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Cytomegalovirus pneumonia in patients with inflammatory bowel disease: a systematic review

  • Antonio Cascio
    Correspondence
    Corresponding author. Tel.: +39 090 2213680; fax: +39 090 692610.
    Affiliations
    Tropical and Parasitological Diseases Unit, Department of Human Pathology, Policlinico “G. Martino”, Via Consolare Valeria n. 1, 98125 Messina, Italy

    AILMI (Italian Association for the Control of Infectious Diseases), University of Messina, Messina, Italy
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  • Chiara Iaria
    Affiliations
    AILMI (Italian Association for the Control of Infectious Diseases), University of Messina, Messina, Italy

    Infectious Diseases Unit - Azienda Ospedaliera Piemonte-Papardo, Messina, Italy
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  • Paolo Ruggeri
    Affiliations
    Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
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  • Walter Fries
    Affiliations
    Department of Internal Medicine, University of Messina, Messina, Italy
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Open ArchivePublished:May 23, 2012DOI:https://doi.org/10.1016/j.ijid.2012.03.008

      Summary

      Background

      Inflammatory bowel disease (IBD) patients are at increased risk of cytomegalovirus (CMV) reactivation, and although CMV pneumonia may be a fatal disease in IBD patients, little information is available on this issue. The objectives of this study were to identify risk factors for the development of CMV pneumonia in IBD patients and to find useful information to better manage this potentially fatal complication.

      Methods

      A computerized search without language restrictions was conducted using PubMed and SCOPUS. An article was considered eligible for inclusion in the systematic review if it reported detailed data on patients with IBD presenting with pneumonia due to CMV.

      Results

      Overall, 12 articles describing the history of 13 patients, published between the years 1996 and 2011, were finally considered. All patients were adults with a mean age of 33 years, and 11/13 were females. Fever and dyspnea were the most frequent symptoms. The most frequent radiological signs were bilateral pulmonary infiltrates. Six cases were complicated by hemophagocytic lymphohistiocytosis. Eight of the 13 were transferred to intensive care units and four of them died.

      Conclusions

      CMV pneumonia should always be suspected in IBD patients who present with fever and tachypnea, especially if the latter is worsening and/or is associated with dyspnea. Treatment must be early and specific.

      Keywords

      1. Introduction

      As with all herpes viruses, cytomegalovirus (CMV) establishes a latent infection in the host following recovery from an acute infection. Activation from this latent state can occur with immunosuppression, other illness, or the use of chemotherapeutic agents. Clinical CMV disease can result from either a primary or a secondary infection; in a primary infection, the virus usually replicates to a higher level and the disease is more severe.
      The role of CMV in inflammatory bowel disease (IBD) remains controversial.
      • Kim J.J.
      • Simpson N.
      • Klipfel N.
      • Debose R.
      • Barr N.
      • Laine L.
      Cytomegalovirus infection in patients with active inflammatory bowel disease.
      Initial studies reported CMV inclusion bodies in colectomy specimens from patients with fulminant or steroid-refractory ulcerative colitis (UC).
      • Kuwabara A.
      • Okamoto H.
      • Suda T.
      • Ajioka Y.
      • Hatakeyama K.
      Clinicopathologic characteristics of clinically relevant cytomegalovirus infection in inflammatory bowel disease.
      Other studies have questioned the pathogenicity of CMV in active IBD by demonstrating a lack of correlation of CMV and the clinical severity of IBD.
      • Matsuoka K.
      • Iwao Y.
      • Mori T.
      • Sakuraba A.
      • Yajima T.
      • Hisamatsu T.
      • et al.
      Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis patients.
      However, despite arguments on the non-pathogenicity of CMV reactivation, the overall existing literature indicates that IBD patients are at increased risk of CMV reactivation, and that the failure to appropriately diagnose and treat these patients promptly leads to significant morbidity and mortality. This increased risk is likely multifactorial, due in part to both iatrogenic immunosuppression and underlying factors related to severe inflammation, possible malnutrition, and inherent immunogenicity.
      • Nguyen M.
      • Bradford K.
      • Zhang X.
      • Shih D.Q.
      Cytomegalovirus reactivation in ulcerative colitis patients.
      Although CMV pneumonia may be a fatal disease in IBD patients,
      • Sato S.
      • Kobayashi H.
      • Saito R.
      • Sasajima T.
      • Orikasa H.
      • Watanabe H.
      • et al.
      A case of steroid-refractory ulcerative colitis complicated with cytomegalovirus pneumonia.
      very little information is available in the international literature on this issue and CMV pneumonia was not mentioned in two recent reviews on possible pulmonary complications during IBD.
      • Basseri B.
      • Enayati P.
      • Marchevsky A.
      • Papadakis K.A.
      Pulmonary manifestations of inflammatory bowel disease: case presentations and review.
      • Casella G.
      • Villanacci V.
      • Di Bella C.
      • Antonelli E.
      • Baldini V.
      • Bassotti G.
      Pulmonary diseases associated with inflammatory bowel diseases.
      The objective of this review was to focus attention on this potentially fatal disease, which we believe to be under-recognized, at least in its initial manifestation, and to try to recognize those characteristics of IBD patients that could be associated with CMV pneumonia.

