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TitleHerpes simplex virus infection of respiratory tract in intensivecare unit

Author(s) Lui, Mei-sze;–÷ ŽŠ

Citation

Issued Date 2012

URL http://hdl.handle.net/10722/173733

Rights Creative Commons: Attribution 3.0 Hong Kong License

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Herpes Simplex virus infection of respiratory tract in

Intensive Care Unit - a single centre experience

By

Dr Lui Mei Sze

(No: 1998256815)

This work is submitted to

Faculty of Medicine of The University of Hong Kong

In partial fulfillment of the requirements for

The Postgraduate Diploma in Infectious Diseases, PDipID (HK)

Date: 10th August 2012

Supervisor: Dr VCC Cheng

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Declaration

I, Lui Mei Sze, declare that this dissertation represents my own work and that it has

not been submitted to this or other institution in application for a degree, diploma or

any other qualifications.

I, Lui Mei Sze also declare that I have read and understand the guideline on “What is

plagiarism?” published by The University of Hong Kong (available at

http://www.hku.hk/plagiarism/) and that all parts of this work complies with the

guideline.

Candidate: Lui Mei Sze

Signature:

Date:

10th August 2012

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Acknowledgement

The author would like to the acknowledge the guidance and supervision from Dr

Vincent Cheng and the Department of Microbiology, Queen Mary Hospital, The

University of Hong Kong, for undertaking the study project. The author would also

like to thank Dr Chan Wai Ming and the Department of Intensive Care Unit, Queen

Mary Hospital, for the support on the study project.

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Abstract (word count: 342 )

Background

Herpes Simplex virus (HSV) is commonly isolated from the specimen of

respiratory tract in hospitalized patients. It can indicate asymptomatic shedding

from respiratory epithelium, viral reactivation with macroscopic airway lesion, or

even pneumonia. There are significant differences in the awareness, interpretation

and management strategies of the condition among departments and hospitals.

Objective

A retrospective case review of clinical features, management and outcomes of

hospitalized subjects from whom HSV is detected in the bronchoalveolar lavage

specimen

Method

The medical records of all the patients with pneumonia and bronchoalveolar

lavage (BAL) being positive for HSV culture, who were admitted between 2004 and

2011 to Queen Mary Hospital, were retrieved from the clinical management system or

record folders. Their demographic data, laboratory results, progress and outcomes

were recorded.

Results

A total of 32 patients were identified over the period of seven years. 81.3% of

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them were emergency admission while 18.8% were elective admission. Most of

them (90.6%) required admission to the Adult Intensive Care Unit. 59.3% (n=19)

required intubation and mechanical ventilation during hospitalization. The mean age

was 57.1 (SD 13.8) year old. 71.9% were male patients. No patients with HSV

detected in BAL had macroscopic lesion on bronchoscopy. No cytological

examination on the BAL was performed. HSV reactivation is commonly associated

other opportunistic pathogens such as Pneumocystis jivoreci (21.9%) and

cytomegalovirus antigenemia (18.8%). Majority of the subjects (90.6%, n=29) with

HSV infection were lymphopenic (absolute lymphocyte count <1 x 109/L) which

could indicate underlying impairment in cell-mediated immunity related to

malnutrition, hematological disorders, use of immunosuppressants. Similar

proportion in the surviving group received anti-viral treatment as compared to the

mortality group (53.8% versus 66.7%, respectively), implicating that treatment with

anti-viral medication might not have important impact on mortality rate.

Conclusion

The awareness of significance of HSV reactivation in lower respiratory tract is

highly variable. Lymphopenic patients are at high risk of HSV reactivation or HSV

pnemonitis. The presence of lymphopenia, or other immunocompromised state

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should prompt the physicians to perform a thorough work-up for HSV infection even

in the absence of macroscopic lesions.

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Body Text (Word count: 3109)

Background

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as Human herpes

virus 1 and 2 (HHV-1 and -2), are members of the herpes virus family, Herpesviridae,

that contains double-stranded DNA. Both HSV-1 and HSV-2 are ubiquitous in

environment and contagious among human. HSVs are predominantly neurotropic, and

possess genes associated with latency in neuronal tissues after primary infection.

Majority of human has been exposed to the virus early in life, which is commonly

asymptomatic or presented as non-specific febrile illness, and shed the virus in

secretions upon reactivation in later life. HSV-1 disease primarily involves the

mouth, eye and the central nervous system. After anchoring to the receptor of

epithelial cells, the envelope of the virus fuses with the cell membrane, followed by

the transport of the viral nucleocapsids cross the cytoplasm to the nucleus of the

infected cells. Assembly of capsids and replication of viral DNA occur. Viral

glycoproteins are processed in the Golgi apparatus and incorporate into cell

membrane, from which the viral envelope is acquired as the virus buds out from the

nucleus.

