CHEST
Postgraduate Education Corner CHEST IMAGING AND PATHOLOGY FOR CLINICIANS
A Patient With Progressive Dyspnea and Multiple Foci of Airspace Consolidation Keith E. Boundy, MD; Armando E. Fraire, MD; and Paulo J. Oliveira, MD, FCCP
CHEST 2014; 145(1):167–172
in his mid-40s with known asthma presented Aman to the ED 1 week after being discharged from
inpatient care at UMass Memorial Medical Center. Ten days prior, he had presented to the hospital complaining of 3 days of progressive dyspnea; a painful, nonproductive cough; fevers; and headaches. Case Report
His history was pertinent for mild asthma that did not require maintenance therapy and IV heroin use in his 20s, complicated by chronic hepatitis C that was successfully treated with interferon and ribavarin 5 years ago. He denied using alcohol or tobacco products, but did report regularly smoking marijuana. He denied any recent exotic travel or sick contacts and had no pets at home. He had diffuse wheezing on auscultation of his lungs and bilateral patchy opacities on his chest radiograph (Fig 1A). His laboratory work revealed an elevated WBC count of 18,900 mm3, with lymphocytosis but no neutrophilia, bandemia, or eosinophilia. His RBC count, platelet count, electrolytes, creatinine clearance, and transaminases were all within normal limits. He was admitted to the Medicine Service and treated for both community-acquired pneumonia (CAP) and an acute asthma exacerbation. He was placed on azithromycin and IV ceftriaxone for the presumed pneumonia along with prednisone and nebulized albuterol/ipratropium for his asthma. His Manuscript received January 15, 2013; revision accepted September 2, 2013. Affiliations: From the Department of Medicine (Drs Boundy and Oliveira) and Department of Pathology (Dr Fraire), University of Massachusetts Medical School, Worcester, MA. Correspondence to: Paulo J. Oliveira, MD, FCCP, Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Massachusetts Medical School, 55 Lake Ave N, Worcester, MA 01605; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0122 journal.publications.chestnet.org
expectorated sputum grew only normal respiratory flora, and both a rapid flu test and a comprehensive respiratory viral panel obtained by nasopharyngeal swab were negative. The appearance of the opacities in his initial chest radiograph (Fig 1A) coupled with his history of IV drug use raised the concern for an opportunistic infection in the setting of an immunocompromised host. He was, thus, tested for HIV, and both his serology and viral load by polymerase chain reaction (PCR) were negative. He transiently defervesced, and he was discharged home 2 days later on oral cefpodoxime, azithromycin, inhaled albuterol, and a short prednisone taper. Unfortunately, his improvement was quite transient, and he returned to the hospital with worsening dyspnea, fevers, and cough despite taking his discharge medications as prescribed. The patient’s initial chest radiograph revealed multiple bilateral, ill-defined areas of airspace consolidation without a clear distribution. He had no pleural effusions, his mediastinum was unremarkable, and he had no obvious masses. His subsequent chest radiograph again showed the same patchy consolidations with overt interval progression since his initial radiograph (Fig 1A) and subsequent presentation (Fig 1B) to the hospital. A high-resolution chest CT scan with IV contrast showed foci of airspace consolidation in a strikingly peribronchovascular distribution with relative sparing of the periphery along with scattered areas of ground-glass attenuation (Fig 1C). The process was most severe in the left lower lobe (Fig 1D) where confluent airspace consolidation could be seen. This study did not reveal any pathologic lymphadenopathy, masses, cavitary lesions, or pleural disease. The patient failed treatment directed at bacterial pathogens responsible for CAP and had no evidence of immunosuppression to suggest an opportunistic infection seen in immunocompromised hosts. However, his symptoms and radiologic findings could still be consistent with a broad array of infectious or noninfectious etiologies. His consolidations could simply be due to resistant or unusual bacterial pathogens that we were unable to culture or the result of a viral CHEST / 145 / 1 / JANUARY 2014
167
pneumonia not detected by the respiratory viral panel previously sent. However, the ground-glass appearance and airspace consolidations could also be consistent with a hypersensitivity pneumonitis, a cryptogenic organizing pneumonia, pulmonary alveolar hemorrhage, autoimmune conditions, or other noninfectious inflammatory processes. Given these entities often require a tissue sample for definitive diagnosis, and the fact that his prior sputum cultures failed to grow any pathogenic organism, the decision was made to take the patient for flexible bronchoscopy with BAL and transbronchial biopsy the following day. The bronchoscopy was uncomplicated and showed evidence of both tracheal and bronchial ulceration (Fig 2A), but without significant secretions. BAL was performed although cultures only grew nonpathogenic oral flora. A right middle lobe transbronchial biopsy specimen was also obtained. The hematoxylin-andeosin-stained section of the transbronchial biopsy specimen showed a mononuclear inflammatory infiltrate primarily located in the interstitium coupled with the absence of a neutrophilic intraalveolar infiltrate consistent with chronic interstitial pneumonitis. The bronchial epithelium revealed squamous metaplasia and large atypical squamous epithelium with evidence of nuclear cytopathic effect (Fig 2B). Further immunohistochemical staining was negative for cytomegalovirus and confirmatory for the ultimate diagnosis (Fig 2C).