      2. Methods

      A computerized search without language restrictions was conducted using PubMed and SCOPUS. The search was performed combining the terms (CMV OR cytomegalovirus OR ganciclovir) AND (IBD OR Crohn OR ulcerative colitis OR inflammatory bowel disease), without limits. Furthermore, all references listed were hand-searched for other relevant articles. An article was considered eligible for inclusion in the systematic review if it reported detailed data on patients with IBD who presented with pneumonia due to CMV. CMV pneumonia was diagnosed in the presence of at least: (1) positive radiology or autopsy findings of pneumonia, and (2) pp65 antigenemia and/or CMV DNA in blood and/or positive anti-CMV IgM and IgG titers, and (3) absence of other cause of pneumonia. In the presence of another cause of pneumonia, the detection of CMV inclusion bodies/immunohistochemical stain/culture in biopsies/autopsy, or PCR on bronchoalveolar lavage (BAL) fluid was considered necessary. The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gotzsche P.C.
      • Ioannidis J.P.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.

      3. Results

      The PubMed search identified 387 publications, a scrupulous analysis of which resulted in 13 eligible articles.
      • Sato S.
      • Kobayashi H.
      • Saito R.
      • Sasajima T.
      • Orikasa H.
      • Watanabe H.
      • et al.
      A case of steroid-refractory ulcerative colitis complicated with cytomegalovirus pneumonia.
      • Sijpkens Y.W.
      • Allaart C.F.
      • Thompson J.
      • van’t Wout J.
      • Kluin P.M.
      • den Ottolander G.J.
      • et al.
      Fever and progressive pancytopenia in a 20-year-old woman with Crohn's disease.
      • Papadakis K.A.
      • Tung J.K.
      • Binder S.W.
      • Kam L.Y.
      • Abreu M.T.
      • Targan S.R.
      • et al.
      Outcome of cytomegalovirus infections in patients with inflammatory bowel disease.
      • Hookey L.C.
      • Depew W.
      • Boag A.
      • Vanner S.
      6-mercaptopurine and inflammatory bowel disease: hidden ground for the cytomegalovirus.
      • Alderson J.W.
      • Van Dinter Jr., T.G.
      • Opatowsky M.J.
      • Burton E.C.
      Disseminated aspergillosis following infliximab therapy in an immunosuppressed patient with Crohn's disease and chronic hepatitis C: a case study and review of the literature.
      • Piton G.
      • Dupont-Gossart A.C.
      • Weber A.
      • Herbein G.
      • Viennet G.
      • Mantion G.
      • et al.
      Severe systemic cytomegalovirus infections in patients with steroid-refractory ulcerative colitis treated by an oral microemulsion form of cyclosporine: report of two cases.
      • de Boer N.K.
      • van Bodegraven A.A.
      • de Graaf P.
      • van der Hulst R.W.
      • Zoetekouw L.
      • van Kuilenburg A.B.
      Paradoxical elevated thiopurine S-methyltransferase activity after pancytopenia during azathioprine therapy: potential influence of red blood cell age.
      • Wolschke C.
      • Fiedler W.
      • Habermann R.C.
      • Janka-Schaub G.E.
      • Kluge S.
      [28-year old female patient with respiratory insufficiency, elevated liver enzymes, pancytopenia and fever].
      • N’Guyen Y.
      • Baumard S.
      • Salmon J.H.
      • Lemoine L.
      • Leveque N.
      • Servettaz A.
      • et al.
      Cytomegalovirus associated hemophagocytic lymphohistiocytosis in patients suffering from Crohn's disease treated by azathioprine: a series of four cases.
      • Lo Presti M.A.
      • Costantino G.
      • Della Torre A.
      • Belvedere A.
      • Cascio A.
      • Fries W.
      Severe CMV-related pneumonia complicated by the hemophagocytic lymphohistiocytic (HLH) syndrome in quiescent Crohn's colitis: harmful cure?.
      • van Langenberg D.R.
      • Morrison G.
      • Foley A.
      • Buttigieg R.J.
      • Gibson P.R.
      Cytomegalovirus disease, haemophagocytic syndrome, immunosuppression in patients with IBD: ‘a cocktail best avoided, not stirred’.
      • Cottone M.
      • Pietrosi G.
      • Martorana G.
      • Casa A.
      • Pecoraro G.
      • Oliva L.
      • et al.
      Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis.
      • Petrache A.
      • Moller M.B.
      • Frederiksen H.
      [Hemophagocytosis associated with cytomegalovirus infection and azathioprine treatment for inflammatory bowel disease].
      One other article (not present in PubMed) was found through the SCOPUS search.
      • Kak V.
      • Havlichek D.
      Fulminant cytomegaloviral pneumonia after infliximab in a patient with Crohn disease.
      Overall, 14 articles describing the history of 16 patients, published between the years 1996 and 2011, were further evaluated. A paper reporting two cases of CMV pneumonia but lacking detailed information about the patients was excluded.
      • Cottone M.
      • Pietrosi G.
      • Martorana G.
      • Casa A.
      • Pecoraro G.
      • Oliva L.
      • et al.
      Prevalence of cytomegalovirus infection in severe refractory ulcerative and Crohn's colitis.
      A case of UC with detectable circulating CMV DNA, in whom respiratory symptoms were present but chest X-ray (performed only once) was negative, was also excluded.
      • Petrache A.
      • Moller M.B.
      • Frederiksen H.
      [Hemophagocytosis associated with cytomegalovirus infection and azathioprine treatment for inflammatory bowel disease].
      A flow-diagram summarizing the literature research approach is shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Flow of information through the different phases of the review.
      Data regarding the clinical characteristics, therapy, and outcome of the 13 patients are given in Table 1. All patients were adults with a mean age of 33 years (median age 28 years, range 18–77 years), and 11/13 were females. Ten suffered from Crohn's disease (CD) and three from UC. The mean length of the IBD before the appearance of respiratory symptoms was 8 years (median duration 4.5 years, range 7 months–30 years). Five CD patients came from Europe, four from North America, and one from Australia.
      Table 1Clinical characteristics, therapy, and outcome of 13 IBD patients with CMV pneumonia
      Author, year [Ref.] (note)Sex/age/nationIBD (duration)IBD therapy (length of treatment)Hematological findingsSymptoms, PE, CMV diagnosis, and treatmentHLHRadiological findingsOutcome
      Sijpkens, 1996
      • Sijpkens Y.W.
      • Allaart C.F.
      • Thompson J.
      • van’t Wout J.
      • Kluin P.M.
      • den Ottolander G.J.
      • et al.
      Fever and progressive pancytopenia in a 20-year-old woman with Crohn's disease.
      F/20/the NetherlandsCD (3 years)Steroids and 5-ASA (3 years); AZA (19 months)Pancytopenia15-day history of fever, headache, mild dyspnea, nonproductive cough, weakness; then severe dyspnea