Reactivation of latent HSV infection may be asymptomatic, though typically, it

gives vesicular lesions or ulcers. DNA of herpes virus passes along nerve axon to

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the nerve ending and epithelial cells, where it gives rise to visible lesions.

Occasionally, shedding of virus may occur without symptoms or visible lesions.

Reactivation can be triggered by diverse stimuli such as sunlight, febrile diseases,

local trauma or physical stress. Common sites of HSV reactivation include

respiratory tract, eyes, oral or genital mucosa and the central nervous system.(1)

Regarding the respiratory tract, the virus could cause cold sore, gingivostomatitis,

tracheobronchitis and even pneumonia.(2) The diagnosis of HSV reactivation is

typically clinical when classical lesions are encountered, and supported by viral

detection or serological studies. Viral detection by means of culture, electron

microscopy, antigen detection by immunofluorescence, or viral DNA amplification by

PCR technique allows earlier confirmation of diagnosis compared to antibody tests.

Herpes virus was reported to be the causative pathogen of pneumonia and erythema

multiforme since 1949 (3). In subsequent decades, Herpes infection has been

repeatedly reported in case report and series as the pathogens causing

tracheobronchitis or infection of lower respiratory tract.(4-8) In intensive care

setting, HSV is commonly recognized in the respiratory tract specimen, regardless of

the presence or absence of macroscopic lesion, and the immune status of the host.(9)

Critically ill patients commonly possess risk factors for HSV reactivation, such as

systemic stress related to the critical illness, heightened stress hormone activity,

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immunocompromised state due to organ failures or drugs, and local airway

trauma.(10) Local trauma as a result of intubation, instrumentation, mechanical

suction, burn could promote squamous metaplasia, which predispose to HSV

reactivation at the airway epithelium.(9) HSV can reach the lower respiratory tract by

aspiration of shed virus from upper respiratory tract, hematogenous spread, or

reactivation of latent infection within the vagal nerve with resultant spread to the

lung.(9) Cell mediated immunity is of paramount importance in controlling and

combating HSV reactivation, or in the other words, recurrent HSV infection could

represent underlying immunocompromised states, albeit subclinical.(11)

Simple isolation of HSV from respiratory tract specimen cannot differentiate true

disease from asymptomatic shedding.(12, 13) The shedding of HSV is convincingly

demonstrated to correlate with increased mortality in critically ill patients.(12, 14-16)

However, whether the viral shedding is simply a marker of the severity of underlying

illnesses, or per se a mediator of fulminant diseases, is still debatable.(10) Of note,

another member of Herpes virus family, the Human Herpes virus 6 (HHV-6),

commonly reactivated in critically ill patients, but was not associated with adverse

outcomes.(17, 18)

The current study aims to review the clinical features, management and

outcomes of critically ill subjects from whom HSV is detected in the bronchoalveolar

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lavage specimen in Queen Mary Hospital.

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Methodology

The medical records of all the patients with pneumonia and bronchoalveolar

lavage being positive for HSV culture, who were admitted between 2004 and 2011 to

Queen Mary Hospital, were retrieved from the clinical management system or record

folders. Demographic data including age, sex, medical illnesses, medication history,

laboratory data , length of hospital stay, and outcome were obtained and analyzed.

Variables were entered into Microsoft excel spreadsheet. Variables are expressed as

mean +/- standard deviation if they are in normal distributions, or median and

interquartile range otherwise.

Results

A total of 32 patients were identified by retrospective review. 24 (75%) of them

were admitted under medical team, 6 (18.8%) were elective surgical admission while

2 (6.3%) were emergency surgical admission. Most of them (90.6%) required

admission to the Adult Intensive Care Unit during hospitalization. 10 (31.2%) of

them had acute respiratory distress syndrome (ARDS). 59.3% (n=19) required

intubation and mechanical ventilation during hospitalization. The mean age was

57.1 (SD 13.8) year old. 71.9% were male patients. 34.4% were ex-smokers or

active smokers. No patients with HSV detected in BAL had macroscopic lesion on

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bronchoscopy, indicating that the reactivation was mostly asymptomatic. HSV

reactivation is commonly associated other opportunistic pathogens such as

Pneumocystis jivoreci and cytomegalovirus antigenemia. 26.9% (n=7) of subjects in

the surviving group had CMV antigenemia concomitant with HSV reactivation. All

of the 7 subjects with concomitant HSV infection and CMV antigenemia received

intravenous gancyclovir as treatment, as compared to intravenous acyclovir or enteral

valacyclovir for those with HSV infection.

