Article, Infectious Diseases

Extracorporeal membrane oxygenation for refractory, life-threatening, and herpes simplex virus 1-induced acute respiratory distress syndrome. Our experience and literature review

in HVS1 infection associated with septicemia/shock is a rare but often fatal in immunocompetent adult as well. We suggest that ECMO might be the selected treatment for severe refractory ARDS in this clinical scenario. It seems to be an effective and useful ultimate therapeutic strategy for preventing death and furthermore permitting near-full pulmonary function recovery.

herpes simplex virus 1 (HSV1) is a member of the Herpesviridae family and has a high prevalence worldwide distribution [1]. Infection with HSV1 is followed by viral latency, which can be disrupted by reactivation episodes. Virus can cause several clinical symptoms in primary infection and during viral reactivation [1]. Previous studies have implicated HSV, especially HSV1, as one of the factors causing pneumonitis/pneumonia in both immunocompro- mised and immunocompetent patients [2-5]. More recent reports have documented high detection rates of HSV1 in respiratory specimens of patients with pneumonia, especially if mechanically ventilated, thus raising the question of its clinical importance [4,6,7].

Although literature presents different opinions regarding the role of HSV1, it seems nowadays established that HSV1 could cause pneumonia as a primary infection even in immunocompetent adults, with a very poor prognosis when treated by conventional therapeutic means [8-16].

We report a first case of HSV1 bronchitis and pneumonia and Acute respiratory distress syndrome complicat- ed, in an otherwise healthy young man, requiring venove- nous (VV) extracorporeal membrane oxygenation as a lifesaving procedure: the rapid and refractory deterio- ration of Respiratory function was intractable by common supportive measures and antiviral drugs alone. Furthermore, we review the relevant literature for cases of immunocom- petent adults with HSV1 pneumonia, focusing on survival rates and therapeutic strategies.

We present an 18-year-old male college student with no known Medical issues. The patient experienced fever (as high as 41?C), dry cough, headache, myalgia, dyspnea, dizziness, and chest discomfort/pain that had been worsening for 7 days. The patient was referred to the emergency department. Medical history was noncontributory. He denied any tobacco, alcohol, and illicit drug use. He lived with his family. There were no allergies. No previous HSV1-related lesions were reported. Medications on admission included

amoxicillin, levofloxacin, and paracetamol started 7 day earlier for a flulike syndrome.

Physical findings revealed a strongly built man with the body temperature of 40.8?C, weight of 95 kg, height of 185 cm, body surface area of 2.22 m2, respiration rate of 30 to 35 breaths/min, heart rate of 115 beats/min, blood pressure of 110/55 mm Hg, and oxygen saturation of 92% to 97% on 100% oxygen, anicteric sclerae, pale conjunctivae, 5-mm round pupils, with sluggish light response. The oropharynx was erythematous without exudates or vesicles. There was no rash or palpable lymphadenopathy. Diffuse inspiratory crackles were heard bilaterally on both lower lung lobes. He had normal S1 to S2 heart sounds, with no murmurs or bruits. Abdomen examination was normal. He had no skin rashes. His neurologic and musculoskeletal evaluation test finding was normal. The eyes were thoroughly examined, and there were no inflammatory, vesicular, erosive, hemorrhagic, or masslike abnormalities. Genitalia examination results were likewise within normal status, and there was no evidence of mucocutaneous vesicular lesions.

When admitted to the medical ward, he was found to be hypoxic and immediately transferred to the intensive care unit (ICU). He was placed on noninvasive biphasic positive airway pressure. Ceftriaxone, azithromycin, meropenem, and caspofungin were administered intravenously empirically.

Chest radiographs showed diffuse bilateral lung in- filtrates and interstitial lung disease with miliaria-like signs

spread across the lower lung. The following day, 36 hours post-hospital entry, an endotracheal tube was inserted and ventilator was set to a pressure assist control of 30 cm2 H2O, 100% oxygen, and positive end-expiratory pressure of +10. Pressors and Drotrecogin alpha were also added.

