ocular manifestation of ebola

Tan, Jaesser T.First Year

OphthalmologyUERM

Outline

• Brief discussion of Ebola• Case of Ebola with Ophthalmic Manifestations• Journals

Ebola• Discovered in 1976 • Single-stranded negative sense RNA Virus• Order: Mononegavirales• Family: Filoviridae– Viral Hemorrhagic Fever in primates

• Genus: Ebolavirus is 1 of 3 members of the Filoviridae family (filovirus),–Marburg virus and Cueva virus

SPECIES• Genus Ebolavirus comprises 5 distinct species: Bundibugyo ebolavirus (BDBV) Zaire ebolavirus (EBOV)

most dangerous Sudan ebolavirus (SUDV) Reston ebolavirus (RESTV)• Taï Forest ebolavirus (TAFV).

• BDBV, EBOV, and SUDV have been associated with large EVD outbreaks in Africa, whereas RESTV and TAFV have not.

• The RESTV species, found in Philippines and the People’s Republic of China, can

infect humans, but no illness or death in humans from this species has been reported to date.

Outbreaks of AFRICA

• The virus is transmitted to people from wild animals and spreads in the human population through human-to-human transmission.

• EVD outbreaks occur primarily in remote villages in Central and West Africa, near tropical rainforests.

Transmission•The virus is spread through direct contact (through broken skin or mucous membranes) withi. sick person's blood or body fluids

(urine, saliva, feces, vomit, sweat and semen)

ii. objects (such as needles) that have been contaminated with infected body fluids.

iii. Infected animals.

Transmission

Animal to human• Consumption of raw

meat• Contact with fruit

bat, pigs, apes- animal handlers

• Animal products (blood, urine and feces.)

Human to human • Close contact with

infected patients• Care personnels of

patient• Health care workers

Prompt and safe burial of dead bodies.No to Autopsy Virus contained in dead body for a period 4 weeks.

Transmission

• Men who have recovered from the illness can still spread the virus to their partner through their semen for up to 7 weeks after recovery.

Pathophysiology

• Endothelial cells, mononuclear phagocytes, and hepatocytes are the main targets of infection. After infection, a secreted glycoprotein (sGP) known as the Ebola virus glycoprotein (GP) is synthesized.

• Ebola replication overwhelms protein synthesis of infected cells and host immune defenses.

• The GP forms a trimeric complex, which binds the virus to the endothelial cells lining the interior surface of blood vessels.

Pathophysiology

• The sGP forms a dimeric protein that interferes with the signaling of neutrophils which allows the virus to evade the immune system by inhibiting early steps of neutrophil activation.

• These white blood cells also serve as carriers to transport the virus throughout the entire body to places such as the lymph nodes, liver, lungs, and spleen.

Incubation Period: 2-21 days

• Morbidity and mortality rates are very high, and they vary with the strain of Ebola

• Fatality rate 25% to 90%• Recovery is slow in those who survive

Prognosis

Why Is Ebola So Deadly?

• Virus usually detected late with more severe signs and symptoms

• Often mistaken for malaria, typhoid fever, dysentery, influenza, or bacterial infections

• Appears in sporadic outbreaks• People die from the massive blood loss, not

necessarily from the disease• 10% Survival rate

Treatment

Treatment

• No ebola virus Disease-specific treatment exists.

• Treatment is primarily supportive in nature and includes minimizing invasive procedures, balancing fluids and electrolytes to counter dehydration

Treatment

• Administration of anticoagulants early in infection to prevent or control disseminated intravascular coagulation

Administration of procoagulants late in infection to control bleeding

Maintaining oxygen levels, pain management, and the use of medications to treat bacterial or fungal secondary infections.

Vaccines

• No vaccine is currently available for humans.• Promising candidates are DNA vaccines or

vaccines derived from adenoviruses, vesicular stomatitis Indian virus (VSIV) or filovirus-like particles (VLPs)

• Vaccines have protected nonhuman primates• DNA vaccines, adenovirus-based vaccines, and

VSIV-based vaccines have entered clinical trials

Preventive

Case of Ebola

Emory Ebola Patient #3

• 43yo male, Physician evacuated from Sierra Leone

• “sickest patient with Ebola virus that we’ve cared for at Emory”

History of Present Illness• Day 1: Fever, malaise, fatigue, headache• Day 2: EVD confirmed by RT-PCR• Day 3: Petechial rash, 1st dose of TKM-100802• Day 4: Admission (9/3/14)

• Exam:• 126/73, 51bpm, 40C 98% O2• Increased work of breathing, petechial rash -> delirium

• Labs: WBC 2.6 PLT 62 AST:155

Hospitalization Course

• Day 6: Severe gastroenteritis and hepatitis• Day 9: AKI and Respiratory distress– Intubation and mechanical ventilation

• Day 11: Cardiac arrhythmias and worsening acidosis

• Day 21: Extubated -> Delirium

Hospitalization Course

• Day 29: Improving mental status– Ambulates with assistance

• Day 35: Dialysis held– Blood test negative for EBOV by RT-PCR

• Day 40: Discharged– 30lb weight loss, easy fatigability, muscle

weakness, word-finding difficulties

Hospitalization Course

• Experimental Treatments• TKM-100802– Day 3-8

• Plasma from a survivor– Day 8, 9, 11, 12, 14 15

Day 70 of Illness11/14/14

• Improving Symptoms– Ambulation improving– Occasional word-finding difficulty– Gaining weight