Figure 1. A, The patient’s initial chest radiograph displaying multiple foci of airspace consolidation. B, Subsequent radiograph displaying clear interval progression. C, High-resolution chest CT scan with IV contrast displays bilateral peribronchovascular consolidations with scattered areas of ground-glass attenuation. D, Foci of dense airspace consolidation in the lung bases and relative sparing of the periphery. 168
Postgraduate Education Corner
Figure 2. A, Fiber-optic bronchoscopy showing tracheal ulceration (arrows). B, Hematoxylin-and-eosinstained section (original magnification 3 100) displaying bronchial tissue with squamous metaplasia, atypical squamous epithelium, and evidence of cytopathic effect with prominent multinucleated giant cells (arrows). C, Positive (orange) immunohistochemical staining (original magnification 3 100) for herpes simplex virus, particularly prominent within cell nuclei.
What is the diagnosis?
journal.publications.chestnet.org
CHEST / 145 / 1 / JANUARY 2014
169
Diagnosis: Herpes simplex virus bronchopneumonia Discussion Clinical Discussion The patient’s biopsy results provided a definitive diagnosis, and he was promptly started on 5 mg/kg IV acyclovir every 8 h; corticosteroids were tapered off quickly and he experienced significant improvement in his symptoms. His rapid clinical response to antiviral therapy further implicated herpes simplex virus (HSV) as the causative agent of his symptoms, rather than an incidental finding. The specificity of the diagnosis highlights the importance of the decision to obtain a tissue biopsy specimen following his highly abnormal but ultimately nonspecific chest imaging, as it allowed for the initiation of prompt therapy with acyclovir. Prior to the advent of acyclovir and given its more typical association with immunocompromised hosts, patients with HSV pneumonitis had high mortality rates,1 demonstrating the importance of making a prompt diagnosis to guide appropriate therapy. Before his biopsy results, he had several pertinent negative findings arguing against an alternative diagnosis. The abrupt nature of the onset of his symptoms suggested an infectious cause as opposed to a more insidious autoimmune disease. Although his initial mild improvement was possibly due to bronchospasm responding favorably to steroids, his failure to improve and progression on standard antibiotic therapy for CAP and subsequently broader-spectrum antibiotics argued against a bacterial infection. The lack of response to corticosteroids also argued against typically steroidresponsive processes such as hypersensitivity pneumonitis or cryptogenic organizing pneumonia. As noted previously, his initial presentation and chest radiograph along with his history of IV drug use were concerning for an opportunistic infection such as Pneumocystis or fungal pneumonia in the setting of HIV infection but this testing was negative. In addition, he had neither hematologic abnormalities nor significant lymphadenopathy on physical examination or imaging to suggest an underlying malignancy or lymphoproliferative disorder. This case is unique as herpes pneumonia is usually described in critically ill patients on mechanical ventilation,2,3 in burn patients,2 following open thoracic surgery,4,5 or in obviously immunocompromised hosts, where disseminated HSV infection is not uncommon.1 It is rarely seen in otherwise immunocompetent individuals where it is only described in case reports.6-9 Upon further discussion with the patient regarding the exact nature of his marijuana use, he informed us that he regularly uses a large-mouth glass pipe requiring deep inhalations and that he had a large, painful “cold 170
