Koushik Tripathy, MD (AIIMS), FRCS (Glasgow), https://eyewiki.org/w/index.php?title=Cogan_Syndrome&oldid=89380, Peripheral subepithelial keratitis that rapidly evolves into interstitial keratitis, Vestibulo auditory symptoms that resemble Menieres disease such as nausea, vomiting, tinnitus, vertigo, Progressive hearing loss that progresses to deafness within 1-3 months, Vestibulo auditory symptoms within two years of eye symptoms, Subconjunctival or conjunctival hemorrhage, Inflammatory manifestations (episcleritis and choroiditis) with or without interstitial keratitis, Audiovestibular symptoms that are different from the Meniere-like symptoms seen in the typical form, 2+ years between ocular and vestibular auditory manifestations. The syndrome of nonsyphilitic interstitial keratitis with audiovestibular dysfunction was first reported by Morgan and Baumgartner in 1934 (1,2). The .gov means its official. Early recognition of this autoimmune disorder and intervention can minimize disabling and irreversible damage. [5] Studies have shown it to produce significant improvement in hearing loss in some patients. These immunosuppressive drugs include methotrexate (Rheumatrex), infliximab (Remicade), or azathioprine (Imuran). 356359., doi:10.1097/00003226-200205000-00005. The condition may also be associated with blood-vessel inflammation (called vasculitis) in other areas of the body that can cause major organ damage or, in a small number of cases, even death. A recent therapeutic option for Cogans syndromes are the TNF-alpha blockers [9, 27]. [8] The symptoms of interstitial keratitis develop rapidly but then resolve slowly and can be either bilateral or unilateral. 6, 2000, pp. Test for hepatic function are usually normal. Making a diagnosis There are no specific diagnostic tests. Select the option that best describes you. There are no clinical trials of treatment in Cogans Syndrome. The site is secure. Many patients will also require additional treatment with other immunosuppressive drugs including Methotrexate, Ciclosporin, Azathioprine, Tacrolimus or Cyclophosphamide. The .gov means its official. The most common symptoms are cardiovascular, neurological and gastrointestinal. [8] Cogan syndrome most commonly affects young adults between 20-30 years old but can be seen at any age, and while the etiology is unknown, infectious triggers, such as upper respiratory tract infection, diarrhea, dental infection, or recent immunization have been reported. J Immunol Res. Cogans syndrome is a rare autoimmune systemic vasculitis characterized by intraocular inflammation and vestibulo-auditory dysfunction (usually neurosensory deafness, but also tinnitus and vertigo) [1]. Grasland et al. Kessel, Aharon, et al. Optimal management of Cogan's syndrome: a multidisciplinary approach COGAN DG. BMC Ophthalmol. 6, 1980, pp. Approximately 70% of the patients have systemic disease, of which vasculitis is considered the pathological mechanism. Al-Shagahin H, Al-Hamaidah A. Cogans Syndrome in a Jordanian patient: A case report. If the vasculitis is widespread, the treatment should be more aggressive: cytotoxic agents. Arterial involvement in Cogans syndrome was also studied. Get the latest in health news delivered to your inbox! Espinoza, Gabriela Mabel, et al. Neurologic manifestations are not specific and can vary from headaches to coma [24]. Susac syndrome is caused by lesions of the retinal, cochlear and cerebral arterioles. No content on this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician. An official website of the United States government. Wegeners granulomatosis frequently affects the eye and ear. Itcan sometimes be triggered by an infection, such as hepatitis B, but the exact cause is uncertain. Cogan's syndrome: An autoimmune inner ear disease . A combined therapy or a step down regimen starting with cyclophosphamide and then switching to methotrexate or cyclosporine A after achieving a partial response may be a promising option [12]. Takayasu arteritisis a type of vasculitis that mainly affects young women. It can sometimes happen after a hepatitis C infection and causes a rash on the lower limbs, joint pain, nerve damage, tummy (abdominal) pain and kidney problems. Fifteen years later, Cody and Williams 2 emphasized the systemic manifestations of this syndrome. Please note the date of last review or update on all articles. Medical Professional. The Ig G antibodies from the patient serum recognized this protein, bounded to human cochlea, inhibited proliferation of cells expressing DEP-1/ CD148 and bounded to connexin 26, which has been