European Review for Medical and Pharmacological Sciences 2010; 14: 481-486 The “reversed halo” sign in pneumonococcal : a review with a case report

V. TZILAS, A. BASTAS, A. PROVATA, A. KOTI, V. TZOUDA, G. TSOUKALAS

4th Respiratory Medicine Department, Athens Chest Disease Hospital, Sotiria (Greece)

Abstract. – The “reversed halo” sign The patient was febrile with a temperature of (RHS) is a distinct radiological sign representing 38.5°C (101.3oF). Her heart rate was 100 to 110 a focal rounded area of ground-glass opacity beats per minute with a sinus rhythm revealed on surrounded by a more or less complete ring of consolidation. Initially, it was reported in two ECG. Respiratory rate was 18 to 20 breaths per cases of cryptogenic organizing pneumonia and minute. She was hemodynamically stable with a was considered to be relatively specific of the blood pressure of 115/70 mm Hg. Auscultation disease. Since then, it has been reported in a of the revealed crackles in the right wide variety of clinical entities, thus reducing its base. specificity. We describe the reversed halo sign in There was no clubbing, cervical or axillary a case of pneumonococcal pneumonia. To the best of our knowledge, this is the first report in lymphadenopathy, skin lesions or joint swelling. English literature. The presence of the “reversed Physical examinations of the rest systems did halo” sign during the resolution phase of pneu- not provide any significant information. monococcal pneumonia has serious implica- Total blood count revealed a mild nor- tions. First, it further reduces its specificity. Sec- mochromic anemia. The exact CBC was as fol- ond, it opens new areas of research regarding lows: Ht: 34.8%, WBC: 10,660/mm3, PLT: its significance in cases of cryptogenic organiz- 215,000 mm3. The erythrocyte sedimentation rate ing pneumonia. was 83 mm.h-1. Laboratory panel regarding liver Key Words: function, renal function, creatine kinase and elec- trolytes, were all within normal limits. Reversed halo sign (RHS), Pneumonococcal pneu- monia, Cryptogenic organizing pneumonia (COP). At presentation the chest X-ray showed a consolidative pattern in the right middle and lower lung fields. A computed tomography of the chest showed extensive areas of consolida- tion with air-bronchogram in the lateral segment Case Report of the middle lobe and the right lower lung. A right sided was also noted (Fig- A 57 year old Caucasian woman presented ure 1). with a 7-days history of fever and non productive The patient was treated with moxifloxacin i.v. cough. She has been receiving clarithromycin (400 mg q.d.). She became afebrile during the (500 mg b.i.d.) by her general practitioner. Due fourth day. to the persistence of fever she was referred to our Sputum and blood cultures were negative, but clinic. At presentation the patient was febrile. the Streptococcus pneumoniae rapid urinary anti- She reported progressive dyspnea on exertion, a gen test was positive. pleuritic pain in the lower right hemithorax and At follow up the patient remained afebrile. constitutional symptoms as malaise and anorexia. Computed tomography of the chest revealed a She denied headaches, nausea, vomiting, diar- clear improvement. In the posterior segment of rhea, dysuria, night sweats, and weight loss. the right lower lobe there was a ring shaped She was currently retired and worked as a opacity surrounding an area of ground glass at- teacher. She was a non smoker and denied tenuation, thus creating the “reversed halo” sign ethanol, drug abuse, exposure to domestic ani- (RHS) (Figure 2). mals and recent travel. No drug allergies were After 3 months a chest X-ray revealed mini- noted. mal residual abnormalities (mild elevation of the

Corresponding Author: Vasilios Tzilas, MD; e-mail: [email protected] 481 V. Tzilas, A. Bastas, A. Provata, A. Koti, V. Tzouda, G. Tsoukalas

Figure 1. Areas of consolidation with air-bronchogram in the lateral segment of the middle lobe and the right lower lobe.

