as published by the WHO.A complete autopsy was conducted on all cases with detailed gross and histopathological analysis. Examinations were performed in the department’s state-of-the-art morgue following guidelines for performing autopsies on presumed COVID-19 cases. Except in the coroner’s autopsy case, postmortem bronchopulmonary samples were collected, immediately placed in viral transport media and sent to the Noguchi Memorial Institute for Medical Research where rRT-PCR was performed.Selected organs  were sampled and fixed in 10% buffered formalin for histopathological studies. Organ slides were made, stained with haematoxylin and eosin and examined by certified histopathologists. Tissue sections were retained in formalin and blocks appropriately stored. Findings from the autopsy were corroborated by both clinical presentations and laboratory outcomes.The first case was a man with hypertension and diabetes who was in his late thirties. He had a non-productive cough, fever (39.5 °C) and had experienced breathlessness for six days before hospital admission. He alleged that he had no contact with a confirmed or probable COVID-19 case. A provisional diagnosis of COVID-19 was made, the patient was isolated, and a nasopharyngeal swab was taken for SARS-CoV-2 testing. The SARS-CoV-2 test result came in after his demise and was negative. Therefore, a coroner’s autopsy was requested and was performed to find out the cause of death . No postMicroscopic sections of the lungs show autolytic changes with bacterial colonization of the bronchioles . The proThe second case was a 60-year-old woman with hypertension who was morbidly obese and had in the past week been diagnosed with diabetes mellitus. She had a three-week history of worsening breathing difficulty, one day of unproductive cough and no history of asthma. She allegedly had no contact with a confirmed or probable case of COVID-19. She was being managed for bronchitis or asthma with no improvement. An initial diagnosis of pulmonary thromboembolism was made. Differential diagnoses were congestive cardiac failure due to hypertension or COVID-19 infection. She was therefore transferred from the emergency centre to the isolation unit. She was managed with intravenous fluids, anticoagulants, antibiotics, insulin and anti-hypertensive medications. A nasopharyngeal swab was taken for a COVID-19 test three days after admission.She experienced palpitation and dyspnoea but no orthopnoea, paroxysmal nocturnal dyspnoea, pedal oedema, calf tenderness or fever. She had an oxygen saturation of 85% at room air and 95% at non-rebreather oxygen, a normal pulse and a blood pressure of less than or equal to 140/90 mmHg throughout admission.She had a marginally increased neutrophil-white blood cell count and a high D-dimer of 1.26 ug/mL . Her liver function test showed deranged liver enzymes. However, renal function tests, C-reactive protein (3.6) and troponin were normal. A computerised tomogram scan was done, the pulmonary vessels were reported as normal .The PCR results for COVID-19 were returned as negative three days after sample collection. She was therefore transferred from the isolation unit to a general medical ward. She later suddenly developed severe respiratory distress, started desaturating and later died. An academic autopsy was ordered by the attending clinical team who queried the PCR COVID-19 result .A postmortem bilateral lung parenchymal swab was taken for SARS-CoV-2 testing. Microscopic examination of the lungs showed severe congestion with foci of haemorrhage. There was a proliferation of fibroblasts and infiltration of macrophages within the interstitium and in the alveolar space; DAD with characteristic hyaline membranes in the alveoli; and interstitial fibrosis and oedema. Fibrin thrombi, mostly located in the subpleural region were noted. The liver and spleen were poorly preserved. Microthrombi were also noted in some of the glomeruli . In the The third case was a 55 year old man with hypertension and diabetes who had a seven-day history of non-productive cough and dyspnoea. He had a fever, general weakness and headache but no chest pains, sore throat, leg swelling, paroxysmal nocturnal dyspnoea or orthopnoea. He had a recent travel history that suggested a COVID-19 exposure.10/L) with platelets at 185 × 1010/L. Liver and renal function tests were normal.The man was in respiratory distress; oxygen saturation- 56% on room air, 82% on non-rebreather oxygen and his temperature was 37.6 °C. His blood pressure was 175/94 mmHg, and his pulse rate was 112 beats per minute regular. He had no pallor of mucous membranes, not jaundiced and hydration was fair. Examinations of the chest revealed reduced air entry in lung bases with crepitations. There were bronchial breath sounds over lower zones. Heart sounds I and II were present, normal and no murmurs were heard. No