A Systematic Review of Treatment Strategies Including Future Novel Therapies in Crimean-Congo Hemorrhagic Fever

Introduction: Crimean-Congo hemorrhagic fever (CCHF) is an acute fetal illness the case fatality rate (CFR), which without treatment is between 26% to more than 80%. Despite the administration of ribavirin as a specific antiviral drug for the treatment of CCHF from many years ago, its clinical efficacy is still controversial. Objectives: This systematic review aimed to evaluate the clinical efficacy of ribavirin, favipiravir, and other treatment options for CCHF, including steroids, immunoglobulin, etc. Method: This systematic review included 31 articles, three factsheet from WHO, CDC, and ECDC, two editorial letters, and two textbooks from 2002 to 2020. The following databases were searched: Google Scholar, PubMed, Medscape, Cochrane, WHO, CDC, and ECDC. Results: The selected results of the above articles were concentrated on the different options of supportive treatment, including steroids, immunoglobulin, etc., as well as the efficacy of antiviral drugs, especially ribavirin and favipiravir. While some studies confirmed the clinical efficacy of ribavirin in the treatment of CCHF, some other studies did not confirm its efficacy. All studies justified that supportive therapies are the mainstay of treatment. Conclusions: The cornerstone of therapy of CCHF is supportive treatment. The clinical efficacy of ribavirin for CCHF treatment is questionable, and further randomized case-control clinical trials are required to confirm and recommend it for CCHF treatment. Also, other treatment strategies, including administration of steroids, immunoglobulin, and monoclonal antibodies (mAbs) require more conclusive data. The promising antiviral drug for CCHF treatment is favipiravir.

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675. Crimean-Congo Hemorrhagic Fever Beyond Ribavirin: A Systematic Review

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.872 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S439-S440

Author(s):

Stephanie P Fabara ◽

Raghavendra Tirupathi ◽

Juan Fernando Ortiz ◽

Urvish Patel ◽

Sashwath Srikanth ◽

...

Keyword(s):

Systematic Review ◽

Clinical Outcomes ◽

Acute Infection ◽

Case Series ◽

Case Fatality ◽

Hemorrhagic Fever ◽

The Other ◽

Duration Of Symptoms ◽

Crimean Congo Hemorrhagic Fever ◽

Significant Difference

Abstract Background The Crimean-Congo Hemorrhagic Fever (CCHF) is a tick-borne virus infection that has been reported in about 30 countries worldwide. Clinical presentation is divided into three phases: pre-hemorrhagic, hemorrhagic, and convalescence. Ribavirin is standard of care treatment for acute infection and prophylaxis. However, the use of other treatments beyond ribavirin is largely unknown. Methods We conducted a systematic review using MOOSE protocol. The inclusion and exclusion criteria are seen in the Prisma diagram. For Bias Analysis we use a Robin-1 tool. Literature review algorithm Results We gathered a total of 10 studies, which included 4 therapeutic plasma exchange (TPE), 2 corticosteroids, 2 IVIG, and 1 with convalescent plasma (CP). TPE in one study showed decreased mortality rate and increased efficacy in patients with severe CCHF. While the other study reported pulmonary embolism related to the use of TPE. Nevertheless, the patients had good outcome in the end. Two case reports used TPE plus ribavirin and supportive measures. Both were discharged home and recovered without sequela. Corticosteroids were found to be beneficial in one study were the case fatality rate was lower with the addition of corticosteroids to ribavirin in severely ill patients (p=0.0014). In a case series of six patients, who received the combination in early stages of the disease had good clinical outcomes with improved survival. IVIG was shown to increase platelet counts in two studies. In the first study, platelet count increased above 150,000/mL in 8.5 +/- 2.5 days. While in the other study the normalization of platelets was seen in 4 - 4.8 days, with no significant difference (P = 0.49). In addition, there was a decrease in the duration of symptoms but there was no statistically significant difference in mortality rates (P = 0.171). CP treatment showed a survival rate of 86% in treated patients. CP was more useful in high-risk patients, defined as having a viral load of 108 copies/mL or more. The main limitations of the studies were the sample size and heterogenicity among the outcomes of the studies. Conclusion TPE, CP, IVIG, and corticosteroids were effective in improving the clinical outcomes of the patients. The use of these treatments beyond ribavirin should be explored in future studies. Disclosures All Authors: No reported disclosures

