Middle East Respiratory Syndrome Coronavirus Infection Dynamics and Antibody Responses among Clinically Diverse Patients, Saudi Arabia.

Middle East respiratory syndrome coronavirus (MERS-CoV) shedding and antibody responses are not fully understood, particularly in relation to underlying medical conditions, clinical manifestations, and mortality. We enrolled MERS-CoV-positive patients at a hospital in Saudi Arabia and periodically collected specimens from multiple sites for real-time reverse transcription PCR and serologic testing. We conducted interviews and chart abstractions to collect clinical, epidemiologic, and laboratory information. We found that diabetes mellitus among survivors was associated with prolonged MERS-CoV RNA detection in the respiratory tract. Among case-patients who died, development of robust neutralizing serum antibody responses during the second and third week of illness was not sufficient for patient recovery or virus clearance. Fever and cough among mildly ill patients typically aligned with RNA detection in the upper respiratory tract; RNA levels peaked during the first week of illness. These findings should be considered in the development of infection control policies, vaccines, and antibody therapeutics.

Transmission of MERS-coronavirus in household contacts.

BACKGROUND: Strategies to contain the Middle East respiratory syndrome coronavirus (MERS-CoV) depend on knowledge of the rate of human-to-human transmission, including subclinical infections. A lack of serologic tools has hindered targeted studies of transmission. METHODS: We studied 26 index patients with MERS-CoV infection and their 280 household contacts. The median time from the onset of symptoms in index patients to the latest blood sampling in contact patients was 17.5 days (range, 5 to 216; mean, 34.4). Probable cases of secondary transmission were identified on the basis of reactivity in two reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays with independent RNA extraction from throat swabs or reactivity on enzyme-linked immunosorbent assay against MERS-CoV S1 antigen, supported by reactivity on recombinant S-protein immunofluorescence and demonstration of neutralization of more than 50% of the infectious virus seed dose on plaque-reduction neutralization testing. RESULTS: Among the 280 household contacts of the 26 index patients, there were 12 probable cases of secondary transmission (4%; 95% confidence interval, 2 to 7). Of these cases, 7 were identified by means of RT-PCR, all in samples obtained within 14 days after the onset of symptoms in index patients, and 5 were identified by means of serologic analysis, all in samples obtained 13 days or more after symptom onset in index patients. Probable cases of secondary transmission occurred in 6 of 26 clusters (23%). Serologic results in contacts who were sampled 13 days or more after exposure were similar to overall study results for combined RT-PCR and serologic testing. CONCLUSIONS: The rate of secondary transmission among household contacts of patients with MERS-CoV infection has been approximately 5%. Our data provide insight into the rate of subclinical transmission of MERS-CoV in the home.

Epidemiology of a Novel Recombinant Middle East Respiratory Syndrome Coronavirus in Humans in Saudi Arabia.

BACKGROUND: Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory illness in humans. Fundamental questions about circulating viruses and transmission routes remain. METHODS: We assessed routinely collected epidemiologic data for MERS-CoV cases reported in Saudi Arabia during 1 January-30 June 2015 and conducted a more detailed investigation of cases reported during February 2015. Available respiratory specimens were obtained for sequencing. RESULTS: During the study period, 216 MERS-CoV cases were reported. Full genome (n = 17) or spike gene sequences (n = 82) were obtained from 99 individuals. Most sequences (72 of 99 [73%]) formed a discrete, novel recombinant subclade (NRC-2015), which was detected in 6 regions and became predominant by June 2015. No clinical differences were noted between clades. Among 87 cases reported during February 2015, 13 had no recognized risks for secondary acquisition; 12 of these 13 also denied camel contact. Most viruses (8 of 9) from these 13 individuals belonged to NRC-2015. DISCUSSIONS: Our findings document the spread and eventual predominance of NRC-2015 in humans in Saudi Arabia during the first half of 2015. Our identification of cases without recognized risk factors but with similar virus sequences indicates the need for better understanding of risk factors for MERS-CoV transmission.

Progress toward malaria elimination in Jazan Province, Kingdom of Saudi Arabia: 2000-2014.