implicated in congenital deafness. The typical form of CS is characterized by: 1. ocular involvement non-syphilitic interstitial keratitis, sometimes associated with iritis, conjunctivitis or subconjunctival hemorrhage, 2. audiovestibular involvement similar to Menieres disease, progressive loss of hearing to the point of deafness within 1-2 months, 3. an interval between the onset of ocular and audiovestibular manifestations of less than 2 years [7]. Inflammation is your immune system's natural response to injury or infection. Vasculitis and Cogan's syndrome. Rheumatic Diseases Clinics of North America, vol. If you experience any significant visual or auditory problems or difficulties with balance, contact your health care professional to be evaluated, especially if these symptoms continue. Cogan's syndrome is a rare disease, which primarily affects young adults; reports that establish the age of onset as ranging from 3 to 50 years have been published [9]. The Importance of FDG-PET/CT in Cogan's Syndrome - PMC About 10 to 30% of patients also have severe . Many cases may be incorrectly diagnosed as idiopathic hearing loss/ deafness, autoimmune inner ear disease and idiopathic recurring ketatitis [12]. [8][12], There are two forms of Cogan syndrome that can be diagnosed based on the onset of symptoms and ocular pathophysiology: the classic form and the atypical form. Cogan's Syndrome: Clinical Presentations and Update on Treatment [7] In 1963, the atypical form of Cogan syndrome, also known as "Logan Syndrome" was first described. [8], Cogan syndrome is typically treated with steroids. It manifests as loss of visual acuity, deafness and central neurological disorders [7]. Cogans syndrome (also Cogan syndrome) is an uncommon disease seen mostly in young adults that can severely affect vision and hearing. 214, no. [1] Cogan syndrome is a diagnosis of exclusion and if interstitial keratitis is detected, syphilis, herpes, chlamydia, tuberculosis, rubeola, mumps, Lyme disease, and parasitic etiologies must be ruled out before determining Cogan syndrome as the main cause for interstitial keratitis. American Academy of Ophthalmology; 2020. but can also rarely present in childhood or later in life, with no . There are fewer than 250 reported cases in literature and it is mostly described in Caucasian patients of both sexes [10, 11]. Arteriography can show stenosis, thrombosis or more lesions that are diffuse like an aneurismal dilation affecting the aortic root [7]. Cogan's syndrome is more than just keratitis: a case-based literature review. Prevention There is no way to prevent Cogan's syndrome. Clinical Features and Outcome of Cogan Syndrome. The Journal of Pediatrics, vol. Cogan D. Syndrome of non-syphilitic interstitial keratitis and vestibulo-auditory symptoms. Hemiparesis or hemiplegia due to a cerebral vascular accident or aphasia do to a transient ischemic event are the most common [2]. There are no specific diagnostic tests. [1] Topical Cyclosporin A may be effective in treating severe anterior segment inflammation in the setting of Cogan syndrome. Ugeskr Laeger. Cogan's syndrome can lead to vision difficulty, hearing loss and dizziness. Accessibility Interstitial keratitis is rarely asymptomatic, and most of the patients present with eye redness, photophobia or eye pain [ 2, 3 ]. Hypersensitivity vasculitis is usually caused by a reaction to a medicine, such as NSAIDs or certain antibiotics, and results in a temporary rash. Temporal arteritis, also known as giant cell arteritis, is a type of vasculitis where the arteries at the side of the head (the temples) become inflamed. Cogan Syndrome - Eye Disorders - Merck Manuals Consumer Version Also it showed similarities with the cell-density enhanced protein tyrosine phosphatase-1 (DEP-1/ CD 148) found in the sensory epithelia of the inner ear and on endothelial cells. [11], Patients with Cogan syndrome should be monitored closely and managed by ophthalmologists, internists, and otolaryngologists. [2] Iritis and subconjunctival or conjunctival hemorrhage are also possible features of the classic form. Takayasu arteritisis usually treated withsteroid medicine. [15] Treatment of Cogan syndrome depends on the severity and the degree of systemic involvement. Find out more about polymyalgia rheumatica. The Vasculitis UK website has more information about hypersensitivity vasculitis. It most commonly occurs in a person's 20s or 30s. Cogan's syndrome is a chronic (long-lasting) disease. Diagnosis There is no single test for diagnosing Cogan's syndrome, so your doctor will consider a number of factors, including a detailed medical history; physical examination; laboratory tests; specialized imaging studies; and . 