bi-pedal oedema was also noticed. The abdomen was soft, non-tender and there was no organomegaly. A diagnosis of bilateral pneumonia to rule out COVID-19 in a patient with diabetes and hypertension was made. Pulmonary embolism was a differential diagnosis. He was managed on intravenous fluids, anticoagulants, antibiotics, insulin and anti-hypertensive medications. He had a low haemoglobin (11.5g/dL) and a high white blood cell count , it is acceptable to report COVID-19 on a death certificate as ‘probable’ or ‘presumed’. (p. 12)[et al.,7 and Xu et al.14The pathological presentation observed in the lungs were consistent with similar cases reported in Beijing and Oklahoma by Barton Bronchopulmonary sampling was not done for SARS-CoV-2 testing for Case 1 as a result of the psychological unpreparedness of the autopsy team for COVID-19 autopsies. Additionally, no immunohistochemical staining was done for histopathological samples collected to show the presence and distribution of immune cells in the lungs. Also, the quality of photomicrographs could have been better if the bodies were better preserved after death.Findings from this study indicate that autopsies are capable of reporting evidence of COVID-19 and provides insights for proper sample management for purposes of diagnosis. More so, the diagnosis of COVID-19 at autopsy is relevant in situations where molecular testing such as rRT-PCR is not available to inform relevant public health action. Bronchopulmonary samples for SARS-CoV-2 testing during postmortem should be taken for presumed COVID-19 cases. More autopsies are required to fully understand the pathogenesis of this disease in Ghanaians.


We describe a case of a 17-year-old male patient who was admitted to the hospital for an evaluation of his recurrent postprandial abdominal pain and fatigue on exertion. He was discovered to have severe post-ductal aortic coarctation (CoA) and uninterrupted left-sided inferior vena cava (IVC) draining into the right atrium crossing anterior to the abdominal aorta. There were no signs of IVC compression. Patient symptoms improved dramatically after CoA stenting on follow up. The presence of uninterrupted left-sided IVC in this particular case created a diagnostic dilemma, and it was of great importance to know such anomaly before the procedure. This association of uninterrupted left-sided IVC with CoA is unusual, and to our knowledge, our case is the first to report such congenital association. Aortic coarctation (CoA) is the sixth most common congenital heart disease (CHD), accounting for 4%-8% of all CHD and occurs in 4 out of 1,000 live births with a male predominance. CoA can occur as an isolated lesion but is often associated with other cardiovascular lesions, such as a bicuspid aortic valve (BAV) in 50%-75% of the cases, aortic arch hypoplasia, subaortic stenosis, mitral valve abnormalities, ventricular and atrial septal defects, and patent ductus arteriosus . On the A 17-year-old male with no previous medical illness was admitted to the hospital with abdominal pain. The patient had a long time history of generalized intermittent abdominal pain that increased postprandial without nausea or vomiting. The patient also had a history of fatigue on exertion. Upon checking vital signs, the patient was found to be hypertensive. There was a discrepancy between the upper (155-160/70-75 mmHg) and lower limbs (100-105/65-70 mmHg) readings. Cardiovascular examination showed a systolic ejection murmur best appreciated at the tip of the left scapula, and bracheo-femoral delay. The abdominal examination was unremarkable. His complete blood count, renal profile, liver profile, troponin, and brain natriuretic peptide were normal. Stool analysis and culture were normal. Electrocardiography revealed sinus rhythm and left ventricular (LV) hypertrophy Figure . An echoThe procedure was done under general anesthesia through the right femoral access. The pre-stenting peak gradient was 60 mmHg, which improved to 4 mmHg using 14 x 39 mm BeGraft aortic stent , which is a balloon-expandable covered stent. This was followed by post-stenting dilation with short non-compliant Z-Med balloon  Figure . No tempCHD can occur as an isolated entity or in combinations. Some of the combinations are common and can predict the presence of each other such as BAV and CoA . The comCongenital anomalies such as left-sided IVC are quite rare and usually do not require any intervention. However, the presence of such an abnormality can cause a diagnostic dilemma and create a challenge when managing other conditions that co-exist. We reported a case of a young man with uninterrupted left-sided IVC and CoA who underwent successful trans-catheter stent implantation. The association of uninterrupted left-sided IVC with CoA is unusual, and to our knowledge, our case is the first to report such a congenital association.