BACKGROUND: The draft Global Technical Strategy for malaria aims to eliminate malaria from at least 10 countries by 2020. Yemen and Saudi Arabia remain the last two countries on the Arabian Peninsula yet to achieve elimination. Over the last 50 years, systematic efforts to control malaria in the Kingdom of Saudi Arabia has successfully reduced malaria cases to a point where malaria is now constrained largely to Jazan Province, the most south-western area along the Red Sea. The progress toward elimination in this province is reviewed between 2000 and 2014. METHODS: Data were obtained from the Ministry of Health case-reporting systems, activity reports, unpublished consultants reports, and relevant scientific published papers. Sub-provincial population data were obtained the national household censuses undertaken in 2004 and 2010. Rainfall data were obtained from the Meteorological Department in Jazan. RESULTS: Between 2000 and 2014 there were 5522 locally acquired cases of malaria and 9936 cases of imported malaria. A significant reduction in locally acquired malaria cases was observed from 2000 to 2014, resulting in an average annual incidence (2010-2014) of 0.3 cases per 10,000 population. Conversely imported cases, since 2000, remain consistent and higher than locally acquired cases, averaging between 250 and 830 cases per year. The incidence of locally acquired cases is heterogeneous across the Province, with only a few health districts contributing the majority of the cases. The overall decline in malaria case incidence can be attributed to coincidental expansion of control efforts and periods of exceptionally low rainfall. CONCLUSIONS: Jazan province is poised to achieve malaria elimination. There is a need to change from a policy of passive case detection to reactively and proactively detecting infectious reservoirs that require new approaches to surveillance. These should be combined with advanced epidemiological tools to improve the definitions of epidemiological receptive and hotspot malaria risk mapping. The single largest threat currently remains the risks posed by imported infections from Yemen.

Respiratory tract samples, viral load, and genome fraction yield in patients with Middle East respiratory syndrome.

BACKGROUND: Analysis of clinical samples from patients with new viral infections is critical to confirm the diagnosis, to specify the viral load, and to sequence data necessary for characterizing the viral kinetics, transmission, and evolution. We analyzed samples from 112 patients infected with the recently discovered Middle East respiratory syndrome coronavirus (MERS-CoV). METHODS: Respiratory tract samples from cases of MERS-CoV infection confirmed by polymerase chain reaction (PCR) were investigated to determine the MERS-CoV load and fraction of the MERS-CoV genome. These values were analyzed to determine associations with clinical sample type. RESULTS: Samples from 112 individuals in which MERS-CoV was detected by PCR were analyzed, of which 13 were sputum samples, 64 were nasopharyngeal swab specimens, 30 were tracheal aspirates, and 3 were bronchoalveolar lavage specimens; 2 samples were of unknown origin. Tracheal aspirates yielded significantly higher MERS-CoV loads, compared with nasopharyngeal swab specimens (P = .005) and sputum specimens (P = .0001). Tracheal aspirates had viral loads similar to those in bronchoalveolar lavage samples (P = .3079). Bronchoalveolar lavage samples and tracheal aspirates had significantly higher genome fraction than nasopharyngeal swab specimens (P = .0095 and P = .0002, respectively) and sputum samples (P = .0009 and P = .0001, respectively). The genome yield from tracheal aspirates and bronchoalveolar lavage samples were similar (P = .1174). CONCLUSIONS: Lower respiratory tract samples yield significantly higher MERS-CoV loads and genome fractions than upper respiratory tract samples.

Scope and extent of healthcare-associated Middle East respiratory syndrome coronavirus transmission during two contemporaneous outbreaks in Riyadh, Saudi Arabia, 2017.

OBJECTIVE: To investigate a Middle East respiratory syndrome coronavirus (MERS-CoV) outbreak event involving multiple healthcare facilities in Riyadh, Saudi Arabia; to characterize transmission; and to explore infection control implications. DESIGN: Outbreak investigation. SETTING: Cases presented in 4 healthcare facilities in Riyadh, Saudi Arabia: a tertiary-care hospital, a specialty pulmonary hospital, an outpatient clinic, and an outpatient dialysis unit. METHODS: Contact tracing and testing were performed following reports of cases at 2 hospitals. Laboratory results were confirmed by real-time reverse transcription polymerase chain reaction (rRT-PCR) and/or genome sequencing. We assessed exposures and determined seropositivity among available healthcare personnel (HCP) cases and HCP contacts of cases. RESULTS: In total, 48 cases were identified, involving patients, HCP, and family members across 2 hospitals, an outpatient clinic, and a dialysis clinic. At each hospital, transmission was linked to a unique index case. Moreover, 4 cases were associated with superspreading events (any interaction where a case patient transmitted to ≥5 subsequent case patients). All 4 of these patients were severely ill, were initially not recognized as MERS-CoV cases, and subsequently died. Genomic sequences clustered separately, suggesting 2 distinct outbreaks. Overall, 4 (24%) of 17 HCP cases and 3 (3%) of 114 HCP contacts of cases were seropositive. CONCLUSIONS: We describe 2 distinct healthcare-associated outbreaks, each initiated by a unique index case and characterized by multiple superspreading events. Delays in recognition and in subsequent implementation of control measures contributed to secondary transmission. Prompt contact tracing, repeated testing, HCP furloughing, and implementation of recommended transmission-based precautions for suspected cases ultimately halted transmission.