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Worldwide epidemiology of Crimean-Congo Hemorrhagic Fever Virus in humans, ticks and other animal species, a systematic review and meta-analysis

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009299 ◽

2021 ◽

Vol 15 (4) ◽

pp. e0009299

Author(s):

Jean Thierry Ebogo Belobo ◽

Sebastien Kenmoe ◽

Cyprien Kengne-Nde ◽

Cynthia Paola Demeni Emoh ◽

Arnol Bowo-Ngandji ◽

...

Keyword(s):

Systematic Review ◽

Low Income ◽

Animal Species ◽

Meta Analysis ◽

Random Effect ◽

Case Fatality ◽

Hemorrhagic Fever ◽

Fever Virus ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus

There are uncertainties about the global epidemiological data of infections due to Crimean-Congo hemorrhagic fever virus (CCHFV). We estimated the global case fatality rate (CFR) of CCHFV infections and the prevalence of CCHFV in humans, ticks and other animal species. We also explored the socio-demographic and clinical factors that influence these parameters. In this systematic review with meta–analyses we searched publications from database inception to 03rd February 2020 in Pubmed, Scopus, and Global Index Medicus. Studies included in this review provided cross-sectional data on the CFR and/or prevalence of one or more targets used for the detection of CCHFV. Two independent investigators selected studies to be included. Data extraction and risk of bias assessment were conducted independently by all authors. Data collected were analysed using a random effect meta-analysis. In all, 2345 records were found and a total of 312 articles (802 prevalence and/or CFR data) that met the inclusion criteria were retained. The overall CFR was 11.7% (95% CI = 9.1–14.5), 8.0% (95% CI = 1.0–18.9), and 4.7% (95% CI = 0.0–37.6) in humans with acute, recent, and past CCHFV infections respectively. The overall CCHFV acute infections prevalence was 22.5% (95% CI = 15.7–30.1) in humans, 2.1% (95% CI = 1.3–2.9) in ticks, and 4.5% (95% CI = 1.9–7.9) in other animal species. The overall CCHFV recent infections seroprevalence was 11.6% (95% CI = 7.9–16.4) in humans and 0.4% (95% CI = 0.0–2.9) in other animal species. The overall CCHFV past infections seroprevalence was 4.3% (95% CI = 3.3–5.4) in humans and 12.0% (95% CI = 9.9–14.3) in other animal species. CFR was higher in low-income countries, countries in the WHO African, South-East Asia and Eastern Mediterranean regions, in adult and ambulatory patients. CCHFV detection rate in humans were higher in CCHFV suspected cases, healthcare workers, adult and hospitalized patients, ticks of the genus Ornithodoros and Amblyomma and in animals of the orders Perissodactyla and Bucerotiformes. This review highlights a significant disease burden due to CCHFV with a strong disparity according to country income levels, geographic regions, various human categories and tick and other animal species. Preventive measures in the light of these findings are expected.

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Immunogenicity of a DNA-Based Sindbis Replicon Expressing Crimean–Congo Hemorrhagic Fever Virus Nucleoprotein

Vaccines ◽

10.3390/vaccines9121491 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1491

Author(s):

Thomas Tipih ◽

Mark Heise ◽

Felicity Jane Burt

Keyword(s):

