ARDS

The differential diagnosis includes:

>	Dengue fever/dengue hemorhagic fever
>	Measles,
>	Measles vaccine reaction
>	Kawasaki disease
>	Mycoplasma infection
>	Bacterial infection (Salmonella)

Progression: Day 1-2 of admission

>	persistent high-grade fever,
>	watery diarrhea 3-4 times/day
>	tachypnea

The patient was given symptomatic and supportive treatment. The ESR was 23 cm/hr.
Progression: Day 3 of admission

body temperature 39 C, PR 180/min, BP 98/44 mmHg

progressive dyspnea, RR 60/min, O2 sat room air 87%, fair capillary refill

lung: rhonchi both lungs

abdomen: liver enlargement 4 cm below right costal margin, spleen 2 cm. below left castal margin

Further Investigations:

> repeated CBC: Hb 9.6 gm/dl, Hct 27.9%, WBC 20,400 cell/mm3 (N51%, L34%, M15%) Platelet 41,000/mm3.

> Stool exam: No WBC or RBC, yellow, mucous, no parasite

> The echocardiogram did not show evidence of arteritis.

> CXR: Bilateral pulmonary infiltration (more at perihilar). No cardiomegaly. (as in Figure 3)

8 hours later her respiratory manifestation deteriorated. She was intubated

> CXR: The infiltration extended to peripheral part of the lungs. there was bilateral pleural effusion (Figure 4)


Figure 3	Figure 4

The diagnosis of "acute respiratory distress syndrome" was made (PaO2/FiO2 = 122).

What is the diagnosis?
" Prolonged fever with respiratory failure with impending shock "
The differential diagnosis includes:

1.	Sepsis: Bacteria, Mycoplasma, Rickettsial infection
2.	Dengue shock syndrome with dual infection
3.	Kawasaki disease
4.	Measles with pneumonia
5.	Viral myocarditis

Managements:
She was transfered to intensive care unit:

>	On ET tube and ventilatory support
>	Cut down CVP 10 cm.
>	Fluid resuscitation and correct acidosis
>	Empirical antibiotic with Cefotaxime 100 MKD
>	Erythromycin per N-G tube was also started
>	Inotropic drug: dopamine
>	Platelet transfusion

Further investigations:

Dengue rapid test (IgM, IgG)	negative
Bedside cold agglutinin:	negative
BUN 112, Cr 0.5, Na 128, K 4.7, Cl 114, TCO2 14
PT 11.3/9.9, PTT 38.3/32, Fibrinogen level 77 mg% (200-400 mg%)
EKG: low voltage, no ST-T change
Echocardiogram: Good contractility, EF 60% (normal >55%), no pericardial effusion
CBC: Hb 7.4mg/dl, Hct 25%, WBC 15,700 cell/mm3 (N 51, L 43, M 6), Platelet. 29,000/mm3 PBS: no fragmented RBC, Toxic granule 1+, Vaculoe 0
LFT: TP 4.3 gm/dl, Alb 2.3 gm/dl, Globulin 2gm/dl, AP 104 U/L (normal 150-420 U/L), AST 125 U/L (normal 3-37), ALT 45 U/L (normal), TB 0.5 mg/dl, DB 0.26 mg/dl
Pleural tapping: PH 7.47, WBC 70, RBC 2,300, LDH 516/699 (ratio 0.73), Protein 2.5/6 (ratio 0.41)
CK-MB 39 U/L (normal 0-25), Troponin-T negative

With the above investigations, dengue infection, mycoplasma infection, Kawasaki and viral myocarditis were unlikely.

Further management and course in the hospital:
The fever subsided 24 hours later. Intravenous cefotaxime was continued. Erythromycin was switched to doxycycline (2.2 mg/kg every 12 hrs) and both drugs were continued for 7 days. With respiratory and hemodynamic support, he gradually recovered. The liver and spleen size decreased. She was extubated on day 9 of admission and was later discharged home. She was well at the time of the follow up for the convalesent serum sample.