Waldenström's macroglobulinemia and large B-cell central nervous system lymphoma: a case report.

BACKGROUND: Waldenström's macroglobulinemia is a low-grade B-cell lymphoma characterized by monoclonal synthesis and secretion of IgM antibodies [3]. The classic symptoms of WM result from blood hyperviscosity. Neurologic symptoms, such as fatigue, dizziness, and blurred vision, are common. The metastatic spread to the CNS, which rarely has been reported, can occur either diffusely or in the form of a mass lesion. CASE DESCRIPTION: We present the case of a 73-year-old woman with intracerebral large B-cell lymphoma and concurrent WM. CONCLUSION: This case illustrates the importance of histopathologic diagnosis by brain biopsy despite an existing diagnosis of systemic neoplasm.

Infectious MERS-CoV Isolated From a Mildly Ill Patient, Saudi Arabia.

Middle East respiratory syndrome coronavirus (MERS-CoV) is associated with a wide range of clinical presentations, from asymptomatic or mildly ill to severe respiratory illness including death. We describe isolation of infectious MERS-CoV from the upper respiratory tract of a mildly ill 27-year-old female in Saudi Arabia 15 days after illness onset.

Margin Analysis: Sarcoma of the Head and Neck.

Head and neck sarcomas are rare but are associated with significant morbidity/mortality and management difficulties. These tumors are best managed in a multidisciplinary setting. Open or core biopsy is essential for histologic diagnosis and grading. Complete surgical tumor resection with negative margins at the first attempt is the best chance for potential cure. In most patients, except those with small resectable low-grade lesions, adjuvant radiotherapy and chemotherapy are added to maximize local control with variable results. Resection margins effect on recurrence rate and treatment modalities in selective types of head and neck sarcomas are discussed in this article.

Sexually transmitted infections case notification rates in the Kingdom of Saudi Arabia, 2005-2012.

INTRODUCTION: Sexually transmitted infections (STIs) are major public health concerns around the world. This study describes the epidemiology of reported STI cases from 2005 to 2012 in the Kingdom of Saudi Arabia. METHODOLOGY: The annual registry was the main source of data as reported by healthcare providers. Case definitions were based on positive human immunodeficiency virus (HIV) antibodies detectable by enzyme-linked immunosorbent assay (ELISA) and confirmed by western blot test for HIV cases. The definitions of other STIs were based on published Centers for Disease Control and Prevention (CDC) definitions. RESULTS: During the study period, 68,886 new cases were reported, with nongonococcal urethritis being the highest STI (25.4) per 100,000 population (25.4), followed by trichomoniasis (9.1), HIV (7), human papillomavirus (HPV) infection (2.9), and syphilis (1.3). The cases included nongonococcal urethritis (n = 35,613; 51.7%), trichomoniasis (n = 12,679; 18.4%), gonococcal urethritis (n = 3,006; 4.4%), syphilis (n = 1,769; 2.6%), HIV (n = 9,843; 14.3%), genital warts (n = 4,018; 5.8%), genital herpes (n = 1,508; 2.2%), and chancroid (n = 450; 0.7%). Saudi contribution to HIV cases increased from 28.9% in the preceding decade to 43.5% in the current study. CONCLUSIONS: Nongonococcal urethritis, trichomoniasis, and HIV were the most commonly reported STIs in the Kingdom of Saudi Arabia.

A Curious Case of Proximal Muscle Weakness with Eosinophilic Polymyositis.

Eosinophilic polymyositis (EPM) is part of a rare disorder, eosinophilic myopathies (EM), which is a form of polymyositis characterized by the presence of eosinophils in muscle biopsy sections and occasionally blood eosinophilia. Herein, we are presenting an interesting case of eosinophilic polymyositis presenting with muscle pain with no other organ systems involved.

Increase in Middle East Respiratory Syndrome-Coronavirus Cases in Saudi Arabia Linked to Hospital Outbreak With Continued Circulation of Recombinant Virus, July 1-August 31, 2015.

