CASE REPORT

Successful Management of Invasive Pulmonary Nocardiosis

and Aspergillosis in a Patient with T-Cell Lymphoma: A Case
Report
Khalid A. Al-Anazi 1, Mahmoud D. Aljurf 1, Fahad I. Al-Mohareb 1, Laila Al-Dabal 2,
Mohammed Zaitoni 2 and Majed Halim 3
1
Section of Adult Hematology and Hematopoietic Stem Cell Transplant, King Faisal Cancer Centre,
King Faisal Specialist Hospital and Research Centre, P.O. Box: 3354, Riyadh 11211, Saudi Arabia.
Sections of 2Pulmonary Medicine and 3Infectious Diseases, Department of Medicine, King Faisal
Specialist Hospital and Research Centre, P.O. Box: 3354, Riyadh 11211, Saudi Arabia.

Abstract: In patients with malignant hematological disorders receiving immunosuppressive therapy, invasive pulmonary
infections are serious complications that are associated with high morbidity and mortality. In immunocompromised hosts
with impaired cellular immunity, two or more organisms may coexist leading to a wide range of clinical and radiological
manifestations.
Reported here is an old man who was diagnosed to have angioimmunoblastic T-cell lymphoma at King Faisal Specialist
Hospital and Research Centre in Riyadh in December 2004. The lymphoma was treated with various immunosuppressive
agents including alemtuzumab. In October 2006, the patient was admitted with severe bronchopneumonia caused by Nocar-
dia asteroides and Aspergillus niger that was complicated by septic shock. The invasive pulmonary infections were suc-
cessfully treated with trimethoprim-sulphamethoxazole, amikacin and liposomal amphotericin-B (amBisome).

Keywords: angioimmunoblastic T-cell lymphoma, invasive pulmonary infections, Aspergillus niger, Nocardia asteroides

Introduction
Infections are the most common cause of morbidity and mortality in patients with malignant disorders
(Neuburger and Maschmeyer, 2006). Despite the availability of various antimicrobial agents,
pneumonia constitutes the sixth cause of death and the number one cause of death from infection
(Waite et al. 2006). Pneumonia can be particularly life-threatening in the elderly, in patients with
pre-existing pulmonary or cardiac conditions and in immunocompromised individuals (Waite et al.
2006; Rolston, 2001).
The spectrum of pulmonary infections depends upon the underlying immunological abnormalities
(Rolston, 2001). In cancer patients, several immunological defects may be present, thus making them
susceptible to a wide range of opportunistic infections (Rolston, 2001). In individuals with impaired
cellular immunity, viral infections e.g. cytomegalovirus (CMV) predominate and may coexist with
bacterial (e.g. Legionella, Nocardia etc), mycobacterial and fungal (e.g. Aspergillus, Histoplasma etc)
infections (Rolston, 2001). However, pulmonary Nocardia and Aspergillus coinfections have been
reported in hematopoietic stem cell transplant recipients and in patients with glomerulonephritis treated
with corticosteroids (Hamadani et al. 2008; Varma et al. 1993).

Case Report
A 67 years old male, a non-smoker, with history of ischaemic heart disease, status post—coronary artery
bypass graft, and bronchiectasis was diagnosed to have angioimmunoblastic T-cell lymphoma (AIBTCL),
stage III B at King Faisal Specialist Hospital and Research Centre (KFSH&RC) in Riyadh in late
December 2004. He presented with: fever, skin rash, generalized external lymphadenopathy and
splenomegaly. The blood counts, blood film and bone marrow biopsy were all normal. The renal and
hepatic profiles as well as the immunoglobulin levels were within normal limits. Serological tests for

Correspondence: Khalid Ahmed Al-Anazi, Associate Consultant, Section of Adult Hematology and Hematopoietic,
Stem Cell Transplant, King Faisal Cancer Centre, King Faisal Specialist Hospital and Research Centre, P.O. Box: 3345,
Riyadh 11211, Saudi Arabia. Tel: 966 – 01 – 4568477; Fax: 966 – 01 – 4568477; Email: [email protected]
Copyright in this article, its metadata, and any supplementary data is held by its author or authors. It is published under the
Creative Commons Attribution By licence. For further information go to: http://creativecommons.org/licenses/by/3.0/.

