Clinical and subclinical characteristics in patients with fever caused by rickettsiaceae treated at military Hospital 103 and Central Military Hospital 108

To describe some clinical and subclinical characteristics of patients with fever caused by Rikettsiaceae. Retrospective combined prospective, descriptive study on 88 patients who were diagnosed with fever caused by Rikettsiaceae were treated at Military Hospital 103 and Central Military Hospital 108.

Journal of military pharmaco-medicine no5-2020 CLINICAL AND SUBCLINICAL CHARACTERISTICS IN PATIENTS WITH FEVER CAUSED BY RICKETTSIACEAE TREATED AT MILITARY HOSPITAL 103 AND CENTRAL MILITARY HOSPITAL 108 Nguyen Hoang Thanh1, Hoang Tien Tuyen1, Pham Van Chung2 SUMMARY Objectives: To describe some clinical and subclinical characteristics of patients with fever caused by Rikettsiaceae Subjects and methods: Retrospective combined prospective, descriptive study on 88 patients who were diagnosed with fever caused by Rikettsiaceae were treated at Military Hospital 103 and Central Military Hospital 108 Results: The rate of male patients was 62.5%; delta residence 88.6%; exposure activities: Doing the gardening: 45.5%, camping soldiers: 21.6% Common pathological background: Hypertension (12.5%), diabetes (5.7%) Symptoms: Sudden fever: 98.9%; hot fever: 100%; chill fever: 78.4% 39.8% of patients had ulcers; all of those patients had only one ulcer at the common sites: Inguinal, perineum (45.5%) and chest, back (30.3%) Enlarged peripheral lymph nodes: 25%; skin hyperemia: 47.7%; maculopapular rash: 28.4%; explosive rale in lung: 27.3%; hepatomegaly and splenomegaly: 18.2%; meningitis: 10.2%; hypotension: 4.2% White blood cells > 10 G/l (33.0%); Hb < 120 g/L (27.3%); platelet < 150 G/l (72.7%); ure > 7.5 mmol/L (11.8%); ALT > 80 U/l (72.7%); total bilirubin > 17 µmol/L (30%); CRP > 100 mg/L (21.4%) Conclusion: Understanding clinical and subclinical characteristics of patients with fever caused by Rickettsiaceae helps physicians diagnose and treat promptly to reduce the cost of treatment and limit deaths * Keywords: Rikettsiaceae; Clinical characteristics; Subclinical characteristics INTRODUCTION Rickettsiosis is a group of diseases that can cause epidemics due to the bacteria genera of Rickettsia and Orientia through arthropod vectors Rickettsiosis share common clinical manifestations such as high fever, vasodilation, maculopapular rash, ulcers, lymphadenitis and Typhos status Moreover, bacteria of the family Rickettsiaceae cannot be cultured in normal environment, the highly sensitive and specific molecular biology method for the diagnosis and identification of pathogens has not been implemented in many health facilities because of the limitations of the testing device Therefore, the diagnosis of diseases caused by Rickettsiaceae faces many difficulties Department of Infectious Disease, Military Hospital 103, Vietnam Military Medical University Clinical Institute of Infectious Diseases, Central Military Hospital 108 Corresponding author: Nguyen Hoang Thanh (hoangthanh27081991hvqy@gmail.com) Date received: 04/6/2020 Date accepted: 22/6/2020 121 Journal of military pharmaco-medicine no5-2020 An in-depth understanding of clinical and subclinical characteristics of patients with fever caused by Rickettsiaceae will be valuable to help physicians diagnose, treat promptly, limit complications, treatment costs and mortality rate Based on the above facts, we conducted this research: To identify some clinical and subclinical characteristics of patients with fever caused by Rickettsiaceae treated at Military Hospital 103 and Central Military Hospital 108 SUBJECTS AND METHODS Subject, location and time of study 88 patients diagnosed with fever caused by Rikettsiaceae were treated at the Department of Infectious Disease, Military Hospital 103 and the Clinical Institute of Infectious Diseases, Central Military Hospital 108 from 01/2014 to 6/2019 + Retrospective study on 62 cases with fever caused by Rickettsiaceae hospitalized and treated from 01/2014 - 5/2018 + Prospective study on 