Digital Gangrene Associated with Scrub Typhus: A Case Series

ABSTRACT.

Rickettsial diseases cover a broad spectrum of illnesses. Scrub typhus is present worldwide, and Orientia tsutsugamushi is the causative agent of this chigger mite–borne infectious illness. Infections exhibit a range of severity, from mild illness to the more severe manifestation of multiorgan failure. We report three cases of scrub fever (55-year-old female, 63-year-old female, and 29-year-old male), all cases developed focal or pan-digital gangrene. All cases were successfully treated by administering doxycycline and additional supportive measures. Digital gangrene is uncommon in scrub typhus. Clinical suspension for early diagnosis and appropriate treatment may avoid further complications.

INTRODUCTION

Scrub typhus is present worldwide, with the earliest reports being from the Tsutsugamushi Triangle, which includes Pakistan to the northwest, Japan to the northeast, and northern Australia to the south.^1,2 Historically, Scrub typhus was first described in China (313 ad) by Hong Ge in a clinical handbook (Zhouhofang) and in Japan (1810 ad) by Hakuju Hashimoto, who described tsutsuga, a destructive disease, in Niigata prefecture.² A systematic review of 140 articles published during 2010–2020 in India found 15.3% cases of scrub typhus. In India, the proportion of cases varied by region: south (55.5%), north (31.5%), northeast (7.4%), east (4.5%), and west (1.1%). The states with the most cases were Tamil Nadu (37.6%), Himachal Pradesh (11%), Karnataka (8.8%), Uttrakhand (8.5%), and Uttar Pradesh (6%).³

A Gram-negative obligate intracellular bacterium called Orientia (formerly Rickettsia) tsutsugamushi causes scrub typhus, commonly known as tsutsugamushi illness or Bush typhus. It is one of the most widespread zoonotic illnesses transmitted to humans by infected Chigger (larval mite) bites (an arthropodvector of the Trombiculidae family). Tsutsugamushi is a combination of two Japanese terms. Tsutsuga means “small and dangerous,” and mushi is an insect or mite (chiggar). The mite can act as both the reservoir and the vector.^1,4

Scrub typhus affects people of all ages, and most cases occur in rural areas, especially in India, China, Korea, Pakistan, Taiwan, Japan, Thailand, Malaysia, and northern Australia.⁴ Most cases of the disease occur during the monsoon and post-monsoon seasons (July and November) and are associated with a significant mortality rate.⁵ Active rice fields are a significant reservoir for transmission, and thus scrub typhus is frequently acquired during occupational or agricultural exposures.^6,7

Fever, headache, myalgia, coughing, and digestive symptoms mark the onset of the disease after an incubation period of 6 to 21 days. A maculopapular rash, localized lymphadenopathy, and eschar where the chigger fed are characteristics of the typical case; these symptoms are seldom seen. In severe cases, vascular damage frequently results in encephalitis and interstitial pneumonia. For untreated classic cases, the case fatality rate was reported to be up to 6%.⁸ Scrub typhus can cause focal or disseminated vasculitis or perivasculitis of digital blood vessels, resulting in focal or pan-digital gangrene.¹ Digital gangrene is rarely reported in scrub typhus. This case report highlights the occurrence of gangrene in scrub fever in the acute phase and the significance of prompt, suitable treatment.

CASE REPORT

Case 1.

A 55-year-old, otherwise healthy female was referred to our hospital in August 2022 with a history of fever and myalgias of 7-day duration, shortness of breath with dry cough for 3 days, and altered sensorium for 1 day. She was a resident of a rural area of Uttar Pradesh, India. On admission to the intensive care unit, clinical examination revealed a pulse rate of 102 bpm, blood pressure (BP) 102/70 mm Hg, respiratory rate (RR) 28 breaths/min, temperature 101°F (38.33°C), pallor, and icterus. Systemic examination revealed mild hepatomegaly and minimal crepitations in bilateral lungs. She had minimal pitting edema of all the limbs and blackish discoloration of the digits of the upper limb and lower limbs except for both thumbs (Figure 1A). All peripheral pulses were normal. Blood was sent for relevant investigations, as summarized in Table 1. On the basis of clinical evaluation of severe sepsis, broad-spectrum antibiotics and other supportive therapy, including intermittent nebulization, were initiated. Chest x-ray posterior–anterior view (CXR) showed bilateral infiltrates. Ultrasonography of the abdomen, urinal analysis, and electrocardiogram (ECG) were normal. Doppler study of the upper and lower limb showed subcutaneous edema and normal study for arteries and veins. Injection of low molecular weight heparin (LMWX) was started as per renal dosage adjustment. On the second day of admission, after a positive serology of scrub, parenteral doxycycline was added to the primary therapy. She gradually improved, with normal renal and hepatic function, and was discharged in stable condition on day 13. She was prescribed aspirin and cilostazol for the next 10 days. On follow-up, the vascular surgeon amputated the remaining necrosed part of the third, fourth, and fifth right-hand fingers over the next 4 to 5 months (Figure 1B and C).