59, no. He saw something that alarmed him and sent me to an eye specialist. The iridocorneal endothelial syndrome - PubMed PMID: 22846458 DOI: 10.1016/j.autrev.2012.07.012 Abstract Objectives: The objective of our study was to review our current knowledge of the aetiopathogenesis of Cogan's syndrome, including viral infection and autoimmunity, and to discuss disease pathogenesis with relevance to pharmacotherapy. the contents by NLM or the National Institutes of Health. Symptoms come and go, or respond well to treatment, but usually the disease is prolonged or even lifelong. Cogan syndrome (CS) is a variable vessel vasculitis first described by the American ophthalmologist David Glendenning Cogan in 1945 [ 1 ], characterized by recurrent non-syphilitic interstitial keratitis associated to vestibule-auditory dysfunction that leads to progressive deafness. It's usually treated with steroid medicine. What is the life expectancy of someone with Cogan syndrome? - Diseasemaps Orsoni JG, Lagana B, Rubino P, Zavota L, Bacciu S, Mora P. Rituximab ameliorated severe hearing loss in Cogan's syndrome: a case report. The diagnosis is difficult in the early stages of the disease [12]. The most recent therapeutic options are TNF-alpha blockers. There is no specific marker to diagnose Cogans syndrome, but screening should include ESR, a complete blood count, infectious agents and antibodies. 8, 1994, pp. It can lead to serious problems like stroke and blindness if not treated quickly. Cogan's syndrome is a rare entity, mostly described in young adult Caucasian patients of either sex, and fewer than 250 cases have been reported in the literature. The Vasculitis UK website has more information about cryoglobulin-associated vasculitis. 12, 2017, pp. [6], In 1945, the ophthalmologist David Glendenning Cogan (19081993) first described the "nonsyphilitic interstitial keratitis and vestibuloauditory symptoms" that would later bear his name. Disclaimer. The condition is fatal in less than 10% of patients. Cogan Syndrome - EyeWiki Hepatomegaly, splenomegaly and liver steatosis have been observed in some cases [7], 23]. A novel therapeutic option in Cogan disease? 2012 Apr;76(4):601-5. doi: 10.1016/j.ijporl.2012.01.017. Unable to load your collection due to an error, Unable to load your delegates due to an error. It took many months to be definitively diagnosed. In 1980, Haynes and co-authors [5] proposed the classification of Cogans syndrome (CS) as typical CS (the one originally defined by Cogan) and atypical CS (chronic and recurrent conjunctivitis, scleritis, uveitis, optic disk edema and retinal vasculitis) [6]. When large amounts of steroids are required or if the disease is severe and is not responding to steroid therapy, other immunosuppressive medications often are recommended. A slit-lamp examination is essential. The novelty in the treatment of the disease is tumor necrosis factor (TNF)-alpha-blockers, but more studies are necessary to establish their efficacy. Hearing loss is sensory in nature and it is often bilateral from the onset of the disease; in some patients, it can be unilateral in the beginning and become bilateral later on [23]. Musculoskeletal manifestation can occur: myalgias, arthritis, arthralgias, synovitis and possibly articular effusion. 4, 1963, pp. 2022 Sep 30;33(3):349-360. doi: 10.31138/mjr.33.3.349. Ndiaye I, Rassi S. Cochleovestibular impairment in pediatric Cogans syndrome. Darougar S, John AC, Viswalingam M, Cornell L, Jones BR. No serological marker for the disease has been found, so the diagnosis is an exclusion one. [1] Systemic manifestations are more frequent in the atypical form and can be used in addition to the ocular manifestations to differentiate between the two types. In some cases, systemic manifestations can be the only manifestation of Cogans syndrome for a long period of time, delaying the diagnosis [23]. [2][5] Interstitial keratitis is the most commonly seen ocular manifestation of Cogans syndrome. Itcan also affect the nerves, causing weakness,pins and needles or numbness, and sometimes damages the kidneys or heart muscle. Cogan Syndrome. Medicine, vol. Sign up to get tips for living a healthy lifestyle, with ways to fight inflammation and improve cognitive health, plus the latest advances in preventative medicine, diet and exercise, pain relief, blood pressure and cholesterol management, andmore. Your doctor also will want to evaluate your nervous system (for example, reflexes, strength and sensation), and check your ears by testing hearing, balance and inner ear function. Renal involvement in Cogan's syndrome | Request PDF - ResearchGate Resident, Fellow, or Student. Cogan's Syndrome: Clinical Presentations and Update on Treatment In some cases, combinations of these medicines are prescribed. 