Since the approval of the first immune checkpoint inhibitor (ICI) 9 years ago, ICI-therapy have revolutionized cancer treatment. Lately, antibodies blocking the interaction of programmed cell death protein (PD-1) and ligand (PD-L1) are gaining momentum as a cancer treatment, with multiple agents and cancer types being recently approved for treatment by the US Food and Drug Administration (FDA). Unfortunately, immunotherapy often leads to a wide range of immune related adverse events (IRAEs), including several severe cardiac effects and most notably myocarditis. While increased attention has been drawn to these side effects, including publication of multiple clinical observational data, the underlying mechanisms are unknown. In the event of IRAEs, the most widely utilized clinical solution is administration of high dose corticosteroids and in severe cases, discontinuation of these ICIs. This is detrimental as these therapies are often the last line of treatment options for many types of advanced cancer. In this review, we have systematically described the pathophysiology of the PD-1/PD-L1 axis  and cardiac effects in pre-clinical models, clinical trials, autoimmune mechanisms, and immunotherapy in combination with other cancer treatments. We have also reviewed the current challenges in the diagnosis of cardiac events and future directions in the field. In conclusion, this review will delve into this expanding field of cancer immunotherapy and the emerging adverse effects that should be quickly detected and prevented. Immunotherapy is an emerging avenue for targeting cancer, particularly for difficult to treat cancers, like melanoma and non-small cell lung cancer . As a taDespite the rise of ICI-induced myocardial diseases, there is a gap in knowledge related to the pathological mechanisms. Several pre-clinical studies have attempted to model the clinical findings but produced discrepant results. Although PD-1 knockout mice display different cardiomyopathies , 9, cardThe PD-1 receptor was discovered in a screen of genes associated with apoptosis and found to be inducible on T- and B-cells , 11. In in vivo, expression is stimulated significantly by interferon-γ (IFN-γ) and with interleukin-1α (IL-1α) and IL-27  are allowed to attack tumor cells. In that regard, immune cell infiltration in the tumor microenvironment may affect the efficacy of immunotherapy . Some tuThe PD-1/PD-L1 axis has progressed rapidly from its discovery to cancer treatment. By employing the immune system against tumor cells, this innovative therapy can be utilized for a number of cancer types. However, IRAEs and autoimmune events were observed even early on in pre-clinical experiments.in vitro.Subsequent work on the PD-1 receptor found that knockout had varying effects based on the background of the mice. Interestingly, PD-1 knockout in C57BL/6 mice displayed a normal phenotype . HoweverIn the more autoimmune susceptible MRL mouse strain, PD-1 knockout led to fatal myocarditis and the formation of autoantibodies against cardiac myosin . The MRL+ T-cell-mediated myocarditis. Blockade of PD-L1 led to increased cardiac inflammation and circulating cTnI. PD-L1 has been found in non-immune cells and the expression in either cardiomyocytes or endothelial cells supports self-tolerance and the progression of cardiotoxic IRAEs.In contrast, Grabie et al.  found thYet due to strain variability in mice, the low rate of myocarditis, and lack of diagnostic modalities in both animals and patients, it is difficult to induce and detect these adverse cardiac effects in pre-clinical models. Additionally, humans and mice are exposed to different antigens, limiting the ability to model IRAEs. In response, an option is to lower immune self-tolerance in mice through genetic modifications .In clinical trials, the occurrence of myocarditis in clinical trials was rare but may be underestimated from lack of routine diagnostic imaging and cardiac monitoring. In an early analysis of ICI-induced myocarditis, 46% of patients also experienced a major adverse cardiac event (MACE), including cardiac arrest or death. Many cases had abnormal electrocardiogram, increased levels of cardiac troponin, and reduced left ventricular EF below 50% . ClinicaRadiation and immunotherapy have been separately utilized to treat cancer, but both have limiting side effects on