26 cases with fever caused by Rickettsiaceae hospitalized and treated from 6/2018 - 6/2019 * Selection criteria: According to the Centers for Disease Control (CDC) criteria for Tick - Borne Rickettsia - 2008 [5]: - Clinical characteristics: Patients over 15 years of age with fever > 38oC, who had one or more of the following criteria: Headache, myalgia, papules, urticaria, anemia, leukopenia, thrombocytopenia or an increase in liver enzymes - Testing: Detect bacterial DNA of family Rickettsiaceae in patient's blood sample or ulcer by PCR test 122 * Exclusion criteria: - Pregnancy, breast-feeding, under 15 years old - Co-infection with other agents such as dengue fever, hepatitis virus, HIV, malaria, measles, Rubbella - Patients have received chemotherapy for any cancer - Patients did not agree to participate in this study Methods * Study design: Cross-sectional combined retrospective and prospective study * Methods: - Identify Rickettsiaceae by Real-time PCR machine (Agilent, USA) at Department of Molecular Biology, Military Central Hospital 108 Firstly, extract DNA from blood or tissue samples with blood genomic DNA isolation Mini Kit (Norgen, Canada) Next, carry out the PCR reaction with the corresponding specificity and sensitivity of 100% and 20 copies/reaction - Data collection through medical records, all medical records were registered under unified form * Research contents: - Distribution of patients by age, gender, living area, history of chronic diseases, history of exposure to risk factors - Clinical symptoms: Features of fever (onset, property, severity, duration), ulcer characteristics, skin rash, lymphadenitis, edema, hypotension, respiratory rate, hepatomegaly, splenomegaly, rales in the lungs, abdominal effusion, mental status changes, meningeal signs Journal of military pharmaco-medicine no5-2020 - Subclinical indicators: Number of red blood cells (T/l); hemoglobin (g/L); the number of white blood cells (G/l); neutrophil leukocytes (%); platelets (G/l); prothrombin rate (%); hepatic enzymes AST, ALT (U/l); albumin (g/L); total bilirubin (µmol/L); urea (mmol/L); creatinine (µmol/L); CRP (mg/L); PCT (ng/mL); changes on cardiopulmonary X-ray in patients having positive results of Rickettsiaceae Realtime PCR * Data processing: Using SPSS software version 22.0 RESULTS AND DISCUSSION Epidemiological characteristics Table 1: Epidemiological characteristics Characteristics The average age (min - max) Number of patients Rate (%) 51.0 ± 16.5 (15 - 84) Age group of 15 - 60 58 65.9 Male 55 62.5 Delta residence 78 88.6 Diabetes 5.7 Hypertension 11 12.5 Alcoholism 2.3 Chronic liver disease 2.3 Others 18 20.5 Do the gardening 40 45.5 Camping soldiers 19 21.6 Unknown 29 33.0 Pathological background Exposure activity The average age was 51.0 ± 16.5 (the youngest was 15, the oldest was 84), which was similar to Vu Minh Dien's study (mean age: 52.7 ± 17.3) [2] The age group < 60 accounted for the highest proportion of 65.9% The rate of males was times higher than that of females, which was different from Vu Minh Dien’s findings (males 55.2% and females 44.8%), and Pham Thi Thanh Thuy’s (males: 50.6% and females: 49.4%) In our opinion, the proportion of male and female reflected the difference in exposure factors as well as subjects in our study who were military personnels and farmers, so male had higher rate than female [3] The prevalence of exposure activities was mainly found in patients doing the gardening (45.5%), 123 Journal of military pharmaco-medicine no5-2020 followed by camping soldiers (21.6%), which was lower than Vu Minh Dien’s study (48.5%), Le Van An’s (46.8%), Cao Thanh Van’s (75.7%) This difference was probably due to the fact that our research location was a military hospital, so there was also a great number of soldiers who usually trained and had field trips; therefore, they were at high risk for Rickettsiaceae fever [1, 4] The highest rate of underlying disease was hypertension (12.5%), followed by diabetes (5.7%); this result was lower than Vu Minh Dien’s findings (24.6%) [2] Clinical and