Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta-1b in MIRACLE clinical trial.

Background: Type I interferons (IFNs) are essential antiviral cytokines induced upon respiratory exposure to coronaviruses. Defects in type I IFN signaling can result in severe disease upon exposure to respiratory viral infection and are associated with worse clinical outcomes. Neutralizing autoantibodies (auto-Abs) to type I IFNs were reported as a risk factor for life-threatening COVID-19, but their presence has not been evaluated in patients with severe Middle East respiratory syndrome (MERS). Methods: We evaluated the prevalence of type I IFN auto-Abs in a cohort of hospitalized patients with MERS who were enrolled in a placebo-controlled clinical trial for treatment with IFN-ß1b and lopinavir-ritonavir (MIRACLE trial). Samples were tested for type I IFN auto-Abs using a multiplex particle-based assay. Results: Among the 62 enrolled patients, 15 (24.2%) were positive for immunoglobulin G auto-Abs for at least one subtype of type I IFNs. Auto-Abs positive patients were not different from auto-Abs negative patients in age, sex, or comorbidities. However, the majority (93.3%) of patients who were auto-Abs positive were critically ill and admitted to the ICU at the time of enrollment compared to 66% in the auto-Abs negative patients. The effect of treatment with IFN-ß1b and lopinavir-ritonavir did not significantly differ between the two groups. Conclusion: This study demonstrates the presence of type I IFN auto-Abs in hospitalized patients with MERS.

Heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir in patients with Middle East respiratory syndrome by cytokine levels.

Animal and human data indicate variable effects of interferons in treating coronavirus infections according to inflammatory status and timing of therapy. In this sub-study of the MIRACLE trial (MERS-CoV Infection Treated with a Combination of Lopinavir-Ritonavir and Interferon ß-1b), we evaluated the heterogeneity of treatment effect of interferon-ß1b and lopinavir-ritonavir versus placebo among hospitalized patients with MERS on 90-day mortality, according to cytokine levels and timing of therapy. We measured plasma levels of 17 cytokines at enrollment and tested the treatment effect on 90-day mortality according to cytokine levels (higher versus lower levels using the upper tertile (67%) as a cutoff point) and time to treatment (≤ 7 days versus > 7 days of symptom onset) using interaction tests. Among 70 included patients, 32 received interferon-ß1b and lopinavir-ritonavir and 38 received placebo. Interferon-ß1b and lopinavir-ritonavir reduced mortality in patients with lower IL-2, IL-8 and IL-13 plasma concentrations but not in patients with higher levels (p-value for interaction = 0.09, 0.07, and 0.05, respectively) and with early but not late therapy (p = 0.002). There was no statistically significant heterogeneity of treatment effect according to other cytokine levels. Further work is needed to evaluate whether the assessment of inflammatory status can help in identifying patients with MERS who may benefit from interferon-ß1b and lopinavir-ritonavir. Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843).

Brucella cardiac implantable electronic device infection: A single-center case series.

BACKGROUND: Cardiac implantable electronic devices (CIEDs), including implantable cardiac defibrillators, pacemakers, and cardiac resynchronization therapy devices, are lifesaving. However, device infections can lead to morbidity and mortality. The aim of this study was to describe the outcome of Brucella CIED infections treated at our center, and to identify risk factors for Brucella infection in patients with CIEDs. Study Settings: Single-center study, Prince Sultan Military Medical City, Riyadh, KSA. METHODS: This case series included all Brucella-related CIED infections treated at a tertiary care center between 2009 and 2020. Data on patient demographics, clinical manifestations, predisposing factors, microbiology, treatment regimens, and outcomes were reviewed. RESULTS: Fifteen patients met the Brucella CIED infection criteria. The mean age was 62.2 years, and 80% were males. Common comorbidities included hypertension (73%), diabetes mellitus (67%), ischemic heart disease (47%), and chronic kidney disease (60%). The mean time to infection following the device implantation was 4.8 years (range: 5 months to 13 years). Fever was detected in 53% of patients, device site swelling in 47%, purulent discharge in 33%, and pain in 27%. The blood culture and serology results were positive in 73% and 80% of patients, respectively. All patients were treated with antibiotics, and the infected device was removed. Seven (46.6%) patients underwent reimplantation with a new device. One patient with dual Brucella and methicillin-sensitive Staphylococcus aureus infection died, and the other 14 patients recovered, with no recurrent infections reported to date. CONCLUSION: Brucella should be considered in CIED infections, particularly in endemic areas. Proper treatment and device removal are essential for good outcomes.

