Maini R, Patil KV, Rainey MG, 1De Villiers F, Ames PRJ.
Departments of Haematology & Microbiology1
Inverclyde Royal Hospital
Larkfield Road
Greenock PA16 0XN
Scotland, UK
Key words: cerebral toxoplasmosis, Waldenstrom’s disease,
SMJ 2008 53(4): 10
Abstract
A 57 year-old gentleman with Waldenstrom’s disease developed ecthyma gangrenosum, molluscum contagiosum and fatal cerebral toxoplasmosis. The emergence of these infections is discussed in the light of drug-induced immune-suppression.
Introduction
Patients with lymphoma are often in a state of immune-suppression due to the disease itself and the treatment they receive.1 We hereby describe the case of a gentleman diagnosed with Waldenstrom’s disease who developed progressive treatment related immune-suppression allowing the emergence of unusual infective manifestations the last of which was fatal.
Clinical History
A 57-year old man with Waldenstrom’s disease, long standing pancytopaenia (Hb 8.1g/dl, N 0.2 x109/l, PLT 8 x109/l) and hypogammaglobulinaemia (IgG-4.60g/l) was admitted to hospital after collapsing at home. His blood pressure was normal upon admission as well as an ECG. Power in the left lower limb was mildly decreased and his upper lip drooled slightly on the left side. Blood, urine and stool cultures were negative and CRP was within range. A lumbar puncture revealed a small number of lymphocytes (30/ml) but no organisms were identified microscopically and cultures for bacteria and fungi were negative. Negative PCR were obtained for HSV, VZV, HSV6, CMV, EBV and enterovirus. A brain CT revealed a 24 mm diameter irregular enhancing ring lesion deep in the right basal ganglia causing a slight midline shift to the left and minimal deformity of the right anterior horn (Figure 1). The left cerebral hemisphere and cerebellum appeared normal. To cover the possibility of bacterial and fungal infections the patient was started on meropenem (2g tds IV), metronidazole (500mg tds IV) and amphotericin B (50mg od IV). In the following days the patient underwent stereo-tactic brain biopsy with platelet support. Histopathology revealed toxoplasmosis and the patient was started on oral pyrimethamine (25mg/qds), sulphadiazine (1.5g/qds) and folinic acid (15mg/od) to be continued for 6 weeks. Toxoplasma serology submitted upon admission later yielded a low positive dye test of 1:250, borderline IgG activity and negative IgM. Severe left sided weakness developed post-operatively and a follow-up CT brain showed an intra-cerebral haematoma at the biopsy site. The patient was managed conservatively maintaining a platelet count above 80 x 109/L. However, three weeks into anti-toxoplasma treatment the patient deteriorated and passed away. An autopsy was not requested.
The patient was initially diagnosed with Waldenstrom’s disease in August 2000, when he presented with fatigue, night sweats, productive cough and cramps in his fingers and legs. Protein electrophoresis showed IgM kappa 32 g/l and bone marrow histology revealed a 90% lymphocytic infiltration. A CT scan of chest, abdomen and pelvis did not reveal any adenopathy or organomegaly. His symptoms subsided with 2 courses of chlorambucil (10mg od for 14 days) that was continued for a total of 13 courses when the IgM kappa reached a plateau at 19 g/l and his marrow showed around 60% clearance from the lymphocytic infiltration. In April 2003, the patient again experienced fatigue and shortness of breath on exertion. His IgM kappa had raised to 29 g/l and chlorambucil was restarted, but the patient remained symptomatic with headaches, sweats, ocular haemorrhages and anaemia (Hb 8.4 g/dl N 6.6 x 109/L, PLT 135 x 109/L). In June 2003 he was commenced on oral fludarabine (80 mg od for 5 days) for three courses covered with oral aciclovir (400mg/bd) and co-trimoxazole (960/mg three times a week) alongside six sessions of plasma exchange.