During July-August 2015, the number of cases of Middle East respiratory syndrome (MERS) reported from Saudi Arabia increased dramatically. We reviewed the 143 confirmed cases from this period and classified each based upon likely transmission source. We found that the surge in cases resulted predominantly (90%) from secondary transmission largely attributable to an outbreak at a single healthcare facility in Riyadh. Genome sequencing of MERS coronavirus from 6 cases demonstrated continued circulation of the recently described recombinant virus. A single unique frameshift deletion in open reading frame 5 was detected in the viral sequence from 1 case.

The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity.

PURPOSE: To evaluate carboplatin, etoposide, and bleomycin (JEB) in children with malignant extracranial germ cell tumors (GCTs). PATIENTS AND METHODS: Malignant GCTs in children aged 0 to 16 years were excised without major morbidity or otherwise biopsied. Stage I testicular and some ovarian GCTs were resected and monitored with alpha-fetoprotein (AFP) ("watch-and-wait" approach). Patients with recurrent stage I disease and all other patients received JEB (etoposide 120 mg/m(2) on days 1 through 3, carboplatin 600 mg/m(2) on day 2, and bleomycin 15 mg/m(2) on day 3). Courses were administered every 3 to 4 weeks until remission, and then two more courses were given. Chemotherapy toxicities were assessed using World Health Organization or Brock grading. RESULTS: Between January 1989 and December 1997, 192 patients were registered. Eight were excluded because either there was no histologic diagnosis (n = 3) or chemotherapy was given off-study (n = 5). The remaining 184 patients had germinoma (n = 20), malignant teratoma (n = 55), embryonal carcinoma (n = 1), yolk sac tumor (n = 107), or choriocarcinoma (n = 1). Forty-seven patients were treated with surgery alone, and 137 patients received JEB. The 5-year survival rate in March 1999 for all 184 patients was 93.2% (95% confidence interval [CI], 87.9% to 96.3%); for the 137 JEB-treated patients, it was 90.9% (95% CI, 83.9% to 95.0%), with an event-free survival rate of 87.8% (95% CI, 81.1% to 92.4%). The median follow-up after JEB treatment was 53 months (range, 0 to 109 months); the median number of courses was five (range, three to eight). Site, stage, and AFP level had prognostic significance. Nonfatal hematologic toxicity was common, but deafness and pulmonary and renal toxicities were rare. One child died of a thoracic tumor and bronchopulmonary dysplasia, and another died of acute myeloid leukemia. CONCLUSION: Conservative surgery, a watch-and-wait approach after complete excision, and JEB for those requiring chemotherapy produced high cure rates and few serious complications.

Presence of Middle East respiratory syndrome coronavirus antibodies in Saudi Arabia: a nationwide, cross-sectional, serological study.

BACKGROUND: Scientific evidence suggests that dromedary camels are the intermediary host for the Middle East respiratory syndrome coronavirus (MERS-CoV). However, the actual number of infections in people who have had contact with camels is unknown and most index patients cannot recall any such contact. We aimed to do a nationwide serosurvey in Saudi Arabia to establish the prevalence of MERS-CoV antibodies, both in the general population and in populations of individuals who have maximum exposure to camels. METHODS: In the cross-sectional serosurvey, we tested human serum samples obtained from healthy individuals older than 15 years who attended primary health-care centres or participated in a national burden-of-disease study in all 13 provinces of Saudi Arabia. Additionally, we tested serum samples from shepherds and abattoir workers with occupational exposure to camels. Samples were screened by recombinant ELISA and MERS-CoV seropositivity was confirmed by recombinant immunofluorescence and plaque reduction neutralisation tests. We used two-tailed Mann Whitney U exact tests, χ(2), and Fisher's exact tests to analyse the data. FINDINGS: Between Dec 1, 2012, and Dec 1, 2013, we obtained individual serum samples from 10,009 individuals. Anti-MERS-CoV antibodies were confirmed in 15 (0·15%; 95% CI 0·09-0·24) of 10,009 people in six of the 13 provinces. The mean age of seropositive individuals was significantly younger than that of patients with reported, laboratory-confirmed, primary Middle Eastern respiratory syndrome (43·5 years [SD 17·3] vs 53·8 years [17·5]; p=0·008). Men had a higher antibody prevalence than did women (11 [0·25%] of 4341 vs two [0·05%] of 4378; p=0·028) and antibody prevalence was significantly higher in central versus coastal provinces (14 [0·26%] of 5479 vs one [0·02%] of 4529; p=0·003). Compared with the general population, seroprevalence of MERS-CoV antibodies was significantly increased by 15 times in shepherds (two [2·3%] of 87, p=0·0004) and by 23 times in slaughterhouse workers (five [3·6%] of 140; p<0·0001). INTERPRETATION: Seroprevalence of MERS-CoV antibodies was significantly higher in camel-exposed individuals than in the general population. By simple multiplication, a projected 44,951 (95% CI 26,971-71,922) individuals older than 15 years might be seropositive for MERS-CoV in Saudi Arabia. These individuals might be the source of infection for patients with confirmed MERS who had no previous exposure to camels. FUNDING: European Union, German Centre for Infection Research, Federal Ministry of Education and Research, German Research Council, and Ministry of Health of Saudi Arabia.