Complete blood count was as follows; leukocyte count, 44 000 m/L with altered differential count (neutrophils 91.6%, lymphocytes 4.8% with CD4+, CD8+, CD16+, and CD56+ reduction), normal erythrocyte values, and platelet count 535.000/dL. Procalcitonin was 5.77 ng/mL. Except for a glucose level of 325 mg/dL, blood chemistry parameters were within reference ranges.

The patient was ventilated with 80% oxygen, a PEEP of 10 mm Hg, and a peak inspiratory pressure (PIP) of 35 mm Hg. arterial blood gases revealed a pH of 7.43, partial pressure of carbon dioxide of 32 mm Hg, partial pressure of oxygen of 45 mm Hg, bicarbonate of 21 mmol/L, and oxygen saturation of 82%. The static pulmonary compliance evaluation was of 25 mL/cm H2O. Coagulation profile disclosed a prothrombin time of 16.4 seconds, international normalized ratio of 1.4, partial thromboplastin time of 28 seconds, and D-dimer values of 832 ng/dL. Urinalysis results were within normal. Lower-extremity Doppler venous ultrasound showed unremarkable results.

Chest radiographs (Fig. 1A) and computed tomography (CT) scan demonstrated an increase in bilateral alveolar consolidation, diffuse on both lung lobes and worse in the

Fig. 1 Upper: evolution of chest x-ray shows diffuse interstitial-alveolar infiltrates and nodular shadows in the lungs on ICU admission (A), an accentuation and dissemination of alveolointerstitial infiltrates and right and left lower lobes atelectasis on day 5 after ECMO initiation (B). Day 15 of ECMO showed a partial resolution of the findings (C) and near complete resolution of the Pulmonary infiltrates at ICU discharge

(D). The insert shows the cannulation setting (the “?-configuration”). Lower: evolution of high-resolution (1.0-mm collimation) CT scans obtained at levels of the bronchus intermedius showing a predominant pattern of bilateral multifocal segmental and subsegmental micronodular ground-glass pulmonary infiltrates. Note the areas of lobar consolidation and interlobular septal thickening. E, Air bronchograms are seen within the consolidations. This pattern is nearly resolved after 20 days of ECMO (F) and completely resolved at ICU discharge (G). The intra-atria cannulae configuration, the “?-configuration” [17], is illustrated in panel C, insert.

lower zones; bilateral nonsegmental nodular shadows, with a possible small effusion; and normal heart/mediastinum.

Electrocardiogram and echocardiogram were normal. Fiber optic bronchoscopy done 12 hours after initiation of mechanical ventilation showed hyperemic tracheal mucosa. Sputum and specimens obtained at bronchoalveolar lavage, and bronchial brush analysis exhibited moderate white blood cells, rare red blood cells, few epithelial cells, and no bacteria, fungus, or mycobacterium. Other pertinent negative laboratory studies were urine culture, blood culture, cardiac enzymes, purified protein derivative tuberculin, antinuclear antibody, cyclic citrullinated peptide, rapid plasma reagin for syphilis, human immunodeficiency virus 1 and 2 antibody, Chlamydia pneumoniae immunoglobulin G (IgG), Chlamy- dia trachomatis IgG and immunoglobulin M (IgM) anti- bodies, Chlamydia psittaci IgG and IgM antibodies, legionella pneumonia antibody, Mycoplasma pneumoniae IgG, Blastomyces dermatitidis antibody, Histoplasma cap- sulatum antibody, Toxoplasma gondii IgG and IgM antibodies, mycobacterial stain and culture, parasites and ova in the stool, and heavy metal (arsenic, lead, mercury, and cadmium) analysis.

Approximately 48 hours after ICU admission, the patient’s respiratory and, consequently, hemodynamic status had deteriorated: arterial blood gases revealed a pH of 7.05, a partial pressure of carbon dioxide of 86 mm Hg, a partial pressure of oxygen of 48 mm Hg, bicarbonate of 29 mmol/L, Base Excess of -12 mEq/L, lactate of 3 mEq/L, and oxygen saturation of 80%, despite increasing ventilator setting (100% oxygen, PEEP 15 mm Hg, and PIP 45 mm Hg). Vasoactive and inotropic support (0.5 ug kg-1 min-1 epinephrine, 1.5 ug kg-1 min-1 norepinephrine) was initiated. The patient became oliguric and was in acute renal failure. A new thoracic x-ray revealed marked evolution in interstitial and alveolar bilateral infiltrates. Computed tomography scan (Fig. 1E) revealed consolidations on both lower lobes, air bronchogram in context, and numerous tiny nodular opacities at the secondary lobule, ubiquitously distributed and symmetrical. Parenchyma could be recognized in the ventilated lung areas.