Majority subjects (90.6%, n=29) with HSV infection were lymphopenic

(absolute lymphocyte count <1 x 109/L) which could be related to underlying

malnutrition, known hematological disorders, use of immunosuppressants or severe

infection.(Table 1) Among the 32 subjects, 2 (6.2%) were HIV carrier, 18 (56.3%)

were taking steroid for long term indication or acute stress coverage, 17 (53.1%) were

on immunosuppressant other than steroid. 11 (34.4%) of them had history of

malignancy (hemic or solid organ). Similar proportion in the surviving group

received anti-viral treatment as compared to the mortality group (53.8% versus 66.7%,

respectively), implicating that treatment with anti-viral medication might not have

important impact on mortality rate.(Table 1) Surviving group was apparently

younger than the mortality group (Figure 1) (mean age 55.9 ±14.1 versus 62.0 ±11.8

respectively). The group with HSV infection who died eventually had much longer

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hospital stay compared to the surviving group (median length of stay LOS 40.0 days,

IQR 35.0, versus 17.5 days, IQR 39.0, respectively)

Discussion

The current retrospective study has found that immuno-deficient status, which

includes the use of immunosuppressants, underlying malignancy or HIV infection, is

an important risk factor for HSV reactivation. Concomittant infections by other

pathogens such as CMV or Pneumocystis jivoreci are relatively common. In the

dataset, HSV reactivation did not manifest as macroscopic lesion in tracheobronchial

trees. Lymphopenia is almost universal among the subjects. Anti-viral treatment

did not have overt bearing on overall mortality rate.

Bronchoscopy allows direct visualization of oropharyngeal and brochial

epithelium, and HSV infection typically manifests as edematous or erythematous

epithelium, ulcers or fibrinous purulent membrane, which are evidence of HSV

tracheo-bronchitis(9). In the retrospective case series, no macroscopic lesions were

reported in the tracheo-bronchial tree of the study subjects. The presence or absence

of oropharyngeal lesions was not documented in majority of the records. Such finding

was consistent with published studies, which also found absence of gross lesion in

many subjects. In a prospective study on 201 nonimmunocompromised subjects

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ventilated for at least 5 days, 42 subjects was diagnosed to have HSV

bronchopneumonitis, based on the fulfillment of all 3 diagnostic criteria: (1) clinical

deterioration, leading to the performance of BAL; (2) HSV detection in the lower

respiratory tract (PCR or culture); and (3) HSV-specific nuclear inclusions in

cytology during BAL, endotracheal aspiration, and/ or bronchial biopsy. Among these

42 subjects, oral-labial lesions were noted in 23 (54%) and none of them had any

bronchial vesicular/ulcerated lesion.(19) Such finding arouses the awareness that HSV

pneumonia can manifest without upper respiratory involvement. When there is no

gross lesion identified in orophargngeal region and tracheo-bronchial trees to

represent Herpes labialis or frank bronchitis, positive culture of HSV in lower

respiratory tract specimen can be a result of asymptomatic viral shedding,

contamination from mouth or upper respiratory tract, or genuine HSV pneumonia.(20,

21)

The diagnosis of HSV pneumonia is challenging, as both clinical features and

radiological findings are non-specific and can be confounded by concurrent infections

by other pathogens. Cytological study can reveal multi-nucleated cells with

intra-nuclear changes and inclusion bodies in the infected tissues which are specific

features of HSV infection, but lacks sensitivity (30% only).(22) On the other hand,

lung biopsy, either by open surgery or transbronchial routes, is also unreliable or even

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not practical, as a result of the risk of procedures, particularly in the setting of

critically ill subjects with respiratory failure on positive pressure ventilation.

According to previous studies, the identification of HSV by histology in lung biopsy

tissue was uncommon, even in subjects with other supportive evidence of HSV

infection.(23, 24) Luyt and coworkers have demonstrated that among the 42

subjects requiring mechanical ventilation who showed clinical deterioration due to

HSV bronchopneumonitis, BAL cytological examination allows the identification of

the characteristic nuclear inclusion body in 30 subjects (71.4%), while such inclusion

body is present in only 7 (16.7%) bronchial biopsies and be present in both BAL and

bronchial biopsy in 5 subjects.(19) Quantitative culture has been proposed to

differentiate between infection versus carrier state. Gooskens J and coworkers found

that quantitative HSV DNA by PCR assays on BAL of immunocompromised hosts

reflect clinical outcomes, with significant higher mortality within 28 days of sampling

if HSV DNA level is higher than 5.5 log.(25) However, the use of results of

quantitative culture to guide prescription of treatment still requires clarification by

further well-designed clinical trials. As a result of the difficulty in differentiating

true infection from carrier or asymptomatic shedding states, the management of

positive HSV culture without macroscopic lesion is still highly debatable.