2, 1986, pp. Health warnings on exercise equipment: Should you worry? [23] published a study that concluded the disease remains restricted to the ear and eye in 17/ 52 (33%) patients with typical CS and 7/ 59 (12%) patients with atypical CS. Granulomatosis with polyangiitis, also called Wegener's granulomatosis, is a type of vasculitis that affects blood vessels in the nose, sinuses, ears, lungs and kidneys. Matteson EL, Choi HK, Poe DS, Wise C, Lowe VJ, McDonald TJ. Purpose of Review Cogan's syndrome (CS) is a rare systemic vasculitis that can severely affect vision and hearing, which may also have significant systemic effects. Hospital or Institution. Thought I had food poisoning, was misdiagnosed for two months,with several trips to the ER and Primary. eCollection 2022 Sep. Am J Case Rep. 2022 Apr 30;23:e935929. The clinical diagnostic tests in patients with Cogan's syndrome should include audiogram, caloric test, echocardiography, Doppler test, and angiography when systemic vasculitis is suspected. Signs of systemic involvement should be searched for in a general medical history, as well as questions regarding weight loss, fever, cutaneous anomalies, hyperesthesia, motor weakness, pain or claudication [12]. The Vasculitis UK website has more information abouteosinophilic granulomatosis with polyangiitis. [1], There have been case reports of positive Chlamydia psittaci and Chlamydia trachomatis antibodies in the setting of Cogan syndrome. eCollection 2018. Life expectancy is shorter in the subset of insulin-dependent diabetic (IDDM) patients who are susceptible to kidney disease. Usually, the first symptom affects either the eye (41%) or the ear (43%) alone. The patient can present with diarrhea, rectal bleeding or melena, abdominal pain sometimes associated with mesenteric arteritis, peptic or colonic ulcerations [7], 8]. 9, 16 June 2020, doi:10.1007/s11882-020-00945-1. Cogan's syndrome is a rare disorder of unknown origin characterized by inflammatory eye disease and vestibulo-auditory symptoms, which primarily affects young white adults, without a hereditary pattern 1.It was first described by an ophthalmologist, Dr David G. Cogan, in 1945, who reported on a "syndrome of non-syphilitic interstitial keratitis (IK) and vestibuloauditory . 173175., doi:10.1177/000348948609500213. The cochlear system follows by an interval of days or weeks [24]; as a general rule, the vestibular syndrome regresses when the auditory deficit appears [7]. COGANS Syndrome. Current Opinion in Rheumatology, vol. For information on the main drugs prescribed for Cogans Syndrome see: For information on other drugs used in the treatment of vasculitis see Glossary of drugs and side effects. Cogan syndrome affects young adults, with 80% of patients between 14 and 47 years. Careers. 2) . Cogan Syndrome. Cornea, vol. The course of the disease varies significantly from patient to patient. and transmitted securely. Recent findings: This article will review the varying clinical presentations of CS and emerging information of systemic . Autoimmune Inner Ear Disease: Immune Biomarkers, Audiovestibular Aspects, and Therapeutic Modalities of Cogan's Syndrome. Henoch-Schnlein purpura is not usually serious and often gets better without treatment. No treatment has been proven to have clear-cut efficacy when the audiovestibular involvement is corticosteroid resistant. 426441., doi:10.1097/00005792-198011000-00003. Several hypotheses have been suggested. 1, 2015, pp. Cogan's syndrome is classified into two groups. HHS Vulnerability Disclosure, Help Learn how UpToDate can help you. This allows for tapering of corticosteroids in 86% of patients. National Library of Medicine There are many types of vasculitis. Cogan syndrome | Radiology Reference Article | Radiopaedia.org The typical form of CS is characterized by: 1. ocular involvement - non-syphilitic interstitial keratitis, sometimes associated with iritis, conjunctivitis or subconjunctival hemorrhage, 2. audiovestibular involvement similar to Meniere's disease, progressive loss of hearing to the point of deafness within 1-2 months, 3. an interval between the . An official website of the United States government. Microscopic polyangiitis is a rare and potentially serious long-term type of vasculitis that most