Efficacy of tocilizumab in patients with severe COVID-19: Survival and clinical outcomes.

BACKGROUND: SARS-CoV-2 is associated with a severe inflammatory response contributing to respiratory and systemic manifestations, morbidity, and mortality in patients with coronavirus disease 2019 (COVID-19). METHODS: Tocilizumab (TCZ) efficacy on mortality and length of hospital stay was retrospectively evaluated in patients who received TCZ and compared with that in controls with a similar severity of COVID-19. The primary endpoint was survival probability on day 28. The secondary endpoints included survival at day 14 and length of hospital stay. RESULTS: Of the 148 patients included in the study, 62 received TCZ and standard of care, whereas 86 served as a control group and received only standard of care. The two groups were similar, although TCZ-treated patients were more likely to exhibit hypertension (46.7% vs. 29.8%), chronic kidney disease (14.5% vs. 1.1%), and high Charlson score (1.18 vs. 1.00; p = 0.006) and less likely to receive corticosteroid treatment (48.5% vs. 93.0%). TCZ was associated with lower mortality on both day 28 (16.1% vs. 37.2%, p = 0.004) and day 14 (9.7% vs. 24.4%, p = 0.022). The hospital stay was longer in the TCZ-treated than in the control group (15.6 ± 7.59 vs.17.7 ± 7.8 days, p = 0.103). Ten patients (16.0%) in the TCZ-treated group developed infections. CONCLUSION: TCZ was associated with a lower likelihood of death despite resulting in higher infection rates and a non-significant longer hospital stay.

Longevity of Middle East Respiratory Syndrome Coronavirus Antibody Responses in Humans, Saudi Arabia.

Understanding the immune response to Middle East respiratory syndrome coronavirus (MERS-CoV) is crucial for disease prevention and vaccine development. We studied the antibody responses in 48 human MERS-CoV infection survivors who had variable disease severity in Saudi Arabia. MERS-CoV-specific neutralizing antibodies were detected for 6 years postinfection.

Abdominal tuberculosis in a tertiary care centre in Saudi Arabia.

OBJECTIVES: Abdominal tuberculosis (ATB) is the second most common type of extra-pulmonary tuberculosis. Though it does not usually pose a significant risk of infectivity, ATB can go unidentified and progress to disseminated infection. The aim of this study is to highlight the incidence and outcome of this infection in a tertiary care centre in the Kingdom of Saudi Arabia (KSA). METHODS: In this retrospective study, we included all ATB patients admitted to our centre between January 1 st, 2010 and December 31, 2018. A total of 42 patients with a median age of 49 (range 18-83 years, 78.6% males) were identified. RESULTS: The most common presentation was abdominal pain, weight loss, and abdominal distension. All the patients were HIV negative; however, 50% had a comorbid condition, mainly diabetes mellitus, chronic renal failure, and liver cirrhosis. Tuberculous peritonitis was the predominant type of ATB. Suspicious and potentially malignant abdominal masses appeared on the abdominal CT scans of six patients. This suggest that TB should be excluded in patients from endemic area presenting with abdominal masses. All patients received standard anti-tuberculous medication for an average duration of 7.4 months. The outcome was excellent with 88%% achieving complete response. Adjunctive corticosteroids were not used, and none of the patients had a surgical complication. CONCLUSION: The diagnosis of ATB is challenging. It can mimic inflammatory bowel disease in young populations and malignancy in middle-aged and elderly population. For this reason, a high index of suspicion with prompt treatment is required to improve the prognosis and prevent complications.

Reinfection, recurrence, or delayed presentation of COVID-19? Case series and review of the literature.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-cov-2), first described in December 2019, has now infected more than 28 million cases with almost one million deaths. Reinfection is not definitely established however disease recurrence is increasingly reported. CASES PRESENTATION: Four patients presented with a second episode of coronavirus disease 2019 (COVID-19) occurring 27-85 following their first illness. The initial episode was mild or asymptomatic while the second attack was severe requiring hospital admission. All four patients had a SARS-CoV-2 PCR test positive in the second episode. The chest-X-ray and/or computerized tomography (CT) scan showed bilateral alveolar shadows. Furthermore, the inflammatory markers were raised in the four patients. Three patients recovered following treatment with favipravir in addition tocilizumab and/or dexamethasone. CONCLUSION: Covid19 reinfection Recurrent COVID-19 is increasingly reported. However; other etiologies including superadded infection or pulmonary embolism should be ruled out, particularly if recurrence occurs less than 3 weeks.

Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome.

BACKGROUND: Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear. METHODS: We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results. RESULTS: A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group. CONCLUSIONS: A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).

Mucormycosis: An 8-year experience of a tertiary care centre in Saudi Arabia.

Mucormycosis is a rare fungal infection with an extremely high morbidity and mortality. Data on the burden of the disease in the Arab world is lacking. The aim of this study is to highlight the incidence and outcome of this infection in a tertiary care center in the Kingdom of Saudi Arabia (KSA). In this retrospective study we included all mucormycosis cases admitted to our center between January 2013 and December 2019. A total of 18 proven patients with a median age of 43.5 years (range 13-72 years, 72% males) were identified. The most common presentation was cutaneous and rhino-orbito-cerebral, followed by gastrointestinal mucormycosis. Apophysomyces variabilisRhizopus oryzae) were the main fungal isolates on molecular testing. Trauma was the chief underlying etiology (41.0%) with motor vehicle accident (MVCs) being the predominant type (43.0%). For this reason, most of our patients were young with cutaneous disease and had a better prognosis. All patients received liposomal amphotericin B alone or in combination with other antifungal agents. Repeated aggressive debridement and reversal of the underlying factor was attempted in all patients. This underscores the lower mortality (27.8%) seen in this group. The diagnosis of Mucorales infection is challenging. A high index of suspicion with prompt treatment is required to improve the high mortality of this aggressive disease. Further studies are needed to understand the epidemiology and outcome of this disease in Saudi Arabia.

COVID-19 co-infection in a patient with brucella bacteremia.

We discuss a patient who presented with fever, chills and rigors, myalgia, sore throat, diarrhea, and abdominal pain. The total white blood cell count was normal. The lymphocyte and platelet counts were within normal limits. There was no contact with confirmed COVID-19 patient, but the disease was circulating at the time of presentation. He admitted to anosmia and hypogeusia. A nasopharyngeal swab r-RT PCR test was positive for the SARS-CoV-2 virus. His chest examination and chest x-ray were normal. The patient had contact with animals and consumed unpasteurized camel milk. Both the blood culture and brucella serology tests were positive. This case illustrates that co-infection can occur and it is important to rule out endemic diseases in patients with COVID-19. Similarly, patients presenting with febrile endemic diseases may be harboring mild SARS-COV-2 virus infections and may need to be screened when the disease is suggested by epidemiological exposure.

Transplant-related strongyloidiasis in solid organ transplant recipients in Saudi Arabia and the Gulf Cooperation Council countries.

BACKGROUND: Strongyloidiasis is a devastating disease with a mortality rate exceeding 50% in immunocompromised patients. The disease usually results from reactivation of a latent infection in a transplant patient. Alternatively, donor-derived transmission of Strongyloides may occur. METHODS: In this review, we report a case of Strongyloides hyperinfection syndrome in a liver transplant recipient to illustrate the severity of this infection. Following this, PubMed was searched for cases of transplant-related strongyloidiasis in the Gulf Cooperation Council (GCC) countries. Demographic data, the clinical presentation of recipients, and donor information were recorded. Methods of diagnosis, treatment planning, and clinical outcomes were documented. RESULTS: A total of 12 transplant-related strongyloidiasis cases were identified. Seventy-five percent of the patients were from Saudi Arabia. Three cases from Kuwait shared common donors. All donors were deceased and native to an area endemic for Strongyloides. Five of the patients shared common donors, raising the possibility of donor-derived infection. Neither the donors nor the recipients underwent screening tests for Strongyloides. Concomitant bacteremia and/or meningitis was seen in 50% of cases (6/12). Moreover, when documented, sepsis was detected in all of the patients who died (three cases). The mortality rate in this series was high (41.7%). CONCLUSIONS: Since this is a preventable condition, early diagnosis and treatment is essential. The screening and treatment of potential transplant recipients and donors proved to be an effective preventive measure. There is a growing need for further studies and implementation of screening policies in the GCC countries to prevent this fatal infection.

Complication of massive trauma by fungal infection and bone tuberculosis.