sore” on his upper lip 3 to 4 weeks before the onset of his symptoms. His description of his cold sore was consistent with herpes labialis. We believe that the most likely route of infection of this patient’s herpes pneumonitis was seeding of his bronchial tree and lung parenchyma during deep inhalations while smoking marijuana with an exposed herpes labialis lesion actively shedding virus. Given its unregulated, illicit nature and varied methods of inhalation, the pathologic effects of recreational cannabis use are less studied compared with tobacco use. There is growing evidence that tetrahydrocannabinol, the primary psychoactive component of cannabis, has localized antagonist effects on both innate and adaptive immunity within the lungs.10 Tetrahydrocannabinol can directly impair alveolar macrophage phagocytosis,11 decrease production of both tumor necrosis factor-a11 and interferon-g,12 and impair cytotoxic T-lymphocyte proliferation and activity.12,13 We postulate that the patient’s chronic use of cannabis further contributed to the HSV bronchopneumonia due to its localized immunosuppressant effects. The corticosteroids used for asthma may have also further compromised the patient and promoted pathologic HSV dissemination. Related to this, herpes tracheobronchitis has been described in patients on mechanical ventilation presenting commonly with refractory bronchospasm despite corticosteroid treatment and responding to treatment with acyclovir and steroid discontinuation.3 Radiologic Discussion The patient’s radiographic findings (Fig 1) of multiple foci of airspace consolidation in a peribronchovascular distribution along with areas of ground-glass attenuation are consistent with prior reports of HSV pneumonitis, which do not vary significantly between compromised and immunocompetent hosts.14-16 Peerreviewed literature of both chest radiography and CT scans in patients with HSV pneumonitis suggests that the diagnosis should be included in the differential when confronted with these findings, but highlight that a diagnosis of HSV pneumonitis can never be made based on imaging alone14-16; evidence of viral cytopathic effect on cytologic and/or histopathologic specimens along with confirmation of HSV presence via culture, viral HSV PCR, or immunohistochemical staining is required. This case highlights both the importance, and also the limits, of diagnostic imaging and the need for more invasive and definitive methods of diagnosis. Once armed with the tissue diagnosis, the widespread bilateral, bronchocentric distribution of his opacities with relative sparing of the periphery are consistent with an inhalational mode of dissemination with viral shedding from the orolabial ulcer acting as the nidus vs the aspiration of HSV Postgraduate Education Corner
containing oropharyngeal secretions described as the mechanism in patients who are on mechanical ventilation.17 Nonetheless, this peribronchovascular distribution of airspace consolidation can be seen in several other pathologic conditions, and again highlights the need for a biopsy to establish a definitive diagnosis. Pathologic Discussion The main histopathologic finding was in the bronchial mucosa. The mucosa reveals areas of necrosis and some very large atypical squamous epithelial cells showing smearing of nuclear chromatin, a change that is nearly pathognomic of viral herpetic infection and necessary to make a firm diagnosis of HSV bronchopneumonitis along with supportive cultures, immunohistochemical staining of specimens,18,19 or both (Fig 2B). This is the same phenomenon seen in a Tzanck smear19 and narrowed the causative agent behind the patient’s symptoms to most likely be a virus of the Herpesviridae family. Immunohistochemistry confirmed this to be HSV, which allowed prompt initiation of antiviral therapy leading to a rapid improvement in the patient’s clinical symptoms. In this case making a definitive tissue diagnosis was important as HSV can be detected by both PCR and viral culture in BAL samples in asymptomatic individuals and does not definitely indicate active disease.20 In fact, asymptomatic shedding of HSV can be found in the saliva of 1% to 5% of normal subjects. The literature also reveals that isolation of HSV from oropharyngeal secretions and lower respiratory tract samples is not uncommon in critically ill, mechanically ventilated patient.3 The clinical importance of this finding is debatable as treatment with acyclovir does not always improve outcomes in such patients. Thus, the viral cytopathic effect is important in attempting to distinguish HSV presence as just a marker of underlying disease severity (innocent bystander) vs a true pathogenic organism. Conclusions The patient was treated with 5 mg/kg IV acyclovir every 8 h and experienced remarkable improvement in his symptoms as his dyspnea significantly diminished and he remained afebrile. After 48 h of IV therapy, he was discharged home on an oral course of 500 mg tid of famciclovir to complete a total of 4 weeks of antiviral therapy. He continued to do well from a clinical perspective on subsequent follow-up. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. journal.publications.chestnet.org
Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Ramsey PG, Fife KH, Hackman RC, Meyers JD, Corey L. Herpes simplex virus pneumonia: clinical, virologic, and pathologic features in 20 patients. Ann Intern Med. 1982;97(6): 813-820. 2. Schuller D. Lower respiratory tract reactivation of herpes simplex virus. Comparison of immunocompromised and immunocompetent hosts. Chest. 1994;106(1_suppl):3S-7S. 3. Luyt CE, Combes A, Deback C, et al. Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care Med. 2007;175(9):935-942. 4. Shimokawa S, Watanabe S, Taira A, Eizuru Y. Herpes simplex virus pneumonia after cardiac surgery: report of a case. Surg Today. 2001;31(9):814-816. 5. Yamaguchi A, Matsumoto S, Hagiwara S, Shingu C, Iwasaka H, Noguchi T. Herpes simplex virus pneumonia following mitral valve replacement. Gen Thorac Cardiovasc Surg. 2010;58(11): 580-583. 6. Alvarez-Uria G, Surinach JM, Ventura A, de la Rosa D, de Gracia J, Fernandez-Sevilla T. Herpetic tracheitis and polybacterial pneumonia in an immunocompetent young man is herpes tracheitis involved in the pathogenesis of bacterial pneumonia? J Clin Virol. 2008;41(2):164-165. 7. Martinez E, de Diego A, Paradis A, Perpiñá M, Hernandez M. Herpes simplex pneumonia in a young immunocompetent man. Eur Respir J. 1994;7(6):1185-1188. 8. Reyes CV, Bolden JR. Herpes simplex virus type-1 pneumonitis in immunocompetent young woman. Heart Lung. 2009;38(6): 526-529. 9. Boland AC, Iveson EH, Elliott MW. An unusual exacerbation of chronic obstructive pulmonary disease (COPD) with herpes simplex tracheitis: case report. J Med Case Reports. 2007;1: 91. 10. Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. 2004;25(1):203-216. 11. Baldwin GC, Tashkin DP, Buckley DM, Park AN, Dubinett SM, Roth MD. Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am J Respir Crit Care Med. 1997;156(5):1606-1613. 12. Yuan M, Kiertscher SM, Cheng Q, Zoumalan R, Tashkin DP, Roth MD. Delta 9-Tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells. J Neuroimmunol. 2002;133(1-2):124-131. 13. Tashkin DP, Baldwin GC, Sarafian T, Dubinett S, Roth MD. Respiratory and immunologic consequences of marijuana smoking. J Clin Pharmacol. 2002;42(suppl 11):71S-81S. 14. Aquino SL, Dunagan DP, Chiles C, Haponik EF. Herpes simplex virus 1 pneumonia: patterns on CT scans and conventional chest radiographs. J Comput Assist Tomogr. 1998;22(5): 795-800. 15. Brodoefel H, Vogel M, Spira D, et al. Herpes-simplex-virus 1 pneumonia in the immunocompromised host: high-resolution CT patterns in correlation to outcome and follow-up. Eur J Radiol. 2012;81(4):e415-e420. 16. Chong S, Kim TS, Cho EY. Herpes simplex virus pneumonia: high-resolution CT findings. Br J Radiol. 2010;83(991): 585-589. 17. Devakonda A, Raoof S, Sung A, Travis WD, Naidich D. Bronchiolar disorders: a clinical-radiological diagnostic algorithm. Chest. 2010;137(4):938-951. 18. Netherton C, Moffat K, Brooks E, Wileman T. A guide to viral inclusions, membrane rearrangements, factories, and viroplasm CHEST / 145 / 1 / JANUARY 2014
171
produced during virus replication. Adv Virus Res. 2007;70: 101-182. 19. Solomon AR, Rasmussen JE, Varani J, Pierson CL. The Tzanck smear in the diagnosis of cutaneous herpes simplex. JAMA. 1984;251(5):633-635.
172
20. Simoons-Smit AM, Kraan EM, Beishuizen A, Strack van Schijndel RJ, Vandenbroucke-Grauls CM. Herpes simplex virus type 1 and respiratory disease in critically-ill patients: real pathogen or innocent bystander? Clin Microbiol Infect. 2006;12(11):1050-1059.