several organs, including the heart. As with other cancer treatments, immunotherapy with radiotherapy is being investigated as a more efficacious treatment option than monotherapy. Although the combination of radiation and immunotherapy is not currently common in practice, it may become more prevalent as ICIs gain more use as front-line treatment options. Some researchers have studied the cardiac side effects of immunotherapy in subsets of patients who underwent prior radiation exposure. While the disease response to ICI was found to be better in irradiated patients, ICI-related pulmonary toxicity was significantly higher in this cohort. The cardiotoxic potential of such combination therapy warrants further studies .Animal and clinical studies show synergistic efficacy of combination therapy with radiation and ICIs , 30, 31.in vitro on cardiomyocytes (The presence of PD-L1 on non-immune cells is associated with self-tolerance from immune cells . Previoumyocytes  and endomyocytes  with themyocytes .The FDA first approved Ipilimumab in 2011 (anti-cytotoxic T-lymphocyte associated protein-4 or CTLA-4). Since accepting Pembrolizumab and Nivolumab in 2014 (anti-PD-1) and Atezolizumab in 2016 (anti-PD-L1), these ICIs have seen expanded use in more cancer types –40. The Combination therapy appeared to induce IFN-γ and tumor necrotic factor (TNF-α) production in mouse cardiac tissue . FurtherCTLA4 knock-in mouse. When this model included PD-1 antibody, severe IRAEs were observed, including inflammation of many organs. The researchers observed dilated cardiomyopathy, myocarditis, and elevated serum cTnI. The combination treatment amplified the severity of autoimmune reaction with more autoreactive T-cells and Tregs.Du et al.  were ablRecently, Wei et al.  created Combination therapy against both PD-1 and PD-L1 can also have negative consequences. Liu et al.  observedPreviously, patients with prior autoimmune diseases were not included in immunotherapy clinical trials. Retrospective studies have shown that there is a similar or slightly higher rate of IRAEs with these patients, although the effects are often manageable without the need to end ICI treatment –54. Curr+ cell counts and there were no changes in the expression of previously observed genes. As the authors concluded, this data may support that prior autoimmune deficiencies can affect the presence of subsequent IRAEs.In a mouse model, experimental autoimmune myocarditis (EAM) was induced by injecting a fragment of cardiac myosin to induce inflammation . TsuruokAt present, there are also different proposed mechanisms as to whether T-cell reactivity to antigens or autoantibody formation play a role in IRAEs . While t+ T-cells. These cells can then differentiate to Th17 effector cells, thereby decreasing Tregs and supporting the formation of autoantibodies.Elevated cardiac troponin levels in serum are a common biomarker for myocardial injury and cardiac troponin T (cTnT) was previously found to be elevated in a majority of ICI-induced myocarditis cases . InteresBased on observations of IgG deposition against cTnI and cardiomyocytes in previous mouse models, Bockstahler et al.  injectedAt present, ICI-related myocarditis is difficult to detect in patients, even with serial testing of cardiac troponin levels. cTnT was previously found to be elevated in a majority of ICI-induced myocarditis cases . HoweverIn contrast, many cases do not display decreased LVEF but a recent study observed decreased global longitudinal strain (GLS), with or without preserved EF, that correlated with MACE . While eAnother obstacle to characterizing these adverse side effects is the lack of robust animal models. PD-1 knockout mice have shown variable phenotypes but some of the seminal work on the PD-1/PD-L1 axis observed a range of autoimmune and cardiac defects. Currently, multimodality treatment options have gained traction for cancer therapy but may also have synergistic, negative side effects. While these side effects are being investigated in clinical trials, radiation and combination immunotherapy protocols could also be utilized in animal models. Based on the clinical experience, a combination immunotherapy treatment could better exhibit ICI-induced myocarditis in an animal model. There is also the utility of genetic models, including recent advancements by Wei et al.  to