in february 2012 , a previously healthy 40-year - old man visited the academic medical center outpatient department , reporting fever , headache , sweating , and nausea .
the signs and symptoms had started 1 day earlier , on the day of his return from a 1-month holiday in borneo . he reported frequent insect bites and exposure to fresh water .
he had taken malaria chemoprophylaxis as recommended , and his vaccinations were up to date .
physical examination indicated that he was afebrile , was hemodynamically stable , and had a discrete macular rash on the trunk but no eschar .
laboratory results showed a hemoglobin concentration ( 16.8 g / dl ) within reference range , a leukocyte count of 4,700 cells / mm with lymphopenia ( 1,090 cells / mm ) , and thrombocytopenia ( 116,000 cells / mm ) .
c - reactive protein ( 42 mg / l ) and serum creatinine ( 1.32 mg / dl ) concentrations were moderately elevated .
a thick smear showed no plasmodia , and a dengue antigen test result was negative . by the next day
, the patient s condition had deteriorated ; he was experiencing chills , his temperature was 39c , and the rash had become more pronounced .
he was admitted to the hospital and given doxycycline ( 200 mg twice a day ) for suspected rickettsiosis or leptospirosis . after admission ,
his condition deteriorated further ; increasing dyspnea progressed to respiratory failure , necessitating intubation and admission to the intensive care unit on the second day after admission .
chest radiograph of 40-year - old man with acute respiratory distress syndrome as a complication of murine typhus . on the fourth day of intubation ,
cultured blood , urine , and bronchial fluid remained sterile , and test results for leptospira , legionella , influenza virus , and hiv were negative . all antimicrobial drugs except doxycycline were discontinued ; doxycycline was continued for a total of 14 days .
serum collected 1 day after admission showed weakly positive igg against r. typhi ; after 7 days , the immunofluorescent antibody titer had increased 4-fold ( from 1:64 to > 1:256 ) .
the patient recovered completely and was doing well at his last follow - up visit . to determine prevalence of such cases
, we conducted a search of published studies mentioning pulmonary manifestations of murine typhus ( details in the technical appendix ) . from 779 records
, we selected 22 cohort studies and 18 case studies that , according to title and abstract , were relevant to our research question .
we differentiated between studies with individual patient data ( case reports and case series ) and studies without individual patient data ( cohort studies ) .
for each study , we recorded year of publication , study design , and country of infection .
we also recorded the presence of pulmonary involvement , defined as cough and any mention of an abnormal finding on chest radiograph , without further distinction .
an overview of study characteristics detailing prevalence of cough and chest radiograph abnormalities is provided in the technical appendix table 1 .
two studies were prospective population - based studies of the causative agent of fever of unknown origin .
specific ; in 17 of these studies , patients had been recruited retrospectively from hospital databases or chart reviews .
the 22 study reports that contained data on the presence or absence of cough together accounted for 1,060 patients with murine typhus .
mean prevalence ( all patients from all studies combined ) of cough was 30.1% ( 95% ci 23.336.9 ) .
data on presence or absence of radiographic abnormalities were mentioned in 9 study reports ( 412 ) . taken together
, these studies evaluated 621 patients and 104 chest radiographs showing abnormalities , leading to a prevalence rate of chest radiograph abnormalities of 16.7% ( 95% ci 8.2125.5 ) .
pulmonary manifestations were also documented by the case studies . among these studies , 2 patients had ards , 7 had bilateral pulmonary infiltrates , 5 had unilateral pulmonary infiltrates , 1 had pulmonary embolism , and 1 had respiratory failure ( no chest radiograph was reported ) ( technical appendix table 2 ) .
we also found that cough occurred more commonly among patients in studies conducted in asia ( 99 [ 38.2% ] of 259 patients ) than among those in studies conducted in the mediterranean region ( 118 [ 25.8% ] of 457 ) and north america ( 56 [ 23.3% ] of 240 ) . in the literature
, we found 7 reported cases of respiratory distress associated with murine typhus ( including the case reported here ) , 2 of which described respiratory distress not classified as ards ( 2,13 ) .
of these 7 case - patients with ards / respiratory distress , 5 ( 71% ) patients were from asia ( 2,3,11,13 ) , 1 was from the mediterranean region ( 4 ) , and 1 was from the united states ( 14 ) .
cough and chest radiograph abnormalities were frequent manifestations of murine typhus . for cough associated with murine typhus , we found a prevalence rate of 30% .
the prevalence of chest radiograph abnormalities was more difficult to ascertain because this result was less often reported and more influenced by bias .
the pulmonary aspects of r. typhi infection are probably the result of damaged pulmonary microcirculation , leading to pulmonary edema .
the case reported here is unusual in that the symptoms progressed rapidly and the response to doxycycline was relatively slow .
it is worth noting that we found no more than 2 reported cases of fatal murine typhus associated with pulmonary system disease ; both were the result of severe disease complicated by ards .
most cases of severe murine typhus with pulmonary manifestations originated in asia , and cough was more frequently a symptom among patients in asia .
the primary strength of our study is the extensive literature search , which covered studies from different parts of the world and included cohort studies and case series .
the main limitation of this study is the retrospective nature of the data collection for most studies , which is prone to bias and renders meaningful statistical analysis of results impossible .
therefore , prospective studies evaluating pulmonary manifestations of murine typhus and possible geographic variation are needed .
although murine typhus usually follows a benign course , severe disease with pulmonary manifestations , including ards , can occur , as described for the patient reported here .
we suggest that murine typhus should be included in the differential diagnosis for any patient who has a fever and respiratory signs and who has been in a typhus - endemic area within the incubation period .
flowchart of study selection for review , table of cohort studies of murine typhus , and table of case studies detailing chest radiograph abnormalities .
 we encountered a case of severe murine typhus complicated by acute respiratory distress syndrome . to determine worldwide prevalence of such cases 
 , we reviewed the literature and found that respiratory symptoms occur in 30% of murine typhus patients . in disease - endemic areas , 
 murine typhus should be considered for patients with respiratory symptoms and fever . 