• New Symptoms– Hair loss, coming out in clumps– Marked decreased hearing L>R– Low back pain– Enthesitis: Bilateral Achilles tendons– Occsional blurry vision bilaterally

• Transient burning lasting for a few seconds, every few days

Day 80 of Illness

• Improving symptoms– Back and joint pains– Tendinitis– Word-finding difficulties

• Worsening symptoms– Blurred vision– Mild light sensitivity– Increased need for reading glasses

Day 80 of Illness• PE• VA 20/15 OU• IOP OD 10mmHg, OS 9

mmHg• SLE

– C/S Quiet OU– K Mild arcus senilis OU– AC D/Q OU– Iris WNL OU, Blue irides OU– Lens Clear OU– Ant Vitreous Quiet

Posterior Segment Examination

Day 80 of Illness

• Posterior Uveitis/Chorioretinitis Inactive– ? Post inflammatory viral changes

• s/p Ebola Virus Disease convalescent

• Plan– Observation– Follow-up 3-4 weeks

Day 97 of Illness12/11/14

• Acute onset of symptoms– Headache and retro-orbital aching sensation– Blurred vision and haloes– Photophobia

• Recommended urgent evaluation– Diagnosis? Acute angle closure

Day 97 of Illness12/11/14

• VA 20/20 OS• IOP 44mmHg OS• SLE OS

– Mild corneal edema, trace cell• Gonioscopic evaluation

– No evidence of angle closure

• Plan:– Diamox 250mg and administered ocular hypertensives decreased 35

mmHg– Pred forte 1% QID OS– Systemic and topical ocular hypotensives

Day 99 of Illness12/13/14

• Primary Diagnosis: Hypertensive Anterior Uveitis

• Interval History– Escalating pain symptoms over next 2 days– Increasing anterior chamber inflammation

• Differential Diagnosis– Herpes simplex virus 1 and 2– Cytomegalovirus– Varicella zoster virus– Toxoplasmosis, syphilis, sarcoidosis, HLA-B27 associated– Ebola virus associated Uveitis

Day 99 of Illness12/13/14

• Plan– Conjunctiva and tear film specimen taken for

Ebola virus PCR– Anterior Chamber Paracentesis for PCR testing– Serologic evaluation for autoimmune/infectious

etiologies– Referral to infectious disease

Ebola virus RT-PCR Positive (12/14/2014)

Ebola virus RT-PCR Positive (12/14/2014)

• Conjunctival swab and tear film pre and 24 hr post procedure were EBOV PCR negative

Day 102 of Illness12/16/14

• Interval History– Worsening vision and eye pain

• VA 20/60 OS, TA 15mmHg• SLE– C/S - 3+ episclera;/scleral injection– K - Diffuse keratic Precipitates– AC – 2-3+ cells with interspersed RBC– Iris - WNL– Lens – Clear– Vit – No vitreous cell

Day 102 of Illness12/16/14

• Plan– Start oral prednisone 80mg/day (1mg/kg)– Topical Prednisolone acetate 1% q2 OS

Day 103 of Illness12/17/14

Day 103 of Illness12/17/14

• VA OS 20/150• IOP OS 15mmHg• Hypopion 0.5mm

• Plan– Continue oral prednisone 80mg/day (1mg/kg)– Topical Prednisolone acetate 1% q1 OS

Day 110 of Illness12/22/14

• Interval History– Improving eye pain

• VA OS 20/800 IOP OS 1mmHg• SLE– C/S – Quiet conjunctiva– K -2+ stromal edema w/ decemet folds– AC – 1+ cells– Iris - WNL– Lens – Clear– Vit – 2+ vitreous haze

Day 110 of Illness12/22/14

Day 110 of Illness12/22/14

• Plan– Continue oral prednisone 80mg/day (1mg/kg)– Difluprednate q2 OS

Day 110 of Illness12/22/14

• Current Diagnosis– Aggressive, acute hypertensive anterior uveitis

progressing to severe panuveitis with hypotony

Uncertainty

1. Management and prognosis at this time• Corticosteroid vs anti-viral

2. Direct viral lytic effect vs immunologic reaction to Ebola

Day 112 of Illness12/24/14

• Readmission• Started antiviral– EBOV specific option – TKM-Ebola aka T-705

Day 117 of Illness12/29/14

• Steroid Injection

Day 118 of Illness12/30/14

Day 118 of Illness12/30/14

• Discharged• Poor prognosis

Day 122 of Illness1/3/15

• Febrile episode• Readmitted

Updates

• Explanation for Vision Improvement remains to be speculations for now.