      PE: fever (41.2 °C), normal breath sounds

      Positive anti-CMV IgM and IgG titers; positive pp65 antigenemia

      AZA stopped, steroids continued; ganciclovir for 17 days
      YesChest X-ray: bilateral interstitial infiltratesCured; follow-up not reported
      Papadakis, 2001
      • Papadakis K.A.
      • Tung J.K.
      • Binder S.W.
      • Kam L.Y.
      • Abreu M.T.
      • Targan S.R.
      • et al.
      Outcome of cytomegalovirus infections in patients with inflammatory bowel disease.
      M/51/USACD (23 years)CSA, 6-MP, steroids, 5-ASA (NR)Lymphopenia, neutropeniaFever (39 °C), dyspnea, diarrhea

      PE: NR

      CMV inclusion in BAL, positive CMV culture from bronchoscopic biopsies, CMV IgM, Pneumocystis carinii organisms and Nocardia species

      6-MP stopped; ganciclovir, trimethoprim/sulfamethoxazole, other antibiotics, and G-CSF
      NRNRDied on day 45 of hospitalization; gastrointestinal bleeding, ARDS, and multisystem failure
      Hookey, 2003
      • Hookey L.C.
      • Depew W.
      • Boag A.
      • Vanner S.
      6-mercaptopurine and inflammatory bowel disease: hidden ground for the cytomegalovirus.
      F/19/CanadaQuiescent CD (9 years)6-MP (18 months)Leukopenia (WBC 2.6 × 109/l)1-month history of fever, chills, poor appetite and a progressively worse nonproductive cough, dyspnea

      PE: fever (39.4 °C), normal breath sounds at admission, fine crackles in both lung fields on day 2

      CMV inclusion in transbronchial biopsy

      Intubated; 6-MP stopped; ganciclovir, immunoglobulin, and steroids
      NRNormal chest X-ray at beginning of diseases and interstitial pattern 2 days afterCured, 6-MP not restarted; follow-up 6 months
      Kak, 2004
      • Kak V.
      • Havlichek D.
      Fulminant cytomegaloviral pneumonia after infliximab in a patient with Crohn disease.
      (not PubMed)
      F/19/USACD (3 years)AZA (NR), 5-ASA (NR); infliximab and steroids (3 weeks)Leukopenia (WBC 0.8 × 109/l)2-day history of fever (up to 40 °C) and bilateral sharp chest pains exacerbated by deep breaths

      PE: normal breath sounds, increasing shortness of breath, and hypoxemia; ICU

      Positive CMV IgM; CMV inclusion in BAL

      Stopping AZA not reported; high-dose ganciclovir
      NRChest X-ray and CT: bilateral infiltratesMechanical ventilation for nearly 2 weeks; cured; follow-up not reported
      Alderson, 2005
      • Alderson J.W.
      • Van Dinter Jr., T.G.
      • Opatowsky M.J.
      • Burton E.C.
      Disseminated aspergillosis following infliximab therapy in an immunosuppressed patient with Crohn's disease and chronic hepatitis C: a case study and review of the literature.
      F/55/USACD (30 years)Steroids (3 months), AZA (4 weeks), infliximab (10 days)NRLow-grade fever, shortness of breath

      PE: NR

      Postmortem lung tissue cultures were positive for Aspergillus fumigatus; CMV pneumonia confirmed by immunohistochemical stains and culture

      AZA stopped
      NRChest X-ray: diffuse bilateral infiltrates (mixed but predominantly alveolar)Died
      Sato, 2007
      • Sato S.
      • Kobayashi H.
      • Saito R.
      • Sasajima T.
      • Orikasa H.
      • Watanabe H.
      • et al.
      A case of steroid-refractory ulcerative colitis complicated with cytomegalovirus pneumonia.
      F/77/JapanUC (7 months)Steroids (6 months), leukocytapheresis (10 weeks)Severe anemia, thrombocytopeniaHigh fever, dyspnea

      PE: NR

      CMV-pp65 antigenemia positive

      Autopsy

      Ganciclovir
      NRGround-glass appearance of both lungsARDS, bilateral pneumothorax; died
      Piton, 2008
      • Piton G.
      • Dupont-Gossart A.C.
      • Weber A.
      • Herbein G.
      • Viennet G.
      • Mantion G.
      • et al.
      Severe systemic cytomegalovirus infections in patients with steroid-refractory ulcerative colitis treated by an oral microemulsion form of cyclosporine: report of two cases.
      F/18/FranceUC (2 years)5-ASA (2 years), steroids (15 days), cyclosporine (3 days)NRSymptoms and PE: NR

