1 Medical Clinic I, Community Hospital, Offenbach, 2 Department of Medical Zoology, Central Institute of the Federal Armed Forces Medical Service, Koblenz, Germany
Introduction
Worldwide there is increasing concern among national and international health organizations over the escalating risk of resurgent vector-borne diseases such as malaria and dengue fever. With respect to malaria, it is estimated that 2300 million people (41% of the worlds population) in more than 100 countries or territories are currently at risk. The global incidence of malaria is believed to be between 300 and 500 million clinical cases per year, with 1.5 to 2.7 million deaths [1]. This translates into one malaria death every 15 to 30 s. Sub-Saharan Africa accounts for more than 90% of total malaria incidence, and most deaths.
In recent years there has been a dramatic increase in international air transport of both passengers and freight. From Germany alone, more than 4.1 million people depart for tropical areas annually [2]. According to monitoring studies conducted during the last two decades, vector insects are frequently found in aircraft arriving at international airports, increasing the likelihood that vector-borne diseases may be spread in this manner [3].
In Germany, the annual influx of persons testing positive for malaria rose substantially during the 1980s and 1990s, peaking at more than 1000 cases in 1996 [4,5]. Though this disease is usually contracted in the tropics from the bites of infected female Anopheles mosquitoes, it can also be transmitted via blood transfusions, bone-marrow transplants, needle-stick injuries, and increasingly by the introduction of infected vectors on aircraft [6]. The last-named route is called airport malaria, first reported in Europe in 1977 [7]. To date, 63 defined cases of airport malaria were reported in Western Europe until 1997 [8].
Among the species of malaria parasites that are regularly imported into Europe, Plasmodium falciparum is increasing in frequency, especially in Germany. Assuming that reported case fatality rates (CFRs) apply only to falciparum malaria, those in Europe have ranged from 0 to 3.6% between 1985 and 1995 [5]. Between 1990 and 1997, the German CFR for falciparum malaria was 3.4±0.9%. During this period, significantly lower CFRs were reported from France (0.46±0.1%) and the United Kingdom (0.75±0.29%) [4,5]. Currently, no CFRs are available for malaria cases acquired autochthonously in Western Europe.
Because falciparum malaria is a life-threatening disease, often associated with organ damage or failure, prompt diagnosis and treatment are essential. We observed a case of falciparum malaria marked by severe renal failure. We have arguments that it represents a novel form of airport malaria and we propose the term baggage malaria.
Case history and clinical outcome, with special attention to renal failure
In December 1997, a 67-year-old female patient was admitted to a regional hospital in Darmstadt County, Germany, suffering from lacunar infarction characterized by reversible paresis of her right forearm. One week later, seemingly recovered, she was discharged. The following week, she experienced high fever (40°C) with sudden onset, and was admitted 2 days later to the community hospital at Offenbach.
The patient initially appeared to be in overall good health (height 1.64 m; weight 72 kg). She was normothermic (37.2°C) and normotonic (110/70 mmHg), with a pulse rate of 90 per min. No cranial nerve paralysis, arm or leg paralysis, symptoms of meningitis, or disorientation were detectable. She appeared exsiccated, but otherwise the differential diagnosis leading to her hospitalization was unclear.
Laboratory tests revealed a leukocyte count of 5.4/nl, a thrombocyte count of 45/nl, and a haemoglobin concentration of 13.7 g/dl. Erythrocytes were normochromic and normocytic. Normal values were obtained for plasmatic coagulation, as well as for serum protein, albumin, urea, creatinine, calcium, glucose, alkaline phosphatase, creatinine kinase, amylase, and lipase. Urinalysis was inconspicuous. Significantly increased values were observed for C-reactive protein (CRP) (111 mg/l), serum glutamine-oxaloacetic transaminase (GOT) (25 U/l), glutamate-pyruvate transaminase (GPT) (36 U/l), gamma-glutamyl transpeptidase (-GT) (44 U/l), lactate dehydrogenase (LDH) (336 U/l), and serum bilirubin (3.1 mg/dl). Thoracic X-ray, sonography of the upper abdomen, and electrocardiogram revealed no pathologies.
At first, the attending hospital physician suspected that the patients recurrent fever and elevated CRP were manifestations of a biliary infection (a diagnosis of pneumonia proffered by the family doctor was rejected). The patient was initially treated with antibiotics (mezlocillin combined with metronidazole) and received fluid therapy. Blood culture showed no bacteraemia.
On the 3rd day after admittance, three recurrent fever peaks were observed, spiking to 40.2°C, which precipitated a second clinical examination to discover the cause of this fever of unknown origin. Additional sonography, thoracic X-ray, bone-marrow cytology, and bone-marrow histology again revealed no pathology. However, counts of leukocytes and thrombocytes decreased steadily to 3.3/nl and 15/nl respectively. A haemogram showed 25% stab cell neutrophils, 66% segmented neutrophils, 5% lymphocytes, and 4% monocytes.
During febrile maxima, the patient suffered from borderline impaired consciousness. Though continuing intravenous fluid substitution was provided at a normal serum creatinine level, the urine production rate decreased to 800 ml per 24 h. Subsequently, clinical signs revealed a sepsis syndrome of unknown origin, with incipient disseminated intravascular coagulation and concomitant haemolysis. Antibiotic treatment was extended by administering gentamicin and vancomycin.