Immune Response ◽

Sindbis Virus ◽

Cytokine Production ◽

Antiviral Drug ◽

Case Fatality ◽

Hemorrhagic Fever ◽

Fever Virus ◽

Virus Vector ◽

Crimean Congo Hemorrhagic Fever ◽

Hemorrhagic Fever Virus

Crimean–Congo hemorrhagic fever virus (CCHFV) infrequently causes hemorrhagic fever in humans with a case fatality rate of 30%. Currently, there is neither an internationally approved antiviral drug nor a vaccine against the virus. A replicon based on the Sindbis virus vector encoding the complete open reading frame of a CCHFV nucleoprotein from a South African isolate was prepared and investigated as a possible candidate vaccine. The transcription of CCHFV RNA and recombinant protein production by the replicon were characterized in transfected baby hamster kidney cells. A replicon encoding CCHFV nucleoprotein inserted in plasmid DNA, pSinCCHF-52S, directed transcription of CCHFV RNA in the transfected cells. NIH-III heterozygous mice immunized with pSinCCHF-52S generated CCHFV IgG specific antibodies with notably higher levels of IgG2a compared to IgG1. Splenocytes from mice immunized with pSinCCHF-52S secreted IFN-γ and IL-2, low levels of IL-6 or IL-10, and no IL-4. No specific cytokine production was registered in splenocytes of mock-immunized mice (p < 0.05). Thus, our study demonstrated the expression of CCHFV nucleoprotein by a Sindbis virus vector and its immunogenicity in mice. The spectrum of cytokine production and antibody profile indicated predominantly Th1-type of an anti-CCHFV immune response. Further studies in CCHFV-susceptible animals are necessary to determine whether the induced immune response is protective.

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Crimean‐Congo hemorrhagic fever‐induced liver injury: a systematic review and meta‐analysis

International Journal of Clinical Practice ◽

10.1111/ijcp.14775 ◽

2021 ◽

Author(s):

Sawai Singh Rathore ◽

Ade Harrison Manju ◽

Qingqing Wen ◽

Manush Sondhi ◽

Reshma Pydi ◽

...

Keyword(s):

Systematic Review ◽

Liver Injury ◽

Meta Analysis ◽

Hemorrhagic Fever ◽

Crimean Congo Hemorrhagic Fever

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Crimean-Congo hemorrhagic fever in pregnancy: A systematic review and case series from Russia, Kazakhstan and Turkey

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2017.02.019 ◽

2017 ◽

Vol 58 ◽

pp. 58-64 ◽

Cited By ~ 11

Author(s):

Natalia Yurievna Pshenichnaya ◽

Hakan Leblebicioglu ◽

Ilkay Bozkurt ◽

Irina Viktorovna Sannikova ◽

Gulzhan Narkenovna Abuova ◽

...

Keyword(s):

Systematic Review ◽

Case Series ◽

Hemorrhagic Fever ◽

Crimean Congo Hemorrhagic Fever ◽

In Pregnancy

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Crimean-Congo hemorrhagic fever-induced liver injury: a systematic review and meta-analysis

10.22541/au.161962547.79756407/v1 ◽

2021 ◽

Author(s):

Sawai Singh Rathore ◽

Ade Harrison Manju ◽

Qingqing Wen ◽

Manush Sondhi ◽

Reshma Pydi ◽

...

Keyword(s):