Whether HSV infection is a true causative agent of pneumonia in critically ill

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still under debate. Cook and coworkers have found that HSV-positive patients had

duration of hospital stay, lengths of intensive care unit admissions, and duration of

ventilator dependence comparable with patients without HSV infections in a

prospective study.(29) A recent case control study has found that HSV-positive

patients had shorted duration of mechanical ventilation than the HSV-negative group

(13 vs. 6 days, respectively; p = 0.002). Mortality did not differ between the HSV+

and HSV- groups, and treatment with acyclovir also did not affect mortality.(30)

However, such conclusions are not consistent in some other studies. Tuxen and

coworkers has found that the presence of HSV in the lower respiratory tract was

associated with prolonged mechanical ventilation and an increased late mortality.(15)

Similarly, De Vos and coworkers have reported the common occurrence of HSV in the

lower respiratory tract of critically ill patients on prolonged mechanical ventilation.

Detection of HSV was significantly associated with prolongation of mechanical

ventilation, ICU stay, and risk of ventilator-associated pneumonia.(31) In the

retrospective study by Linseen, higher HSV load was associated with increased

14-day in-hospital mortality.(32) Therefore, further large-scale prospective studies are

required to clarify the impact of HSV reactivation on the prognosis of hospitalized

and critically ill subjects.

Though studies have reported adverse effects of HSV reactivation on clinical

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outcomes, evidence to support commencement of anti-viral treatment is still

controversial. Acyclovir is the treatment of choice for HSV infection, while

Gancyclovir also possess activity against HSV in addition to CMV in spite of higher

risk of side effects. Large scale randomized controlled study about its effect on

patient’s outcome is still lacking. Case reports or series have found potential

beneficial effects of acyclovir, including relief of bronchospasm (8) unresponsive to

other treatment, post-thoracotomy/cardiac surgery patients with pneumonia (33, 34),

interstitial pneumonia with ARDS (35), tracheobronchitis (36) or following liver

transplantation(20). However, such impact of treatment on outcomes is not consistent

in other studies.(29, 37) Tuxen and coworkers have undergone a double-blinded

randomized study on the use of intravenous acyclovir to prevent HSV reactivation and

assess its impact on outcome in seriously ill subjects with acute respiratory distress

syndrome. Acyclovir successfully prevented HSV reactivation in most subjects (HSV

reactivation was 6% in the acyclovir group versus 71% in the control group, p<0.001),

but it did not reduce the severity of respiratory failure, the duration of ventilator

support, or mortality.(28) The benefits of prescription of anti-viral agents have to be

balanced against the possible side effects of treatment. At present, the use of anti-viral

agents in subjects with HSV reactivation in respiratory tract would likely be based on

(1) any unexplained clinical deterioration/visible lesions, (2) underlying

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immunocompromized state or risk factors, (3) evidence of lung parenchymal infection

by cytological or histological examination of specimen.(9)

The current study identified 32 subjects with positive BAL culture for HSV

over a period of 8 years. The study is limited by the retrospective design, and the

results might be prone to bias due to missing data. The sample size of the current

study is relatively small, which could affect the interpretability and generalizability of

the results. The current study did not include subjects with burns. The study has

reflected the fact that HSV culture positive subjects were mostly

immunocompromised, with more than half being put on immunosuppressants. It is

plausible that HSV reactivation predominantly affects immuno-deficient group.

However, the finding can also reflect bias related to physician practice, as physicians

tend to request for more complete microbiological tests on BAL specimen of

immunocompromised subjects including viral culture, PCP tests, while less

comprehensive list of tests may be performed for non-/less immunocompromised

group. The documentation of presence or absence of oro-labial lesions is also

incomplete in medical records, so despite that fact that bronchial lesions are not found

in the whole study sample, contamination from active lesion of upper aero-digestive

tract cannot be ruled out. No cytological examination of the BAL specimen was

performed for the 32 samples, so whether the HSV comes from epithelial shedding or

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true pneumonia is not confirmed. The study is also limited by lacking a control

group for comparison, and being a retrospective study without blinding or

randomization. Therefore, the findings of the current study cannot serve as a guide

for the indication of anti-HSV treatment or conclude on whether HSV reactivation is

an important prognostic marker particularly in critically ill subjects. On the other

hand, the almost universal finding of lymphopenia, which could reflect sub-clinical

impairment in cell-mediated immunity, among the affected subjects should prompt the

physicians in requesting the tests in appropriate clinical setting.