Clinical Medicine: Case Reports 2008:1 65–71 65

Al-Anazi et al

CMV, Epstein-Barr virus (EBV), hepatitis and IV fluids at rate of 50–80 cc/hour. Initially the
C virus and HIV were negative. Computed patient had partial response then he started to have
tomography (CT) scans of chest, abdomen and higher pyrexia and respiratory distress. On
pelvis showed numerous small lymph nodes 6/11/2006, the patient was experiencing high grade
in mediastinal, mesenteric and retroperitoneal fever and rigors and his BP dropped to 85/45
areas in addition to splenomegaly with focal mmHg. Septic screens were repeated and the IV
splenic lesions. Skin biopsy showed atypical antibiotics were replaced by IV meropenem 1 gram
lymphohistiocytic changes. A right axillary thrice daily and IV vancomycin 1 gram twice daily.
lymph node biopsy revealed diffuse infiltration Later on, BP improved and fever started to subside.
with: immunoblasts, lymphocytes, polymorphs, A repeat CT scan of the chest showed: bronchiectatic
plasma cells, histiocytes and eosinophils with cavities involving the lower lobes of both lungs,
considerable proliferation of small blood vessels. bilateral nodular infiltration, areas of segmental
The immunohistochemical stains showed positive: consolidation and bilateral pleural thickening
CD1A, CD3, CD4, CD7, CD8, CD15, CD20, (Fig. 1). Echocardiogram showed no vegetations,
CD21, CD30, CD45, CD68 and S100. The gene pericardial effusions or valvular defects and brain
rearrangement studies revealed a monoclonal CT scan showed no evidence of space occupying
T-cell population. The AIBTCL was treated lesions. Bronchoscopy was performed and BAL
with: prednisone, mycophenolate mofetil and fluid showed scattered lipid laden macrophages
subcutaneous alemtuzumab: 30 mg/month for and gram positive rods identified later on as
4 months. Thereafter the patient developed: Nocardia asteroides (N. asteroides). Special stains
CMV infection treated with IV ganciclovir and for fungi were positive and the fungus was
pulmonary embolism treated with IV heparin then identified as Aspergillus niger (A. niger). BAL fluid
oral warfarin. On 29/10/06, the patient was was negative for acid fast bacilli, pneumocystis
readmitted with two week history of: fever, cough carinii, viral cytopathy and malignant cells.
productive of yellowish sputum and mild dyspnea. Meanwhile, the previously taken sputum cultures
He denied any associated chest or abdominal pain, grew branching gram positive rods identified
headache or bleeding from any site. Physical as N. asteroides. However, sputum cultures
examination revealed an unwell elderly male who were negative for acid fast bacilli, candida and
was in mild respiratory distress. The temperature aspergillus. Aspergillus galactomannan test was
was 38.7 oC, blood pressure (BP): 112/68 mmHg, positive. Consequently, the following management
pulse rate: 92/minute, respiratory rate: 20/minute modifications were made: vancomycin was stopped
and oxygen saturation was 93% on room air. There and meropenem was continued, IV liposomal
was pallor but no cyanosis, leg oedema, jaundice amphotericin-B (amBisome) 5 mg/kg/day was
or external lymphadenopathy. The inspiratory commenced in addition to oral trimethoprim-
volume was decreased and coarse crackles were sulphamethoxazole (TMP/SMZ) 960 mg thrice
heard over mid and lower lung fields bilaterally. daily as well as IV amikacin 15 mg/kg/day. Later
There was no abdominal distension, tenderness or on, the patient started to improve clinically and
palpable organomegaly. Cardiovascular and radiologically and oxygen requirements decreased
neurological examinations did not reveal any gradually. One week later, the patient sustained
abnormality. Full blood count (FBC) showed: his hemodynamic stability and his clinical
WBC: 1.83 × 10 9 /L, Hb: 109 g/L and PLT: improvement so IV meropenem was discontinued.
315 × 109/L. Differential cell count (DCC) showed On 20/11/2006, IV amikacin was stopped and IV
neutrophils of 1.1 and lymphocytes of 0.3. Renal amBisome was replaced by oral voriconazole. Two
and hepatic profiles were all within normal limits. days later; the patient was totally asymptomatic
Blood, urine, stool cultures and CMV antigen test and his physical examination showed few basal
were all negative. Chest radiography showed crackles with good air entry bilaterally. FBC
bronchiectatic changes involving both lower lobes showed WBC: 2.25 × 109/L with neutrophils of
and bilateral nodular infiltration consistent with 1.4, Hb: 94 g/L and PLT: 147 × 109/L. Renal and
severe pneumonia. The patient was commenced hepatic profiles were normal. He was discharged
on IV tazobactam-piperacillin: 4.5 grams thrice on: voriconazole 200 mg orally twice daily and
daily and gentamicin 2 mg/kg IV twice daily in TMP/SMZ 960 mg orally thrice daily for 6 weeks
addition to oxygen via mask at 2–4 Liter/minute in addition to warfarin, omeprazole, prophylactic

