Clinicopathological study on rickettsial spotted fever from south India

Abstract

In a prospective study conducted between November 2006 and April 2008 of 35 patients (male:female ratio 2:1) with proven rickettsial spotted fever, a generalised rash with involvement of palms and soles were seen in 80% of patients. Vasculitis on histopathology of rash was seen in 54%.

Keywords

Spotted fever Rickettsiae histopathology

Introduction

Rickettsiae are emerging, or re-emerging, as major pathogens all over the world. The spotted fever group comprises a large group of tick, mite and flea-borne zoonotic infections caused by Rickettsiae. Spotted fever group rickettsioses are caused by a variety of rickettsial species, including Rocky Mountain spotted fever (RMSF), boutonneuse fever, North Asian tick typhus, Queensland tick typhus, rickettsial pox and Japanese spotted fever. RMSF is the prototypical and most severe and is caused by Rickettsia rickettsii.¹

The rickettsial rash appears by days 3–5 in most cases, in 20% after day 6 and not at all in 9–16% of cases.^2–4 The appearance of the rash includes various stages: erythematous macules (1–5 mm in diameter) usually occur first on the ankles and wrists and later on the trunk, palms and soles. The macules consist of small areas of vasodilation that blanch on pressure and soon become maculopapular because of leakage of fluid from the injured, infected blood vessels. As the infection progresses, the rash becomes petechial after ≥ 6 days owing to central hemorrhage as a result of damage to the vascular endothelium in 40–74% of cases.^2,5,6

A rash involving the palms and soles, considered to be typical of RMSF, occurs in only 36–82% of patients with a rash and appears after five days of illness in 43%. An eschar occurs in some spotted fever group rickettsioses at the site of the tick bite, but rarely in rocky mountain spotted fever.¹

The diagnosis of spotted fever is confirmed either by culture, antigen detection, nucleic acid detection and fourfold rise in titre of specific antibodies or seroconversion.⁷ In resource-poor endemic settings, defervescence of fever after 48 h of initiating doxycycline is considered strongly suggestive of rickettsial infection.⁸

Histopathologic examination of the rash in spotted fever reveals features of vasculitis. In early lesions, the infiltrates consist of a perivascular lymphohistiocytic infiltrate along with extravasated red blood cells and oedema of the dermis. This progresses later to leucocytoclastic vasculitis. Basal cell vacuolisation, lymphocytic exocytosis, fibrin thrombi and capillary wall necrosis are also seen infrequently.⁹ There is, however, a paucity of studies describing the clinical and histopathological features of rickettsial spotted fever.

Materials and methods

A prospective study of patients with rickettsial spotted fever was conducted in a tertiary care hospital in south India between November 2006 and April 2008. Our study was approved by the institutional review board (IRB). A written and signed informed explanatory consent was taken from all patients who participated.

Children aged < 6 months and those with viral exanthems and drug-induced rashes were excluded on the basis of history and examination. Clinical and histopathological features were noted. Cutaneous findings looked for included the type and extent of rash, the presence of an eschar, and involvement of palms and soles.

The following inclusion criteria for patients were used: (1) duration of fever ≥ 5 and ≤ 15 days; (2) a positive serum IgM ELISA test and/or a positive skin biopsy nested polymerase chain reaction (PCR) for spotted fever; (3) a negative IgM ELISA for scrub typhus; and (4) fever responding to specific therapy for rickettsiae (defervescence of fever observed within 48 h of initiation of doxycycline).

Histopathological features looked for from a 3-mm punch skin biopsy at the site of the rash were the following: epidermal necrosis; the presence of purpura; telangiectasia; the type of perivascular infiltrate; the presence of endothelial swelling and endothelial cell necrosis; and the presence of transmural infiltrate.

A diagnosis of vasculitis was made if transmural inflammation had one of the following three features: (1) fibrinoid necrosis of blood vessel wall; and/or (2) endothelial cell necrosis; and/or (3) karyorrhectic debris.

Transmural inflammation with only extravasated red blood cells without the features mentioned above was termed vasculopathic reaction. Perivascular inflammation without transmural inflammation was termed vasculopathic reaction even if accompanied by the three features mentioned above. A diagnosis of perivascular inflammation was made when there were inflammatory cells around blood vessels without any of the three features mentioned above.

IgM ELISA tests for scrub typhus and spotted fever were considered positive with a value of ≥ 16 units. DNA extracted from skin biopsies was subjected to nested PCR to detect gltA, ompA, ompB and 17 kDa genes specific for spotted fever group rickettsia as reported previously.¹⁰

Results

A total of 35 patients fulfilled the case definition criteria for rickettsial spotted fever, of whom 30 were proven by PCR and/or ELISA. The male:female ratio was 1.2. The mean duration of rash at presentation was 6.7 days (SD ± 3.6). A large majority (80%) had a generalised rash; with involvement of the palms and soles (Figure 1) in 83%. The demographics and clinical features of the study population including the type of rash seen are shown in Table 1.

