INTRODUCTION

Legionella pneumophila, a Gram-negative intracellular aerobic bacillus, can cause a wide spectrum of clinical manifestations, ranging from a mild flu-like illness (Pontiac fever) to fulminant multi-organ involvement (Legionnaires disease), characterised by severe pneumonia, diarrhoea, encephalopathy, shock, hepatic dysfunction and renal failure^[1,2].

It was first described in 1977 and is known to cause both community-acquired and nosocomial infections^[3]. It has been estimated that between 2 and 15% of community-acquired Legionella infections result in hospitalisation^[4]. Immunosuppression and exposure to contaminated water storage and distribution systems are major risk factors for developing Legionellosis^[3].

Very rarely, it has been associated with different haematologic conditions, resulting in thrombocytopenia and severe bleeding diathesis, including thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) and immune thrombocytopenic purpura (ITP).

We report a rare case of L. pneumophila causing ITP, which resolved with treatment of the underlying infection and systemic steroids. We also review previously published cases of thrombocytopenia associated with L. pneumophila in the literature.

CASE DESCRIPTION

A 53-year-old male had a history of active tobacco and marijuana smoking as well as remote exposure to tuberculosis several decades ago, for which he completed six months of isoniazid. He presented to an outside hospital with three days of fevers, chills and productive cough associated with nausea and vomiting. His vitals revealed a temperature of 38°C, heart rate 107/min, blood pressure 121/82 mmHg, respiratory rate 24/min and oxygen saturation 96% on room air. A computed tomography (CT) angiogram showed no pulmonary embolism but demonstrated a left lower lobe consolidation consistent with pneumonia (Fig. 1). A complete blood count showed a white blood cell count of 15,000/ µl, neutrophilia 88%, bandemia 6%, haemoglobin 13.7 g/dl and a platelet count of 21,000/µl. Chemistry showed hyponatraemia with serum sodium 129 mEq/l, blood urea nitrogen 14 mg/dl, serum creatinine 0.8 mg/dl and total bilirubin of 0.8 mg /dl. Liver function tests, lactate dehydrogenase (LDH) and haptoglobin were noted to be within normal limits. Virology work-up was negative for influenza A/B, respiratory syncytial virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on polymerase chain reaction testing. Blood, sputum and urine cultures were negative. Urine antigen testing detected L. pneumophila serotype 1 antigen; broad spectrum antibiotics were switched to azithromycin. The patient was discharged home to complete a course of oral azithromycin.

The following day, he presented again to the same outside hospital reporting six episodes of large-volume haemoptysis, which led to readmission. A repeat complete blood count showed a white blood cell count of 7,800/µl, haemoglobin 13 g/dl and a worsened platelet count of 9,000/µl. Due to severe thrombocytopenia in combination with life-threatening haemoptysis, he was transferred to our hospital for haematology consultation. A peripheral blood smear showed severe thrombocytopenia with giant platelets consistent with ITP (Fig. 2). Human immunodeficiency virus (HIV) 1/2, hepatitis B and C serology were negative. Serum vitamin B12 and folate were within normal limits. He was started on intravenous immunoglobin 1 g/kg and prednisone 60 mg daily for symptomatic ITP. His platelet count normalised to 204,000/µl on day four of therapy, with resolution of haemoptysis. After discharge, he completed a full ten-day course of azithromycin and continued to follow up with haematology for tapering of prednisone. He had a repeat CT chest four weeks after discharge, which showed resolution of left lobe pneumonia (Fig. 3).

DISCUSSION

We performed a comprehensive literature search on PubMed with keywords ‘Legionella pneumophila' and ‘thrombocytopenia'. We screened the results by reviewing the abstract and the full manuscript to identify relevant articles which met our criteria. We retrieved seven articles and extracted data on eight patients. We cross-checked the references of the selected articles to identify any additional articles which met our criteria. We have summarised the clinical details of all patients with L. pneumophila and thrombocytopenia, including our own patient, in Table 1.

Of all the patients included in our literature review, one other patient had ITP, two had TTP, one had HUS, three had thrombocytopenia with acute renal failure and one had thrombocytopenia of unclear aetiology. Six patients had identifiable risk factors for contracting L. pneumophila, which included significant smoking, solid organ transplant, exposure to contaminated water or travel to an area with known outbreaks of L. pneumophila. Diagnostic work-up for L. pneumophila included urine antigen testing and direct/indirect immunofluorescent assay for antibodies or culture. One patient had a negative urine antigen but a positive immunofluorescent assay for antibodies against L. pneumophila. This could be because the urine antigen test is specific for L. pneumophila serotype 1 only, while most outbreaks of Legionnaires disease in the community are attributed to other serotypes^[5]. All patients received treatment with either fluoroquinolone or macrolide. Treatment for thrombocytopenia varied based on the associated haematologic disease; two patients had a negative outcome despite treatment.

ITP is characterised by immune-mediated destruction of platelets. It is a diagnosis of exclusion but certain infections, medications, pregnancy and immune disorders have been associated with this condition^[1]. Among infections, HIV, cytomegalovirus, streptococcus, mycoplasma, brucella, varicella zoster virus and Helicobacter pylori are the usual triggers^[1,5]. Corticosteroids and intravenous immunoglobin are the standard initial therapy for patients with ITP who experience severe bleeding. L. pneumophila can activate the complement cascade by binding to the C1q component independently^[6]. Platelets express C1q receptor on their surface; interaction between immune complexes containing C1q and the receptor result in platelet activation, aggregation and consumption, leading to thrombocytopenia^[6].

TTP and HUS are thought to be a continuum of the same disease process. It occurs due to a deficiency of the von Willebrand factor (vWF)-cleaving protease ADAMTS13, which leads to formation of large vWF multimers^[5]. These multimers are not easily degraded: they bind to platelets and damage endothelial cells, forming extensive microthrombi throughout the circulation, resulting in consumption of platelets and destruction of red cells^[5]. TTP can either be hereditary due to genetic mutations in the ADAMTS13 gene or acquired in the setting of a trigger, which over-activates the immune system^[5]. Riggs et al. demonstrated the presence of L. pneumophila in the lung tissue autopsy specimen of a patient diagnosed with TTP^[7]. Chiaraviglio et al. showed that L. pneumophila can directly infect endothelial cells causing their death, and stimulate the release of vWF multimers into the bloodstream^[4]. It is hypothesised that antibodies against L. pneumophila cross-react and target ADAMTS13, inhibiting its function, resulting in an acquired form of TTP^[5]. Regardless of the aetiology, TTP is treated with steroids and plasmapheresis, which removes auto-antibodies as well as large vWF multimers from the circulation.

CONCLUSION

L. pneumophila is a rare cause of acute thrombocytopenia. It has been associated with life-threatening haematologic diseases such as ITP, TTP and HUS, which can result in major bleeding as well as thrombosis. It is important for internists to consider L. pneumophila in the differential for any patient presenting with pneumonia and severe thrombocytopenia. History of significant smoking, immunosuppression, exposure to contaminated water or travel to an area with known outbreaks of L. pneumophila are major risk factors for developing Legionellosis. Earlier detection and intervention can lead to prevention of critical bleeding and better outcomes.