66 Clinical Medicine: Case Reports 2008:1

 Invasive nocardiosis and aspergillosis

Figure 1. A high resolution CAT scan of the lungs.

The CAT scan shows: bronchiectatic changes, areas of pneumonic consolidation and diffuse nodular pulmonary infiltration.

valganciclovir as well as ventolin and atrovent tions of cytotoxic drugs e.g. CHOP regimen
inhalers. Thereafter, the patient had regular follow (cyclophosphamide, doxorubicin, vincristine and
up at the hematology outpatient clinic and he prednisone) have been employed in the treatment
remained clinically stable. of AIBTCL. The clinical outcome is generally poor
and most of the deaths are infection related (Dogan
et al. 2003).
Discussion Expression of CD52 occurs in 40% of patients
AIBTCL, an intermediate grade/aggressive mature with peripheral T-cell lymphoma. Although other
peripheral T-cell lymphoma, was first described factors may play a role in the in vivo response to
in the 1970s as a distinct clinical syndrome alemtuzumab (Campath 1H), an anti-CD52 mono-
characterized by: pruritic skin rash, generalized clonal antibody, the estimation of CD52 expression
l y m p h a d e nopathy, hepatospleno me ga ly, may provide a rationale for the selection of patients
hypergammaglobulinemia, anemia and constitutional with a higher probability of treatment response
B symptoms. It occurs in elderly individuals and (Pacciluga et al. 2007). The feasible chemoim-
has no known etiology, although it has associa- munotherapy (CHOP and alemtuzumab) combina-
tions with: various infections (e.g. EBV, CMV, tion has been shown to be an effective therapeutic
hepatitis C virus, human herpes viruses 6 and 8, modality for peripheral T-cell lymphoma, produc-
tuberculosis and cryptococcus), antibiotics and ing high rates of complete remission, but has also
autoimmune disorders (e.g. rheumatoid arthritis, been associated with hematologic toxicity
vasculitis and thyroid disease) (Dogan et al. 2003). e.g. severe neutropenia and infectious complica-
Lymph node histology shows distinctive partial tions including reacivation of CMV and Jacob-
effacement of normal architecture by polymorphic Creutzfeldt virus, invasive pulmonary aspergillosis
inflammatory infiltrates including large blasts and (IPA) in addition to bacterial sepsis and pneumonia
marked vascular proliferation. The monoclonal (Gallamini et al. 2007).
T-cell population expressing CD3 and CD4 All neutropenic patients with pyrexia of
and the multiple clonal cytogenetic abnormalities unknown etiology having normal chest
are the other distinguishing features. Unfortu- roentgenograms should undergo high resolution
nately there is no curative treatment, however, CT scanning as these scans have been shown to
single agents such as corticosteroids, cyclosporine- have 87% sensitivity and 57% specificity in
A, alpha-interferon, thalidomide, fludarabine detecting pneumonic infiltrations in febrile
and 2-chlorodeoxyadenosine as well as combina- neutropenic patients with unknown foci of infection