Further laboratory tests for the etiologic agents showed:

Hemoculture:

no growth

Pleural fluid culture:

no growth

BAL specimen culture

no growth

Hemagglutination inhibition (HI) for dengue infection:

negative (<1:20 for all subtypes)

Mycoplasma titer:

negative (40 and < 40)

Immunofluorescent antibody test (IFA) for murine typhus

negative

Immunofluorescent antibody test (IFA) for scrub typhus

positive *

	IgM titer	IgG titer
1st specimen (D20 of the disease)	>1,600	>1,600
2nd specimen (D32 of the disease)	800	>1,600

Final diagnosis: Scrub typhus with acute respiratory distress syndrome

Discussion:
1. The serology test (IFA for scrub typhus) of this case is strongly indicated "scrub typhus". Scrub typhus is diagnosed on the basis of either a single IFA titer against O. tsutsugamushi >1/400 or a 4-fold or greater rise in IFA titer to at least 1/200.
2. Although maculopapular rash was found in 7 - 30% of childhood scrub typhus (ref 1, 2), the rash usually mild. The pattern of rash in this patient which started at face and spreaded to neck, trunk and all extremities in a few days is more likely be the reaction of "measles vaccine" which she got 13 days prior to the occurence of the rash.
3. The clinical course of "prolonged fever" with some other non specific symptoms (hepatomegaly, splenomegaly and diarrhea) which later accompanied by serious manifestation "acute respiratory distress syndrome" in this case was most likely due to "scrub typhus".

Scrub typhus (mite-borne typhus)
Etiology: Rickettsiae: Orientia tsutsugamushi
Reservoir host: Field rodents
Vector: Mite (ไร, แมงแดง) (Chigger ไรอ่อน)
Epidemiology: Scrub typhus is confined to a definite geographic region. It extends from northern Japan and far eastern Russia in the north, to northern Australia in the south and to Pakistan and Afghanistan in the west. Male > Female, Rural > Urban
In Thailand: Rainy month (June-November),
Incubation period: 6-21 days (almost 10-12 days)
Clinical manifestration:
Mild form to severe form. Symptoms and signs of scrub typhus in Thai children from 2 reports are shown in Table 1(ref 1,2).

> Symptoms and signs were nonspecific.

> The observed body temperature pattern was "high intermittent fever".

> In the report (ref 1), "Although 8 patients reported past diarrhea or had diarrhea at the time of presentation, it was not severe and was not the major cause of admission or outpatient visit. Three patients with diarrhea also had nausea and vomiting"

> In the report (ref 1), " Eschar, present in 68% of the patients, is a very useful sign in making the diagnosis. Although eschar was described as an ulcer, surrounded by a red areolar and often covered by a dark scab, one-third of the eschars in our children did not have the dark scab. They were found in moist intertriginous areas, such as the genitalia and the perineum."

> In the report (ref 1) "The rash was maculopapular. It was not easily recognized without careful observation and was present for a few days in each patient."

> In the report (ref 1), " The average liver enlargement was 3.5 cm below the right costal margin, excluding the 2 patients with hemoglobinopathy. In all patients the liver was nontender."

> In the report (ref 1) "Tachypnea was present in 13 patients (43%). Chest auscultation was normal in all 13 patients. Chest roentgenograms were obtained in 11 of 13 patients. They showed various degrees of perihilar peribronchial interstitial infiltrations. However, the course of pneumonitis in these patients was mild and did not progress to the life-threatening adult respiratory distress syndrome.