      Positive anti-CMV IgM and IgG titers; positive pp65 antigenemia; blood CMV DNA: 150,000 gEq/ml; CMV inclusion in BAL

      Ganciclovir for 28 days, steroids
      NRChest X-ray: diffuse bilateral infiltratesRelapse of UC and CMV infection 2 months later, new course of ganciclovir; cured;

      follow-up not reported
      De Boer, 2008
      • de Boer N.K.
      • van Bodegraven A.A.
      • de Graaf P.
      • van der Hulst R.W.
      • Zoetekouw L.
      • van Kuilenburg A.B.
      Paradoxical elevated thiopurine S-methyltransferase activity after pancytopenia during azathioprine therapy: potential influence of red blood cell age.
      F/26/the NetherlandsCD (16 years)AZA and 5-ASA (10 years), steroids (NR)PancytopeniaFever, myalgia, coughing, and diarrhea

      PE: NR

      Positive anti-CMV IgM and IgG titers

      AZA and 5-ASA stopped, no antivirals
      NRChest X-ray: normal; chest CT: bilateral pneumoniaCured; follow-up 10 months
      Wolschke, 2010
      • Wolschke C.
      • Fiedler W.
      • Habermann R.C.
      • Janka-Schaub G.E.
      • Kluge S.
      [28-year old female patient with respiratory insufficiency, elevated liver enzymes, pancytopenia and fever].
      F/28/GermanyCD (11 years)AZA (2 years)Pancytopenia

      (WBC 2.0 × 109/l, Hb 7.4 g/dl, PLT 99 × 109/l)
      High fever, dyspnea, cough

      PE: bi-basal crepitations, SaO2 86%, ICU, intubated

      BAL CMV DNA: 300 gEq/ml; blood CMV DNA: 7000 gEq/ml

      Stopping AZA not reported; ganciclovir + prednisone + etoposide + CSA
      YesChest X-ray: bilateral pleural effusion, infiltrates on the right lungCured; follow-up not reported
      Nguyen, 2011
      • N’Guyen Y.
      • Baumard S.
      • Salmon J.H.
      • Lemoine L.
      • Leveque N.
      • Servettaz A.
      • et al.
      Cytomegalovirus associated hemophagocytic lymphohistiocytosis in patients suffering from Crohn's disease treated by azathioprine: a series of four cases.
      F/38/FranceCD (NR)AZA (2 years)CytopeniaSymptoms, PE, and diagnosis: NR

      AZA stopped; steroids, ganciclovir/valganciclovir, foscarnet, polyvalent immunoglobulins
      YesBilateral involvementDied
      Lo Presti, 2011
      • Lo Presti M.A.
      • Costantino G.
      • Della Torre A.
      • Belvedere A.
      • Cascio A.
      • Fries W.
      Severe CMV-related pneumonia complicated by the hemophagocytic lymphohistiocytic (HLH) syndrome in quiescent Crohn's colitis: harmful cure?.
      F/32/ItalyQuiescent CD (6 years)AZA (8 months)Pancytopenia (WBC 1.26 × 109/l, Hb 8.1 g/dl, PLT 53 × 109/l)3-day history of fever and weakness

      PE: temp. 39.0 °C, tachypnea, normal breath sounds, SaO2 82%, worsening dyspnea, ICU

      Blood CMV DNA: 2670 gEq/100,000 cells

      AZA stopped; ganciclovir/valganciclovir
      YesChest X-ray: diffuse bilateral infiltratesCured; follow-up 12 months
      van Langenberg, 2011
      • van Langenberg D.R.
      • Morrison G.
      • Foley A.
      • Buttigieg R.J.
      • Gibson P.R.
      Cytomegalovirus disease, haemophagocytic syndrome, immunosuppression in patients with IBD: ‘a cocktail best avoided, not stirred’.
      (2 cases)
      F/32/AustraliaUC (10 years)AZA, 5-ASA (2 years)Pancytopenia7-day history of fever, lethargy, myalgia, and headache

      PE: productive cough, right basal crepitations, SaO2 86%, ICU, intubated

      CMV IgM was positive; blood CMV DNA: 294,000 gEq/ml, BAL CMV DNA positive

      AZA stopped; ganciclovir + foscarnet + steroids
      YesChest X-ray: consolidation with small bilateral pleural effusions; CT: bilateral mid-lower zone alveolar infiltrates, early consolidationCured
      M/22/AustraliaCD (3 years)AZA (1 year)Pancytopenia2-week history of fatigue, malaise, fevers and sore throat

      PE: temp. 39.0 °C, tachycardia, bi-basal crepitations

      CMV serology, positive IgM but negative IgG antibodies; CMV PCR of serum and BAL were positive