subclinical characteristics Table 2: Clinical characteristics Number of patients Rate (%) Sudden 87 98.9 Hot 88 Chill Freezing cold Symptoms Number of patients Rate (%) Congestive skin 42 47.7 100.0 Maculopapular rash 25 28.4 69 78.4 Hemorrhage rash 1.1 12 13.6 Lymphadenopathy 22 25 Phew 2.3 Symptoms Fever Mean temperature 35 39.8 Circuit and body temperature dissociation 3.4 One 35 100.0 Hypotension 4.5 Two 0.0 Mean breathing frequency 9.1 Breathing rate > 25 cycles/minute 4.5 Shoulder, arm 12.1 Explosive rale 24 27.3 Chest, back 10 30.3 Humid rale 4.5 Abdomen, ribs 3.0 Hepatomegaly 9.1 Inguinal, perineum 15 45.5 Splenomegaly 9.1 Thigh, butt 6.1 Abdominal effusion 4.5 9.1 Meningeal syndrome 10.2 Ulcer appearance Number of ulcers Head neck Position of ulcers and Disorder of consciousness 124 39.42 ± 0.46 C 19.64 ± cycles/minute Journal of military pharmaco-medicine no5-2020 All patients had fever; its common characteristics were sudden fever, hot fever, chill fever, average fever duration was 11.76 ± 4.3 days; the proportion of patients with sudden fever in our study was higher than Vu Minh Dien’s findings (71.9%) and Pham Thi Thanh Thuy’s (64.9%) This difference may be due to the time of hospitalization among the different studies 39.8% of patients had only one ulcer; the most common site was inguinal, perineum (45.5%) and chest, back (30.3%) The proportion of peripheral lymphadenopathy was found in 25% of patients, higher than Vu Minh Dien’s study (23.4%) but lower than Pham Thi Thanh Thuy’s (63.7%); the difference can be due to variation in subjects, hospitalization time and lymph nodes identification criteria in each study [2, 3] Common respiratory symptoms were explosive rale (27.3%); this result was similar to the study by Vu Minh Dien [2] The rate of hepatomegaly and splenomegaly in our study (9.1%) was similar to Vu Minh Dien’s findings (12.6% of hepatomegaly and 6.6% of splenomegaly) but lower than Pham Thi Thanh Thuy’s (55.0% and 17.9%, respectively) and Hamaguchi’s (hepatomegaly and/or splenomegaly: 43.7%) The difference may be due to different criteria for identifying hepatomegaly, splenomegaly and subjects [3, 6] The incidence of meningitis (10.2%) in our study was similar to the neurological manifestation rate seen in 18 cases (10.8%) of the total of 167 cases of bacterial diseases of the Rickettsia family in the study by Vu Minh Dien, of which patients had encephalitis and 12 patients had meningoencephalitis [2] Meningitis and encephalitis syndrome occurred in 9/72 patients with fever in a report from Thailand [8] Table 3: Subclinical characteristics Number of patients Rate (%) Number of patients Rate (%) Hb < 120 g/L 24/88 27.3 CRP > 100 mg/L 3/14 21.4 White blood cells > 10 G/L 29/88 33.0 PCT > 10 ng/mL 2/48 4.2 Neutrophil leukocytes > 70% 47/88 53.4 AST > 80 U/L 66/88 75 Platelet < 150 G/L 64/88 72.7 ALT > 80 U/L 64/88 72.7 Injury 32/79 40.5 Total bilirubin > 17 µmol/L 24/80 30 Interstitial thickening 5/79 6.3 Albumin < 35 g/L 40/60 66.7 Lateral infiltration 8/79 10.1 Prothrombin < 70% 2/20 10 Widespread infiltration 4/79 5.1 Ure > 7.5 mmol/L 10/85 11.8 Blurred rib diaphragm angle 11/79 13.9 Creatinin > 110 µmol/L 6/85 7.1 Subclinical index Chest X-ray Subclinical index 125 Journal of military pharmaco-medicine no5-2020 Anemia was seen in 27.3% of patients In our opinion, mild anemia may be associated with high fever for many days, as well as patients’ poor nutritional status; severe anemia may be associated with gastrointestinal bleeding and myelosuppression or macrophage activation - a phenomenon that has been reported in study by Loussaief [7] Leukocytosis was seen in 33% of patients, this result was similar to Vu Minh Dien’s (35.7%) and Hamaguchi’s study (40.7%) [2, 6] Thrombocytopenia accounted for 72.7%; physiologically, the bacteria of the Rickettsiaceae family are found mainly in vascular endothelial cells causing microvascular damage, stimulating platelet consumption that lead to a decreased total blood platelets The degree of thrombocytopenia was a major prognostic factor in the