often developsin middle-aged people. Treatment is based on immunosuppressive agents, mainly corticosteroids as first-line choice. Don't miss your FREE gift. Cogan's Syndrome: Clinical Presentations and Update on Treatment Symptoms come and go, or respond well to treatment, but usually the disease is prolonged or even lifelong. It can lead to deafness or blindness if untreated. The same study demonstrated the induction of clinical features of Cogans disease in animals after passive transfer of peptide-specific antibodies or active immunization with autoantigen peptide. Get helpful tips and guidance for everything from fighting inflammation to finding the best diets for weight lossfrom exercises to build a stronger core to advice on treating cataracts. A report of two cases and review of the literature. EyeRounds.org. 433-439. Surveying for infections is usually negative, although evidence of Chlamydia infection was reported in some cases [23]. Bethesda, MD 20894, Web Policies Cogan's syndrome is a rare inflammatory disease . Next review due: 17 February 2026, a rash that looks like small bruises or reddish-purple spots (this may be less obvious on brown or black skin), flu-like symptoms, such as a high temperature and an aching body, pain and stiffness in the shoulders, neck and hips, which is often worse after waking up. [1][2] This syndrome was described by Dr. David G Cogan from the Massachusetts Eye and Ear Infirmary in 1945 as a 'syndrome of nonsyphilitic interstitial keratitis and vestibuloauditory symptoms'. Advanced search . My first symptom happened when I was 17 years old back in 1957. 2023 by The President and Fellows of Harvard College, Do not sell my personal information | Privacy Policy. Definition Cogan syndrome (CS) is a chronic inflammatory disorder characterized by recurrent interstitial keratitis (IK) and audiovestibular symptoms including hearing loss, tinnitus, and vertigo (Cogan 1945; Cheson et al. Pathologic examinations of the proximal portion of the aorta in patients with Cogan's syndrome have shown generalized dilatation and narrowing of the coronary arteries in the region of the aortic valve [17]. The earliest corneal findings are bilateral faint white subepithelial infiltrates similar to those found in viral keratoconjunctivitis, but located in the peripheral cornea measuring 0.5 to 1 mm in diameter [26]. 95, no. The most common symptoms include red, painful, light-sensitive or blurred vision; hearing loss (which may become profound and permanent); vertigo (dizziness); poor balance; nausea and vomiting; fever, fatigue and weight loss. But in vasculitis, for some reason the immune system attacks healthy blood vessels, causing them to become swollen and narrow. Polymyalgia rheumatica is a type of vasculitis that's closely related totemporal arteritis. Occasionally, if the disease has damaged blood vessels in the ear, cochlear implantation may be used to restore some sense of hearing. Similarities with polyarteritis nodosa have been noted in the histopathologic features of the affected vessels: prominent infiltration of large veins and muscular artery walls with lymphocytes and neutrophils; focal degeneration and fibrosis in the vessel walls have also been described [9]. Cogan's Syndrome | SpringerLink Frequent cardiac involvement in CS is aortic insufficiency, present in 15% of the cases; almost half of them require valve replacement to prevent the development of left ventricle insufficiency that can be fatal [7]. Vasculitis - NHS [1] However, diagnosing the type of Cogans syndrome can be difficult because the timing and association of the ocular and vestibulo-auditory symptoms are highly variable, with some patients not developing interstitial keratitis at the onset of the disease and some even developing it years later. 21, no. A sense of imbalance may be treated with antihistamines, such as meclizine (Antivert), or benzodiazepines, such as diazepam (Valium) or clonazepam (Klonopin) and bed rest. Cogan syndrome (also Cogan's syndrome) is a rare disorder characterized by recurrent inflammation of the front of the eye (the cornea) and often fever, fatigue, and weight loss, episodes of vertigo (dizziness), tinnitus (ringing in the ears) and hearing loss. Early recognition of this autoimmune disorder and intervention can minimize disabling and irreversible damage. The main treatment issteroid medicine, whichis usually used in lower doses than for temporal arteritis. Diagnosis is by a doctor's evaluation and blood tests to rule out other diseases. 