Every Nook and Cranny

Scrub typhus is a mite-borne tropical infection caused by the gram-negative intracellular parasite Orientia tsutsugamushi from the Rickettsiaceae family that is known to occur in certain parts of Asia and Australia. Although this entity is well known in the Sub Himalayan belt and southern part of India, very few cases have been described in Delhi, the capital state in North India. Scrub typhus, like most other tropical infections, is found most often during the postmonsoon season.^1,2

Patients with scrub typhus present with fever in addition to a variety of nonspecific symptoms and findings. These often manifest within 10 days of being bitten by a mite. Malaise, headache, myalgias, lymphadenopathy, and maculopapular or petechial rash are common. If present, the rash manifests on the 3^rd to 5^th day of fever.³ Disseminated vasculitis due to scrub typhus can frequently result in multiorgan system involvement. Pulmonary involvement often leads to acute respiratory distress syndrome (ARDS) with an incidence of 8%-10%.^1,4 Acute kidney injury, mostly mild and nonoliguric, has been reported in up to 2/3 cases.^4-6 The cardiac myocyte is a known target cell affected by scrub typhus, and therefore patients commonly present with myocarditis.⁷ Liver involvement in scrub typhus is evident through elevated liver enzymes and can occur without other clinical evidence of the illness.^4,6,8,9 As in dengue, patients often develop thrombocytopenia, but normal hemoglobin in scrub typhus differentiates it from dengue.^6,8

Given the nonspecific presentation, it can be challenging to diagnose and treat scrub typhus. The gold standard for diagnosis is the detection of IgM antibodies to Orientia tsutsugamushi using an indirect immunofluorescence assay (IFA). For patients from endemic regions, it may be necessary to show a four-fold increase in titers two weeks apart to distinguish from background immunity. Presence of the characteristic eschar, as discussed below, is highly suggestive of scrub typhus. The treatment of choice is doxycycline or azithromycin for seven days.^10,11 Early initiation of doxycycline when considering either scrub typhus or leptospirosis is appropriate and may be life-saving.

Medical decision making is fraught with uncertainty, and physicians must use their experience, evidence base, and cognitive heuristics wisely to care for patients effectively. For this patient, the region of Delhi experiences massive outbreaks of dengue every year during the time the patient presented to the hospital, whereas rickettsia infections are relatively uncommon. The clinical presentation was conceivably consistent with either dengue or scrub typhus, though somewhat more suggestive of the latter. Once the serological diagnosis of recent or concomitant dengue was obtained, however, scrub typhus was considered even less. The team called upon Occam’s razor or the heuristic that the simplest and most unifying explanation for any given problem is the one most likely to be correct and that other, less satisfactory explanations (in this case, scrub typhus) are “shaven off.” The patient was managed conservatively for dengue. Only when his condition worsened did the team recognize this conflicting information without dismissing it, consider alternative possibilities, and reexamined the patient.

An eschar can be an important clue in the diagnosis of scrub typhus, though it is not often obvious. The presence of this necrotic skin lesion with black crust is highly suggestive of scrub typhus, and in the right clinical context, it is virtually diagnostic. However, it is uncommon (9.5%-45%) in most of the studies from the Indian subcontinent (ie, high specificity but low sensitivity).^1,12 An eschar is often found in obscure locations such as the axillae or groin, areas that may easily be missed or overlooked. Eschars may be seen in a variety of other infectious diseases, including rickettsia pox, Rocky Mountain spotted fever, other members of the spotted fever group, tularemia, and cutaneous anthrax. Given this patient’s lack of improvement, repeated examination revealed an eschar in the right axilla, a finding that was either missed or still evolving at the time of presentation.

This case illustrates the challenges in interpreting the significance of multiple positive serological tests in the context of an undifferentiated clinical syndrome. Possible reasons for a positive dengue serology could have been persistent antibodies from a previous infection, recent asymptomatic infection, concurrent infection, or cross-reactivity with flaviviruses such as West Nile Virus or Japanese Encephalitis.¹³ The patient also had positive IgM antibodies against Legionella pneumophila, but the urinary antigen was negative. In view of a negative antigen test, low specificity of the serologic test, low incidence of legionellosis in the Indian subcontinent, and absence of therapeutic response to a trial of fluoroquinolones, the diagnosis of legionellosis was considered unlikely in this patient.

With rapid advancements in technology, the importance of history taking and physical examination is at risk of being overshadowed. Approximately 80% of correct diagnoses in medicine can arrive through history and physical examination alone.^14,15 In this case, Occam’s razor combined with multiple serological tests was relied on to create the likely list of diagnoses. However, recognition of the limitations of these heuristics and tests proved critical. The life-saving diagnosis was only made when the clinicians returned to basics, looked in every nook and cranny, and found the eschar on physical examination.