Postgraduate Education Corner
Postgraduate Education Corner CHEST IMAGING AND PATHOLOGY FOR CLINICIANS
A Patient With Progressive Dyspnea and Multiple Foci of Airspace Consolidation Keith E. Boundy, MD; Armando E. Fraire, MD; and Paulo J. Oliveira, MD, FCCP
CHEST 2014; 145(1):167–172
in his mid-40s with known asthma presented Aman to the ED 1 week after being discharged from
inpatient care at UMass Memorial Medical Center. Ten days prior, he had presented to the hospital complaining of 3 days of progressive dyspnea; a painful, nonproductive cough; fevers; and headaches. Case Report
His history was pertinent for mild asthma that did not require maintenance therapy and IV heroin use in his 20s, complicated by chronic hepatitis C that was successfully treated with interferon and ribavarin 5 years ago. He denied using alcohol or tobacco products, but did report regularly smoking marijuana. He denied any recent exotic travel or sick contacts and had no pets at home. He had diffuse wheezing on auscultation of his lungs and bilateral patchy opacities on his chest radiograph (Fig 1A). His laboratory work revealed an elevated WBC count of 18,900 mm3, with lymphocytosis but no neutrophilia, bandemia, or eosinophilia. His RBC count, platelet count, electrolytes, creatinine clearance, and transaminases were all within normal limits. He was admitted to the Medicine Service and treated for both community-acquired pneumonia (CAP) and an acute asthma exacerbation. He was placed on azithromycin and IV ceftriaxone for the presumed pneumonia along with prednisone and nebulized albuterol/ipratropium for his asthma. His Manuscript received January 15, 2013; revision accepted September 2, 2013. Affiliations: From the Department of Medicine (Drs Boundy and Oliveira) and Department of Pathology (Dr Fraire), University of Massachusetts Medical School, Worcester, MA. Correspondence to: Paulo J. Oliveira, MD, FCCP, Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Massachusetts Medical School, 55 Lake Ave N, Worcester, MA 01605; e-mail: [email protected] © 2014 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.13-0122 journal.publications.chestnet.org
expectorated sputum grew only normal respiratory flora, and both a rapid flu test and a comprehensive respiratory viral panel obtained by nasopharyngeal swab were negative. The appearance of the opacities in his initial chest radiograph (Fig 1A) coupled with his history of IV drug use raised the concern for an opportunistic infection in the setting of an immunocompromised host. He was, thus, tested for HIV, and both his serology and viral load by polymerase chain reaction (PCR) were negative. He transiently defervesced, and he was discharged home 2 days later on oral cefpodoxime, azithromycin, inhaled albuterol, and a short prednisone taper. Unfortunately, his improvement was quite transient, and he returned to the hospital with worsening dyspnea, fevers, and cough despite taking his discharge medications as prescribed. The patient’s initial chest radiograph revealed multiple bilateral, ill-defined areas of airspace consolidation without a clear distribution. He had no pleural effusions, his mediastinum was unremarkable, and he had no obvious masses. His subsequent chest radiograph again showed the same patchy consolidations with overt interval progression since his initial radiograph (Fig 1A) and subsequent presentation (Fig 1B) to the hospital. A high-resolution chest CT scan with IV contrast showed foci of airspace consolidation in a strikingly peribronchovascular distribution with relative sparing of the periphery along with scattered areas of ground-glass attenuation (Fig 1C). The process was most severe in the left lower lobe (Fig 1D) where confluent airspace consolidation could be seen. This study did not reveal any pathologic lymphadenopathy, masses, cavitary lesions, or pleural disease. The patient failed treatment directed at bacterial pathogens responsible for CAP and had no evidence of immunosuppression to suggest an opportunistic infection seen in immunocompromised hosts. However, his symptoms and radiologic findings could still be consistent with a broad array of infectious or noninfectious etiologies. His consolidations could simply be due to resistant or unusual bacterial pathogens that we were unable to culture or the result of a viral CHEST / 145 / 1 / JANUARY 2014
167
pneumonia not detected by the respiratory viral panel previously sent. However, the ground-glass appearance and airspace consolidations could also be consistent with a hypersensitivity pneumonitis, a cryptogenic organizing pneumonia, pulmonary alveolar hemorrhage, autoimmune conditions, or other noninfectious inflammatory processes. Given these entities often require a tissue sample for definitive diagnosis, and the fact that his prior sputum cultures failed to grow any pathogenic organism, the decision was made to take the patient for flexible bronchoscopy with BAL and transbronchial biopsy the following day. The bronchoscopy was uncomplicated and showed evidence of both tracheal and bronchial ulceration (Fig 2A), but without significant secretions. BAL was performed although cultures only grew nonpathogenic oral flora. A right middle lobe transbronchial biopsy specimen was also obtained. The hematoxylin-andeosin-stained section of the transbronchial biopsy specimen showed a mononuclear inflammatory infiltrate primarily located in the interstitium coupled with the absence of a neutrophilic intraalveolar infiltrate consistent with chronic interstitial pneumonitis. The bronchial epithelium revealed squamous metaplasia and large atypical squamous epithelium with evidence of nuclear cytopathic effect (Fig 2B). Further immunohistochemical staining was negative for cytomegalovirus and confirmatory for the ultimate diagnosis (Fig 2C).