We report a middle aged man who was admitted with severe necrotising fasciitis following a motor vehicle accident (MVA). Histopathology of the excised tissue suggested mucormycosis while a bone tissue culture revealed fully sensitive Mycobacterium tuberculosis. He received intravenous liposomal amphotericin B combined with multiple surgical debridements and ended with right shoulder disarticulation. In addition he completed a nine months course of anti-tuberculosis treatment. He remained stable one year following his admission. We believe that trauma contributed to both conditions by direct inoculation of fungal spores and through immunological reactivation of old healed tuberculosis focus. This case highlights the importance of considering diagnosis of invasive fungal infections following MVA.

Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-ß1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial.

The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-ß1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-ß1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02845843. Registered on 27 July 2016.

A rickettsia infection from Saudi Arabia.

We here present a young patient who developed fever, headache, maculopapular skin rash and an eschar 3 days following a tick bite. Serology for Rickettsia was consistent with acute spotted fever group (SFG) infection. He had a dramatic response to doxycycline. Vectors for rickettsia transmission are shown in a number of studies from Saudi Arabia while human serological studies from Oman revealed that these infections are common among the rural population. Surprisingly, despite the existence of potential vectors, this disease is rarely reported from the Arab Gulf countries. To the best of our knowledge this is the first case report of SFG acquired within Saudi Arabia. SFG should be considered in the differential diagnosis of febrile illness and exposure history.

Corrigendum to "Colonic basidiobolomycosis presenting with intestinal obstruction and a normal eosinophil count" [IDCases 17 (2019) e00565].

[This corrects the article DOI: 10.1016/j.idcr.2019.e00565.].

Isolation and deisolation of patients admitted with presumptive pulmonary tuberculosis. Can it be shortened?

OBJECTIVES: To determine the ideal number of sputum acid-fast bacilli (AFB) smears and polymerase chain reaction (PCR) required for discontinuing TB isolation among patients with suspected pulmonary TB.  Methods: This was a single-center, record-based retrospective study of all admitted patients diagnosed with culture-proven pulmonary TB between 2010 and 2018. The study was conducted at Prince Sultan Military Medical City (PSMMC) in Riyadh, Saudi Arabia, a large tertiary care center consisting of 1,200 beds. Data were obtained from our TB notification records. Patients with smear-positive TB were investigated. Only the first 3 sputum smears for AFB were included in the analysis. The  PCR results for Mycobacterium tuberculosis (MTB) were also included in the study. The incremental yield of the second and third smears was assessed.  Results: Overall, 240 patients were MTB-culture positive. A total of 126 (52.5%) patients were smear and culture positive, whereas 114 were culture positive but smear negative. Of 126 patients who were AFB smear positive, 98 (77.8%) were detected in the first specimen, 13 (10.3%) in the second specimen, and only 9 (7.1%) in the third specimen. Polymerase chain reaction for MTB was positive in 122 (96.8%) smear-positive patients. Four patients did not undergo a PCR test.  Conclusion:  A single Xpert MTB/resistance to rifampicin test detected all smear-positive patients, whereas the third smear did not significantly contribute to MTB isolation.

Ten-year experience of Q fever endocarditis in a tertiary cardiac center in Saudi Arabia.

BACKGROUND: Q fever endocarditis (QFE) is considered rare in the Middle East, with only a few cases reported in Saudi Arabia. The aim of this study is to report on the experience of our centre on QFE. METHODS: We searched the medical records for cases of QFE at our cardiac center from 2009-2018. Demographic data, clinical features, serology and echocardiography results, treatments, and outcomes were assessed. RESULTS: Five hundred and two cases of infective endocarditis were detected over the 10 years period. Among the 234 patients with blood culture-negative endocarditis (BCNE), 19 (8.10%) had QFE. All patients had a previously diagnosed congenital heart disease except for one patient with rheumatic heart disease. Eleven patients had received a bovine jugular vein-related implant, e.g., a Melody valve (seven patients) or Contegra conduit (four patients). Coinfection was detected in three patients, and immunologic and embolic phenomena were observed in five patients. All patients received a combination of hydroxychloroquine and doxycycline, with good outcomes. Only two patients required surgery while on treatment. Two patients died several months after treatment; the cause of death was not identified. CONCLUSION: This study indicates that Q fever exists in our population. The majority of the patients had congenital heart disease (CHD) and underwent bovine jugular vein implants. Patients with CHD are at increased risk of infective endocarditis. Bovine jugular vein implants increase the risk of infective and possibly QFE. Proper exclusion of Q fever is warranted in all BCNE and possibly in culture-positive endocarditis cases in areas endemic to Q fever. KEY POINTS: We presented the largest series of Q fever endocarditis cases in Saudi Arabia. We showed that Q fever is not rare in the Middle East and suggest that it should be considered in all blood culture-negative endocarditis cases.