> Pleural effusion and ARDS can occur in scrub typhus. The study by Chiu YH, et al (ref 3) which reviewed showed that in 66 cases (adults) of scrub typhus, 47 cases had abnormal CXR findings. There were diffuse bilateral reticulonodular infiltration in 25 cases, ground glass opacity in 16 cases, patchy infiltration in 11 cases, focal atelectasis in 10 cases, coarse nodules in 6 cases, large areas of consolidation in 4 cases, hilar adenopathy in 16 cases, Kerley's B lines in 9 cases, pleural effusion in 8 cases and cardiomegaly in 8 cases. In the other study by Grant Dorsey, et al (ref 4) the pulmonary involvement was found in 4 of 39 scrub typhus patients. The findings included lobar pneumonia, pleural effusion, interstitial pneumonitis and ARDS.

> Central nervous system (CNS) involvement is another complication of scrub typhus. It ranges from aseptic meningitis to frank meningoencephalitis.

> In the report (ref 1), "The mean leukocyte count on admission was 9,240 cells/mm3 (range, 4600 to 15 800). Leukocytosis <100,000/mm3 was present in 12 (40%) patients. The mean percentage of polymorphonuclear neutrophils was 56 (range, 40 to 83). Only 2 patients had polymorphonuclear leukocytosis. There was no significant increase in the number of atypical lymphocytes."

> O. tsutsugamushi does not grow on artificial media. Its isolation requires mice or chick embryo or tissue
culture inoculation, which is potentially hazardous. Thus the diagnosis of scrub typhus relies mainly on
serologic methods.

> The standard reference methods are the IFA test (ref 5) and the indirect immunoperoxidase test (ref 6) using yolk sac-propagated or cell culture-derived O.tsutsugamushi antigens. The specificity and sensitivity
of the IFA test are 0.96 and 0.54, respectively, at the
cutoff titers used in our study(ref 5). In Thailand the IFA test is available through Ministry of Public Health Laboratory (ref 7).

> Treatment: Doxycyclin 2.2 mg/kg/day orally for 5 days is the drug of choice. The alternative drug is chloramphenicol. The average interval to defervescence after treatment is 29 hr. ( range, 6-72 hr.) (ref 1).
Cases of scrub typhus poorly responsive to doxycycline and chloramphenicol had been recently reported from northern Thailand (ref 8). One recent randomized clinical trial had shown that rifampin might be useful in treating these poorly responsive cases (ref 9).

References:

1.	Sirisanthana V, Puthanakit T, Sirisanthana T. Epidemiologic, clinical and laboratory features of scrub typhus in 30 Thai children. Pediatr Inf Dis J 2003;22:341-5.
2.	Silpapojakul K, Chupuppakarn S, Yuthasompob S, et al. Scrub and murine typhus in children with obscure fever in the tropics. Pediatr Infect Dis J 1991;10:200–3.
3.	Choi YH, Kim SJ, Pae HJ,Tsutsugamushi disease: Radiologic features. Available from www.thoracicrad.org
4.	Grant Dorsey, Richard A Jacobs. Pulmonary manifestation of rickettsial illness.Available from www.chestnet.org
5.	Brown GW, Shirai A, Rogers C, Groves MG. Diagnostic criteria for scrub typhus: probability values for immunofluorescent antibody and Proteus OX-K agglutinin titres. Am J Trop Med Hyg 1983;32:1101–7.
6.	Yamamoto S, Minamishima Y. Serodiagnosis of tsutsugamushi fever (scrub typhus) by the indirect immunoperoxidase technique. J Clin Microbiol 1982;15:1128–32.
7.	Chenchittikul M. Rickettsial infection. In: Warachit P, Poonwan N, Saengkijporn S, eds. Handbook of laboratory diagnosis. 1st ed. Bangkok: Department of Medical Sciences, Ministry of Public Health, 1998:247–56.
8.	Watt G, Chouriyagune C, Ruangweerayud R, et al. Scrub typhus infections poorly responsive to antibiotics in northern Thailand. Lancet 1996;348:86–9.
9.	Watt G, Kantipong P, Jongsakul K, et al. Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial. Lancet 2000;356:1057–61.