Clinical Medicine: Case Reports 2008:1 67

Al-Anazi et al

(Heussel et al. 1999). The favorable safety record, serum or in the BAL fluid help to confirm the
the good diagnotic yield and the frequent therapeutic diagnosis (Herbrecht et al. 2004). However, the
implications strongly support the use of BAL diagnosis of IPA can only be confirmed by histo-
for the evaluation of pulmonary infiltrates in logical determination of invasion of lung tissue
neutropenic immunocompromised patients. BAL by Aspergillus species or presence of positive
should be combined with the analysis of several cultures for Aspergillus in a sample obtained from
sputum cultures as the combined diagnostic yield a sterile site by an invasive procedure e.g. lung
may reach 63% (Peikert et al. 2005). Current biopsy (Kristan et al. 2002; Ascioglu et al. 2002;
management strategies for febrile neutropenic Maertens et al. 2004). Open lung biopsy has very
patients emphasize on risk assessment (Picazo, low morbidity and is recommended to establish
2005). The development of risk stratification the diagnosis of IPA. In a retrospective study
models has allowed the identification of low risk performed in patients with malignant hemato-
patients who can exclusively be treated with oral logical disorders suspected of having IPA clini-
antimicrbials as outpatient (Sipsas et al. 2005). The cally and radiologically, only 53% of patients were
most important determinants of infection risk are proven to have IPA, the remaining 47% of patients
the severity and the duration of neutropenia were shown to have other etiologies e.g. organiz-
(Picazo, 2005). Monotherapy with the newer broad ing pneumonia, pulmonary hemorrhage or pneu-
spectrum antimicrobials has tended to replace the monia due to other infections e.g. tuberculosis,
classic combination therapy. Prompt initiation of CMV and candida (Kim et al. 2002). Recent stud-
empirical antimicrobial treatment has remained the ies have also shown that the lesions of IPA in
gold standard. However, empirical administration neutropenic immunocompromised patients differ
of glycopeptides, e.g. vancomycin, without from those in non-neutropenic individuals in that
documentation of gram-positive infection is they predominantly consist of angioinvasion and
no longer favored. The initiation of empirical intraalveolar hemorrhage and that the innate host
antifungal therapy in persistently febrile neutropenic defences largely contribute to the histological pat-
patients has become a common practice, especially terns observed in IPA (Stergiopoulou et al. 2007).
recently, after the introduction of the new, more Optimal therapeutic stratigies include: prevention
effective and less toxic antifungal agents (Sipsas of contamination in at high risk patients, early
et al. 2005). initiation of antifungal therapy, surgical resection
During the past several decades, there has been in patients having hemoptesis and lesions close to
a steady increase in the frequency of opportunistic lage blood vessels and treatment of the underlying
fungal infections in immunocompromised indi- disease condition so as to restore a certain degree
viduals (Ascioglu et al. 2002). IPA is the most of immunity. The crude mortality is high and is
common fungal pulmonary infection in immuno- strongly correlated not only with the type and the
compromised patients (Herbrecht et al. 2004). The stage of the underlying disease but also with the
main risk factors for aspergillosis are: hematopoi- extent of aspergillosis (Herbrecht et al. 2004;
etic stem cell and solid organ transplants, hema- Patterson et al. 2000).
tologic malignancy, AIDS and various pulmonary For many years, treatment of severe fungal
disorders (Patterson et al. 2000). The diagnosis of infections had been limited to amphotericin-B
IPA is based on: clinical, radiological and myco- and flucytosine. Fortunately, the past few years
logical data. The clinical signs have low specific- have brought remarkable advancements in
ity. The most typical CT scan findings are: nodules antifungal pharmacotherapy as several new
with or without the halo or the air crescent sign antifungals have been introduced (Battegay and
(Herbrecht et al. 2004). High resolution MDCT Fluckiger, 2003). With the advent of the new
angiography has been shown to be a feasible tech- triazoles e.g. voriconazole and the lipid formula-
nique to depict directly vessel occlusion in the tions of amphotericin-B in addition to the echi-
setting of suspected fungal infection, particularly nocandins e.g. caspofungin, invasive aspergillosis
for early diagnosis of angioinvasive pulmonary has become treatable. The lipid formulations of
aspergillosis in immunocompromised hosts (Son- amphoteircin-B have shown a clear advantage in
net et al. 2005). The sensitivity of microscopy and reducing the side effects e.g. nephrotoxicity of
culture of non-invasive collected samples is low. amphotericin-B (Battegay and Fluckiger, 2003).
Galactomannan and nucleic acid detection in the Caspofungin has been shown to be as effective