Figure 1. A, The patient’s initial chest radiograph displaying multiple foci of airspace consolidation. B, Subsequent radiograph displaying clear interval progression. C, High-resolution chest CT scan with IV contrast displays bilateral peribronchovascular consolidations with scattered areas of ground-glass attenuation. D, Foci of dense airspace consolidation in the lung bases and relative sparing of the periphery. 168
Postgraduate Education Corner
Figure 2. A, Fiber-optic bronchoscopy showing tracheal ulceration (arrows). B, Hematoxylin-and-eosinstained section (original magnification 3 100) displaying bronchial tissue with squamous metaplasia, atypical squamous epithelium, and evidence of cytopathic effect with prominent multinucleated giant cells (arrows). C, Positive (orange) immunohistochemical staining (original magnification 3 100) for herpes simplex virus, particularly prominent within cell nuclei.
What is the diagnosis?
journal.publications.chestnet.org
CHEST / 145 / 1 / JANUARY 2014
169
Diagnosis: Herpes simplex virus bronchopneumonia Discussion Clinical Discussion The patient’s biopsy results provided a definitive diagnosis, and he was promptly started on 5 mg/kg IV acyclovir every 8 h; corticosteroids were tapered off quickly and he experienced significant improvement in his symptoms. His rapid clinical response to antiviral therapy further implicated herpes simplex virus (HSV) as the causative agent of his symptoms, rather than an incidental finding. The specificity of the diagnosis highlights the importance of the decision to obtain a tissue biopsy specimen following his highly abnormal but ultimately nonspecific chest imaging, as it allowed for the initiation of prompt therapy with acyclovir. Prior to the advent of acyclovir and given its more typical association with immunocompromised hosts, patients with HSV pneumonitis had high mortality rates,1 demonstrating the importance of making a prompt diagnosis to guide appropriate therapy. Before his biopsy results, he had several pertinent negative findings arguing against an alternative diagnosis. The abrupt nature of the onset of his symptoms suggested an infectious cause as opposed to a more insidious autoimmune disease. Although his initial mild improvement was possibly due to bronchospasm responding favorably to steroids, his failure to improve and progression on standard antibiotic therapy for CAP and subsequently broader-spectrum antibiotics argued against a bacterial infection. The lack of response to corticosteroids also argued against typically steroidresponsive processes such as hypersensitivity pneumonitis or cryptogenic organizing pneumonia. As noted previously, his initial presentation and chest radiograph along with his history of IV drug use were concerning for an opportunistic infection such as Pneumocystis or fungal pneumonia in the setting of HIV infection but this testing was negative. In addition, he had neither hematologic abnormalities nor significant lymphadenopathy on physical examination or imaging to suggest an underlying malignancy or lymphoproliferative disorder. This case is unique as herpes pneumonia is usually described in critically ill patients on mechanical ventilation,2,3 in burn patients,2 following open thoracic surgery,4,5 or in obviously immunocompromised hosts, where disseminated HSV infection is not uncommon.1 It is rarely seen in otherwise immunocompetent individuals where it is only described in case reports.6-9 Upon further discussion with the patient regarding the exact nature of his marijuana use, he informed us that he regularly uses a large-mouth glass pipe requiring deep inhalations and that he had a large, painful “cold 170
