Six days after return, he developed a fever of up to 40.5°C and dark-coloured watery diarrhoea with nausea and vomiting. His general practitioner suggested a viral infection and treated him with ibuprofen. The fever remained high and on the 7^th day of illness, his general condition deteriorated. On presentation at the hospital, he additionally was complaining of pain upon swallowing.

On admission, he was sleepy, but fully oriented, afebrile and pale. No signs of meningitis were found. The lungs were clear and the heart sounds normal. BP was 150/85 mmHg and the pulse rate 95/min. Blood films showed P. falciparum with a parasitaemia of 9.5%. Initial laboratory results were Hb 14.6 g/dl, WBC 8.14/nl, PLT 12/nl, CRP 162.8 mg/l (normal range < 5 mg/l), creatinine 6.09 mg/dl, urea 208 mg/dl, LDH 805 U/l, GOT 69 U/l, GPT 197 U/l. Blood culture, urine culture and serology for hepatitis A, B, C and HIV were negative. Chest x-ray and ultrasound were unremarkable except for mild hepatosplenomegaly. Pharyngitis sicca was diagnosed by the ENT consultant.

Treatment with quinine i.v. was initiated with a loading dose of 7.0 mg/kgBW and continued at a rate of 10 mg/kgBW every eight hours for four hours over 10 days. Parasitaemia decreased to 2.7% within three days and was cleared by day five. He was put on intermittent hemodialysis after developing acute renal failure. Antibiotic coverage with imipenem was started.

On day 5 of hospitalization, respiration deteriorated and the patient was intubated. The chest x-ray revealed patchy infiltrates of the upper left lobe and on bronchoscopy bronchial obstruction with viscous mucus was seen. This was cleared and in the material obtained Aspergillus fumigatus was cultured abundantly. The circulating antigens of 0.8 remained below the positive cut-off of 1.0 given by the laboratory. The anti-Aspergillus antibody titre remained below the positive cut-off of 1:160 – 1:320. Therapy with voriconazol and caspofungin was started immediately.

Falciparum malaria can lead to suppression of both humoral and cell-mediated immunity. Humoral immunity is impaired through reduced production of specific antibodies, while cell-mediated immunity is modulated by inhibition of dendritic cells, which is crucial as they initiate all adaptive and several innate immune responses, and also impairment of T cell and macrophage function plays a role [1,7,8].

Inhibition of key enzymes involved in oxidative burst by the malaria-pigment haemozoin seems to be one of the most important mechanisms contributing to the disruption of macrophage function. Both in vitro and in vivo studies showed that large proportions of resident macrophages as well as circulating monocytes and leucocytes are loaded with haemozoin and consequently lose their ability to phagocytose and kill ingested germs such as fungi [9]. Especially the latter seems to play a role in invasive fungal infection, because pulmonary macrophages are the major line of defence for Aspergillus spp., as they are eliminating spores from the lungs [10]. The central role of phagocytes in the defence of fungal infections is underlined by the following observation: In patients suffering from chronic granulomatous disease, an inherited immunodeficiency due to a NADPH oxidase defect, Aspergillus spp. is the most frequent fungal pathogen and pneumonia the major cause of death, because here phagocytes fail to generate reactive antimicrobial oxidants which impairs oxidative burst [11]. The malaria-induced inhibition of macrophages seems to appear late in the acute phase of the disease and persists for various lengths of time after recovery, as haemozoin stays in the affected macrophages for several months [10]. While haemozoin induces functional inhibition of macrophages, the availability of macrophages at the site of infection (in the case presented the lung) is questionable, as during malaria infection macrophages in the blood are likely concentrated where parasitized red blood cells are concentrated. These organs include spleen, liver and bone marrow, but not the lung.

In the case presented, as in the four other published cases, inhibition of macrophages leading to aspergillosis was most likely malaria-associated as no other cause was found. Other mechanisms such as inhibition of humoral and antigen-specific T-cells response are unlikely to be a strong factor for malaria-induced immunosuppression in the acute phase of the disease in a patient without prior malaria infection or semi-immunity. Prolonged and profound neutropenia, the single most important and common risk factor for invasive aspergillosis, was neither present in this case nor in the patients published.

In contrast to the previously described fatal cases, no other malaria-related complication such as cerebral malaria or ARDS was seen in this case, but in two of the other published cases. The patient responded quickly to malaria treatment with rapid clearance of parasites. Invasive aspergillosis became clinically apparent only after malaria parasites had been eradicated and after the patient had started to improve already which is not surprising, as it is known that malaria-induced immunosuppression occurs late in the acute phase of the disease. Whether the initial presentation of pain upon swallowing was already related to the beginning of the Aspergillus infection is not clear. The Aspergillus antigen detection with a magnitude below 1.0 was interpreted as negative despite extensive Aspergillus growth in the culture. However, in many settings now a positive cut-off of 0.5 is used, therefore the maximal antigen magnitude of 0.8, which was measured after the positive culture result, would meet the criteria for a positive result. There are also several studies which showed that galactomannan ELISA is not as sensitive in invasive aspergillosis as anticipated [12]. The negative anti-Aspergillus antibody titre could be an additional marker for severely impaired immune response to Aspergillus due to malaria-induced immunosuppression.

Voriconazole is a triazol antifungal that is considered first-line-treatment for invasive aspergillosis [13]. Because of the progressive and life-threatening course of the disease, caspofungin, which belongs to the echinocandins, a new class of anti-fungals, was administered additionally. Early recognition and immediate treatment with two potent anti-fungals may have been the key to successful treatment of invasive aspergillosis and the first described survival of a patient.