Liver Injury ◽

Case Fatality Rate ◽

Meta Analysis ◽

Case Series ◽

Case Fatality ◽

Hemorrhagic Fever ◽

Fatality Rate ◽

High Case Fatality Rate ◽

Crimean Congo Hemorrhagic Fever ◽

Pooled Prevalence

Background: Crimean-Congo hemorrhagic fever (CCHF) is a fatal acute tick-borne viral infection and a substantial emerging global public health threat. This illness has a high case fatality rate of up to 40%. The liver is one of the important target organs of the CCHF virus. Objective: The aim of this meta-analysis to evaluate the correlation between CCHF and liver injury and draw more generalized inferences about the abnormal serum markers of liver injury such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) in CCHF patients. Methods: A literature search was accomplished for published eligible articles with MEDLINE/PubMed and Embase databases. All eligible observational studies and case series were included from around the world. The inclusion criteria were articles describing liver injury biomarkers AST and ALT amongst patients diagnosed with CCHF. Results: Data from 18 studies, consisting of 1238 patients with CCHF were included in this meta-analysis. The overall pooled prevalence of at least one raised liver injury biomarker was 77.95% (95% CI, I2 = 88.50%, p < 0.0001). Similarly, pooled prevalence of elevated AST and ALT was 85.92% (95% CI, I2 = 85.27%, p < 0.0001) and 64.30% (95% CI, I2 = 88.32%, p < 0.0001) respectively. Both Egger and Begg-Mazumdar’s tests detected no apparent publication bias in all three meta-analyses(p > 0.05). Conclusion: These elevated liver injury biomarkers have been identified as significant prognostic factors. Hence, Physicians must recognize and continuously monitor these biomarkers, since these aid early stratification of prognosis and the prevention of severe outcomes in infection with such a high case fatality rate.

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New aspects about Crimean-Congo hemorrhagic fever (CCHF) cases and associated fatality trends: A global systematic review and meta-analysis

Comparative Immunology Microbiology and Infectious Diseases ◽

10.1016/j.cimid.2020.101429 ◽

2020 ◽

Vol 69 ◽

pp. 101429 ◽

Cited By ~ 5

Author(s):

Hassan Nasirian

Keyword(s):

Systematic Review ◽

Meta Analysis ◽

Hemorrhagic Fever ◽

Crimean Congo Hemorrhagic Fever

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104. Plague Meningitis - A Systematic Review of Published Cases, Antimicrobial Treatment, and Outcomes

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.104 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S65-S65

Author(s):

Katharine Cooley ◽

Shannon Fleck-Derderian ◽

Christina Nelson

Keyword(s):

Systematic Review ◽

Case Fatality Rate ◽

Case Reports ◽

Treatment Strategies ◽

Case Fatality ◽

The United States ◽

Antimicrobial Treatment ◽

Recent Analysis ◽

Fatality Rate ◽

Bubonic Plague

Abstract Background Plague meningitis is a rare but serious manifestation of infection with the bacterium Yersinia pestis. The risk factors, clinical evolution, and optimal treatment strategies of plague meningitis are not well understood, and data is limited to sporadic case reports. To advance knowledge of this condition and support clinical practice recommendations, we conducted a systematic review of published cases of plague meningitis. Methods We reviewed PubMed Central, Medline, Embase, and other databases for publications on plague meningitis in any language. Articles that contained reports of patients with plague meningitis plus information on patient outcome were included. Results Among 1,090 articles identified in our search, we found 54 articles describing 83 cases eligible for inclusion. Cases occurred between 1898 and 2015; mean age of patients was 20.5 years (range 6 wks - 64 yrs) and 65% were male. Most patients lived in the United States (23%), Argentina (18%), Vietnam (12%), or China (12%). Four patients (5%) had primary plague meningitis. More than half (59%) of patients developed meningitis secondary to primary bubonic plague; the remainder developed meningitis secondary to other or unknown forms of plague. Of patients with a bubo, 51% had an axillary bubo. The most common symptoms were fever (66%), nuchal rigidity (43%), and headache (35%); 23 patients had focal neurologic deficits such as cranial nerve abnormality. Case fatality rate was 96% (n=23/24) for patients who did not receive antimicrobial treatment and 42% (n=25/59) for patients treated with antimicrobials. Case fatality rate by antimicrobial received, including patients who received multiple antimicrobial classes, was 50% for sulfonamides (n= 38), 50% for fluoroquinolones (n=2), 19% for aminoglycosides (n=21), 11% for chloramphenicol (n=19), and 0% for tetracyclines (n=14). Conclusion Plague meningitis has a high fatality rate, but antimicrobial treatment can improve patient outcomes. Having an axillary bubo may be a risk factor for developing plague meningitis – in contrast to our findings, a recent analysis found that only 24% of patients with bubonic plague had buboes in the axillary region. Additional research would be helpful to investigate this association further. Disclosures All Authors: No reported disclosures

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