      AZA stopped; ganciclovir
      YesChest X-ray: NR; CT scan: bilateral, patchy alveolar opacificationCured; follow-up 16 months
      5-ASA, 5-aminosalicylic acid; ARDS, acute respiratory distress syndrome; AZA, azathioprine; BAL, bronchoalveolar lavage; CD, Crohn's diseases; CMV, cytomegalovirus; CSA, cyclosporine; CT, computed tomography; F, female; G-CSF, granulocyte colony stimulating factor; gEq, genome equivalents; Hb, hemoglobin; HLH, hemophagocytic lymphohistiocytosis; IBD, inflammatory bowel disease; ICU, intensive care unit; M, male; 6-MP, 6-mercaptopurine; PE, physical examination; NR, not reported; PLT, platelets; UC, ulcerative colitis; WBC, white blood cell count.
      Nine patients were under treatment with azathioprine (alone in four cases and associated with 5-aminosalicylic acid, steroids, and/or infliximab in the others), two patients were under treatment with 6-mercaptopurine (in one case associated with steroids, cyclosporine A, and 5-aminosalicylic acid), one patient was under treatment with steroids and leukocytapheresis, and one was on steroids plus cyclosporine A and 5-aminosalicylic acid. The mean length of treatment with azathioprine before the appearance of respiratory symptoms was 30 months and the median was 19 months.
      Signs and symptoms were reported in all but two cases.
      • Piton G.
      • Dupont-Gossart A.C.
      • Weber A.
      • Herbein G.
      • Viennet G.
      • Mantion G.
      • et al.
      Severe systemic cytomegalovirus infections in patients with steroid-refractory ulcerative colitis treated by an oral microemulsion form of cyclosporine: report of two cases.
      • N’Guyen Y.
      • Baumard S.
      • Salmon J.H.
      • Lemoine L.
      • Leveque N.
      • Servettaz A.
      • et al.
      Cytomegalovirus associated hemophagocytic lymphohistiocytosis in patients suffering from Crohn's disease treated by azathioprine: a series of four cases.
      Fever was present in 11 cases, dyspnea or reduced oxygen saturation (SaO2) was reported in eight cases, cough in five cases, and chest pain in one case. Worsening dyspnea necessitating mechanical ventilation was reported in eight cases. Normal breath sounds at lung auscultation on patient admission were found in four cases, basal crepitations in three cases, and in the remaining cases auscultation results were not reported.
      Radiological findings were described in all but one case.
      • Papadakis K.A.
      • Tung J.K.
      • Binder S.W.
      • Kam L.Y.
      • Abreu M.T.
      • Targan S.R.
      • et al.
      Outcome of cytomegalovirus infections in patients with inflammatory bowel disease.
      Diffuse bilateral infiltrates were described in nine cases. A mixed but predominantly alveolar pattern was described in a case in whom an Aspergillus fumigatus infection was also documented.
      • Alderson J.W.
      • Van Dinter Jr., T.G.
      • Opatowsky M.J.
      • Burton E.C.
      Disseminated aspergillosis following infliximab therapy in an immunosuppressed patient with Crohn's disease and chronic hepatitis C: a case study and review of the literature.
      Alveolar infiltrates were described in two cases in whom no other cause of pneumonia was diagnosed. Chest X-ray performed at the beginning of the disease failed to identify signs of pneumonia in two cases.
      • Hookey L.C.
      • Depew W.
      • Boag A.
      • Vanner S.
      6-mercaptopurine and inflammatory bowel disease: hidden ground for the cytomegalovirus.
      • de Boer N.K.
      • van Bodegraven A.A.
      • de Graaf P.
      • van der Hulst R.W.
      • Zoetekouw L.
      • van Kuilenburg A.B.
      Paradoxical elevated thiopurine S-methyltransferase activity after pancytopenia during azathioprine therapy: potential influence of red blood cell age.
      Methods used to diagnose CMV pneumonia were reported in all but one case.
      • N’Guyen Y.
      • Baumard S.
      • Salmon J.H.
      • Lemoine L.
      • Leveque N.
      • Servettaz A.
      • et al.
      Cytomegalovirus associated hemophagocytic lymphohistiocytosis in patients suffering from Crohn's disease treated by azathioprine: a series of four cases.
      Diagnosis was made by the detection of CMV inclusion bodies/immunohistochemical stain/culture in biopsies/autopsy in five cases,
      • Papadakis K.A.
      • Tung J.K.
      • Binder S.W.
      • Kam L.Y.
      • Abreu M.T.
      • Targan S.R.
      • et al.
      Outcome of cytomegalovirus infections in patients with inflammatory bowel disease.
      • Hookey L.C.
      • Depew W.
      • Boag A.
      • Vanner S.
      6-mercaptopurine and inflammatory bowel disease: hidden ground for the cytomegalovirus.
      • Alderson J.W.
      • Van Dinter Jr., T.G.
      • Opatowsky M.J.
      • Burton E.C.
      Disseminated aspergillosis following infliximab therapy in an immunosuppressed patient with Crohn's disease and chronic hepatitis C: a case study and review of the literature.
      • Piton G.
      • Dupont-Gossart A.C.
      • Weber A.
      • Herbein G.
      • Viennet G.
      • Mantion G.
      • et al.
      Severe systemic cytomegalovirus infections in patients with steroid-refractory ulcerative colitis treated by an oral microemulsion form of cyclosporine: report of two cases.
      • Kak V.
      • Havlichek D.
      Fulminant cytomegaloviral pneumonia after infliximab in a patient with Crohn disease.