68 Clinical Medicine: Case Reports 2008:1

 Invasive nocardiosis and aspergillosis

as and generally better tolerated than liposomal (Yildiz and Doganay, 2006). The median time
amphotericin B when given as empirical antifun- between the onset of symptoms and the diagnosis
gal therapy in patients with prolonged neutrope- of nocardia infection is about 30 days (Matulionyte
nia having persistent pyrexia (Walsh et al. 2004). et al. 2004). Clinically mild symptoms are com-
It has demonstrated clinical efficacy when admin- mon, but variable and nonspecific radiological
istered as first-line empirical therapy in patients changes including extensive nodular lung
with persistent febrile neutropenia, as salvage involvement that resemble cannonballs of metastatic
therapy in patients refractory to or intolerant of cancer may be encountered (Pifarre et al. 2001;
standard antifungal therapies and as combination Hui et al. 2003; Tripodi et al. 2001). Recurrence
therapy in difficult-to-treat patients refractory to of the infection and complications may also occur
or intolerant of standard therapies (Maertens, (Matulionyte et al. 2004). The diagnosis depends
2006). Voriconazole has become a primary thera- upon a high degree of suspicion so as to alert
peutic modality for invasive aspergillosis, despite microbiologists and pathologists to employ special
the concerns about the development of drug-resis- methods for identification of the organism (Yildiz
tant fungi (Aperis and Mylonaki, 2006). Studies and Doganay, 2006). Early diagnosis of pulmonary
in patients with invasive aspergillosis have shown nocardiosis can be established upon culturing
that voriconazole use led to better responses and specimens of lung lesions obtained by BAL or
improved survival and resulted in fewer severe fine-needle aspirate (Tripodi et al. 2001). Suscep-
adverse effects than the standard approach tibility studies and tests of antibiotic synergism
of initial therapy with amphotericin B (Herbrecht should guide the therapy (Tripodi et al. 2001). The
et al. 2002). isolates are usually susceptible to: TMP/SMZ,
In case of intolerance to or failure of treatment carbapenems, amikacin, ceftriaxone, ciprofloxacin
with caspofungin or voriconazole, one of the new and tazobactam-piperacillin (Yildiz and Doganay,
echinocandins e.g. micafungin or triazoles e.g. 2006; Matulionyte et al. 2004; Hui et al. 2003;
posaconazole can be used as an alternative salvage Tripodi et al. 2001). Despite the development of
antifungal therapy (Walsh et al. 2007; Herbrecht drug resistance in some strains, the sulpha combi-
et al. 2004). nations e.g. TMP/SMZ are still the first line agents
Nocardia infections develop in patients with in the management of nocardiosis and carbapenems
underlying lung pathology e.g. cystic fibrosis, should be used as an alternative therapeutic
bronchiectasis or chronic obstructive airway dis- modality in severely ill patients (Yildiz and
ease as well as in immunocompromised individu- Doganay, 2006; Matulionyte et al. 2004). A syner-
als e.g. those receiving corticosteroids and other gistic combination of a beta-lactam/beta-lactamase
immunosuppressive agents, organ transplant inhibitor with ciprofloxacin or amikacin followed
recipients and cancer patients specially those with by a short course of TMP/SMZ may result in
lymphoreticular neoplasms. The most commonly eradication of nocardial disease and may reduce
involved organs are: the lungs, the central nervous the need for long-term therapy (Tripodi et al. 2001).
system and the skin (Yildiz and Doganay, 2006; Delayed diagnosis, systemic infection and neuro-
Matulionyte et al. 2004; Pifarre et al. 2001; Hui logical involvement carry poor prognosis, while
et al. 2003). However, disseminated infections are early recognition of the organism and prompt treat-
rather uncommon. The most frequently isolated ment have good outcome and may result in
species is N. asteroides (Matulionyte et al. 2004; complete cures (Yildiz and Doganay, 2006;
Hui et al. 2003). Pulmonary nocardiosis is an Matulionyte et al. 2004).
important cause of opportunistic infections in The patient presented was severely immuno-
immunocompromised hosts and the incidence of compromised and had several predisposing
this infection is increasing (Yildiz and Doganay, factors for the invasive pulmonary infections
2006; Hui et al. 2003). It commonly presents as a encountered including: his advanced age; having
chronic debilitating illness with radiological multiple medical illnesses including bronchiecta-
manifestations resembling pulmonary tuberculosis sis; having the T-cell lymphoma treated with
or lung cancer (Yildiz and Doganay, 2006; various immunosuppressive drugs including cor-
Matulionyte et al. 2004). In immunocompromised ticosteroids; having a recent CMV infection and
hosts, a fulminant disease resembling acute bacterial having moderately severe neutropenia prior to and
pneumonia may occasionally be encountered during the latest hospitalization. We believe that