creatSX took the lead in writing the review while CT contributed sections of the Early Pre-clinical and Clinical Studies. UCS conceived the review subject and outline while both UCS and SP provided feedback and additional references. UCS also aided the creation of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background: Giant hypothalamic hamartomas (HHs) are extremely rare lesions, for which the treatment is challenging. While minimally invasive treatments such as radiofrequency thermal coagulation and laser ablation have improved seizure outcomes, multiple operations are often required. This study investigated the value of one-stage stereo-array radiofrequency thermocoagulation based on stereotactic electroencephalography (SEEG) for pediatric giant HHs.Methods: We analyzed the clinical data of six patients with giant HHs (masses with a maximum diameter >30 mm) who underwent stereotactic electrode implantation between November 2017 and April 2019. After a multidisciplinary discussion, we designed a high-density focal stereo-array electrode implantation strategy. SEEG-guided bipolar coagulations were performed between two contiguous contacts of the same electrode, or between two adjacent contacts of different electrodes.Results: Among the six patients, three were male and three were female, with an average age of 5.08 ± 4.73 years ; the average follow-up duration was 20.17 ± 5.49 months. One patient had previously undergone open surgery. Four patients had gelastic seizures, one had gelastic and tonic seizures, and one had gelastic and generalized tonic-clonic seizures. The number of implanted electrodes ranged from 3 to 7, with an average of 5.33. One patient had transient diabetes insipidus after the operation, and no child had fever or new hormone metabolisms disorder after surgery. Four patients had Engel I classification outcomes (free from disabling seizures), and two patients had Engel II classification outcomes.Conclusion: Although the exploration of epileptic activity and the extent of ablation are limited by the number of SEEG electrodes for the complete disconnection. One-stage high-density focal stereo-array SEEG-guided radiofrequency was safe and effective for treating pediatric giant HH patients. It can be an alternative method to treat giant HHs where LITT is unavailable. Hypothalamic hamartomas (HHs) are rare congenital abnormalities  that typPreviously, craniotomy was the first choice for HH treatment , but thiSix consecutive patients  with a confirmed HH diagnosis who underwent SEEG-guided RF-TC at Children's Hospital of Fudan University  between November 2017 and April 2019 were enrolled in this retrospective study. All patients had HH manifesting as seizures with or without precocious puberty. No cases of HH-associated epilepsy without gelastic seizures enrolled in our case series. Giant HH was defined as masses with a maximum diameter >30 mm , 22. Thiwww.mccauslandcenter.sc.edu/mricro/mricron), Brainsuit (www.brainsuite.org) and Amira . The key point of the RF-TC strategy is to achieve sufficient coagulation of the interface of the hamartoma with the hypothalamus. The trajectory of the coagulation electrodes was set to pass through the interface using 3D image planning software . According to the shape and location of the hamartoma, we designed the electrode implantation scheme as: (1) for giant HHs with broad interfaces attached to the floor of the third ventricle, the electrodes were designed to disconnect the pedicel in a stereo-manner  T1-weighted sequence  and a 3D coronal FLAIR sequence (1 mm) with fat suppression were obtained as well as long-term video scalp electroencephalography (EEG). Based on the information obtained, strategies for electrode implantation were designed after multidisciplinary discussions. All HH patients with seizures underwent SEEG implantation following a previously described protocol with modifications . We usedo-manner ; (2) foro-manner ; (3) theBefore thermal coagulation, post-implantation assessments including: (1) the exact contact location observed using postoperative 3D computed tomography scan, which was co-registered with the preoperative 3D T1-weighted MRI; (2) intracranial video EEG was performed to monitor both ictal and interictal activity; (3) seizure foci mapping during intracranial video EEG recording.The electrode contacts