Because of persistent anaemia (Hb 8.2 g/dl) and neutropaenia (N 0.4 x 109/L) despite granulocyte colony stimulating factor (480mg/od S/C for 5 days) the patient underwent another bone marrow biopsy that showed a shift from purely lymphocytic infiltration to a 90% lympho-plasmocytic infiltration. In view of the latter combined oral fludarabine and cyclophosphamide (400mg bd PO) was commenced in early November 2003, but only one course was tolerated because of persistent pancytopaenia. In an attempt to reduce the marrow infiltration rituximab (375 mg/m2) was administered weekly for four doses but with no effect. Marrow aplasia had ensued (Hb 9.0 x 109/L, N 0.2 x 109/L, N 1.5 x 109/L, PLT 72 x 109/l) with hypogammaglobulinaemia (IgG 0.60 g/l) and the patient was started on regular platelet, red cell and intravenous immunoglobulin support.
In
January 2004 he started subcutaneous desferrioxamine as serum ferritin had risen
to 6114 mg/l.
In February 2004, he started on oral thalidomide (initially 50mg/od subsequently
titrated up to 100mg/od) and oral dexamethasone (2mg/od on alternate days). In
2004 he had an episode of bacteraemia with Streptococcus sanguis (March), one of
septicemia with Pseudomonoas aeruginosa (August) and one with Citrobacter
braakii (November): he was successfully treated with intravenous antibiotics
including meropenem, gentamicin and ertapenem. In October 2004 he developed
ecthyma gangrenosum due to the same Pseudomonas for which he received oral
ciprofloxacin (750mg/bd). In July 2005 he developed pustules (from 3mm to 1cm in
diameter) on his chest, hands and inner right thigh due to molluscum contagiosum.
Discussion
Our patient underwent a number of treatments for Waldenstrom’s disease that produced severe immune suppression. Fludarabine induces marked CD4 lymphopaenia that may last several years;(1) our patient received four courses of fludarabine between March and November 2003 and quite likely the succession of chlorambucil, fludarabine and cyclophosphamide promoted bone marrow aplasia with pancytopaenia and hypogammaglobulinaemia. Neutropaenia weakens the first line of defence against infectious agents, and the phagocytic capability of mononuclear cells was worsened by the low serum and eventually mucosal level of immunoglobulins. Rituximab induced B cell depletion by may have negatively impacted on hypo- gammaglobulinemia with blunting of primary and secondary antibody response. (2)
In addition our patient had been on low dose thalidomide for almost two years. Thalidomide prevents an inflammatory response by blocking the release of tumour necrosis factor alpha and interleukin-12.(3) Finally our patient developed iron overload despite adequate chelation. Iron is an important growth factor for bacteria and can increase the risk of infection. (4) In vitro studies demonstrated that free iron enhances the infectivity of certain micro-organisms confirmed by animal studies where excess iron converted mild infections into severe ones. (5)
Depressed
humoral or cellular immunity causes increased susceptibility to infections with Pseudomonas aeruginosa or other pathogens. (6,7) Apart
from one septic episode of Pseudomonas Aeruginosa our patient also developed ecthyma
gangrenosum in the absence of Pseudomonas Aeruginosa bacteremia. The
non-bacteraemic type of ecthyma gangrenosum is viewed as an early lesion at the
portal of entry of the bacteria evolving into septicaemia,(7,8)
whereas others suggest that this represents a transient form of bacteraemia with
seeding to the skin. (9)
Molluscum contagiosum is a benign superficial skin disease with very limited extension in the immune-competent host. In our patients the size of the lesions was similar to the “giant” (equal o greater than 15 mm) and often multiple lesions seen in patients with human immunodeficiency virus (HIV/AIDS).(10) Our patient was not tested for HIV during his illness as he lacked relevant “high risk” factors.
Cerebral
toxoplasmosis is relatively frequent in patients with acquired immune deficiency
syndrome, with or without lymphoma, (10,11) much rarer in common
variable immunodeficiency (12) and has been reported only once in
Waldenstrom’s disease. (13) The relevance of our case does not lie
much in being the second case of cerebral toxoplasmosis in Waldenstrom’s
disease rather in the unique sequential development of ecthyma gangrenosum,
molluscum contagiosum and cerebral toxoplasmosis never reported in the same
patient. Any of these infections in isolation or combination testifies to a
severe degree of disease and drug induced immune suppression. With the benefit
if retrospection we should have been aware of this risk and recalled the
aphorism “primum non nocere”.
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