Figure 3. After 3 months there is a minimal elevation of the right hemidiaphragm and a linear opacity in the right right hemidiaphragm and a linear opacity in the lower lung field. right lower lung field) (Figure 3). It must be stressed that the patient never re- ceived corticosteroids. To the best of our knowl- edge this is the first time in English literature that Review the reversed halo sign is described in pneumono- coccal pneumonia. Non Infectious, non Neoplastic Causes The “reversed halo” sign is a focal rounded area of ground-glass opacity surrounded by a Cryptogenic Organizing Pneumonia more or less complete ring of consolidation1. (COP) Initially it was reported in the context of cryp- Classically, the reversed halo sign was corre- togenic organizing pneumonia and was consid- lated with Cryptogenic Organizing Pneumonia ered to be characteristic of this disease. Howev- (COP). COP is one of the seven Idiopathic In- er the reversed halo sign has been described in terstitial . Formerly known as Bron- a variety of diseases. Its evaluation should be chiolitis Obliterans Organizing Pneumonia made with extreme caution taking into account (BOOP) the ATS/ERS consensus of the Idio- history, clinical examination and other radio- pathic Interstitial Pneumonias clearly encour- logical findings. ages the embracement of the term COP2. The latter term is preferred in order to avoid confu- sion with airway diseases such as constrictive . Although relatively rare, COP has become a well characterized clinical entity with a specific pathological background in the con- text of a negative aetiological investigation. The histological hallmark is the presence of intralu- minal buds of connective tissue within alveolar ducts and alveoli. These can extend from one alveolus to the next through the pores of Kohn, thus creating a “butterfly” pattern3. Organiza- tion of connective tissue can be seen within bronchioles in the form of proliferative bronchi- olitis but this is not obligatory. Alveolar epithe- lial injury is believed to be the triggering event and the primary damage takes place on the alve- Figure 2. Follow-up CT reveals significant improvement. The “reversed halo” sign is recognized in the posterior seg- olar level. Lung architecture is usually pre- ment of the right lower lobe. (The patient herself proceeded served. Giant cell, granuloma or hyaline mem- to examination by a CT of the thorax). branes are absent.

482 The “reversed halo” sign in pneumonococcal pneumonia

The RHS in COP was first reported by which showed noncaseating granulomas with Voloudaki et al. in two patients4. This paper is stains and cultures negative for fungi and acid very important because it also offers CT-patho- fast bacilli. logic correlation. The central area of ground Recently, Kumazoe et al.9 also reported the glass attenuation corresponded to alveolar septal RHS in a case of biopsy proven inflammation and cellular debris while the ring (transbronchial). In this case it is important that of consolidation corresponded to the above men- besides the RHS there were also nodules with tioned histological pattern of Organizing Pneu- perilymphatic distribution (subpleural, perifissur- monia. al) which are considered characteristic of sar- The Authors concluded that since these fea- coidosis10. tures had not been described in any other disease, they might be characteristic features of COP. Exogenous Lipoid Pneumonia The actual term “reversed halo” sign was pro- Kanaji et al.11 reported the RHS in a patient posed by Kim et al5. The purpose of his study with exogenous lipoid pneumonia due to inhala- was to evaluate its value in the diagnosis of COP. tion of paint spray. Initially, CT revealed multi- 31 patients with COP were examined. Patients ple, bilateral nodules. After 5 months some of the with associated collagen vascular diseases or oth- nodules exhibited the RHS. er known causes of Organizing Pneumonia were excluded. The RHS was identified in 6 patients Wegener’s Granulomatosis (19%). It was not seen in any patients with We- Agarwal et al.12 described the RHS in a patient gener’s granulomatosis (14 patients), diffuse with Wegener’s granulomatosis. It is important bronchoalveolar carcinoma (10 patients), chronic that high resolution CT besides the RHS also re- (5 patients) or Churg- vealed a cavitating mass. Hence, it seems that the Strauss syndrome (1 patient). Therefore, the Au- RHS was present at an intermediate stage before thors concluded that the reversed halo sign was the development of cavitation. relatively specific for a diagnosis of COP and can be considered another diagnostic adjunct. Since then several reports in medical litera- Infectious Causes ture, correlate the reversed halo sign with other clinical entities thus questioning its diagnostic Fungal specificity regarding COP. The RHS is also reported in a case of minocy- Paracoccidioidomycosis cline induced Organizing Pneumonia6. Paracoccidioidomycosis, also known as South American blastomycosis, is a frequent endemic Non Specific Interstitial Pneumonia mycosis in Latin America, especially in farm (NSIP) workers13. Gasparetto et al.14 reviewed the high Ueda et al.7 reported a case of a 39 year old resolution CT findings in 148 patients with male who presented with chest discomfort, dry proven paracoccidioidomycosis. Besides the cough and dyspnea. High resolution CT showed known findings of interlobular septal thickening, ground glass opacities with bibasilar distribution. parenchymal bands, ground-glass opacities, cen- Loss of lung volume was indicative of a fibrotic trilobular nodules, the reversed halo sign was disorder. The RHS was also observed. A biopsy recognized in 15 patients (10%). There was no specimen was obtained during video assisted tho- zone predilection and in 2 cases the reversed halo racic surgery, which established the diagnosis of sign was the only finding. 3 patients underwent NSIP. surgical lung biopsy and a CT-pathologic correla- tion was possible. The central area of the lesions Sarcoidosis consisted of alveolar septa inflammation com- Marlow et al.8 were the first to report the RHS posed of macrophages, lymphocytes, plasma in sarcoidosis. They used the term “fairy ring” cells and some giant cells, with relative preserva- sign based on Celtic mythology. CT findings in- tion of the alveolar spaces. The periphery of the cluded multiple thick rings of consolidation lesion (i.e. the peripheral rim of consolidation while the central areas of the lesions comprised seen on high resolution CT) consisted of dense of normal appearing lung parenchyma. Diagnosis intraalveolar cellular infiltrate without any signs was established with transbronchial lung biopsy of organizing pneumonia. This paper is very im-