With the patient’s condition near fatal, we decided to attempt VV-ECMO implantation in the ICU via femoroju- gular access with our innovative cannulation technique (?-configuration; Fig. 1C, insert) as previously reported [17]. The scope was to maximize extracorporeal blood oxygen- ation albeit setting the mechanical ventilation in a very protective manner.

The ECMO equipment used was a Rotaflow Maquet Centrifugal Pump (Maquet, Rastatt, Germany) and a hollow fiber membrane oxygenator (Quadrox-D Oxygena- tor; Maquet), connected with biocoated tubes (Bioline; Maquet). For the patients’ cannulation, we used the HLS percutaneous venous and arterial cannulae by Maquet. Peripheral femorojugular cannulation was performed at bedside: cannulae were inserted using Seldinger’s technique, and cannulae position was assisted with transesophageal echography guidance.

Heparin infusion, applied directly within the ECMO circuit, with a preoxygenator stopcock, was monitored and titrated every 2 hours by a bedside activated PTT measurement (Hemochron Jr. Signature plus; ITC Europe, Milano, Italy) aiming at 1.5 times the normal values of activated PTT.

Data are reported in Table 1. Our ventilation strategy during ECMO was as follows: once maximal ECMO flow was achieved, ventilation was gradually reduced to avoid ventilation-induced lung injury. Protective ventilator set- tings were set to pressure control, PIP of 25 cm H2O or greater, and PEEP between 10 and 15 cm H2O, depending on pressure/volume curves. Values were all calculated with ventilator’s built-in application (Draeger Evita XL; Draeger Medical AG, Lubeck, Germany). Positive end-expiratory pressure was set to 2 cm H2O above the lower inflection point curve. Controlled respiratory frequency was reduced to 8 to 10 breaths/min. Inspired oxygen fraction was reduced to 0.5 or lower, whenever possible [18]. Extracorporeal membrane oxygenation flow was constantly adjusted to keep an arterial saturation of 95% or more with normal CO2 levels.

After the first 6 days, as pulmonary compliance ameliorated, recruitment maneuvers were performed twice a day. From day 10, the patient was treated with continuous positive airways pressure with day-by-day longer intervals of spontaneous breathing. Bronchoscopy and Prone positioning were applied according to clinical conditions. Lungs were evaluated periodically by CT scan, thoracic x-ray, and daily Lung ultrasound examinations [19]. Blood was transfused when required to reach Hemoglobin levels of 12 to 14 mg/dL. A Swan-Ganz catheter was inserted to measure cardiac output (CO), Pulmonary vascular resistance, pulmonary blood gas analysis, and continuous SO2 in pulmonary artery. SpO2 was monitored continuously as well. Central venous blood gas analysis was obtained from a central venous catheter (tip positioned in the distal portion of the superior vena cava). Circuit monitors included pre-oxygenator and post-oxygenator blood gas analysis and pressure.

Cardiac output and mixed venous oxygen saturation (SvO2) were continuously recorded.

As reported in Table 1, in the first 6 days, ECMO flow

was fixed at 8 L/min (60% of patient’s CO = 14 L/min), to obtain systemic blood saturation of higher than 95%. The oxygenator FiO2 was set to 100%, and gas flow was set to 1:1 with blood flow. Later on, it was titrated to patient’s PaCO2.

During extracorporeal assistance, a tracheostomy was performed. The patient remained stable on ECMO without any significant complications during the complete course.