Figure 1.

(A and B) Gangrene of all digits of both upper and lower extremities except both thumbs, (C) status after three months of follow up, and (D) status after 5 months of follow-up.

Table 1.

Relevant clinical and investigational characteristics of patients

Parameters on day of admission	Normal range	Case 1	Case 2	Case 3
Comorbidity	–	None	Hypertension	None
Eschars	–	No	No	Yes
Lymphadenopathy	No	No	No	Present
Splenomegaly	Normal size	No	No	No
Hepatomegaly	Normal size	Yes	Yes	Yes
Hemoglobin (g/L)	13–17	12.1	11.5	13.2
Total leukocyte count (per liter)	4.0–11.0 × 109	20,902	14,500	16,200
Platelet count (per liter)	150–400 × 109	74	132	102
T. Bill (D) (mg/dL)	<1.0	4.6 (2.6)	2.8 (1.8)	2.9 (1.9)
S. ALT (U/L)	<45	356	187	294
S. AST (U/L)	15–37	292	119	211
S. ALP (U/L)	30–120	596	201	198
Serum albumin (g/L)	3.4–5.0	2.9	3.1	4.2
Serum sodium (mEq/L)	136–145	137	132	142
Serum potassium (mEq/L)	2.6–4.5	3.9	3.2	4.1
Blood urea (mg/dL)	18–55	104	58	74
Serum creatinine (mg/dL)	<1.2	2.3	1.9	1.7
Random blood sugar (mg/dL)	70–140	102	132	110
Malaria (smear and Ag)	Negative	Negative	Negative	Negative
Dengue serology	Negative	Negative	Negative	Negative
Leptospira serology	Negative	Negative	Negative	Negative
Autoimmune panel	Negative	Negative	Negative	Negative
Viral markers (HBsAg, HCV, HIV)	Not reactive	Not reactive	Not reactive	Not reactive
Blood and urine culture	Sterile	Sterile	Sterile	Sterile
Thyroid profile	Normal	Normal	Normal	Normal
Lipid profile	Normal	Normal	Normal	Not done
Outcome	–	Successful	Successful	Successful

HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; S. ALT = serum alanine aminotransferase; S. ALP = serum alkaline phosphatase; S. AST = serum aspartate aminotransferase; T. Bill (D) = total bilirubin (direct).

Case 2.

A 63-year-old female, recently diagnosed with hypertension, presented with fever, body ache, dry cough for 6 days, and blackish discoloration of the left great toe and second and third toes (Figure 2). The patient was from a rural area of Bihar, India. Her physical examination revealed a pulse rate of 100 bpm, BP 130/72 mm Hg, RR 20/min, and temperature of 100.1°F (37.83°C). She had mild pallor and icterus and mild hepatomegaly. Bilateral lung auscultation revealed occasional crepitations. Her BP was controlled on amlodipine 5 mg once a day. She had no addiction or any significant previous history. All peripheral pulses were normal. Her relevant investigations are summarized in Table 1. Her CXR, ECG, abdominal ultrasonography, and color Doppler study of both legs were normal. Investigations showed mild anemia, leukocytosis, thrombocytopenia, and hepatic and renal dysfunction. She was given ceftriaxone, LMWX, and other supportive therapy. After positive serology of scrub typhus, doxycycline was added for 1 week. She improved gradually and was discharged on the 8th day of admission.

Figure 2.

Gangrene of the first three toes of the left foot.

Case 3.

A 29-year-old male, otherwise healthy and a farmer by occupation, presented with complaints of high-grade fever associated with chills for 6 days, dry cough, and breathlessness for 3 days. He had no history of chronic drug exposure and no significant past health history. His vitals include a pulse rate of 102 bpm, BP 126/72 mm Hg, RR 22/min, and temperature of 102°F (38.89°C). All digits on both legs were blackish (Figure 3A). Peripheral pulses were palpable. He had mild pallor, icterus, palpable inguinal lymph nodes, and eschar on the tip of his nose (Figure 3B). Systemic examination revealed minimal crepitations in both lung fields and mild hepatomegaly; otherwise the examination was normal. Blood was sent for investigation (Table 1). His ECG, abdominal ultrasound, and urine analysis were normal, but his CXR revealed bilateral heterogeneous opacities. Color Doppler study of both legs for arteries and veins was normal. He was initially managed with ceftriaxone, LMWX, and other supportive treatments. After a positive serology result for scrub typhus, doxycycline was added. The patient showed a positive response, and after 3 days of therapy, the fever subsided. His liver and kidney function tests returned to normal. The patient was discharged in stable condition on day 12 with instructions to follow up and given aspirin and cilostazol for the next 7 days.