Figure 1.

(a) Maculopapular rash over the abdomen. (b) Purpuric rash over the legs. (c) Retiform purpuric rash over the legs. (d) Purpuric rash over the palms.

Table 1.

Demography and clinical features of the study population.

	n (%)
Gender
Male	19 (54)
Female	16 (46)
Median age at onset of fever with rash (years) (IQR)	5 (2.5–14.94)
Children aged < 10 years	25 (71)
Mean duration of rash at presentation (days) (SD)	6.7 (±3.6)
Presence of eschar	2 (6)
Type of rash
Retiform purpuric	11 (31)
Maculopapular	9 (26)
Maculopapular and purpuric	7 (20)
Purpuric	3 (8)
Erythema multiforme like	2 (6)
Maculopapular and retiform purpuric	2 (6)
Macular	1 (3)
Site of rash
Generalised	28 (80)
Localised to upper and lower limbs	4 (11)
Localised to upper limb	2 (6)
Localised to trunk	1 (3)
Involvement of palms and soles
Present	29 (83)
Absent	6 (17)

Skin biopsy showed vasculitis in 54%. This was of a mixed inflammatory type comprising both neutrophils and lymphocytes in all except one, which had predominantly lymphocytic infiltration. Vasculopathic reaction was seen in 29% and perivascular inflammation only in 17%. Endothelial swelling was found in all except one. Endothelial cell necrosis was seen in all patients with vasculitis except one who had fibrinoid necrosis instead.

Necrosis of the epidermis was seen in nine (26%). These had retiform purpuric lesions clinically. Medium vessel vasculitis was seen in four, two of whom did not show any involvement of small calibre blood vessels.

Figures 2 –4 highlight the major histopathological changes seen. Their characteristics are summarised in Table 2.

Figure 2.

Vasculopathic reaction with endothelial swelling shown by arrow (haematoxylin and eosin [H&E], ×400).

Figure 3.

Small vessel vasculitis (transmural infiltrate of lymphocytes), few histiocytes and occasional neutrophils with karyorrhectic debris (arrow) and fibrinoid necrosis (arrow head) (H&E, ×100).

Figure 4.

Medium vessel vasculitis (H&E, ×200).

Table 2.

Histopathological findings seen in the study population.

Histopathology	n (%)
Epidermal necrosis	9 (26)
Endothelial swelling	34 (97)
Endothelial cell necrosis	18 (51)
Presence of purpura	18 (51)
Telangiectasia	28 (80)
Presence of transmural inflammatory infiltrate	35 (100)
Vasculitis	19 (54)
Vasculopathic reaction pattern	10 (29)
Perivascular inflammation	6 (17)

Discussion

Rickettsial spotted fever is often presumptively diagnosed when patients present with skin rash and persistent febrile illness with or without a clear history of tick bite, especially in resource-poor countries. The large majority with rickettsial spotted fever have a generalised rash, predominantly on the palms and soles.⁹

Although skin biopsies are often performed to confirm the diagnosis, the spectrum of cutaneous histopathology in rickettsial spotted fever has not been well described.

A mixed vasculitis was seen in 54% of our patients as opposed to 73% of patients showing leucocytoclastic vasculitis with neutrophilic infiltrate and nuclear dust in a study by Kao et al.¹² These lesions with leucocytoclastic vasculitis also showed notable epidermal change including basal cell vacuolar degeneration with mild interface lymphocytic exocytosis. The majority (97%) of our biopsies had endothelial swelling or necrosis. Mild endothelial swelling and no necrosis was reported in one patient with spotted fever caused by Rickettsia africae. There were no epidermal changes seen in these four patients.¹³

Medium-sized vessel involvement has not been reported with rickettsiae, though we saw it with four (11.4%) of our patients. Two of these patients had isolated medium vessel vasculitis, while the other two had a combination of medium and small vessel vasculitis. Epidermal changes, predominantly extensive keratinocyte necrosis, was seen in nine patients. Retiform purpuric lesions were also seen in these nine patients.

Our study had some limitations. Antigen detection could not be done due to non-availability of monoclonal and polyclonal antibodies. Convalescent serum samples were not taken in the five patients who were PCR-negative but fulfilled the clinical-serological diagnostic criteria for spotted fever, thus adding a maximal 16% discrepancy to figures.

In summary, generalised rash with involvement of the palms and soles was the commonest presentation of spotted fever. Purpuric rash was seen in a higher proportion of our patients. In our study on the histopathology of rickettsial infection, vasculitis with mixed inflammatory infiltrate was seen in about half of the patients. Apart from the predominant small vessel vasculitis, a small proportion of the biopsies (11%) also showed a medium vessel vasculitis.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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