On day 2, a second fiber optic bronchoscopy examination revealed a narrowed and diffusely erythematous mucosa with numerous ulcerated vesicles throughout the entire airway. Sputum, tracheobronchial aspirate, and bronchial brush cytologies revealed clusters of enlarged epithelial cells with small eosinophilic intranuclear inclusions of type A Cowdry bodies. Multinucleated ground-glass nuclear changes of

Table 1 Respiratory and hemodynamic parameters during ICU stay and ECMO

1 h before ECMO

12 h after ECMO initiation


day 10



48 h after ECMO explanation

Hemodynamic values

CO (L/min)/CI (L/min ? m2)





MAP (mm Hg)






Mechanical ventilation setting













PIP (cm H2O)






PEEP (cm H2O)






TV (mL)












Pulmonary compliance (mL/cm2)





Oxygenation index


Murray score


ECMO setting

ECMO flow (L/min and L/min ? m2)




ECMO gas flow (L/min)



ECMO FiO2 (%)




Laboratory values

WBC count (N ? 1000/mL)






Hb (g/dL)






Platelet count (N ? 1000/mL)






Procalcitonin (ng/mL)





N 0.05

Serum creatinine (mg/dL)






Blood gas values/organ perfusion

Radial artery blood samples







pco2 (mm Hg)






po2 (mm Hg)






SO2 (%)






Lac (mmol/L)






BE (mmol/L)






HCO3 (mmol/L)






Pulmonary artery blood samples

pco2 (mm Hg)




po2 (mm Hg)




SO2 (%)




Central venous samples

pco2 (mm Hg)




po2 (mm Hg)




Scvo2 (%)





Preoxygenator samples

pco2 (mm Hg)




po2 (mm Hg)




SO2 (%)




Postoxygenator samples

pco2 (mm Hg)



po2 (mm Hg)



SO2 (%)




BRF (%) (preoxygenator SO2-ScO2)/ (postoxygenator So2-ScO2) ? 100

– 5.52 5.09 1.91 –

Patients BSA= 2.22 m2. All reported data are the mean of 3 consecutive measures. CV indicates controlled volume; BiPAP, bilevels positive airways pressure; CPAP, continuous positive airways pressure; FiO2, fraction inspired oxygen; MV, respiratory minute volume; TV, tidal volume; BSA, body surface area; CI, cardiac index; PaCO2, arterial carbon dioxide tension; paO2, arterial oxygen tension; WBC, white blood cells; Hb, hemoglobin concentration; SO2, oxygen saturation; Lac, lactate concentration; BE, base excess; HCO3, Bicarbonate concentration; ScvO2, Central venous oxygen saturation; BRF, blood recirculation fraction with calculation formula [17].

Table 2 Timeline

PTC indicates procalcitonin; Rx, x-ray; PCT, Procalcitonine; NIV, noninvasive ventilation.

HSV were found as well. With these cytologic findings, acyclovir (15 mg/kg, 3 times a day) was promptly initiated. Subsequent tests for HSV1 IgG and IgM antibodies showed positive results, and quantitative real-time polymer- ase chain reaction (PCR) assays (88.000 viral genomes) reaffirmed the diagnosis of HSV pneumonia. Herpes simplex

virus type 2 antibody IgG test result was negative.

acyclovir therapy resulted in respiratory, febrile, and general status improvement. On the 10th day of ECMO, after the negative result of the HSV test, the Meduri protocol was initiated. On day 15 of ECMO, lung functions sig- nificantly improved: pulmonary compliance reached 60 cm H2O, with x-ray, CT, and lung ultrasound findings improving dramatically (cleaning of infiltrates; Fig. 1C, F). Venovenous ECMO weaning was started, and support was reduced by progressive extracorporeal blood flow lessening as previously reported [17]. On day 18, the patient was trailed off the ECMO to moderate ventilator setting (FiO2 <=

0.5; PIP <= 23 cm H2O, PEEP b 10 mm Hg) and decannulated

after 12 hours with blood gas analysis with a satisfactory range. Subsequent to weaning patient from ECMO, he

remained on mechanical ventilation until standard extubation criteria were met. After 7 days without ECMO, chest radiographs and CT revealed significant clearing of the parenchymal infiltrates (Fig. 1D, G). At this point, the patient was discharged from the ICU and transferred to the medical ward. Twelve days after ECMO removal, he was discharged from the hospital. The patient’s hospital course is described briefly in Table 2.