Clinical Medicine: Case Reports 2008:1 69

Al-Anazi et al

the immunosuppressive therapy administered to Herbrecht, R., Denning, D.W., Patterson, T.F., Bennet, J.E., Greene, R.E.,
Oestmann, J.-W., Kern, W.V., Marr, K.A., Ribaud, P. et al. for the
this patient, particularly alemtuzumab, contributed Invasive Fungal Infections Group of the Europian Organisation for
not only to the development of both invasive lung Research and Treatment of Cancer and the Global Aspergillus Study
infections, but also to the reactivation of CMV, Group 2002. Voriconazole versus amphotericin B for primary therapy
of invasive aspergillosis. N. Engl. Med. J., 347:408–15.
particularly as he developed neutropenia and Herbrecht, R., Natarajan-Ame, S., Letscher-Bru, V. and Canuet, M. 2004.
lymphopenia several months following this Invasive pulmonary aspergillosis. Semin. Respir. Crit. Care Med.,
immununotherapy. He presented with severe bron- 25:191–202.
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Mildenberger, P. and Thelen, M. 1999. Pneumonia in febrile neutro-
infiltration in addition to segmental consolidation penic patients and in bone marrow and blood stem-cell transplant
radiologically. As he did not have appropriate anti- recipients: use of high-resolution computed tomography.
microbial cover initially, he developed the septic J. Clin. Oncol., 17:796–805.
Hui, C.H., Au, V.W., Rowland, K., Slavorinek, J.P. and Gordon, D.L. 2003.
shock. However, the septic episode was success- Pulmonary nocardiosis revisited: experience of 35 patients at diag-
fully managed with meropenem, vancomycin in nosis. Respir. Med., 97:709–17.
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Sung, K.W., Kim, W.S. et al. 2002. Importance of open lung biopsy
Thereafter, the antimicrobial therapy was modified in the diagnosis of invasive pulmonary aspergillosis in patients with
when nocardia and aspergillus were cultured from hematologic malignancies. Am. J. Hematol., 71:75–9.
sputum and BAL fluid. Subsequently, the patient Kristan, S.S., Kern, I. and Music, E. 2002. Invasive pulmonary aspergil-
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Maertens, J. 2006. Caspofungin: an advanced treatment approach for sus-
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