Intestinal microvillous dystrophy: a variant of microvillous inclusion disease or a new entity?

We report three patients with intestinal microvillous dystrophy, two of whom were siblings. The relatively delayed clinical presentation and the lack of classical microvillous inclusions distinguish these cases from the previously described microvillous inclusion disease (MVID). There appears to be an underrecognized spectrum of microvillous disorders leading to fatal intractable secretory diarrhea in infants. In our three cases the diagnosis was suggested by periodic acid-Schiff (PAS) and alkaline phosphatase preparations of a jejunal biopsy specimen showing thinning or absence of brush border staining, which was confirmed by electron microscopy. The latter showed poorly developed and haphazardly arranged microvilli with intracytoplasmic vesicular bodies but no true inclusions. As in MVID, the prognosis of intestinal microvillous dystrophy is poor. The occurrence of the disease in two siblings of consanguinous parents suggests an autosomal recessive inheritance, and like MVID, genetic counselling of affected families is essential.

Histologic and immunohistochemical investigation of neuroblastomas and correlation with prognosis.

Forty-one confirmed cases of childhood neuroblastoma diagnosed over a 13-year period were reviewed and reclassified. Most of the tumors were stained using a peroxidase antiperoxidase method for neuron specific enolase (NSE), protein gene product (PGP) 9.5, and S100 protein, all of which have previously been reported to be positive in some neuroblastomas. The relation to prognosis of the histology and immunohistochemistry was studied. There was a significant trend toward improved survival with increasing degree of differentiation, and with decreasing mitosiskaryorrhexis index (MKI) in the stroma-poor group. There was no significant correlation between immunohistochemical staining and survival, although the presence and amount of staining for all three markers tended to increase with tumor differentiation. This study concludes that histologic classification in neuroblastoma is helpful in assessing prognosis but that the clinical features are generally more reliable as indicators of prognosis. The immunohistochemistry of markers used did not contribute towards assessment of prognosis.

'Clustering'--real or apparent? Probability maps of childhood cancer in the West Midlands Health Authority region.

The West Midlands Regional Children's Tumour Registry collects detailed information on all cases of childhood cancer in the West Midlands Health Authority Region (WMHAR). The distribution by electoral ward of all cases diagnosed in the WMHAR between 1980 and 1984 has been determined. Analysis has also been performed for leukaemias/non-Hodgkin's lymphomas alone. We suggest that this latter grouping should be universally employed, owing to the difficulty of accurately separating out cases of leukaemia. Both spatial analyses showed several wards with significantly excessive rates on the basis of their cumulative Poison probability. Observed/expected ratios of 3-35 were seen for cases in significant wards, which are similar to the ratios seen in analysis of incidence around nuclear installations. However, further detailed consideration of these individual significance levels in the light of the number of statistically significant wards which would occur by chance alone, due to the multiple use of the test, accounted completely for the number of wards obtained in each of the groups considered. Thus, apparent 'clustering' of cases could be mere statistical artefact. In the WMHAR, therefore, using the technique of probability mapping, no true spatial pattern of incidence was found, other than that which would occur by chance alone. This, in a large area without nuclear installations and an even mix of rural and industrialised regions, could be seen as control data for those studies which have considered cases of childhood leukaemia around nuclear facilities, where the observation of single point clusters associated with suspected sites restricts assessments of spatial pattern in the rest of the area.(ABSTRACT TRUNCATED AT 250 WORDS)

Humoral reaction in the inflamed colon in Hirschsprung's disease and ulcerative colitis.

An immunological study of B cells in patients with colitis that was associated with Hirschsprung's disease was undertaken and compared with that in patients with ulcerative colitis and in normal controls. There was an appreciable increase in IgA and a decrease in IgG in both disease groups. Humoral reaction in colitis associated with Hirschsprung's disease seems to be indistinguishable from that in ulcerative colitis and possibly in other inflammatory bowel diseases.