A 1-month follow-up chest radiograph and respiratory functional tests revealed normal lungs. At a 12-month follow-up, the patient demonstrated complete and stable pulmonary recovery without sequelae: his respiratory function, blood gas analysis, and CT remained stable without any sign of regional lesions. There was no recurrence of the herpes infection.

Some species of herpes virus, such as HSV1, HSV2, HSV6, HSV8, varicella-zoster, and cytomegalovirus, can cause pneumonia. herpes simplex virus pneumonia, first described in 1949, is a Rare occurrence and almost exclusively observed in immunocompromised hosts, asso- ciated with prolonged mechanical ventilation or chronic

Case no. (reference)

Patient’s age (y)/sex

Hypoxemia/ ARDS

Chest Rx findings

Diagnostic tests

Outcome/days from appearance

Mechanical ventilation duration (d)


et al [12]


et al [13]

Martinez et al [9]


et al [10]


et al [11]

Reyes [8]


67 +- 15/11

F-17 M 33/M




Yes/yes Yes/yes Yes/yes

Yes/yes Yes/yes Yes/yes


Pulmonary infiltrates

Interstitial and alveolar bilateral infiltrates

Bilateral nodular upper lobe opacities

Bilateral diffuse air space disease with small left pleural effusion Bilateral alveolar consolidation, diffuse on both lung lobes and worse in the lower zones


BAL bronchial wash

Bronchial mucosa cytologies and histology/ HSV antibody titers BAL cultures/HSV serum antibodies Immunochemical stains. Tracheobronchial biopsy

Tracheobronchial aspirate and bronchial brush.


Dead/15 d

Dead 70%,

alive 30% Alive

Alive Alive Alive

8 +- 7



F indicates female; M, male; BAL, broncho-alveolar lavage.

disorders. It usually manifests as an acute respiratory distress syndrome [1-8,13,14].

Table 3 Characteristics of previously reported cases of HSV pneumonitis in immunocompetent adult healthy patients

As in our case, published reports dating from 1982 [5,7-16] have evidenced the possibility of HVS1 pneumo- nitis in previous healthy adult immunocompetent patients (Table 3). In these cases, HVS infection seemed to be associated with higher morbidity and mortality (70% vs 33%) [13]. These finding were then confirmed by different studies [14,15].

The diagnosis of HSV pneumonia is based on micro- scopic findings of viral cytopathic cellular changes in sputum, tracheal aspirate, bronchial brush, bronchioalveolar lavage, or tissue studies.

Confirmatory test is done by HSV IgG and IgM antibody serology, immunofluorescence, or immunohistochemistry with anti-HSV antibodies of the abovementioned specimens or PCR [1,4,5,7,20].

In regard to transmission, HSV1 is acquired through contact with oral secretions, gingivostomatitis in child- ren, or recurrent labialis in older hosts. The pathogene- sis of HSV1 pneumonia may follow a retrograde contiguous extension or aspiration of oral/lip infection, hematogenous spread from extra genital lesions or other sources, and reactivation of the original virus within vagal ganglia. The Pathologic changes may be focal or diffuse ulceration of the tracheobronchial mucosa with or without necrotizing pneumonia and interstitial pneu- monitis [1,2,7,20].

In our patient, a history of herpetic labialis or stoma- titis was never proved; cutaneous and genital vesicles were not found on his physical evaluation. Perhaps, a late-first HSV infection and consequent hematogenous spread or reactivation of a latent HSV1 dorsal root ganglia and nerve ending were the source of the pulmonary infection.

radiographic imaging (chest radiography and CT) demonstrated bilateral lobar pneumonia, scattered opacities, changes of air consolidation, and, in more severe situations, as our reported case, the typical changes of acute respiratory distress syndrome [2,6,10,21].

We have found sporadic reports regarding HSV1 pneumonitis in adults without risk factors (Table 3); however, numerous cases of HSV pneumonia are reported from autopsy due to misdiagnosis and high mortality among ARDS patients [1]. Similar to the reported case, significant hypoxemia was documented in all patients; it appears to be the predominant feature of HVS-related pneumonitis, and mechanical ventilation was demanded in all patients.