Figure 3.

(A) Gangrene of all digits of both feet. (B) Eschar on the nose tip.

DISCUSSION

Scrub typhus may vary in severity from mild and self-limiting to being lethal. The primary target cells for O. tsutsugamushi are macrophages and endothelial cells. It primarily resides in the macrophages of the liver and spleen and spreads into several organs through endothelial cells via hematogenous and lymphatogenous routes.⁹ The bacteria then induce perivasculitis and focal or systemic vasculitis in numerous organs, along with other consequences.¹⁰ A few symptoms of respiratory system involvement include interstitial pneumonitis, noncardiogenic pulmonary edema, radiographic infiltrates, and respiratory failure. Cardiac involvement can present as dysrhythmia in 7% to 16% of cases, as well as myocarditis and pericarditis. Rarely, myositis and rhabdomyolysis have been observed in specific situations.¹¹ Encephalitis, meningoencephalitis, and other specific neurological impairments are examples of neurological complications. The prognosis is poor when rickettsial illnesses are complicated by acute renal failure.¹² Hepatic injury may be complicated by hepatic failure. Acute hearing loss is also reported in some cases.^10,12 The other serious complications in rickettsial infections are thrombosis of major blood vessels, severe sepsis syndrome, and death.¹³ In 91 Indian studies, 11,535 severe scrub typhus cases with organ involvement were reported. Hepatitis (40.5%), thrombocytopenia (28.4%), acute respiratory distress syndrome (ARDS) (20.5%), acute renal injury (19.2%), meningitis (16.4%), shock (16.2%), and myocarditis (15.5%) were the most prevalent complications of scrub typhus. This systematic review, including 75 studies, found overall 6.3% fatality rates. Case fatality rates were highest in myocarditis (42.4%), followed by shock (39.6%), meningitis (35.5%), acute kidney injury (34.6%), ARDS (26.8%), hepatitis (23.2%), and thrombocytopenia (21.9%).³

In the literature, there are few case reports of digital gangrene complicating rickettsial illnesses.^1,7,11,14,15 The pathophysiology of gangrene most likely involves small-vessel occlusion, and hypotension, vascular inflammation, and disseminated intravascular coagulation could all be contributors.¹⁵ Gangrene caused by vasculitis can have both infectious and noninfectious causes. The infective disease includes syphilis, leprosy, viral hepatitis, HIV, leptospirosis,¹⁶ meningococcemia,¹⁷ measles, scarlet fever, and enteroviral exanthems. Noninfectious diseases, including antiphospholipid syndrome, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and systemic lupus nephritis, frequently affect small blood vessels and cause digital gangrene.¹ Clinical suspicion of the scrub typhus diagnosis is primarily determined by epidemiology, and the characteristic eschar with support of investigations showing normal or low leukocyte count, thrombocytopenia, hyponatremia, and elevated transaminase levels.^8,11 The cornerstones of laboratory diagnosis include serologic assays (indirect fluorescent antibody, indirect immunoperoxidase, and enzyme immunoassays). Eschars are a more successful source of Orientia genes for polymerase chain reaction amplification than blood.⁸ Due to its low sensitivity, the Weil–Felix test is not generally advised as a diagnostic test.^11,14

The recommended treatment includes doxycycline (100 mg twice daily for 7–15 days), azithromycin (500 mg for 3 days), or chloramphenicol (500 mg 4 times a day for 7–15 days). In Thailand, some instances of scrub typhus have better results with azithromycin and rifampin than with doxycycline or chloramphenicol.⁸

On the basis of the clinical and investigational evaluation, all the relevant differential diagnoses were ruled out, and the final diagnosis of scrub typhus was established. Thus, we conclude that the patients’ digital gangrene resulted from scrub typhus vasculitis. All patients recovered successfully.

In conclusion, because serology becomes positive late in the course of the disease, clinical suspicion is required before treatment may begin. When contemplating the potential infectious cause of digital gangrene, it is crucial to keep in mind the potential association with scrub typhus. Therefore, unintended complications from rickettsial disease can be avoided by early diagnosis and adequate treatment.