On the 6th day, the patient's prothrombin ratio (international normalized ratio) and antithrombin III dropped to 62 and 57% respectively. The activated partial thromboplastin time increased to 45 s, and the concentration of haemoglobin decreased from 13.7 to 9.6 g/dl. The reticulocyte count was 14%, and the patient's haptoglobin was 0.83 g/l. Helmet cells could now be detected in the blood smear. Urea and creatinine levels remained normal. The recurrent fever peaked at 40.6°C. Under a hypothesis of severe disseminating bacterial infection, the antibacterial regimen was extended to seven intravenously administered antibiotics, including doxycycline.
Since a microangiopathic-haemolytic anaemia was suspected, several blood components were substituted (6 erythrocyte concentrates, 16 thrombocyte concentrates, 6 units of fresh frozen plasma, 300 ml 7s-immunoglobulins (Pentaglobin®), and 5500 IU antithrombin III). At day 7, the high recurrent fever decreased rapidly to 36.3°C, but the as yet unknown disease was producing a progressive acute respiratory distress syndrome, associated with increasing oliguria, requiring continuous venovenous haemodialysis beginning at day 10. Moreover, intubation with controlled ventilation was necessary because of severe gas exchange disorder (pO2<55 mmHg) and alveolar hypoventilation (pCO2 82 mmHg).
On the 9th day of treatment, concurrent with initiation of artificial respiration, a diagnosis of falciparum malaria was made by positive blood smear, revealing a parasitaemia of 10%. All forms of microgametocytes and macrogametocytes were detectable in the peripheral blood. Retrospectively, malaria parasites could also be detected in the bone marrow sample obtained on the 3rd day.
The disease was treated with 1250 mg mefloquin (3 doses Lariam® per day, administered by stomach tube), quinine (8 mg/kg body weight per day, administered intravenously for 8 days), and doxycycline (2x100 mg per day, administered intravenously for 6 days). Three days after specific treatment, the parasite index decreased to less than 1%.
Although the antimalaria therapy was successful, multi-organ failure appeared with severe capillary leakage syndrome, which persisted for several weeks. Overall, 33 bronchoscopic lavages were performed because of severe fibrinous haemorrhagic tracheobronchitis. During the initial period, continuous haemodialysis was required. Subsequently, intermittent haemodialysis was administered three times per week for more than 100 days. Despite complete restitution of urinary flow, severe renal tubular acidosis occurred repeatedly towards the end of the haemodialysis regimen. Renal bicarbonate excretion normalized automatically.
Further complications included a perforated ulcus duodeni and an exudative pancreatitis in the presence of cholecystolithiasis. Surgical therapy comprised gastric resection (Billroth's operation II), cholecystectomy, and choledochus revision. Additionally, decompensation of an autonomous thyroid adenoma occurred during the 5th month of treatment.
After 160 days of hospitalization, 135 of them in an intensive care unit, the symptom-free but visibly weakened patient was released for rehabilitative therapy. One year later, she appeared to be in good health, without sequelae.
Epidemiology of autochthonous and airport malaria in Germany
Since the patient had neither travelled to falciparum-endemic areas nor visited international airports, and with iatrogenic transmission excluded, an epidemiological analysis was conducted to determine the route of infection. We developed three plausible scenarios.
First, the patient might have been infected by imported Anopheles species or by autochthonous vectors. However, the months of November and December 1997 were exceptionally cold, so survival of vector-competent tropical or subtropical anophelines can safely be excluded in this case. Additionally, the two principal malaria vectors in Germany, Anopheles messae and An. atroparvus, which were involved in the 194651 Berlin vivax epidemic [9], are only susceptible to P. falciparum when daily temperatures are 18°C for
6 weeks. These conditions did not prevail in Germany during the summer of 1997, effectively excluding the possibility that falciparum sporozoites could have matured in native anophelines.
Second, it is possible that an infected exotic Anopheles was transported in the wheel bays of a foreign aircraft and released when the bays were opened during the approach to landing. Significantly, the patients home is located in the approach corridor of Frankfurt Airport. Landing planes open their wheel bays at heights between 500 and 1000 m. We know that mosquitoes and other vectors can survive travel in wheel bays of a Boeing 747B for at least 9 h with external temperatures between -42°C and -54°C [3], but no information is available on the survival of mosquitoes emerging from wheel bays under landing conditions. Nevertheless, in the winter of 1997, any tropical or subtropical mosquito entering the Darmstadt area by this means would have been immediately immobilized because the average daily temperature during this period was well below 0°C.
The third and most likely scenario involves baggage malaria, the importation of an infected mosquito in luggage arriving from a malarious area. Further investigations revealed that at the time of our patient's first hospital admission, another patient suffering from falciparum malaria was being treated in a neighbouring ward of the same institution. This individual had been admitted shortly after he returned from a trip to Kenya. At no point during his journey had he undergone chemoprophylaxis against malaria, nor had his aircraft been subjected to disinfection. Obviously, this person had not brought his travel luggage with him to the hospital, but infected mosquitoes escaping from his belongings in Darmstadt may well have found their way to our victim.
Conclusions
The severity of the above case compels us to make two recommendations. First, given the increasing incidence of airport or baggage malaria, this disease should always be considered in the differential diagnosis of patients presenting with severe recurrent fever of unknown origin coupled with microangiopathic haemolytic anaemia and renal or other organ failure, even though these individuals may not have travelled to malaria-endemic areas. Second, the minimally toxic but effective aircraft disinfection procedures recommended by the World Health Organization and practiced by over 80 countries worldwide should at once be implemented to reduce the transportation and spread of disease vectors.
Notes
Correspondence and offprint requests to: Dr Michael Faulde, Central Institute of the Armed Forces Medical Service, Department of Medical Zoology, PO Box 7340, D-56065 Koblenz, Germany.
References