As in most viral diseases, the phenomenon of spontaneous recovery from the infection without treatment may occur. Specific anti-HVS is effective in reducing the time of pulmonary recovery, limiting morbidity, and mortality. Prognosis depends on the Recovery time of pulmonary function and on the response to supportive therapy [1-4,6,7]. With conventional therapy, the mortality ranges from 70% to 100% [1,2,4,5,7,13-16]. In our case, mechanical ventilation did not increase Blood oxygen saturation sufficiently, a circumstance that encouraged us to advocate blood oxygen- ation by means of extracorporeal support.

Extracorporeal membrane oxygenation outside the oper- ating room was pioneered in the late 1960s; the first successful use of ECMO was reported in 1972 [22]. It provides support for the heart and lungs using VV or venoarterial pumping via an artificial lung. In recent years, ECMO has improved (eg, heparin-coated circuitry, centrif- ugal pump, percutaneous peripheral cannulation, etc), decreasing complications and improving outcome. Extracor- poreal membrane oxygenation has been shown to be

lifesaving and beneficial especially for patients with cardiac or pulmonary acute insufficiency [23].

According to the literature [16,17,19,23], ECMO could be the lifesaving method of choice, allowing the reparative processes to take place during the refractory stages of pulmonary dysfunction and systemic hypo-oxygenation: ECMO may act as a bridge to pulmonary recovery.

In the present case, the indication for VV-ECMO was indeed the presence of refractory ARDS, so severe that the patient was at risk of cardiac arrest and/or death despite aggressive medical treatment and mechanical ventilator support. Therefore, we found it important to initiate ECMO before multiple organ failure or cardiac arrest is witnessed.

Based on our experience with ECMO for other types of refractory ARDS, we find that extracorporeal pulmonary support might have potential benefits not only for tissue and organs oxygenation but, indirectly, for hemodynamic instability not responding to conventional measures as well. In the reported case, all supportive treatments failed to improve lung function, whereas ECMO resulted in rapid improvement of blood gases analysis, tissue oxy- genation parameters, a complete reversibility of lung failure, and survival despite a severe documented pulmonary dys- function. It is also noteworthy that acyclovir would have been the ideal treatment but was unsuitable in our case because of severe and rapid respiratory impairment: during the 18-day period of extracorporeal assisted blood oxygen- ation, it proved possible to reduce ventilator lung injury and to stimulate the pulmonary recovery with adequate treatment based on ventilator protective setting, suitable airway cleaning, specific antiviral therapy and, when the signs of active viral infection disappeared, high doses of corticoste- roids (Meduri protocol). The role of corticosteroids in treatment of HSV infections is still controversial [1,13,16]; however, for cases of viral infections, where complications are believed to be secondary immunopathologic reactions (encephalitis, hemolytic, myocarditis, etc), the administra-

tion of steroids has been recommended.

We report a rare case of an otherwise healthy and immunocompetent young man, presenting with an over- whelming acute HSV1 pneumonia that dramatically pro- gressed to refractory ARDS. This life-threatening acute respiratory failure required ECMO for blood oxygenation and patient’s stabilization. The ECMO support permitted HSV1 therapy admission and resolved the critical condition. In our experience, for nonresponders to Conventional treatment, the early institution of ECMO may be lifesaving before manifestation of further multiorgan failure.

We believe that this is the first reported case of HSV1- induced ARDS with sustained refractory respiratory failure treated with ECMO. We propose that ECMO associated with aggressive physiopathologic treatment (antiviral-specific therapy and corticosteroids) be considered as a “bridge to lung recovery” strategy in cases with severe respiratory failure after HVS1 pneumonitis.

Massimo Bonacchi MD Gabriella Di Lascio MD Guy Harmelin MD Cardiac Surgery

Medical and Surgical Critical Care Department

University of Florence

Florence, Italy E-mail address: [email protected]

Andrea Pasquini MD Adriano Peris MD

Anesthesia and Intensive Care Unit

Emergency Department Careggi Teaching Hospital

Florence, Italy

Guido Sani MD

Cardiac Surgery Medical and Surgical Critical Care Department

University of Florence

Florence, Italy



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