1. PDF Cogan's syndrome - Orphanet Other rare manifestations are: cerebellar syndrome, pyramidal syndrome, epilepsy, spinal cord disease, meningeal syndrome, encephalitis, facial palsy, peripheral neuropathy [7,23]. Bonaguri C, Orsoni JG, Zavota L, Monica C, Russo A, Pellistri I. Anti-68 kDa antibodies in autoimmune sensorineural hearing loss: are these autoantibodies really a diagnostic tool? The most common symptoms of Cogan's syndrome include: More rarely, Cogan's syndrome can cause enlarged lymph nodes, rash, chest pain, arm pain and shortness of breath. Etanercept therapy for immune-mediated cochleovestibular disorders: a multi-center open-label, pilot study. Typical and atypical Cogan's syndrome: 32 cases and review of the [1] Infliximab is now commonly used along with corticosteroids, especially in those who have failed combinations of steroids and DMARD therapy. More than 50% of patients have associated diffuse systemic manifestations. Vogt-Koyanagi-Harada syndrome associates audiovestibular involvement with uveitis, alopecia, poliosis and vitiligo [7]. Microscopic polyangiitis is usually treated withsteroid medicineor other medicines that reduce the activity of the immune system. [5], Systemic involvement can be seen in up to 80% of patients. Weisenthal RW. The cause is not known. Whilst we make every effort to keep up to date, any information that is provided by Vasculitis UK should not be a substitute for professional medical advice. This peptide was similar to autoantigens as SSA/ Ro and the reovirus III major core protein lambda 1. Cogan's Syndrome | SpringerLink 4752., doi:10.1097/00002281-199901000-00008. [3] Since 1945, only several hundred cases have been reported in the literature. However, most patients are able to manage their symptoms and limit complications of the disease with treatment. sharing sensitive information, make sure youre on a federal SHAH, P., et al. 8600 Rockville Pike The vestibular system is the first one affected in Cogans syndrome. If you have CS the chances are it is not going to be the cause of your death. Patients with ear and eye involvement alone have a good prognosis and an average life expectancy [15]. Shimura, Masahiko, et al. The prognosis of typical CS is excellent with life-threatening aortic insufficiency (AI) developing in only 10% of reported cases. 20, no. Typical and atypical Cogans syndrome: 32 cases and review of the literature. Accessibility Currently, there is no specific serum autoantibody used in the diagnostic workup of CS. May 24, 2007; Available from: http://www.EyeRounds.org/69-CogansInterstitialKeratitisVestibuloauditory.htm. Cogan syndrome can occur in children, and is particularly difficult The syndrome affects primarily young adults, involves another organ in 2/3 cases and gives a clinical picture of systemic disease reminiscent of vasculitis in 1/3 This page was last edited on February 6, 2023, at 14:50. Cogan's syndrome--clinical guidelines and novel therapeutic approaches. Cogan syndrome - Wikipedia Patients who suffer from microscopic polyangiitis often have inflammatory eye involvement. Other studies have shown that up to 70% (63% of the cases of Yamanishi [20]) of the patients with Cogans syndrome have underlying systemic disease in addition to ocular and audiovestibular dysfunctions. Cogan's syndrome: a cause of progressive hearing deafness. The actual number of people with Cogans syndrome could be higher than reported. Other cardiac lesions observed in patients with Cogans syndrome are: coronaritis, coronary stenosis, pericarditis, arrhythmia, mitral insufficiency, myocardial necrosis and myocarditis [7, 24]. The diagnosis should be suspected whenever there are ocular abnormalities closely followed or preceded by audiovestibular symptoms. The Academy uses cookies to analyze performance and provide relevant personalized content to users of our website. The disease appears to result from an autoimmune reaction directed against an unknown common autoantigen in the cornea and inner ear. Cogan syndrome is a rare autoimmune disease involving the eye and the inner ear. Autoimmune Inner Ear Disease: Immune Biomarkers, Audiovestibular [2], Patients with the atypical form of Cogan syndrome typically present with inflammatory ocular manifestations, such as episcleritis and choroiditis, with or without interstitial keratitis along with audiovestibular symptoms that are different from the Meniere-like symptoms seen in the typical form of Cogan syndrome. Grasland A, Pouchot J. The possibility of systemic vasculitis must be considered and investigated at any stage of Cogan's disease.
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