      by polymerase chain reaction (PCR) on bronchoalveolar lavage (BAL) fluid in three cases,
      • Wolschke C.
      • Fiedler W.
      • Habermann R.C.
      • Janka-Schaub G.E.
      • Kluge S.
      [28-year old female patient with respiratory insufficiency, elevated liver enzymes, pancytopenia and fever].
      • van Langenberg D.R.
      • Morrison G.
      • Foley A.
      • Buttigieg R.J.
      • Gibson P.R.
      Cytomegalovirus disease, haemophagocytic syndrome, immunosuppression in patients with IBD: ‘a cocktail best avoided, not stirred’.
      by PCR on peripheral blood in one case,
      • Lo Presti M.A.
      • Costantino G.
      • Della Torre A.
      • Belvedere A.
      • Cascio A.
      • Fries W.
      Severe CMV-related pneumonia complicated by the hemophagocytic lymphohistiocytic (HLH) syndrome in quiescent Crohn's colitis: harmful cure?.
      by serology accompanied by a positive pp65 antigenemia in one case,
      • Sijpkens Y.W.
      • Allaart C.F.
      • Thompson J.
      • van’t Wout J.
      • Kluin P.M.
      • den Ottolander G.J.
      • et al.
      Fever and progressive pancytopenia in a 20-year-old woman with Crohn's disease.
      by a positive pp65 antigenemia later confirmed by autopsy in one case,
      • Sato S.
      • Kobayashi H.
      • Saito R.
      • Sasajima T.
      • Orikasa H.
      • Watanabe H.
      • et al.
      A case of steroid-refractory ulcerative colitis complicated with cytomegalovirus pneumonia.
      and only by serology in one case.
      • de Boer N.K.
      • van Bodegraven A.A.
      • de Graaf P.
      • van der Hulst R.W.
      • Zoetekouw L.
      • van Kuilenburg A.B.
      Paradoxical elevated thiopurine S-methyltransferase activity after pancytopenia during azathioprine therapy: potential influence of red blood cell age.
      Six cases were complicated by hemophagocytic lymphohistiocytosis (HLH).
      • Sijpkens Y.W.
      • Allaart C.F.
      • Thompson J.
      • van’t Wout J.
      • Kluin P.M.
      • den Ottolander G.J.
      • et al.
      Fever and progressive pancytopenia in a 20-year-old woman with Crohn's disease.
      • Wolschke C.
      • Fiedler W.
      • Habermann R.C.
      • Janka-Schaub G.E.
      • Kluge S.
      [28-year old female patient with respiratory insufficiency, elevated liver enzymes, pancytopenia and fever].
      • N’Guyen Y.
      • Baumard S.
      • Salmon J.H.
      • Lemoine L.
      • Leveque N.
      • Servettaz A.
      • et al.
      Cytomegalovirus associated hemophagocytic lymphohistiocytosis in patients suffering from Crohn's disease treated by azathioprine: a series of four cases.
      • Lo Presti M.A.
      • Costantino G.
      • Della Torre A.
      • Belvedere A.
      • Cascio A.
      • Fries W.
      Severe CMV-related pneumonia complicated by the hemophagocytic lymphohistiocytic (HLH) syndrome in quiescent Crohn's colitis: harmful cure?.
      • van Langenberg D.R.
      • Morrison G.
      • Foley A.
      • Buttigieg R.J.
      • Gibson P.R.
      Cytomegalovirus disease, haemophagocytic syndrome, immunosuppression in patients with IBD: ‘a cocktail best avoided, not stirred’.
      In one other case with severe anemia and thrombocytopenia who died due to acute respiratory distress syndrome (ARDS), HLH was apparently not diagnosed.
      • Sato S.
      • Kobayashi H.
      • Saito R.
      • Sasajima T.
      • Orikasa H.
      • Watanabe H.
      • et al.
      A case of steroid-refractory ulcerative colitis complicated with cytomegalovirus pneumonia.
      Concomitant infections, one with Pneumocystis carinii (jiroveci) and Nocardia species and another with Aspergillus fumigatus, were diagnosed in two fatal cases.
      • Papadakis K.A.
      • Tung J.K.
      • Binder S.W.
      • Kam L.Y.
      • Abreu M.T.
      • Targan S.R.
      • et al.
      Outcome of cytomegalovirus infections in patients with inflammatory bowel disease.
      • Alderson J.W.
      • Van Dinter Jr., T.G.
      • Opatowsky M.J.
      • Burton E.C.
      Disseminated aspergillosis following infliximab therapy in an immunosuppressed patient with Crohn's disease and chronic hepatitis C: a case study and review of the literature.
      In all the other cases another possible diagnosis of interstitial pneumonia was ruled out.
      Azathioprine and 6-mercaptopurine were stopped in 7/9 and 2/2 cases, respectively. Ganciclovir was used in 11 cases; in one case no antiviral agent was used because the diagnosis was made post mortem
      • Alderson J.W.
      • Van Dinter Jr., T.G.
      • Opatowsky M.J.
      • Burton E.C.
      Disseminated aspergillosis following infliximab therapy in an immunosuppressed patient with Crohn's disease and chronic hepatitis C: a case study and review of the literature.
      and in one case the pneumonia resolved without antiviral treatment after the withdrawal of azathioprine.
      • de Boer N.K.
      • van Bodegraven A.A.
      • de Graaf P.
      • van der Hulst R.W.
      • Zoetekouw L.
      • van Kuilenburg A.B.
      Paradoxical elevated thiopurine S-methyltransferase activity after pancytopenia during azathioprine therapy: potential influence of red blood cell age.
      Ganciclovir was used alone or associated with foscarnet and/or intravenous (IV) immunoglobulins (three cases). Oral valganciclovir was used after IV ganciclovir in two cases. Eight of the 13 cases were transferred to an intensive care unit and four of them died.