sore” on his upper lip 3 to 4 weeks before the onset of his symptoms. His description of his cold sore was consistent with herpes labialis. We believe that the most likely route of infection of this patient’s herpes pneumonitis was seeding of his bronchial tree and lung parenchyma during deep inhalations while smoking marijuana with an exposed herpes labialis lesion actively shedding virus. Given its unregulated, illicit nature and varied methods of inhalation, the pathologic effects of recreational cannabis use are less studied compared with tobacco use. There is growing evidence that tetrahydrocannabinol, the primary psychoactive component of cannabis, has localized antagonist effects on both innate and adaptive immunity within the lungs.10 Tetrahydrocannabinol can directly impair alveolar macrophage phagocytosis,11 decrease production of both tumor necrosis factor-a11 and interferon-g,12 and impair cytotoxic T-lymphocyte proliferation and activity.12,13 We postulate that the patient’s chronic use of cannabis further contributed to the HSV bronchopneumonia due to its localized immunosuppressant effects. The corticosteroids used for asthma may have also further compromised the patient and promoted pathologic HSV dissemination. Related to this, herpes tracheobronchitis has been described in patients on mechanical ventilation presenting commonly with refractory bronchospasm despite corticosteroid treatment and responding to treatment with acyclovir and steroid discontinuation.3 Radiologic Discussion The patient’s radiographic findings (Fig 1) of multiple foci of airspace consolidation in a peribronchovascular distribution along with areas of ground-glass attenuation are consistent with prior reports of HSV pneumonitis, which do not vary significantly between compromised and immunocompetent hosts.14-16 Peerreviewed literature of both chest radiography and CT scans in patients with HSV pneumonitis suggests that the diagnosis should be included in the differential when confronted with these findings, but highlight that a diagnosis of HSV pneumonitis can never be made based on imaging alone14-16; evidence of viral cytopathic effect on cytologic and/or histopathologic specimens along with confirmation of HSV presence via culture, viral HSV PCR, or immunohistochemical staining is required. This case highlights both the importance, and also the limits, of diagnostic imaging and the need for more invasive and definitive methods of diagnosis. Once armed with the tissue diagnosis, the widespread bilateral, bronchocentric distribution of his opacities with relative sparing of the periphery are consistent with an inhalational mode of dissemination with viral shedding from the orolabial ulcer acting as the nidus vs the aspiration of HSV Postgraduate Education Corner
containing oropharyngeal secretions described as the mechanism in patients who are on mechanical ventilation.17 Nonetheless, this peribronchovascular distribution of airspace consolidation can be seen in several other pathologic conditions, and again highlights the need for a biopsy to establish a definitive diagnosis. Pathologic Discussion The main histopathologic finding was in the bronchial mucosa. The mucosa reveals areas of necrosis and some very large atypical squamous epithelial cells showing smearing of nuclear chromatin, a change that is nearly pathognomic of viral herpetic infection and necessary to make a firm diagnosis of HSV bronchopneumonitis along with supportive cultures, immunohistochemical staining of specimens,18,19 or both (Fig 2B). This is the same phenomenon seen in a Tzanck smear19 and narrowed the causative agent behind the patient’s symptoms to most likely be a virus of the Herpesviridae family. Immunohistochemistry confirmed this to be HSV, which allowed prompt initiation of antiviral therapy leading to a rapid improvement in the patient’s clinical symptoms. In this case making a definitive tissue diagnosis was important as HSV can be detected by both PCR and viral culture in BAL samples in asymptomatic individuals and does not definitely indicate active disease.20 In fact, asymptomatic shedding of HSV can be found in the saliva of 1% to 5% of normal subjects. The literature also reveals that isolation of HSV from oropharyngeal secretions and lower respiratory tract samples is not uncommon in critically ill, mechanically ventilated patient.3 The clinical importance of this finding is debatable as treatment with acyclovir does