483 V. Tzilas, A. Bastas, A. Provata, A. Koti, V. Tzouda, G. Tsoukalas portant for two reasons. First, it questioned the ules in LYG are usually multiple with bilateral specificity of the RHS for COP. Second, it sug- distribution. They can cavitate (20-40%) or ex- gested that this sign can be seen in patients with hibit the “halo sign”. Benamore et al.19 reported a active and without organizing pneumo- case of histological proven LYG exhibiting the nia. Since then there have been more reports of RHS. The patient initially presented with the the RHS in infectious diseases. more typical nodular opacities (as described be- fore), which progressed into the RHS. Zygomycosis, In a study by Wahba et al.15, 189 patients with proven and probable fungal pneumonia were ex- amined (132 with invasive pulmonary aspergillo- Discussion sis, 37 with zygomycosis and 20 with fusariosis). The RHS was recognized in 8 patients (4%). The RHS can be seen in a variety of diseases Most of them (7) suffered from hematological (Table I). The interpretation should be based on malignancies. Although the majority of the pa- information from history, clinical examination tients had invasive pulmonary aspergillosis, the and other radiological findings (Table II). The RHS was found almost exclusively in patients clinical context of the patient is crucial. Immuno- with zygomycosis (7 patients with zygomycosis compromised patients (especially with hemato- and 1 patient with invasive pulmonary aspergillo- logical malignancies) are considered to have an sis). Thus, the frequency of the RHS reached infection until proven otherwise. A recent travel 10.8% in zygomycosis. Long-term follow up in 7 to areas with a high incidence of paracoccid- patients showed that the reversed halo sign ioidomycosis or tuberculosis is significant. The evolved into cavitation in 5 of them (after a mean RHS loses part of its significance if other radio- period of 32.6 days). logical signs are present (i.e. centrilobular or per- In conclusion, the presence of the RHS in an ilymphatic nodules, tree in bud pattern, cavita- immunocompromised patient susceptible to op- tion, and mediastinal lymphadenopathy). The portunistic infection is compatible with fungal RHS can be seen in COP but it cannot obviate infection. In such cases due to the greater possi- the need for tissue confirmation. In cases where bility of zygomycosis the administration of am- steroid treatment is initiated without a biopsy photericin B based therapy is preferred, since (patient desire or poor status) the clinician should voricanozole although the drug of choice in in- reconsider the diagnosis if a prompt improve- vasive aspergillosis is not active against Zy- ment is not achieved or if a relapse occurs while gomycetes species16,17. the patient is still on a high steroid dosage (i.e. Of course the radiological findings cannot be a substitute for bronchoalveolar lavage or tissue confirmation. Table I. Diseases exhibiting the “reversed halo” sign. Tuberculosis Ahuja et al.18 reported the RHS in a 15 year A. Non infectious, non neoplastic diseases 4-6 old male with tuberculosis. High resolution CT 1) Cryptogenic Organizing Pneumonia (COP) * 2) Non Specific Interstitial Pneumonia (NSIP)7 also showed centrilobular nodules, subcarinal 3) Sarcoidosis8,9 and left hilar lymphadenopathy. 4) Exogenous lipoid pneumonia11 5) Wegener’s granulomatosis12 B. Infectious diseases Neoplastic Causes 1) Fungal infections 1a Paracoccidioidomycosis14* Lymphomatoid Granulomatosis 1b Zygomycosis15* 15 Lymphomatoid granulomatosis (LYG) is a rare 1c Invasive aspergillosis 2) Tuberculosis18 EBV related T-cell rich, B-cell lymphoprolifera- 3) Pneumonococcal pneumonia tive disorder. Grade I, II and III are described. C. Neoplastic diseases Grade III equals to angiocentric lymphoma. High 1) Lymphomatoid granulomatosis19 resolution CT findings include areas of consoli- dation, thin walled cysts, interlobular septal *Papers referring not just in case reports but to a series of thickenings, pleural effusion and nodules. Nod- patients.

