Viral infections in orthopedics: A systematic review and classification proposal

Table 1 Study characteristics of articles dealing with hepatitis C virus patients undergoing total knee arthroplasty/total hip arthroplasty or other major orthopedic surgery

Author (year)	Study design	Inoculated groups and number of subjects	Risk factors/outcome measures	Outcomes	Follow-up
Best (2014)	Retrospective cohort study of non-cirrhotic HCV positive individuals and HCV negative patients who underwent TKA/THA in the USA from 1990-2007	Group 1: 26444 HCV patients, 14452 subjected to THA (51.2% males) and 11992, to TKA (36.5% males); Group 2: 8336822 HCV negative patients, 2968679 subjected to THA (42.6% males), and 5370202 subjected to TKA (36.2% males)	Gender, Age, LOHS, Comorbidities, post-operative bleeding, thrombocytopenia, transfusion reaction, cardiac complications, peripheral vascular complications, urinary complications, acute renal failure, myocardial infarction, pulmonary embolism, pneumonia, deep venous thrombosis, blood transfusion, osteomyelitis, and infection	LOHS, age, rates of total complications, and post-operative bleeding	Not specified
Chowdhury (2017)	Retrospective registry study with a propensity-matched cohort including HCV patients and uninfected participants who have undergone TKA, THA, and spine procedures in the USA between 2006-2014	Group 1: 1131 (52% males) with HCV; Group 2: 95161 (56% males) non-HCV individuals, and after propensity score matching, 1131 non-HCV patients were matched to the HCV group, and the cohort consisted of 2262 patients	Mortality within 30- or 90-d, readmission, and complications within 30 and 90 d	Mortality assessment, complication, and readmission rate evaluation	Up to 30 and 90 d post-operatively or upon complication
Pour (2011)	Retrospective case-control study with a control group matched at a 2:1 ratio with asymptomatic HCV patients subjected to THA and TKA from 1995-2006 in the USA	Group 1: n = 39 (29 males) HCV patients who have undergone THA; Group 2: n = 80 (60 males) patients who have undergone THA (control group); Group 3: n = 32 (15 males) HCV patients subjected to TKAGroup 4: 64 (30 males) patients subjected to TKA (control group)	Αge, gender, BMI, need for transfusion, preoperative PLTS, LOHS, and the complication rate	Complication assessment (wound, mechanical, fracture, reoperation, revision); Length of hospital stay	101 mo (range 66-140) for the HCV patients subjected to THA; 94 mo (range 45-131 mo) for the control group subjected to THA, 117 months (range 67-150 mo) for the HCV patients subjected to TKA; 98 mo (range 49-133 mo) for the control group subjected to TKA

TKA: Total knee arthroplasty; THA: Total hip arthroplasty; HCV: Hepatitis C virus; LOHS: Length of hospital stay; PLTS: Platelets; BMI: Body mass index.

Table 2 Study characteristics of the included articles dealing with the Ross River Virus

Author (year)	Study design	Inoculated groups and number of subjects	Outcomes	Follow-up
Chen (2014)	In vitro and in vivo animal interventional study	For the in vitro experiment: 21-day-old male and female C57BL/6 WT mice were inoculated in the thorax with 104 PFU of RRV. Those mice received 500 μg of anti-IL-6 antibody injections on days 0 and 2, 4, 6, 8 post-infection. For the in vivo investigation: Serum samples from 14 Ross River virus patients (7M and 7F) were obtained, and serum from 13 healthy individuals (7M). Synovial fluid samples from 12 RRV-induced polyarthritis patients (6M) were retrieved and from 6 healthy individuals (3M).	The animal part of the study investigated whether RRV replicates in the bone (murine model) and viral titers were measured. μCT imaging was used to assess the impact of the infection on bone architecture and loss. The role of IL-6 on bone loss was evaluated. The human part of the study looked at OPG, RANKL, and TRAP5b levels in RRV-positive patients.	Not specified
Soden (2000)	Prospective observational study involving humans	Biopsy tissue from inflamed knees from 12 patients was retrieved.	Histological examination of the synovial membrane. RT-PCRto look for the presence of viral RNA	The follow-up was performed at 3-mo intervals until 6 m following symptom resolution

RANKL: Receptor activator of nuclear factor kappa beta (NF-kB ligand); TRAP5b: Tartrate-resistant acid phosphatase serum band 5 (TRAP5b); WT: Wild type; RT-PCR: Reverse transcription-polymerase chain reaction; μCT: Micro-computed tomography; RRV: Ross River virus; M: Male; F: Female; IL-6: interleukin 6.