Characteristics and outcome of viral pneumonia caused by influenza and Middle East respiratory syndrome-coronavirus infections: A 4-year experience from a tertiary care center.

BACKGROUND: After the emergence of new influenza viruses, the morbidity and mortality of viral pneumonia have received a great attention. OBJECTIVES: The objective of this study is to describe the epidemiologic, clinical and laboratory changes, and outcomes of viral pneumonia caused by influenza and the Middle East respiratory syndrome-coronavirus (MERS-CoV) infections. METHODS: In a retrospective cohort study, the medical records of all patients diagnosed with viral pneumonia at Prince Sultan Military Medical City, Riyadh, Saudi Arabia, during the period from January 2012 to December 2015 were screened. Cases who were > 18 years old and were confirmed by a respiratory viral panel to have viral pneumonia either MERS-CoV or influenza viruses were included in the analysis. Sociodemographic, clinical, laboratory, and outcome data were extracted from patients' medical files. The data were analyzed descriptively and inferentially to identify the predictors of poor outcome. RESULTS: A total of 448 patients with confirmed viral pneumonia were included, of those, 216 (48.2%) were caused by influenza A (non H1N1)/influenza B, 150 (33.5%) by H1N1, and 82 (18.3%) by MERS-CoV. The majority of patients presented with fever (82%), shortness of breath (64%), and flu-like symptoms (54.9%), particularly in MERS-CoV infected cases (92%). The peak incidence of viral pneumonia was in early spring and autumn. The mortality rate was 13.8%, and it was significantly higher among MERS-CoV cases. The predictors of death were age > 65 years, male gender, and associated comorbidities particularly diabetes mellitus, hypertension, and chronic kidney diseases. The number of comorbid illnesses was directly related to the increase in mortality in this group of patients. CONCLUSION: Viral pneumonia caused by influenza and MERS-CoV carries a high mortality rate, particularly among MERS-CoV infected cases. Old age, male gender, and comorbid illnesses are predictors of poor outcome. Routine testing for newly emergent viruses is warranted for adults who have been hospitalized with pneumonia.

Colonic basidiobolomycosis presenting with intestinal obstruction and a normal eosinophil count.

Gastrointestinal basidiobolomycosis (GIB), caused by Basidiobolus ranrum, is a rare fungal infection with a limited geographic distribution. The majority of the cases are reported from the warm areas of Arizona in USA, Saudi Arabia and Iran. We report a middle aged patient who was admitted to hospital with suspected metastatic colonic carcinoma. He presented with constipation, anorexia and weight loss. Computed tomography scan disclosed a mass involving the mid and distal sigmoid colon and hypodense lesion in hepatic segment IV. Excised tissue during a Hartmann's surgery showed an extensive eosinophil-rich transmural inflammation with mural necrotizing granulomas and several broad septated fungal hyphae. He was commenced on voriconazole following surgery. The diagnosis of basidiobolomycosis was established by histopathological examination. Since the diagnosis was not suspected preoperatively tissue culture for fungi was not collected. However molecular testing confirmed the diagnosis of GIB. Therapy involved a combination of surgical resection of the mass and prolonged voriconazole treatment. Increased awareness among physicians is needed for early diagnosis and treatment of GIB.

A case series of actinomycosis from a single tertiary care center in Saudi Arabia.

Actinomycosis is an uncommon but curable chronic infection caused by Actinomyces spp. The cervicofacial region is the most susceptible to infection; however, other sites may also become infected. Data on the current prevalence of this rare disease in Riyadh, Saudi Arabia is lacking. We herein report a case series of four patients with actinomycosis from a single tertiary care center in Riyadh, Saudi Arabia. Three patients presented to us with slowly progressing actinomycosis and one patient developed an acute abdomen, secondary to viscus perforation. Two of the patients had cervicofacial disease, including hard palate actinomycosis. Tissue cultures were sent for three patients; however, tests for actinomycosis were negative. Subsequently, the diagnosis was made through histopathological examination. Therapy involved a combination of surgical resection and debridement and prolonged antimicrobial treatment tailored to each patient. The cases reported in this series highlight the difficulty in diagnosing actinomycosis. For most patients, the diagnosis was delayed or accidentally discovered on histopathological examination. We conclude that increased awareness among physicians is needed for early diagnosis and treatment of actinomycosis.