within the HH were selected for RF-TC. This process involved gradually increasing the coagulation power from 0 to 3.5 W over 15 s, holding the coagulation power at 3.5 W for 45 s, which was performed under general anesthesia. A contiguous bipolar RF-TC using one electrode was considered to be one-dimensional, while RF-TC using coupling contacts from two electrodes in one plane was two-dimensional. Three-dimensional cross-bonding of various electrode contacts provided a novel method to optimize SEEG-guided RF-TC . ThroughFollow-up included recording seizure outcomes according to Engel's classification , as wellA summary of the characteristics and results of the children who underwent SEEG-guided RF-TC is presented in n = 1), only in deeper area (n = 1), only near the interface (n = 2) , whereas other seizure types were not elicited . All pat (n = 2) . The conSeizure outcomes were analyzed in all children for at least 11 months of clinical follow-up. The average duration of follow-up was 20.17 ± 5.49 months. All patients achieved an obvious decrease in seizure frequency. Four patients had Engel I classification outcomes (free from disabling seizures) and two had Engel II classification outcomes. Tonic seizures disappeared but gelastic seizures continued in patient No. 2, while gelastic seizures disappeared but generalized tonic-clonic seizures continued in patient No. 4. However, all residual seizures showed significantly decreased frequency in both patients.We analyzed the records for evidence of any SEEG or RF-TC-related complications, including infection, hemorrhage, medical complications, and hardware-related complications . Based oHH is a rare congenital disorder characterized by precocious puberty, seizures, and mental retardation . TraditiAlthough laser ablation is a safe and effective alternative treatment for gelastic seizures related to HH, the treatment for giant HH is still challenging. A recent study reported that two Delalande type IV hamartoma patients failed to achieve seizure freedom after laser ablation . MRI-guiThe main weakness of SEEG-guided RF-TC is the limited range of thermal coagulation. To solve this problem, we used dense stereotactic electrode array implantation to cover the lesions, especially sites where the hamartoma base was connected with normal structures. On the basis of the single electrode thermocoagulation, 3D cross-bonding of contacts between electrodes was further used to maximally destroy the hamartoma, especially the pedicles of hamartoma attachment, which had good effects. Using this method, we were able to fully record the discharge in the hamartoma and destroy it fully in one stage, with good efficacy. If the patients have residual seizures, additional surgery could be applied . As showBecause giant HHs are often so large and closely connected to important structures of the hypothalamus, there is still a chance for complications, including DI and hyponatremia, but these complications were transient and did not result in long-term impairment of the patients' quality of life. As most of our patients were younger, recovery may be better.SEEG-guided RF-TC is a unique and promising technique that can be used to directly manipulate HH based on both SEEG and MRI signals. SEEG could show ictal activity of gelastic seizures in HH. Although the exploration of SEEG and the extent of ablation were restricted by the number of SEEG electrodes, ablation using multiple SEEG electrodes enabled maximum ablation. One-stage high-density focal stereo-array SEEG-guided radiofrequency was safe and effective for treating pediatric giant HH patients. It can be an alternative method to treat giant HHs where LITT is unavailable.All datasets generated for this study are included in the article/supplementary material.The studies involving human participants were reviewed and approved by the Medical Ethics Committee of Children's Hospital of Fudan University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.MW and YZho: study concept and design, data collection and analysis, drafting and revision of manuscript, and full responsibility of data. YZha and WS: data collection, analysis, and manuscript revision. SZ and YW: data collection and statistical analysis. HL and RZ: study concept and design, critical revision, and review of final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.