484 The “reversed halo” sign in pneumonococcal pneumonia

Table II. Clinical approach to the reversed halo sign.

Immunocompromised patient (especially Fungal infection (especially zygomycosis) hematological malignancies) Administer amphotericin-B (not voricanozole unless a diagnosis of aspergillosis is established) Resident of or recent travel to Latin America Paracoccidioidomycosis Immigrant from countries with endemic tuberculosis, Tuberculosis close contact with known tuberculosis, health care professional, positive Mantoux, positive Quantiferon test Clinical presentation compatible with COP COP (fever, cough, mild dyspnea), exclusion of other diseases (especially infectious)

COP: Cryptogenic Organizing Pneumonia, HRCT: High Resolution Computed Tomography. more than 20 mg of prednisolone per day). Any sue sampling because it was thought to be uneth- extrapulmonary symptoms are not compatible ical, since the patient had improved and was with COP and should point to other diagnoses asymptomatic. (Table III). It is very important that the RHS was seen To the best of our knowledge this is the first during the resolution phase. Potentially the RHS time in English literature that the reversed halo represents a phase during the resolution proce- sign is described in pneumonococcal pneumonia. dure. It is possible that in the context of COP, the The diagnosis was based on the Streptococcus RHS signifies the initiation of an effective heal- pneumoniae rapid urinary test which is a ing process. Hence, studies should take place try- sensitive and specific method20. Pneumonococcal ing to address the following questions: (1) Is pneumonia is a recognized cause of Organizing steroid therapy mandatory in patients with COP Pneumonia21-23. Hence, we recognize the possi- presenting the RHS or is spontaneous resolution bility that the infection could have triggered an possible? (2) Do patients with COP exhibiting uncontrolled inflammatory process that persisted the RHS have a smaller rate of relapses? It is after the aetiological agent had disappeared. known that COP is characterized by a high rate There are also reports of spontaneous improve- of relapses (ranging from 9% to 58%)27-29. Such ment as well as improvement with macrolides in studies could shed light into the pathogenesis of patients with COP24-26. We did not proceed to tis- COP and explain the impressive improvement under steroid therapy. In conclusion the RHS is seen on a wide vari- Table III. Learning points. ety of diseases. It cannot support a specific diag- nosis. Its evaluation is directly related to the clin- 1) The “reversed halo” sign is not specific enough for a ical context in which it has developed. diagnosis of COP and by no means can it obviate the need for a lung biopsy. 2) Always exclude the possibility of an infectious cause when facing the “reversed halo” sign on HRCT based on history, physical examination and References laboratory examinations. 3) Look for findings on HRCT strongly indicative of 1) HANSELL DM, BANKIER AA, MACMAHON H, MCLOUD other diseases (i.e. centrilobular or perilymphatic TC, MÜLLER NL, REMY J. Fleischner Society: glos- nodules, cavitation, mediastinal lymphadenopathy). sary of terms for thoracic imaging. Radiology 4) In cases where lung biopsy is not performed (patient 2008; 246: 697-722. desire or poor status) and infection is thoroughly 2) AMERICAN THORACIC SOCIETY/EUROPEAN RESPIRATORY SO- excluded, if treated as COP expect a significant im- CIETY. International multidisciplinary consensus provement under steroid therapy. If the clinical and classification of the idiopathic interstitial pneumo- radiological improvement delays significantly or if a nias. Am J Respir Crit Care Med 2002; 165: 277- relapse takes place while on high dose of steroids 304. (i.e. more than 20 mg of prednisolone per day 3) COLBY TV. Pathologic aspects of bronchiolitis oblit- reconsider the diagnosis and the possibility of tissue erans organizing pneumonia. Chest 1992; based diagnosis. 102(Suppl. 1) 38S-43S.

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