      4. Discussion

      Analysis of the retrieved cases showed many interesting points, including the gender distribution, IBD subtype, high fatality rates, initial difficulties in diagnosis, possible complication with HLH, and, finally, the best therapeutic approach.
      The gender distribution in IBD has been investigated thoroughly in recent decades. Population-based studies have shown no predominance of any sex in UC, whereas data from CD point to slight differences, with female/male ratios that range from 1.1:1 to 2.2:1.
      • Brant S.R.
      • Nguyen G.C.
      Is there a gender difference in the prevalence of Crohn's disease or ulcerative colitis?.
      These data do not explain the female/male ratio in our series of 5.5:1. Several hypotheses may be considered to explain this finding. First, women are more susceptible to CMV pneumonia; second, women develop more severe forms that result in a diagnosis; and third, younger women (the mean age in our series was 33 years) may be more exposed to CMV through their children. However no data on maternal status were reported in the retrieved reports.
      Concerning the disease subtype, CD was the underlying disease in 77% of the cases. A possible explanation for this is that immunosuppression is more common in CD compared to UC.
      Eleven out of 13 (85%) patients retrieved in our review were on treatment with thiopurines (nine with azathioprine and two with 6-mercaptopurine) when they developed CMV pneumonia. Thiopurines can be considered a standard therapy for IBD according to the most recent guidelines.
      • Mowat C.
      • Cole A.
      • Windsor A.
      • Ahmad T.
      • Arnott I.
      • Driscoll R.
      • et al.
      Guidelines for the management of inflammatory bowel disease in adults.
      • Lichtenstein G.R.
      • Hanauer S.B.
      • Sandborn W.J.
      Management of Crohn's disease in adults.
      • Dignass A.
      • Van Assche G.
      • Lindsay J.O.
      • Lemann M.
      • Soderholm J.
      • Colombel J.F.
      • et al.
      The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management.
      • Travis S.P.
      • Stange E.F.
      • Lemann M.
      • Oresland T.
      • Bemelman W.A.
      • Chowers Y.
      • et al.
      European evidence-based consensus on the management of ulcerative colitis: current management.
      However, it is becoming apparent that compared to other immunomodulators/biologicals typically used, thiopurines carry a disproportionately higher risk of the reactivation of viral infections, beyond CMV, including activating warts (human papillomavirus) with possible resulting cervical dysplasia/cancer,
      • Seksik P.
      • Cosnes J.
      • Sokol H.
      • Nion-Larmurier I.
      • Gendre J.P.
      • Beaugerie L.
      Incidence of benign upper respiratory tract infections, HSV and HPV cutaneous infections in inflammatory bowel disease patients treated with azathioprine.
      and Epstein–Barr virus leading to an increased risk of related lymphomas.
      • Beaugerie L.
      • Brousse N.
      • Bouvier A.M.
      • Colombel J.F.
      • Lemann M.
      • Cosnes J.
      • et al.
      Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.
      Thus, for fear of another future CMV reactivation, it is possible that switching these patients from a thiopurine to an alternative treatment after recovery from CMV pneumonia may be safer than resuming the thiopurine.
      CMV pneumonia is one of the most important opportunistic infections in the immunocompromised host. Clinically, CMV pneumonia usually shows an interstitial pattern, but nodules may also be present on chest radiographic films. It is usually rapid in onset, with respiratory symptoms of less than 2 weeks in duration. Fever, nonproductive cough, and dyspnea that progresses to hypoxia are common in severe cases. Hypoxia frequently necessitates assisted mechanical ventilation.
      • Meyers J.D.
      • Flournoy N.
      • Thomas E.D.
      Risk factors for cytomegalovirus infection after human marrow transplantation.
      Since there is no pathognomonic clinical finding in CMV pneumonia, BAL examination or transbronchial biopsy are generally required for diagnosis. However, no consensus exists regarding the specific criteria for establishing this diagnosis and to rule out potentially coexisting opportunistic infections.
      • Uberti-Foppa C.
      • Lillo F.
      • Terreni M.R.
      • Puglisi A.
      • Guffanti M.
      • Gianotti N.
      • et al.
      Cytomegalovirus pneumonia in AIDS patients: value of cytomegalovirus culture from BAL fluid and correlation with lung disease.
      Other causes of interstitial pneumonia reported in IBD patients are: P. jiroveci, miliary tuberculosis, varicella pneumonia, nocardiosis, histoplasmosis, influenza, adenovirus infection, Q fever, and legionellosis.
      • Itaba S.
      • Iwasa T.
      • Sadamoto Y.
      • Nasu T.
      • Misawa T.
      • Inoue K.
      • et al.
      Pneumocystis pneumonia during combined therapy of infliximab, corticosteroid, and azathioprine in a patient with Crohn's disease.
      • Stas P.
      • D’Hoore A.
      • Van Assche G.
      • Geboes K.
      • Steenkiste E.
      • Penninckx F.
      • et al.
      Miliary tuberculosis following infliximab therapy for Crohn disease: a case report and review of the literature.
      • Lawrance I.C.
      • Radford-Smith G.L.
      • Bampton P.A.
      • Andrews J.M.
      • Tan P.K.
      • Croft A.
      • et al.
      Serious infections in patients with inflammatory bowel disease receiving anti-tumor necrosis factor-alpha therapy: an Australian and New Zealand experience.
      • Monaghan T.M.
      • Norton B.
      Varicella pneumonia in an immunocompromised inflammatory bowel disease patient.
      • Lemyze M.
      • Tavernier J.Y.
      • Chevalon B.
      • Lamblin C.
      [Severe varicella zoster pneumonia during the course of treatment with azathioprine for Crohn's disease].
      • Stratakos G.
      • Kalomenidis I.
      • Papas V.
      • Malagari K.
      • Kollintza A.
      • Roussos C.
      • et al.