not always improve outcomes in such patients. Thus, the viral cytopathic effect is important in attempting to distinguish HSV presence as just a marker of underlying disease severity (innocent bystander) vs a true pathogenic organism. Conclusions The patient was treated with 5 mg/kg IV acyclovir every 8 h and experienced remarkable improvement in his symptoms as his dyspnea significantly diminished and he remained afebrile. After 48 h of IV therapy, he was discharged home on an oral course of 500 mg tid of famciclovir to complete a total of 4 weeks of antiviral therapy. He continued to do well from a clinical perspective on subsequent follow-up. Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. journal.publications.chestnet.org
Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
References 1. Ramsey PG, Fife KH, Hackman RC, Meyers JD, Corey L. Herpes simplex virus pneumonia: clinical, virologic, and pathologic features in 20 patients. Ann Intern Med. 1982;97(6): 813-820. 2. Schuller D. Lower respiratory tract reactivation of herpes simplex virus. Comparison of immunocompromised and immunocompetent hosts. Chest. 1994;106(1_suppl):3S-7S. 3. Luyt CE, Combes A, Deback C, et al. Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care Med. 2007;175(9):935-942. 4. Shimokawa S, Watanabe S, Taira A, Eizuru Y. Herpes simplex virus pneumonia after cardiac surgery: report of a case. Surg Today. 2001;31(9):814-816. 5. Yamaguchi A, Matsumoto S, Hagiwara S, Shingu C, Iwasaka H, Noguchi T. Herpes simplex virus pneumonia following mitral valve replacement. Gen Thorac Cardiovasc Surg. 2010;58(11): 580-583. 6. Alvarez-Uria G, Surinach JM, Ventura A, de la Rosa D, de Gracia J, Fernandez-Sevilla T. Herpetic tracheitis and polybacterial pneumonia in an immunocompetent young man is herpes tracheitis involved in the pathogenesis of bacterial pneumonia? J Clin Virol. 2008;41(2):164-165. 7. Martinez E, de Diego A, Paradis A, Perpiñá M, Hernandez M. Herpes simplex pneumonia in a young immunocompetent man. Eur Respir J. 1994;7(6):1185-1188. 8. Reyes CV, Bolden JR. Herpes simplex virus type-1 pneumonitis in immunocompetent young woman. Heart Lung. 2009;38(6): 526-529. 9. Boland AC, Iveson EH, Elliott MW. An unusual exacerbation of chronic obstructive pulmonary disease (COPD) with herpes simplex tracheitis: case report. J Med Case Reports. 2007;1: 91. 10. Wolff AJ, O’Donnell AE. Pulmonary effects of illicit drug use. Clin Chest Med. 2004;25(1):203-216. 11. Baldwin GC, Tashkin DP, Buckley DM, Park AN, Dubinett SM, Roth MD. Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am J Respir Crit Care Med. 1997;156(5):1606-1613. 12. Yuan M, Kiertscher SM, Cheng Q, Zoumalan R, Tashkin DP, Roth MD. Delta 9-Tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells. J Neuroimmunol. 2002;133(1-2):124-131. 13. Tashkin DP, Baldwin GC, Sarafian T, Dubinett S, Roth MD. Respiratory and immunologic consequences of marijuana smoking. J Clin Pharmacol. 2002;42(suppl 11):71S-81S. 14. Aquino SL, Dunagan DP, Chiles C, Haponik EF. Herpes simplex virus 1 pneumonia: patterns on CT scans and conventional chest radiographs. J Comput Assist Tomogr. 1998;22(5): 795-800. 15. Brodoefel H, Vogel M, Spira D, et al. Herpes-simplex-virus 1 pneumonia in the immunocompromised host: high-resolution CT patterns in correlation to outcome and follow-up. Eur J Radiol. 2012;81(4):e415-e420. 16. Chong S, Kim TS, Cho EY. Herpes simplex virus pneumonia: high-resolution CT findings. Br J Radiol. 2010;83(991): 585-589. 17. Devakonda A, Raoof S, Sung A, Travis WD, Naidich D. Bronchiolar disorders: a clinical-radiological diagnostic algorithm. Chest. 2010;137(4):938-951. 18. Netherton C, Moffat K, Brooks E, Wileman T. A guide to viral inclusions, membrane rearrangements, factories, and viroplasm CHEST / 145 / 1 / JANUARY 2014
171
produced during virus replication. Adv Virus Res. 2007;70: 101-182. 19. Solomon AR, Rasmussen JE, Varani J, Pierson CL. The Tzanck smear in the diagnosis of cutaneous herpes simplex. JAMA. 1984;251(5):633-635.
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