• On going research and studies

Journals

What we know about ocular manifestations of Ebola (Majid Moshirfar,1 Carlton R Fenzl,2 Zhan Li3November 2014)

• Ocular signs observed in both the acute and late settings

• Conjunctival injection– 58% of infected patients– Often presents bilaterally

• Subconjunctival hemorrhage• Excessive lacrimation • Unclear pathophysiology of manifestations

What we know about ocular manifestations of Ebola (Majid Moshirfar,1 Carlton R Fenzl,2 Zhan Li3November 2014)

• Subacute/chronic ophthalmic manifestations:– Two pathways: • they may rapidly progress to a more intense

hemorrhagic state where death is nearly inevitable• they may enter a convalescent phase.

– at risk for uveitic episodes.

• Despite the complexity of findings, treatment required only topical steroids and cycloplegia.

Late Ophthalmologic Manifestations in Survivors of the 1995 Ebola Virus Epidemic in Kikwit, Democratic Republic of the Congo

(Colebunders et at 1999)

• Cumulative total of suspected cases of EBO hemorrhagic fever (EHF) was 316, of whom 245 (77%) died

• acute phase of EBO infection– conjunctival injection

• 48% and 58%• a relatively early sign of EHF

– bilateral conjunctivitis • acute phase of the epidemic was highly predictive for the diagnosis of an EBO infection;

– subconjunctival hemorrhages also been reported– blurred vision or blindness

• etiology of these ocular manifestations remains unclear • Ophthalmologic examinations considered potentially risky procedures for

health care workers – the nurse-ophthalmologist died during the EBO epidemic

Late Ophthalmologic Manifestations in Survivors of the 1995 Ebola Virus Epidemic in Kikwit, Democratic Republic of the Congo

(Colebunders et at 1999)

• Twenty (28%) of the 71 EBO survivors were enrolled in a 3-month follow-up study

• Three participants (15%) presented with ocular manifestations during the convalescent period of their infection

• fourth EBO survivor outside this cohort, who also had ocular problem

• all 20 EBO survivors and the additional noncohort patient met the clinical definition for infection with EBO that was used during the epidemic. Moreover, serologic results (ELISA) were positive for EBO infection for all 21 patients

• The clinical features of the 4 EHF cases during the acute EHF illness were similar to the clinical features observed in other EHF patients.

Late Ophthalmologic Manifestations in Survivors of the 1995 Ebola Virus Epidemic in Kikwit, Democratic Republic of the Congo

(Colebunders et at 1999)

• 15% or 3/20 survivors of the 1995 Ebola outbreak in the Democratic Republic of the Congo enrolled in a follow-up study and 1 other survivor

• Developed ocular manifestations after being asymptomatic for 1 month. – Complained of ocular pain, photophobia,

hyperlacrimation, and loss of visual acuity. • Ocular examination revealed uveitis in all 4

patients.

Late Ophthalmologic Manifestations in Survivors of the 1995 Ebola Virus Epidemic in Kikwit, Democratic Republic of the Congo

(Colebunders et at 1999)

• 4 cases, the diagnosis of uveitis was confirmed by an ophthalmologist.

• The pathogenesis of this uveitis may be a delayed hypersensitivity reaction to viral antigens

• All patients improved with a topical treatment of 1% atropine and steroids

Ocular Manifestations of Ebola Virus Disease: An Ophthalmologist’s Guide to Prevent Infection and Panic

(Enzo Maria Vingolo et al. 11 March 2015)

• The main problem in assessing human-to-human Ebola virus transmission

• Minimum infectious dose of the microorganisms is unknown

• EVD patients – unlikely seek specialized healthcare, as

ophthalmologic care– likely to seek emergency services and

hospitalization

Ocular Manifestations of Ebola Virus Disease: An Ophthalmologist’s Guide to Prevent Infection and Panic

(Enzo Maria Vingolo et al. 11 March 2015)

• Conjunctivitis– key early EVD sign– typically bilateral, asymptomatic, and nonicteric– appear even 6-7 days before patients seek EVD-related

care• Persistent and nonhemorrhagic conjunctivitis in EVD

– good prognostic factor• Summarizing, bilateral, asymptomatic, and nonicteric

conjunctivitis is one of the earliest and most frequent signs of EVD and has an important prognostic value.

Ocular Manifestations of Ebola Virus Disease: An Ophthalmologist’s Guide to Prevent Infection and Panic

(Enzo Maria Vingolo et al. 11 March 2015)

• Uveitis:– Late Ophthalmologic Symptom– 20% of convalescent patients– asymptomatic for up to 1-2 months– characterized by ocular pain, photophobia, hyperlacrimation, and loss of

visual acuity• Pathogenesis of uveitis

– delayed hypersensitivity reaction to RNA viral antigens• Uveitis can be treated with topical steroids• patients are considered safe and not infectious

– Even with detectable in tears of acute-phase EVD patients• Nevertheless, PPE must always be adopted in patients with ascertained

epidemiological risk.

Ebola warning for ophthalmologists(Rose Scneider, May 09, 2015)

• “Ebola virus can remain viable in some body fluids for an extended period of time after the initial onset of the disease”

• “If the Ebola epidemic continues, ophthalmologists throughout the world will be seeing patients with post-Ebola uveitis, will need to recognize and treat this condition, and will need to take appropriate increased precautions in performing surgical procedures on these patients,”

– Russell N. Van Gelder, AAO president