research by Pham Thi Thanh Thuy [3] Lung damage on X-ray were often seen with the manifestations: Blurred angle of diaphragm (13.9%), lateral infiltration (10.1%), interstitial thickening (6.3%) Due to differences in the language described on X-ray film, the statistics of lung lesion characteristics in our study were different from Vu Minh Dien’s (33.2% of interstitial lung lesions, 2.3% of both parenchymal and interstitial lesions on X-ray) [2] The group of patients with fever caused by Rickettisa in Pham Thi Thanh Thuy’s study had a higher rate of lung lesions on X-ray than our study: Among 54.2% of patients with lung lesions, 50% of nodular lattice lesions in or sides; nodular infiltrates: 1.4%; the lung lobes infiltrates: 126 13.8%; thickening of lung lobes: 5.6% [3] This difference was due to our retrospective research design, poor quality of X-ray, limited details of lesions The proportion of patients with elevated levels of AST, ALT was 75% and 72.7%, respectively Liver dysfunction is a very common manifestation of fever caused by Rickettsiaceae, all parameters of liver function may be affected Thus, CDC chose an elevated liver enzymes as one of the criteria for Rickettsiaceae fever suspicion [5] CONCLUSION Rickettsiaceae fever was common in male (62.5%); delta residence (88.6%); exposure activities were mainly found in patients who the gardening (45.5%), followed by camping soldiers (21.6%); common underlying diseases of hypertension (12.5%), diabetes (5.7%) Sudden fever: 98.9%; hot fever: 100%; chill fever: 78.4% 39.8% of patients had only one ulcer at the common sites such as inguinal, perineum (45.5%) and chest, back (30.3%) Fever caused by Rickettsiaceae often cause multiple organ damage: Enlarged lymphadenitis: 25%; congestive skin: 47.7%; maculopapular rash: 28.4%; explosive rale in lung: 27.3%; hepatomegaly and splenomegaly: 18.2%; meningitis: 10.2%; hypotension: 4.2% White blood cells > 10 G/L (33%); Hb < 120 g/L (27.3%); platelet < 150 G/L (72.7%); urea > 7.5 mmol/L (11.8%); ALT > 80 U/L (72.7%); total bilirubin > 17 µmol/L (30%); CRP > 100 mg/L (21.4%) Journal of military pharmaco-medicine no5-2020 REFERENCES Lê Văn An Nghiên cứu lâm sàng dịch tễ học chẩn đoán bệnh sốt mò kỹ thuật khuếch đại gen bệnh nhân điều trị Bệnh viện Trung ương Huế Tạp chí Y học Thực hành 2008; 521:68-73 Vũ Minh Điền Đặc điểm lâm sàng, cận lâm sàng kết điều trị bệnh Rickettsia Bệnh viện Nhiệt đới Trung ương (3/2015 - 3/2018) Luận án Tiến sỹ Y học Trường Đại học Y Hà Nội 2019 Phạm Thị Thanh Thủy Nghiên cứu đặc điểm lâm sàng, phương pháp chẩn đốn điều trị bệnh sốt mị Luận án Tiến sỹ Y học Trường Đại học Y Hà Nội 2007 Cao Thành Vân Nghiên cứu số đặc điểm lâm sàng, cận lâm sàng thường gặp kết điều trị bệnh sốt mò Bệnh viện Đa khoa Quảng Nam (từ năm 2015 - 2017) Tạp chí Y học Thực hành 2018; 568:54-61 CDC Tick-born Rickettsial disease case report Centers for Disease Control and Prevention (CDC) 2008 Hamaguchi S, Cuong NC, Tra DT, et al Clinical and epidemiological characteristics of scrub typhus and murine typhus among hospitalized patients with acute undifferentiated fever in Northern Vietnam The American Journal of Tropical Medicine and Hygiene 2015; 92(5):972-978 Loussaief C, Toumi A, Ben HB, et al Macrophage activation syndrome: Rare complication of murine typhus Pathologie Biologie 2014; 62(1):55-56 Silpapojakul K, Ukkachoke C, Krisanapan S, et al Rickettsial meningitis and encephalitis Archives of Internal Medicine 1991; 151(9):1753-1757 127 ... patients with fever caused by Rickettsiaceae treated at Military Hospital 103 and Central Military Hospital 108 SUBJECTS AND METHODS Subject, location and time of study 88 patients diagnosed with fever. ..Journal of military pharmaco-medicine no5-2020 An in- depth understanding of clinical and subclinical characteristics of patients with fever caused by Rickettsiaceae will be valuable... with fever caused by Rikettsiaceae were treated at the Department of Infectious Disease, Military Hospital 103 and the Clinical Institute of Infectious Diseases, Central Military Hospital 108 from