Table 3 Study characteristics of the included articles dealing with Chikungunya virus infection

Author (year)	Virus information	Study design	Inoculated groups and number of subjects	Outcome measures	Follow-up
Chang (2017)	Colombian patients infected by CHIKV	Case-control study of 38 participants with CHIVK and chronic arthritis and 10 location-matched controls without CHIKV or arthritis	Group 1: Out of 907 patients who were clinically (424) and laboratory (483) confirmed for CHIKV, 38 individuals with chronic arthritis post-infection were selected; Group 2: 10 matched controls without CHIKV/arthritis were considered	Synovial fluid samples were analyzed by PCR, and mass spectrometry for viral proteins. No virus could be detected.	Not specified
Chen (2015)	Chikungunya virus from infected patients' serum. CHIKV-mCherry strain was also used	In vitro study utilizing serum from 14 CHIK patients and 7 healthy individuals; In vivo animal study utilizing 25 d-old C57BL/6 mice infected with CHIKV/mCherry	Group 1: Serum from 14 CHIKV patients (8F 6M) was collected between the 3rd and 22nd week post-infection; Group 2: Serum from 7 (4F and 3M) healthy individuals was also used; Group 1: 25 d-old mice were infected with 20 μL 105 PFU CHIKV-mCherry in the ventral side of the foot. Group 2: Consisted of the control group of mice.	For the in vitro study: Serum RANKL/OPG ratio was measured; For the in vivo study: Day 3 post-infection peak swelling was measured until day 10. Levels of RANKL and OPG were measured inside the joint during days 1, 3, 7 and 15 post-infection.	Days 1, 3, 7, and 15 post-infection
Goupil (2016)	Chikungunya virus SVO 476-96	In vivo animal study featuring IRF 3/7 C57BL/6 mice (M and F > 8 wk old) and C57BL/6J mice (> 8 wk old only F)	Group 1: 11 IRF mice were intradermally injected with 2 × 104 PFU; Group 2: 9 control C57BL/6j mice were injected with 2 × 104 PFU	Intact hindlimbs were collected and scanned μCT to evaluate the difference between the morphology of two types of mice (joint, trabecular bone). Histopathological evaluation was also performed. On day 5, post-infection 4 mice were euthanized due to being lethargic, and 6 mice died due to rapid progression of the illness	For the IRF mice 1, 2, 3, 5, 6, 7th day post-infection;For the C57BL/6J mice 7, 14, 21st day post-infection
Hawman (2013)	Chikungunya SL15649 from serum sample	In vivo animal study featuring 3-week-old C57BL/6J mice and congenial rag_/- mice	Group 1: 55 mice were inoculated in the left rear footpad with 103 PFU (10 μL). MAbs (200 μg each of CHK-152 and CHK-166) were administered intraperitoneally on days -1 and 3 for prophylaxis studies. For therapeutic studies, MAbs were administered on days 21 and 25 post-infection; Group 2: Control mice were subject to mock-infection	Duration of CHIKV infection in tissues was assessed, and associated histopathological changes were evaluated	Day 3 and weeks 1, 2, 4, 6, 12, 16

CHIKV: Chikungunya virus; PCR: Polymerase chain reaction; WT: Wild type; RT-PCR: Reverse transcription polymerase chain reaction; μCT: Micro-computed tomography; M: Male; F: Female; IL-6: Interleukin 6; PFU: Plaque-forming unit; MAbs: Monoclonal antibodies.

Table 4 Proposed viral classification scheme

Proposed pathogenetic mechanism	Viruses involved	Evidence supporting the proposed mechanism
Direct infection and subsequent inflammation	Ross Rover and Zika viruses	RRV causes arthritis with its RNA coinciding with the appearance of symptoms; Evidence of human osteoblasts being primarily infected
Inflammation primarily through autoimmune mechanisms such as cross-reactivity	CHIKV	CHIKV causes arthritis in the absence of evident infection. Other supporting information includes rheumatoid factor negative RA and exclusive presence in the synoviocytes. Animal studies implicate a potential role of primary infection
Systemic manifestations resulting in immunosuppression	HCV and HIV	Greater rates of microbial infections in HCV patients post-surgery. Greater rates of infections post-surgery pre-HAART. High rates of mechanical and medical comorbidities

RRV: Ross River virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; CHIKV: Chikungunya virus; HAART: Highly active antiretroviral therapy; RA: Rheumatoid arthritis; hOBs: Human osteoblasts.