In the current study, over a period of eight years, only 32 specimens were found

positive for HSV in BAL and cytological examination was not routinely ordered,

which probably reflects low awareness among clinicians for HSV reactivation in

hospitalized subjects leading to low request rate for the tests. The common

occurrence of HSV reactivation in non-immunocompromised subjects should arouse

more awareness among physicians for requesting the diagnostic tests in appropriate

setting. In the current study, the mortality rate among the group receiving anti-viral

agent is similar to the group without treatment, which concur with previous studies.

After demonstrating HSV reactivation, the use of this piece of information in

prognostic stratification and guiding treatment requires further well-designed clinical

trials.

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Table 1: Characteristics of study subjects

All (N=32) Survival

group

(N=26)

Mortality

group (N=6)

Demographics

Age [mean, SD] 57.1, 13.8 55.9, 14.1 62.0, 11.8

Gender

Male

Female

23 (71.9%)

9 (28.1%)

19 (73.1%)

7 (26.9%)

4 (66.7%)

2 (33.3%)

Smoking status

Active smoker

Ex-smoker

Non-smoker

4 (12.5%)

7 (21.9%)

21 (65.6%)

4 (15.4%)

6 (23.1%)

16 (61.5%)

0 (0%)

1 (16.7%)

5 (83.3%)

Drinking status

Chronic drinker

Non-drinker

5 (15.6%)

27 (84.4%)

4 (15.4%)

22 (84.6%)

1 (16.7%)

5 (83.3%)

Clinical presentation

Post-operative pneumonia 6 (18.8%) 5 (19.2%) 1 (16.7%)

ARDS 14 (43.8%) 9 (34.6%) 5 (83.3%)

Blood WCC on day of HSV sample

(x 109/L)

[median, IQR]

8.0, 10.8 8.1, 12.1 8.1, 7.0

Blood Lymphocyte on day of HSV 0.54, 0.42 0.54, 0.36 0.61, 0.81

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sample (x 109/L)

[median, IQR]

Absolute lymphocyte count < 1 x

109/L

29 (90.6%) 25 (96.2%) 4 (66.7%)

Macroscopic bronchial lesions on

bronchoscopy

0 (0%) 0 (0%) 0 (0%)

CMV antigenemia 7 (21.9%) 7 (26.9%) 0 (0%)

Pneumocytis jivoreci pneumonia 6 (18.8%) 5 (19.2%) 1 (16.7%)

Medical comorbidities

Chronic respiratory diseases * 6 (18.8%) 6 (23.1%) 0 (0%)

Diabetes mellitus 5 (15.6%) 2 (7.7%) 3 (50%)

Cirrhosis 7 (21.9%) 4 (15.4%) 3 (50%)

Chronic renal failure 8 (25%) 6 (23.1%) 2 (33.3%)

Acute renal failure 11 (34.4%) 8 (30.8%) 3 (50%)

On long term steroid 14 (43.8%) 12 (46.2%) 2 (33%)

Acute steroid use 4 (12.5%) 4 (15.4%) 0 (0%)

On immunosuppressant 17 (53.1%) 15 (57.7%) 2 (33%)

HIV carrier 2 (6.2%) 2 (7.7%) 0 (0%)

Malignancy

Hemic maglinancy /

myeloproliferative disease

Solid organ malignancy

11 (34.4%)

8 (25%)

3 (9.4%)

10 (38.5%)

8 (30.8%)

2 (7.7%)

1 (16.7%)

0 (0%)

1 (16.7%)

Post liver/renal transplantation

Liver transplantation

8 (25%)

4 (12.5%)

7 (26.9%)

3 (11.5%)

1 (16.7%)

1 (16.7%)

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Renal transplantation 4 (12.5%) 4 (15.4%) 0 (0%)

Treatment and outcome

Treated with Antiviral

Yes

No

18 (56.2%)

14 (43.8%)

14 (53.8%)

12 (46.2%)

4 (66.7%)

2 (33.3%)

LOS in acute hospital, in days

[median, IQR]

34.4, 39.0 17.5, 39.0 40.0, 35.0

Mortality 6 (18.8%) -- --

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