      Cough and fever in a female with Crohn's disease receiving infliximab.
      • Dotson J.L.
      • Crandall W.
      • Mousa H.
      • Honegger J.R.
      • Denson L.
      • Samson C.
      • et al.
      Presentation and outcome of histoplasmosis in pediatric inflammatory bowel disease patients treated with antitumor necrosis factor alpha therapy: a case series.
      • Rahier J.F.
      • Papay P.
      • Salleron J.
      • Sebastian S.
      • Ellul P.
      • Teich N.
      • et al.
      Influenza A (H1N1)v infection in patients with inflammatory bowel disease: a case series.
      • Ahmad N.M.
      • Ahmad K.M.
      • Younus F.
      Severe adenovirus pneumonia (AVP) following infliximab infusion for the treatment of Crohn's disease.
      • Nausheen S.
      • Cunha B.A.
      Q fever community-acquired pneumonia in a patient with Crohn's disease on immunosuppressive therapy.
      • Epping G.
      • van der Valk P.D.
      • Hendrix R.
      Legionella pneumophila pneumonia in a pregnant woman treated with anti-TNF-alpha antibodies for Crohn's disease: a case report.
      Furthermore, in cases of atypical pneumonia without a proven opportunistic infection, azathioprine-associated interstitial pneumonitis may be considered, which heals after withdrawal of the drug.
      • Ananthakrishnan A.N.
      • Attila T.
      • Otterson M.F.
      • Lipchik R.J.
      • Massey B.T.
      • Komorowski R.A.
      • et al.
      Severe pulmonary toxicity after azathioprine/6-mercaptopurine initiation for the treatment of inflammatory bowel disease.
      • Nagy F.
      • Molnar T.
      • Makula E.
      • Kiss I.
      • Milassin P.
      • Zollei E.
      • et al.
      A case of interstitial pneumonitis in a patient with ulcerative colitis treated with azathioprine.
      The chest X-ray was initially negative in two of the patients in this study. This finding is not unusual in CMV pneumonia. A recent paper has described a case in whom a chest CT scan was also initially unremarkable.
      • van Duin D.
      • Miranda C.
      • Husni E.
      Cytomegalovirus viremia, pneumonitis, and tocilizumab therapy.
      Finally, HLH was contextually present in six cases and was probably triggered by the CMV infection. HLH is a potentially fatal hyperinflammatory syndrome characterized by histiocyte proliferation and hemophagocytosis. HLH may be inherited (primary, familial), which occurs generally in infants, or may be secondary to severe infection, malignancy, or a rheumatologic condition, occurring at any age.
      • Gupta S.
      • Weitzman S.
      Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy.
      HLH may cause systemic inflammatory response syndrome, ARDS, and septic shock.
      • Raschke R.A.
      • Garcia-Orr R.
      Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults.
      Without treatment, familial HLH is often rapidly fatal, and the reported mortality for secondary HLH can exceed 50%. In the presence of cytopenia (affecting two or more lineages in the peripheral blood) a diagnosis of HLH should be suspected. However, the first assumption about a patient with pancytopenia on azathioprine therapy is that the pancytopenia is drug-related. Bone marrow suppression can occur after a delay, but is reversible upon discontinuation of the drug. The absence of severe bone marrow hypocellularity is evidence against a direct role of azathioprine in the pancytopenia.
      • Sijpkens Y.W.
      • Allaart C.F.
      • Thompson J.
      • van’t Wout J.
      • Kluin P.M.
      • den Ottolander G.J.
      • et al.
      Fever and progressive pancytopenia in a 20-year-old woman with Crohn's disease.
      From the analysis of our data we cannot extrapolate an indication of the best treatment for CMV pneumonia. For patients with CMV esophagitis, colitis, or rectal ulcers, improvement in clinical symptoms is usually noted during the first week of therapy with valganciclovir, ganciclovir, or foscarnet. In bone marrow transplant recipients with CMV pneumonia, IV ganciclovir is usually given concurrently with immune serum globulin or hyperimmune globulin. However, there are no convincing data to show that immune or hyperimmune globulin enhances efficacy. As a result of this experience, immune serum globulin is often administered to patients with HIV infection and suspected CMV pneumonia as an adjunct to ganciclovir or foscarnet.
      • Uberti-Foppa C.
      • Lillo F.
      • Terreni M.R.
      • Puglisi A.
      • Guffanti M.
      • Gianotti N.
      • et al.
      Cytomegalovirus pneumonia in AIDS patients: value of cytomegalovirus culture from BAL fluid and correlation with lung disease.
      The duration of therapy is usually about 2 weeks, but this may be extended to 3 weeks or longer in patients with severe disease or a primary infection. In patients with CMV disease and viremia, therapy should be continued until resolution of CMV viremia, because the risk of relapse is lower in patients who do not have detectable CMV DNA after ganciclovir therapy.
      This study has many limitations because the literature data on this topic are few and heterogeneous. Epidemiological data on the incidence of CMV pneumonia in patients with IBD cannot be extrapolated. A prospective, structured, multicenter study would be necessary to determine the real epidemiological scenario of this potentially fatal complication.
      In conclusion, CMV pneumonia should be suspected in IBD patients who present fever and tachypnea, especially if the latter is worsening and/or is associated with dyspnea. Chest X-ray should be repeated if negative and CT may be advisable. CMV serology and PCR in the blood should be performed, as well as a search for CMV in BAL. While awaiting the virological results, we recommend the prompt initiation of antiviral therapy. In the presence of cytopenia (affecting two or more lineages in the peripheral blood) a diagnosis of HLH should be suspected.
      Conflict of interest: None of the authors have any conflicts of interest associated with the work presented in this manuscript.

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